...

YDRAZINE SULF ATE B. Chemical Name: C. Common Name:

by user

on
Category: Documents
1667

views

Report

Comments

Transcript

YDRAZINE SULF ATE B. Chemical Name: C. Common Name:
YDRAZINE SULF ATE
B. Chemical Name:
Hydrazinium Sulfate, Hydrazonium Sulfate
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
—
([email protected]
@lesults)
99.0% min.
99.3%
E. Information about how the ingredient is supplied:
White Crystalline Powder
F. Information about recognition of the substance in foreign
pharmacopoeias:
USP 23, Indian Pharmacopoeia3ti Ed.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Gold, J. Use of Hydrazine Sulfate in terminal and Preterminal Cancer patients: results of
investigational new drug (lND) study in 84 valuable patients. Oncology. 1975; 32(l): 110
Chkbowski, R. T., Bulcavage, L, and Grosvenor, M. Hydrazine Sulfate in Cancer
patients with weight loss. A placebo-controlled clinical experience. Cancer. 1987; 59(3):
406-410.
—
Bairaq A. Theophylline versus cafl?eine:comparative effects in treatment of idiopathic
apnea in the preterm infant. J Pediatr. 1987; 110:636.
Ekenberg, M. G. and Kang, N. Stability of titrated caffeine solutions for injectable and
external use. Am. J Hotp Pharm. 1984;41 :2405.
H. Information about dosage forms used:
I.
Information about strength:
60mg 3 timesfd
J. Information about route of administration:
Orally
K.
_—_
Stability data:
Melts at about 254°
Oxidizing Agents
Bases
L. Formulations:
M. Miscellaneous Information:
_—_
Page -2-
\
...
,.
CERTIFICATE
5047’(?
OF AUALYSIS
-----------------------
PRC)DUCT : HYDUIIVE
# 773-
SULFATE REAGENT
RELEASE #: N
A.C.S.
CODE:G61O24
G~E:
LoT#
:L60914J
RESULT
------
SPECIFICA!XYONS
.------ ..-—-f
PWDER
~
CCXW’ORHS
1.
DESCRIPTION
2.
rdentificati on
WHITE CRYSTtiE
\_
To pass iZt3f-
3.
Rasidue
0.05% max.
0.01%
4.
Insoluble
0.005*
0.0025%
5.
6.
Ass
,
Heavy Metals
7,
chloride
on
--
Ignition
matter
Date
—
99.3%
t—._
< 0.001%
0.002% max.
0.001%
o
0.002%
0.005% m-.
.
< 0.0003%
max.
TONY mTcmTT
:04/09/97
10690
max.
,~99.0% min.
Iron
8.
—..
ATTENTION:
Pasties test
by :
Prepared
—..
.
A. HAZAFU
Approwd
—----.--——
.—. — . ..—.
——
by :
._. -_. —_
/
.-.
_____
-’.
.,.
. -. ---—
QUALITY
CONTROL REPORT
CHEMICAL NAME .:HYDRAZINE SULFATE A. C. S. REAGENT
MANUFACTURELOT NO. :609141
PHYSICAL TEST
OUSP
SPECIFICATION TEST STANDARD..
— /BP_/MERCK_/NF_/WT._/CO.
sPEcs._.
I)DESCRIPTION.:
WHITE TO ORTHORHOMBICCRYSTALS .GLASS-LIKE
PLATES OR PRISMS.
2)SOLUBILITY.:
SOLUBLE IN ABOUT 33 PARTS OF COLD WATER;FREELY SOLUBLE IN HOT
WATER.INSOLUBLE IN ALCOHOL.
___
3)MELTING POINT.:
MELTS AT ABOUT 254 degree.
.=.
K
4)SPECIFIC GRAWTY. :
5)IDENTIFICATION.:
A)A SOLUTION RESPONDS TO THE TESTS FOR SULFATE.
FAILS.:
PASSES.:
COMMENTS.:
DATE.:
ANALYST SIGNATURE.:
PREPACK TEST.:
RX’l?’EST.:
DATE. :
DATE. :
INITIAL.:
INITIAL.:
Page 1 of 6
Hydrazine Sulfate
.—
——.
(!!ll?
-~
Use your web browser’s “Back” key to return to previous topic.
Hydrazine Sulfate
.**** ~TER~L
sAFE~
DATASHEET****
Hydrazine
Sulfate
11070
****SECTION
1 . cHEMICAL
PRODUCT
——=
AND COMPANY
****
IDENTIFICATION
MSDS Name: Hydrazine Sulfate
Catalog Numbers:
H320 500, H320-500, H320500
Synonyms:
Diamine Sulfate; Hydrazine Monosulfate;
Hydrazini~
sulfate.
Fisher Scientific
Company Identification:
1 Reagent Lane
Fairlawn, NJ
O741O
For information, call:
201-796-7100
201-796-7100
Emergency Number:
For CHEMTREC assistance, call: 800-424-9300
For International CHEMTREC assistance, call: 703-527–3887
**** SECTION
2 – COMPOSITION,
INFORMATION
ON INGREDIENTS
****
+----------------+--------------------------------------+----------+-----------+
Chemical Name
I EINECS#
I
CAS #
I
1%
I
1---------------- l-------------------------------------\---;;;---- l-----------l
I 233-110-4 I
\HYDRAZINE SULFATE
10034-93-2
+----------------+--------------------------------------+----------+-----------+
Hazard Symbols: T
Risk Phrases: 23/24/25 43 45
**** SECTION
3 – HAZARDS
IDENTIFI~TION
****
EMERGENCY OVERVIEW
Appearance:
white.
Danger! Corrosive. Carcinogen. May be harmful if swallowed.
Sensitizer. May cause lung damage. May cause severe eye irritation
and possible injury. May cause liver and kidney damage. May cause
severe skin irritation and possible burns. May cause severe
respiratory and digestive tract irritation with possible burns. May
cause cancer based on animal studies. Material is shock sensitive and
potentially explosive.
Target Organs: Blood, kidneys, central nervous system, liver.
.-=
Potential Health Effects
Eye:
Contact with eyes may cause severe irritation, and possible eye
May cause eye injury.
burns.
Skin:
May cause skin sensitization,
an allergic reaction, which becomes
Page
Hydrazine Sulfate
evident upon re-exposure to this material. May cause severe skin
irritation with possible burns, especially if skin is wet or moist.
Ingestion:
May cause liver and kidney damage. May cause severe digestive tract
irritation with abdominal pain, nausea, vomiting and diarrhea. May
cause corKosion and permanent tissue destruction of the esophagus and
digestive tract. Exposure may cause anemia and other blood
abnormalities. May be harmful if swallowed.
Inhalation:
Irritation may lead to chemical pneumonitis and pulmonary edema. May
cause livex and kidney damage. May cause severe irritation of the
upPer respiratory tract with pain, burns, and inflammation. May cause
effects similar to those described for ingestion.
Chronic:
Prolonged or repeated skin contact may cause sensitization
dermatitis and possible destruction and/or ulceration. May cause
liver and kidney damage. May cause cancer according to animal
studies. May cause digestive tract disturbances.
**** SEC-TION 4 _ F~RsT AID ~URES
****
Eyes :
Immediately flush eyes with plenty of water for at least 15 minutes,
occasionally lifting the upper and lower lids. Get medical aid
immediately.
Skin:
Get medical aid immediately. Immediately flush skin with plenty of
soap and water for at least 15 minutes while removing contaminated
clothing and shoes.
Ingestion:
Do NOT induce vomiting. If victim is conscious and alert, give 2-4
cupfuls of milk or water. Get medical aid immediately.
Inhalation:
Get medical aid immediately. Remove from exposure to fresh air
immediately. If not breathing, give artificial respiration. If
breathing is difficult, give oxygen.
Notes to Physician:
Treat symptomatically
and supportively.
Antidote:
No specific antidote exists.
**+* CJECTION 5 _ FIRE FIGHTING
MEAsUms
****
General Information:
AS in any fire, wear a self-contained
breathing apparatus in
pressure-demand,
MSHA/NIOSH
(approved or equivalent), and full
can form
protective gear. Dusts at sufficient concentrations
explosive mixtures with air. Combustion generates toxic fumes.
Greatly
Material is shock sensitive and potentially explosive.
increases the burning rate of combustible materials. Violently
decomposes when heated under confinement.
Extinguishing Media:
For small fires, use water spray, dry chemical, carbon dioxide 01
chemical foam.
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
NFPA Rating: Not published.
Explosion Limits, Lower: Not available.
Upper: Not available.
General
—
—
Information:
Use proper
in Section
personal
8.
protective
Spills/Leaks:
Sweep up, then place into a suitable
generating dusty conditions.
**** SECTION
Handling:
Wash
thoroughly
7 _ -LING
after handling.
container
and STO~GE
Remove
equipment
as indicated
for disposal.
Avoid
****
contaminated
clothing
and
2 of 6
Page 3 of 6
Hydrazine Sulfate
wash before reuse. Use with adequate ventilation. Minimize dust
generation and accumulation. May form flammable dust-six mixtures.
Loosen closure cautiously before opening. Do not get on skin and
clothing. Empty containers retain product residue, (liquid and/or
vapor) , and can be dangerous. Do not ingest or inhale. Avoid
mechanical shock and friction. DO not pressurize, cut, weldr braze,
solder, drill, grind, or expose empty containers to heat, sparks or
open flames.
Storage:
Keep away from heat, sparks, and flame. DO not Store near
combustible materials. Store in a tightly closed container. Store in
a cool, dry, well-ventilated
area away from incompatible substances.
**** SECTION
E – EXPOSURE
CONTROLS,
PERSONAL
PROTECTION
Engineering Controls:
Use process enclosure, local exhaust ventilation,
engineering controls to control airborne levels.
****
or other
Exposure Limits
-––––––-----+–––-----–––------+
+--------------------+-------------------+------NIOSH
IOSHA - Final PELsI
ACGIH
Chemical Name
I
I
I
l-------------------l-------------------l ------------------- 1----------------- I
\none listed
Inone listed
I HYDFU%ZINE SULFATE
Inone listed
+--------------------+-------------------+-------------------+-----------------+
OSHA Vacated PELs:
HYDRAZINE SULFATE:
No OSHA Vacated PELs are listed
Personal
Protective
for this chemical.
Equipment
Eyes:
Wear appropriate protective eyeglasses or chemical
safety goggles as described by OSHA’S eye and face
protection regulations in 29 CFR 1910.133.
Skin:
Wear appropriate
exposure.
protective
gloves
to prevent
Wear appropriate
exposure.
protective
clothing
skin
Clothing:
to prevent
skin
Respirators:
Follow the OSHA respirator regulations found in 29cFR
1910.134. Always use a NIOSH-approved
respirator when
necessary.
**** SECTION
9 – pHySIC~
Physical State:
Appearance:
Odor:
pH :
Vapor Pressure:
Vapor Density:
Evaporation Rate:
Viscosity:
Boiling Point:
l?reezing/Meltin9 Point:
Decomposition
Temperature:
Volubility:
Specific Gravity/Density:
Molecular Formula:
Molecular Weight:
****
sECTION
AND CH~IC~
Properties
****
Solid
white
None reported.
1.3 (0.2M solution)
Negligible.
Not applicable.
Negligible.
Not available.
Not available.
489 deg F
Not available.
Soluble in water.
1.4 (water=l)
H4N2.H2S04
130.12
10
-
sT~ILITy
~
R~cTIIJITy
****
Chemical Stability:
Stable under normal temperatures and pressures. Substance is shock
sensitive and thermally unstable.
Conditions to Avoid:
Mechanical shock, incompatible materials, temperatures above 160’C.
Page40f6
[email protected] Sulfate
Incompatibilities
with Othex Materials:
Oxidizinq aqents, combustible materials, sodium amide.
$-azardous Decomposition
Products:
Nitrogen oxides, carbon monoxide, oxides of sulfur, carbon
Hazardous Polymerization:
Has not been reported.
**** SECTION
11 . TOXICOLOGICAL
INFO~TION
dioxide.
****
RTECS# :
CAS# 10034-93-2: MV9625000
LD50/Lc50:
CAS# 10034-93-2: Oral, mouse: LD50 = 74o mg/kg; Oral, rat: LD50 =
601 mg/kg.
Carcinogenicity:
HYDRAZINE SULFATE California: carcinogen
NTP: Suspect carcinogen
OSHA: Possible Select carcinogen
Epidemiology:
Oral and intraperitoneal
administration
of hydrazine salts t
o animals have produced lung and liver carcinomas.
Teratogenicity:
No information available.
Reproductive Effects:
No information available.
Neurotoxicity:
No information available.
Mutagenicity:
please refer to RTECS# MV9625000 for specific information.
Other Studies:
Skin irritation, guinea pig: slight. Eye irritation, rabbit:
severe.
**** SECTION
Ecotoxicity:
No information
Environmental
Fate:
No information
Physical/Chemical:
No information
Other:
None.
INFOPJIATION ****
available.
reported.
available.
***+ sECTION
Dispose of in
RCRA D-Series
RCRA D-Series
RCRA F-Series:
RCRA P–Series:
RCRA U–Series:
Not listed as
12 - ECOLOGIC=
13 _ DISpOSAL
CONSIDERATIONS
****
a manner consistent with federal, state, and local regulations.
Maximum Concentration
of Contaminants: Not listed.
Chronic Toxicity Reference Levels: Not listed.
Not listed.
Not listed.
Not listed.
a material banned from land disposal according to RCRA.
**** SECTION
US DOT
Shipping
Name:
14 - T~SpORT
INFORMATION
****
Hazard Class:
UN Number:
Packing Group:
CORROSIVE SOLID,ACIDIC, INORGANIC, N.O.S.
(HYDRAZINE SULFATE)
8
UN3260
II
No information
available.
IMO
IATA
No information
RID/ADR
No information
Canadian TDG
Shipping Name:
Hazard Class:
UN Number:
available .
available.
CORROSIVE
8(9.2)
UN1759
SOLIDS
NOS
(HYDRAZINE
SULFATE)
Page 5 of 6
Hydrazine Sulfate
**** SECTION
15 _ ~GULATORy
INFORMATION
****
US FEDEPAL
TSCA
CAS# 10034 -93-2 is listed on the TSCA inventory.
Health & Safety Reporting List
None of the chemicals are on the Health k Safety Reporting List.
Chemical Test Rules
None of the chemicals in this product are under a Chemical Test Rule.
Section 12b
None of the chemicals are listed under TSCA Section 12b.
TSCA Significant New Use Rule
None of the chemicals in this material have a SNUR under TSCA.
SAPA
—=_
—
Section 302 (RQ)
None of the nhemicals in this material have an RQ.
Section 302 (TPQ)
None of the chemicals in this product have a TPQ.
SARA Codes
CAS # 10034-93–2: acute, chronic, reactive.
Section 313
This material contains HYLXAZINE SULFATE (CAS# 10034-93-2,
>99%),which is subject to the reporting requirements of Section 313
of SARA Title III and 40 CFR Part 373.
Clean Air Act:
This material does not contain any hazardous air pollutants.
This material does not contain any Class 1 Ozone depletors.
This material does not contain any Class 2 Ozone depletors.
Clean Water Act:
None of the chemicals in this product are listed as Hazardous
Substances under the CWA.
None of the chemicals in this product are listed as Priority
Pollutants under the CWA.
None of the chemicals in this product are listed as Toxic Pollutants
under the CWA.
OSHA:
None of the chemicals in this product are considered highly hazardous
by OSHA.
STATE
HYDRAZINE SULFATE can be found on the following state right to know
lists: New Jersey, Florida, Pennsylvania, Minnesota, Massachusetts.
The following statement(s) is(are) made in order to comply with
the California Safe Drinking Water Act:
WARNING: This product contains HYDRAZINE SULFATE, a chemical known to
the state of California to cause cancer.
California No Significant Risk Level:
CAS# 10034-93-2: no significant risk level = 0.2 ug/day
European/International
Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 23/24125
‘Toxic by inhalation, in contact with skin
and if swallowed.
R 43 Nay cause sensitization by skin contact.
R 45 May cause cancer.
Safety Phrases:
s 44 If you feel unwell, seek medical advice (show
the label where possible) .
S 53 Avoid exposure - obtain special instructions
before use.
WGK (Water Danger/Protection)
CAS# 10034-93-2:
Canada
CAS# 10034-93-2 is listed on Canada’s DSL/NDSL List.
This product has a WHMIS classification
of D2A, E.
CAS# 10034–93-2 is not listed on Canada’s Ingredient Disclosure List.
Exposure Limits
**** SECTION
MSDS
Creation
Date:
16 _ ~DITIONAL
9/22/1995
Revision
INFO~TION
#3 Date:
****
9/02/1997
Page 6 of 6
Hydrazine SuIfate
The information above is believed to be accurate and represents the best
information currently available to us. However, we make no warranty of
merchantability
or any other warranty, express or implied, with respect to
such information, and we assume no liability resulting from its use. Users
should make their own investigations
to determine the suitability of the
information for their particular purposes. In no way shall Fisher be liable
for any claims, losses, or damages of any third party or for lost profits
or
any special, indirect, incidental, consequential or exemplary
damages, howsoever arising, even if Fisher has been advised of
the possibility of such damages.
--------------------------------------------------------------------------------
_—_
.
2016
usP<2j ~~
/ Reagents
Reagent Specifications
I
-
i
/
—.
.
Spectral purily— Measure in a l-cm cell at 300 nm, with a
suitable spectrophotometer, against air as the blank: its absorbance is not more than 0.08.
Hexanes (suitable for use in ultraviolet spectrophotometry);
usually a mixture of several isomers of hexane (C6H IA),predominantly n-hexane, and methylcyclopentane (C6H 12)—Use ACS
reagent grade.
Hexanitrodipheny lamine (Dipicrylamine),
[email protected]—Yellow-gold powder or prisms. Explosive. Usually contains about 15% of water as a safety precaution. Insoluble in
water, in alcohol, in acetone, and in ether soluble in glacial acetic
acid and in alkalies.
Wafer, Me/hod I (921): not more than 16%.
Hexanophenone, Cl 2H160—176.26-Yellow
liquid.
Assay—Inject an appropriate specimen into a suitable gas
chromatography (see Chromatography (62 I )) equipped with a
flame-ionization detector, helium being used as the carrier gas.
The following conditions have been found suitable: a 30-m X
0.25-mm capillary column coated with a 1-pm layer of phase G3;
the injection port temperature is maintained at 280”; the detector
temperature is maintained at 300°; the column temperature is
maintained at 180° and programmed to rise 10° per minute to
280”. The area of the C,[email protected] peak is not less than 98’%of the
total peak area.
Refractive index (83 1): 1.511 f 0.002 at 20°.
Hexokinase and Glucose-&phosphate Dehydrogenase Suspension—Use a suitable grade. 1
Suitability—When
used in the assay of Iactulose, determine
that a suitable absorbance-versus-concentration slope is obtained,
using USP Lactulose RS, the reagent blank absorbance being
not more than 0.020.
Histamine Dlhydroehloride, C5H9N3 ~2HC1—184.07—Use USP
Histamine Dihydrochloride RS.
Hydrazine Hydrate, 85% in Water, (NH2)2 [email protected]&06Colorless liquid.
Assay—Transfer 600 mg, accurately weighed, to a 100-mL
volumetric flask. Dilute with water to volume, and mix. Pipet
10 mL into a suitable beaker, add 1.0 g of sodium bicarbonate
and 50.0 mL of 0.1 N iodine VS. Titrate the excess iodine with
0.1 N sodium thiostdfate VS,using starch TS as the indicator.
Perform a blank determination, and make any necessary correction. Each mL of 0.1 N iodine is equivalent to 12.52 mg of
(NHJ2 H20. Not less than 83% is found.
Hydrazine Dihydrochloride, (NH2)2. 2HC1—104.97—White
powder.
Assay—Dissolve about 34 mg, accuratel weighed, in 50 mL
of water. Add carefully while stirring, 1 g o /’sodium bicarbonate.
[Caution—There may be a rapid evolution of carbon dioxide.]
Titrate with 0.1 N iodine solutlon, determining the endpoint pctentiometrically. Perform a blank determmation, and make any
necessary corrections. Each mL of 0.1 N iodine solution is equiv, alent to 2.63 mg of (NH2)2. 2HCI. Not less than 9870 is found.
/b-
H drazine Sulfate,
age t =
-.
(NH2)2, H2SO*—130.19Use
ACS
re-
Hydriodic Acid, HI—127.91—Use ACS reagent grade (containing not less than 47.0% of HI).
NoTE—For Methoxy Determination (see (43 I ) ), use hydriodic acid that is labeled “for alkoxyl determination,” or that
is purified as directed under Merhoxy De[erminarion (431). Use
this grade also for alkoxyl determinations in assays in the individual monographs.
Hydrochloric Acid, HC1—36.46--Use ACS reagent grade.
Hydrochloric Acid, DUuted(10 percent)—Prepare by mixing
226 mL of hydrochloric acid with sufficient water to make 1000
mL.
Hydrofluoric Acid, HF—20.01—Use ACS reagent grade.
Hydrogen Peroxide, 30 Percent, HzOz—34.01—Use ACS reagent grade.
Hydrogen Peroxide Solution—Use Hydrogen Peroxide Topical Soiution.
Hydrogen Sulfide, H2S—34.08—Colorless,
poisonous gas,
heavier than air. Soluble in water. Is generated by treating fer-
rous sulfide with diluted sulfuric or diluted hydrochlor~c aei~
Other sulfides yielding hydrogen sulfide with d}luted acids UJ
be used. Is also available in compressed form m cyhnders. ~:,
Hydrogen Sulfide Detector Tube-A
fuse-sealed gla~s. tube’h
designed that ga~ may be passed through It and contammg SWI.
able absorbing falters and support media for the mdlcato~ :,&
latter consisting of a suitable lead salt.
NOTE—A suitable detector tube that, conforms to the mono
graph specification is available from National Draeger, Inc., p:o,
Box 120, Pittsburgh, PA 15230-0120 as Reference Number 67
19001, Measuring Range 1 to 20 ppm. Tubes having conditi~
other than those specified in the monograph may be used m
accordance with the section entitled Tests and Assays in &
General Notices.
1:
Hydroquinone, C,5H’$(OH)2-1 10.1 l—Fine, colo[less or whii~
needle crystals. Darkens on exposure to air and llght. Sohtit
i,
in water, in alcohol, and in ether.
Assay—Weigh accurately about 250 mg, and dissolve itt’t
mixture of 100 mL of water and 10 mL of 0.1 N sulfuric ad
in a 250-mL conical flask. Add 3 drops of a 1 in 100 solufi~
of diphenylamine in sulfuric acid, and titrate with 0.1 N eerie
sulfate VS until the solution is red-violet in color. Each mu of
0.1 N eerie sulfate is equivalent to 5.506 mg Of C6H.4(OH)Z. Na
l..:
less than 99% is found.
Melting range (74 1): between 172° and 174°.
3’-Hydroxyacetophenone,
C8H801—136. 15—Light br~wn
powder chips and chunks. Melts at about 96°. Sparingly soluble
in chloroform, yielding a clear, light yellow solution.
,,,,
Assay—Inject an a propriate specimen into a suitable ‘gas
chromatography (see Ci romatograplty (621)) equipped with a
flame-ionization detector, helium being used as the carrier gas
The following conditions have been found suitable: a 0.25-nrm
X 30-m capillary column coated with G 1; the detector and the
injection port temperature are maintained at 300°; the column
temperature is maintained at 180” and programmed to rise 10’
per minute to 280° and held at that temperature for 10 minutes
The area of the main peak is not less than 97% of the total peak
area.
%
4’-Hydroxyacetophenone,
HOC6H.COCHJ—136.1 %Gray
powder, melting at about 109”.
.{!::
crystals.
Assay—Transfer about 700 mg, accurately weighed, to a suit.
able container, and dissolve in 50 mL of acetone. Add 100 @
of water, mix, and titrate with 0.5 N sodium hydroxide VS, de
termining the endpoint potentiometrically. Perform a blank d~
termination, and make any necessary correction. Each mL of 0,~
N sodium hydroxide is equivalent to 69.06 mg of C7H603: “’rid
:.;:
less than 97% is found.
Me/ting range (741): over a range of 2“ that includes 216°.
p-Hydroxybenzoic
4-Hydroxybenzoic
(CH2)2—180.20-Use
Acid, C7H603—138.12—white
Acid Isopropyl Ester, HOC6H4COOCH.
a suitable grade.32
Melting range (741 ): between 84° and 87°.
l-Hydroxybenzotriazole
Hydrate,
. it..
,i!’
C6H5N30. xH20—135~fi
(anhydrous)—White crystalline powder. Sparingly soluble iq *
cohol yielding a clear, pale yellow solution.
>!4
2-Hydroxybenzyl Alcohol, C, [email protected]
flake$.
in chloroform, and in ethe~ soluble,@
Very soluble in alcohol,
15 parts water and in benzene.
.)(
Assay—Inject an appropriate specimen into a gas chromate
graph (see Chromatography (62 1)), equipped with a ffame-ioti
ization detector, helium being used as the carrier gas. The fallowing conditions have been found suitable: a 0.25-mm X 31MIJ
capillary column coated with a l-gin layer of phase G2; the h
jection port temperature is maintained at 250°; the detec+or te~
perature is maintained at 300°; and the column temperature ~
maintained at 150° and programmed to rise 10° per minute W
280°. The area of the C7H802 peak is not less than 99% of the
total peak area.
Melting range (74 1): between 83° and 85°.
,.
4-HydroxyisophthaIic
Acid, CgH604—182.13—Colorlcs~
branched needles. Freely soluble in alcohol and in ether.
Melting range (74 I): between 314° and 315°, with decom
position.
1
..4
-.
REAGENTSAND SOLUTIONS
A fraction from petroleum containing about
of n.hexane.
DESCRIPTION- Colorless,
mobile,
highly
90 per
cent
SOLUBILCTY
- Miscible with water.
wr. PERML-1.03
liquid.
P
DISTtLLATtON RANGE - NOC less than 95 per cent, distils
between 67° and 70”, Appendix 5.3.
WT.PERML- At 20°, 0.670 to 0.677 g, Appendix
5.19.
5.19.
:NH2.NH2,H2SOi
= 130.12
ydraadne Sulphate
C~s—&ut
99.0 per cent of N2H6S04.
~ESCRtIYTtON
-
L
NON-VOLATIIE
MArrER - When evaporated on a water-bath
and dried to constant weight at 105°, leaves not more than
0.01 per cent w/v of residue.
SOLUBIUTY -
powder.
---
Freely soluble in water; practically insoluble
MELTtNGPOINT- About 254°, Appendix
Appendix
Of the Indian Pharmacopoeia.
White, crystalline
————
in alcohol.
CHLORIDE -1
.4adPhosphate
Histamine
g, Appendix
flammable
IRON -1
g
5.11.
complies with the limit testfor chlorides,
3.2.2.
g complies with the limit test for i?wn, Appendix
3.2.5.
HistamineDihydrochlorkk
: C5HJJj,2HCl
DESCRI~ION - White crystalline
powder.
.
= 184.07
Not more than 0.05 per cent, Appendix
SLJLPHATEDASH -
Freely soluble in water and in ?nerbyialco-
SOLUBILIIY -
bo[; soluble in alcohol.
WLnw
POINT -
Abour 250°, Appendix 5.11.
m-Histidirle
Monohydrochioride
N:CH.NH.CH:C.
CHZ.CH(NHJ.
COOH,HC1= 191.62
1
,.
DESCRIPTION - w%&,
..
.,.>
@.
,, .
.-
soLuBIm_Y
crystalline powder.
Soluble in water.
-
Loss ON DRYXN3 - Loses not more than 9.0 per cent of its
weight, when dried to constant weight at 105”, Appendix
5.8.
.$
. .
StJX.PMATED
ASH- Not more thart 0.1 per cent, Appendix
3.2.7.
ASSAY - Carry
out the method fOr the detenvzination of
ni~mgen, Method A, Appendix 3.3.5, using 0.15 g and 7
ml of nitrogen-jlt?e stdpbun”c acid. Each ml of 0.1 N sulpburic acid is equivalent to 0.00639 g of C6H9N302,HC1.
Hohnhm
Oxide
DESCRIPTION -
:
HOZ03= 377.86
A yellow
solid.
Holmium
peddO13tt?
sOhltiO~
A 5 per cent WIVsufiwion of Lmltniutn oxide in 1.4 M
percblon’c
-e
acid.
Hydrate:NHJWH2,H20= 50.06
DESCRIPTION -
cal odour.
Clear, colorless
[email protected]
: HI = 127.91
Add
Constant-boiling
hydriodic
acid contains
55.o xr ant
W?Wof HI (limits, 54.0 to 56.0).
Almost coloudess liquid when freshly
made, but rapidly becoming yellow to brown owing to
the liberation of iodine.
DESCR.IPTtON-
SOLUTWTY - Miscible in all proportions with water and
with aicobo[.
BOILING mm
-
About 127°, Appendix
5.3.
WT.PERML- At 20”, about 1.7 g, Appendix
5.19.
CHLORIDEANDBROhUDE- To 0.2 ml add 15 ml of water, 50
mg of sodium sulpbate, 5 ml of dilute ammonia solution
and 20 ml of 0.1 N silvernitrate, shake and filter; to the fil.
. trate add 10 ml of dilute nitn’cacid. The opalescence produced is not greater than the standard opalescence obtained in the [imit lesl for chlorides, Appendix 3.2.2.
tuaterand add 1 ml
of ban”um cblon”de solution. The turbidity produced
should not be greater than the standard opalescence obtained in the limit test for sulpbates, Appendix 3.2.8.
SULPHATE- Dilute 1 ml with 50 ml of
soLtrBmtYY- Practically insoluble in water.
Ii
ASSAY- Weigh accurately about 0.1 g and dissolve in 20
ml of water. Add 3 g of sodium bicarbonate and titrate
with 0.1 N iodine, using starch so[ution as indicator.
Each ml of 0.1 N iodine is equivalent to 0.003253 g of
N2H5S04.
I
ContaitLs not less than 99.0 per cent of C&NIOz.HCl. calculated with reference to the substance dried to constant
weight at 105”.
#
3.2.7.
liquid with an ammonia-
NON-VOIATILEMAmR - When evaporated
on a waterbath, and dried to constant weight at 105”, leaves not
more than 0.5 per cent w/w of residue.
ASSAY
- Weigh accurately about 0.6 g into a stoppered
flask containing about 10 ml of water, dilute with 25 ml of
water and titrate the free iodine with 0.1 N sodium tbio-
A-189
...
s
PHYSICAL
TESTSAND DETERMINATIONS
?,”
:1=
,>,.:.
.. ; .>i
,,<
,,
:.
. . .
?’
Size
No.
::.
.-..
TABLE2
Kinematic
Viscosity Range
(Centistokes)
3
30
0.84
5.6
2(I to
100
1.15
5.6
2.8 to 3.2
2,8 [0 3.2
2.8 [0 3.2
60 to
300
1.51
5.6
2.8 to 3.2
200 [0
1100
2.06
5.6
3.7
to
4.3
2.74
5.6
4.6
to
5.4
3.70
5.6
4.6
to
5.4
4.97
6.76
5.6
5,6 to
6.4
5.6
6.8
7.5
600 to 3000
3A
Inside Diameter
of Tube R
(mm) (t 2VO)
5.6
5 to
2A
Inside Diameter
of Tube N
(mm)
O.tj’i
3.5” to 10
1
..
Volume Bulb C
(ml)
(* 5“/0)
4
2000 to
4A
6000 to 30,000
5.
20,000 to 100,000
10,000
to
350mlfllmumflowCimc;
200minimumflow[tmcforail
ocher
SizCs
. ..
:.
...
..
,.
..
..:”..
anytime while the flow time is being measured, [he determination must be repeated.
Calculate the kinematic viscosity in centiscolws (V)
from the equation:
v= ct.
where
t = time in seconds for the meniscus to fall from
Eto F
. ..
C = the constant
of the viscometer,
by observations
on a liquid
determined
of known
viscosity.
Method
C : (Using the Rotating Viicometer)
The rotating viscometer measures the shearing forces in a
liquid medium placed between two coaxial cylinders one
of which is driven by a motor and the other is caused to
revolve by the rotation of the first. Under these conditions,
the viscosity becomes a measurement of the angle of deflection of the cylinder caused to revolve, expressed in
newton metres.
Method– Operate the Rotating Viicometer in accordance with the manuhxurer’s instructions and carry
out the determination of viscosity of the liquid being
examined, at the temperanire and angular velocity or
shear rate specified in the individual monograph.
Calculate the dynamic viscosity (n) in centipoises.
5.19WEIGHT PER ~
AND SPECIFIC
GRAVITY
WeightperMiliilitre
Theweight
permillilitre
ofa liquid
istheweight
ing of
1 ml of a liquid when weighed in air at 25°, unless
otherwise specified.
Method : Select a thoroughly clean and dry pycnometer.
Cdlibrate the pycnometer by filling it with recently boiled
and cooled tcater at 25“ and weighing the contents.
Assuming that the weight of I ml of water at 25° when
weighed in air of density 0.0012 g per ml, is 0.99602 g,
calculate the capacity of the pycnometer. (Ordinary deviations in the density of air from the value given do not affect
the result of a determination significantly). Adjust the
temperature of the substance to be examined, to about 2(Y
and fill the pycnometer with i[. Adjust the temperature of
the filled pycnometer to 25°, remove any excess of the
substance and weigh. Subtract the tare weight of the
pycnometer from the filled weight of the pycnometer.
Determine the weight per millilitre by dividing the weight
in air, expressed in g, of the quantity of liquid which fills
the pycnometer at the specified temperature, by the capacity expressed in ml, of the pvcnometer at the same tempe.
rature.
Specific
Gmvity
The specific gravity of a liquid is the weight of a given
volume of the liquid at 25° (unless otherwise specified)
compared with the weight of an equal volume of warerat
the same temperature, all weighings being taken in air.
Method :Proceed as described under
Wt. per ml. Obtain
the specific gravity of the liquid by dividing [he weight of
the liquid contained in the pycnometer by the weight of
water contained, both determinedat25“ unless otherwise
directed’in the individual monograph.
A-137
I
>UU>L411LG>
12831-C
Sulphate. _/$
Hydrazine
-
3024;
-.7h~draz~nej: 10034-93-2
CAS —
fJul-
pirafe).
solubleI in about 33of water.freely
ubie in ho[ MaIer: practically insoluble in aico.,oI A 0.2M soiu[ion in water has a pH of 1.3.
H~drazine suipnalc is employed in various industrial processes II is used in the preparation of
h,ydrazine hydrate which is applied after a soluuon of platlnic chloride for corncal [amoing (see
Chloropiatinic \cid. p.1693).
‘–-ystals.
An account
of the successful
treatment
or industrial
hydrazine
poisonlrrg with pyridoxine.—
J. K. Kirklin
eI
al.. New Engl. J, Med., !976, 294, 938.
A report of faral choroidal
melanoma
In a yorker
who
had been exposed to hydrazine
for 6 years — D. M.
Albert
and C. A. Puliafito
(Iener),
New Eng/. J Med.,
1977.296,
634.
The use of hydrazinc
sulphatc
by a laboratory
worker
was associamd
with
Ihe development
of a syndrome
similar 10 syslemtc lupus .ccyehematoaus — P. J, Durant
J. Med., 1980,
and R. A. Harris
(letter),
Nrw
Eng/
303, 584.
A discussion
agent.—
W
or hydrazme
sulpha~c as an antineoplastic
J. Am mrd Am.. 198C, 243,
Regeison.
337.
12832-k
! minutes. and then Sodium n!tn[c 300 mg ln[ravcnousl!
for 3 mmutcs. Treatment
was a!mcd aI ortiucmg
mclhaemoglobmaemia
to !nactwate
Lhc suiphidc
In addl[[on
he received sodium thmarupnate
12.5 g bj Intravenous
Med., 1976.
Injaion
— R. J St]ne tr al,. .4nn. [nrrrn
85.756.
Sulphide.
Or
1000
Further
refcrences~
W.
W“. Burnelt
er al
Can
1277; R. P. Sml!h (letter),
med.
ibid.,
An J., 1977, 117,
1978. f/8. 775; f~”. ~. Burnett and E. G. King (let~er).
Ibjd., 776: J. Am med Ass., 1978. 239, 1374.
of \dveme Effects. After exposure to
hydrogen sulph]de place the patient in fresh air,
give inhalations of oxygen and, if necessary,
assist the respiration. Antibiotics may be neccssar} if pulmonar: inrection occurs The conjunctival sacs should bc carefully washed out if cye
[rrlts lion IS set ere
[n severe poisoning, amyl nltritc inhalal!on and
sodium n!trite b} Intravenous injcc:ion have been
suggested
Treatment
A br!cf review or the management
or sulphidc polsonPharmg — R P Sm:th
and R. E Gossel]n,
A Ret
~ac
& ToX,{
)976,
/6, 189,
–——-LC successful
rreti, mcnt or a 41. >ear-old
man with
rc hydrogen
!ulphldc
potsonmg using oxygen. amyl
!te )nhalatmns
(or 30 seconds OUI of each m!nutc for
mg and above
and
mm: er fsl. (letter).
Lancer.
H
Greenwood
eI al.. Br.
16!
included
dllabLlm
and d?sa~hna
of a cohol —
J975.
1
5S3
&
M
Tw
Sec alw
~
J clrn. phormor.. 19Y5.~’
12833-a
to OL.S
,Manganese
poisoming.
A bencfi$ial
respnsc
h>aroxyrryptophan,
UP 10 3 g dally.
was achtevcd ,n ~
patlem m whom the symptoms of ~nganesc
poisoning
P
Sml~h
and
R
E
J
Gosselm,
~1. 93
sulphide is widely employed m
many industrial processes.
H ydroxyestrone
Diacetate.
1r&H ydroxy
oestrone Diacctate. 3, 16cwDihydroxyestra1,3,5( 10)-tnen- 17-one diacctate.
CZ1HZ605=370.4.
CAS — 566-76-7
(hydroxyestrone);
faiiao
-
1247-71-8
diacetate
is a
deriva[ivc
of
osxrone. II is claimed to have minimal systemic
effects when given by mouth but to
oestrogetric
retain effects on the vaginal mucosa. It is used in
the treatment of vaginitis and associated disordCrs.
Proprietary Names
Colpoginon
(ltoizot. Spain): Colpogynon (Lcsbommorics
de
i“liepatrol.
SwitzJ;
Colparmc4r
(Millet.
Arg.:
Arrphar-Rolhmd. Fr.).
::z:t’(:;i~er.,
Swi::.);
(fAa/ec-Pharma,
BrlXco, IW1.:,fl-chmlrc
(Ci[ag-Chemw,
SwtI:./.
,
12836-r
5-Hydroxytryptophan.
5-HTP; Ro-0783/B.
2-Amino-3 -(5-hydroxy- lH-indol-3-yl)propionic
acid.
C,,
H,ZN20,
=220.2.
CAS — 56-69-9.
NOTE.The
is generally
form of 5-hydroxytryptophan
the L-form.
10 levcdopa.—
1. Mena
●f
d.,
,Vfi
J.
(diacetate),
Hydroxycstrone
10 rcapond
Engl J Med., 1970, 282.5.
Mearal
[email protected]&
Of 107 patients with, cndoge~
depression gw?n L-5-hydroxytryp~
Ophan dally m dlv,d~
dascs by mouth
for al least 5 weeks,
the majonl,
rapidly
obraincd
a
beneficial
response.—
1. Sa~
Mtinch mtd Wschr.. 1972. 114. i 7J 3, ,trer
Am me$
A,., 1972. 222. 1085, Further strrdrcs m depression N,
Hydroxyethylpromethazine
Chloride.
H2S=34.08.
(2- Hydroxyethyl)dimethyl[ 1-methyl-2 -(phenCAS — 7783-06-4.
othiazin- 10-yl)cthyl]ammonium chloride.
A colorless
inflammable gas with a characteris- C19H2jClN20SQ 364.9.
tic odour; the irttcnsity of the smell gives no CAS — 7647-63-4 (hydroxyefh.vlprometha:
inf).’
indication of conccmration.
2090-54-2 (chloride).
Adverse Effecss. Hydrogen suiphide poisoning is a Hydroxyethylpromethazinc chloride is an anticommon industrial hazard and IS cncoumered in histamine.
such places as chemical works. mines, sewage
Proprietary !+traes
works, and stores of decomposing protein: con- Aprobit
(Recip, Swed j.
centrations of 0.1 10 0.2% in the atmosphere may
+ fatal in a fcw minutes. Pulmonary irritation,
cma. and respiratory failure usually occur 12835-x
.er acute Poisoning; prolonged exposure tolow Hydroxymethylnicotinamide.
Nicotiny]mcconcentrations may give rise to severe conjuncti- thylamide; N-Hydroxymc!hylnicotinamidc. Nvitis with photophobia and corncal opacity, irrita- Hydroxymethylpyrid inc-3-carboxamidc.
tion of the respiratory tract, rhinitis, bronchitis, C7HNNZO:==152.2.
stomati[is. pharyngitis. digestive disturbances,
headache. Iassnsadc, and skin rashes. There are CAS — 3.569-99-1.
some similarities to pisoning with cyanides.
Crystals. M.p. 1410 to 142°. Sparingly soluble in
freely soluble in hot water
and
alcohol:
A discussion of pmsonmg by hydrogen
sulphjde.—
,!.an- water
csv 1978. 1, 28 Comments.—A Donnie (Iew). Ibid.. and alcohol.
219. C.H. B Bjnns (Ieuer).
ibid, 501, A Downlc (leIHydroxymcthylnicot inamidc is a cho)cretic and
ter). ibid
has been used in :hc treatment of various disordConcemrattons
of about
200 ppm caused irritation
01
ers of the gall-bladder.
the respiratory
tract and. on prolonged
exposure, pulm~
ppm
lrritauon
to the eyes occurred
al Corrcenlra.
t]ons of less than 50 ppm — Mc(hods for Iht LSr(ec[ion
In Air, H.vdrogen Sulphtde. Lonof TOXIC Substances
don. HM Stalloner\ Office. 1969.
or ?W
Uses.
Hydrogen
R.
Sulphuretted Hydrogen.
nor! oedcma
Tot IcIty to the CXS
could occur suddenly
at concentrations
m excess of 500 ppm and immediate
follow
concenwa[lons
m
excess
death
migh!
amca
Saerc
insomnia
in a 33-y~r-O1d
wOrnan fOllOwlng ~
nlghtl! Oroac accldcnt responded to 4 COnsccutlvc
of .- S-hydroxyrryptophan
Iotallmg
3 g.— M Webc ~M
L.mcrr, 1981, /, 1365.
J G K[rkcr (Ictler),
Further
referencm:
LXCUP. Med., 1979.
12834-t
Hydrogen
w::
n! :n: pupil. hyperrctlcxla.
ala~la.
was some similarity
to the efrects
used cllnicall}
5-Hydroxytryptophan is a precursor of scrotonin
(SCC p.1753) and has been used clinically in
at[cmpls to treat disorders believed 10 be associated with serotonin deficiency.
Changes jn mod,
mostly elevation,
were observed In 7
neurological
palients
without
afrec!wc
disorders
and I
healthy
subJeCl given
L-5- hydroxytryplophan
100 10
30Q mg by intravenous
infusion m sodium chloride lnjec[Ion. Carbidopa
was also glvcn [o reduce the severity of
voml[ing
which always occurred
30 IO 90 minutes afler
Infusion
and to increase
the amount
or L-5- hydrox~tryptophan
entering
!hc brain
Veurotoxtmly
occurred
Kline er al.. Am. J. Psycffiaf.. 1964. 121. 379. ~
Iru pharm. Abstr.. 1965, 2, 9t g: T. Pemsonand B +
S.
Rom
(letter),
Lmcer.
1967,
2.
9S7;
G.
AcIa psychiaf. sccsrui.. 197S, ~7. 239: L.
Neurops.vchobjo[ogy,
1980.6, 230
After
oral
administration
d’Elia eI atJ. van HIdc,
of ,L- 5,-hydroxyYryplophan
wti
~ pcrrphcral
dczarboxylaac
mhrbitor,
mild to m~emk
Improvement
was obtained
in 6 of 7 chrOnic undiffcr~
tiated schizophrenic
patients W~ were. resistant to pbm
Of 4 chronic pamno!d ~hlzophrcnic paumu
othiazincs.
who were rcsisrant
to phenothlazmcs
2 became wand
I
afwr :rcmment with 5-hydroxytryptophan
Improved.
.Somc schizophrenic
patients
abnormality
in serotonin
metabolism.—
al.. Scienct,
t972. 177, 1124.
Further
studies
in
Archs gen. Psychiat.,
ib!d 29, 597.
schizophrenia:
V.
might have in
R. J. Wyan a
Zarconc
1973. 28. 843; R. J. Wyatt
er d.
a al.
Mwtlanus.
Comment on the usc of the invcarigational
drug L-$-hydroxytryptophan
in the Ireatmcnl
of mpdc.
nus and the view that in general its usc should bc dr+
couragcd.
L-5-Hydroxytryptophan
is usually effecuvc m
Poslirypxic
intention
myoclonus,
a r,arc condition. but
ma: exacerbate
some other myoclonlc
syndromes
Srp
nifican!
adverse effects,
cs~ially
gastrn-inicstmal
duuhanccs.
arc almost univecsal. even when given with I
PrI pheral dacarboxylasc
inhibitor
such as carbidops –
1569.
R. R Young. J. Am. med. Ass.. 1980.243.
~.~.HvdroxYtrYpl~phan
with Mrbidopa was adminis[crcd
to ZI’ frmcnts
with
myoclonus
and
16 pa[ients *Isb
other neurological
disorders, Following
administration
h
mouth of maximum
doass of 0.4 to 2 g daily with carb
rdopa 100 to 300 mg daily more than 50% improvcmcnl
was obtained in 11 of I S paticn!s with intention m}cclo
nus due 10 anoxia or other brain damage, only 1 patImI
obtatned no improvement
and in 3 it was 90% or mom
sore: patmrts derived sustained benefit ror more than 3
years No benefit was obtained
by 2 pa[]cnrs wi[h arhc.
toIIc cerebral
palsy, 2 with multiple
sclerosis. 2 wI~
esscnual
wcmor.
4 wilh cerctxllar
intention
tremor. I
wltl!
infantile
spasms.
2 with
dystonla
musculom~
dcfo:mans,
2 wilh central
pain syndromes.
or 3 ~lr~
Idlopa[hlc
cpilcpy;
some Lsencfil was obtained
m I
Patlcn( with myoclonus
epilqrsy
and ]n I or 2 par!enu
with familial
essential mycclonus
Sldc-effects
includ~
ano:cxra, nausea. dlarrhoea,
and occasional vomt[ing ad
were reduced by prochlorpcra zinc or rrlmethobenzamld~
and d!phenoxylate:
prior admlnistra:ion
of carbldo~
im
I or 2 days before therapy also reduced the gastro+nlm
tinal s]dc-effects.
During
the first week of thcraP! 3
F-arlents developed dyspnoca followed by hypxvcnr!iatlm
and Ilghtheadutncss,
with fainting
in I; pulmonarj
fum”
[Ion tests rcmaused normal.
Varying
degrees of mcnul
simulation
occurred in 10 patients: these were rcvc~lb~c
on cwagc
reduction and frqucnlts
disappeared or dtm~
mshcd after
4 to 6 weeks wilhout
reduction,
but 2
paucnrs
rquired
concurrent
adm]nistrat!on
of peT’he
naz:?c
10 maintain
thcw antimvoclon]c
dosage. Olhd
side-:frccts
included
mydriasis.
b-lurrlng of vl$.10n aM&
mm. ? pain, and bradycardiz
— M
H Van VJOer~ ~r “Encl. J Med.. 1977. 296. 70. Comment — T L
\.*
Mr.nsal. -ib/d., 101.
StuCics suggesting that the Irca;m .nt of inrcntiOn m!e
clon-s w]th L-5-hydroxytryprophan
and carbtdopa [r 1
70->= r-old man unmasked
an abnornrallty
In his abll!t!
to ‘c:abolisc
kynurcnrne
and resulted
In the dr$’el~
mcr’ of a sclcroderma -like illness — E, M Stern~r!
Z
Eng{ J Med., 1980. 303. 782
al.. \e*
Fu-. ncr references
D. Chadwick
cr al., Lancer
19’S. 2“
J3J J Dct_ca” and J C Richardson
(Ic[ter).
ibid
‘~~
J F!
11?!
Growdon
er al . Neurolog>,
W
M
Carroll
and P. J
Mlnneap.,
1976
Br mf’d
Walsh.
“
_Hydrobenzoist
Hydrastinine
carradenst.s
L..
USris
And canadtne.
rsr~
vol.
L
G
Brauer,
Ed.
(Acadcrmc
Press.
New
Nickles.
Inow.
S.vm 1, 90 (1939).
Industrial
the action of sodium hypochloritc on urea in the
P=X=ICC Or NaQH’ B,I,~.~ Final Rwr~ 36% Moncr+ff.
York.
Audrieth,
by
prcpn
469-472. Toxicsty data: Witkin,
Arch Irrd Healrh
13, 34 ( 1956)
Toxicology
study: Back, Thomas, Ann Rev.
Phcrrmacof.
10. 395
( 1970).
Review
of carcinogmtclry
studies 1.4RC Monogmphs 4, 127-136 ( 1974); of iosscology:
J. App/. Tomcol 11, 447-450 ( 1991).
R. von Burg, T. Stout,
Books:
L. F. Audneth,
B.
A. Ogg. The Chemisrr-y of H-v.
drazme (Wiley,
New
York.
195 I); C. C. Clark. Hydrazrrre
Syn -
1963)
,draatinca:
Hope
er
et ai. ibid. 19M.
-m. Bull. 27, 1947
,Wn Lerters 22, 619
+aworth, Pinder, J
,., Nature 165, 529
,. 293, 121 (1960)
Letters
1963, 859.
m 29, 2328 ([964):
769). Biosynthesis
963),
I
pp
(Mathmson
Chcm..
Baltlmore.
1953).
Reviews’
JkwsuJ Chem. 18,
Troyan,
lrrd. Eng. C)rem. 45, 2608-2612
(1 953); Zimmer,
Chern Zrg.
79, 599-605 ( 195S); Hudson
er rsf., “H ydrazine””
m .MeiJor’s
vol. VIII. SUPPI 11. Nlrrogen (Parr 2), 69-114 (1 967): Jones
#n Compre/rerrs# w Inorganic Cherrrwwy vol. 2, J. C. Bailar. Jr
cr a/., Eds
W Sch!cssl
(Pergamon
Press, Oxford,
1973)
EncJ.dopedm
of
in Kirk .O!hmer
Chemical
nology
13 (John
York,
vol.
1995)
pp
Wile)
&
Sons.
NCW
p 250-265:
H
Tech-
4th
cd.,
otl} hq, fuming m
of ammoma.
Bums
air. Penetrating odor rcscrm
with
flame.
violet
salts
R.
hydrolyze
Patch,
M.
V.
I
XV (Springer.
rol.
116-.
[a]#
;+W
-127’
slight}y sol
.oln): 4.2
as . mine
on
d$
merctal
produc!
s6, bps ~
17w.
frcczmg.
1.0036.
wmghs
bplo~
1
1.3-
-6,7 -met hylencdl
C.. H..NOJ.
!\rre.
-,, -.,,
6.76%, O 23.167c.
Will, &.r, 20, 86
![. 241,136 (1910).
bplw
120.Y.
?)
NjH4
LDW
Dlhydrochlondc.
mp
19&.
Caulwrr
which
(John
WIIC!
3435.3441
& Son~,
H}drazjnc
Scwn!h
Annual
Kind-
orgamc
h>dra~nc
denvs.
Structure
study
chlorine
sc.atmgcr
for
l~,08rC,
are
ye].
solvents
Debbie,
d)otonic:
Tl”kl.
utennc
root;
yellow
rh,zome
and
aceae.
centg
not
]nlmrncdnte
ftbcrs
and
57 Iv.:
59 orall}
white
crystalline
rockcl
Ijquld,
T or below
n~ I 42842
less 304
sralnlcss
and
316
cd.,
USE:
etc.):
In
but
fuel
H,h’NH:. H20
of NaOH,
C H O
I i2-f83’”.
‘[a]#
fatnt
charactcnstjc
dll
eye !mlmtion.
not
stamlcss
~’)A
Molybdenum
not bc used.
with
waler
Mtxture
With methanol.
L’sE:
Reduc8ng
ag.wl,
cat:Il:’sl.
and
SICCIS
very
alcohol
C-Stujj.
solbent
Inorganic
mol
from
3914
Chcm -
493 (1983 to
.Yame Index
bejbrt
<. S 24.64~C
2NH3. aq
using
HzSO,
H,NNH
in
waler
at
[Ca(OCl\,
Starch,
glue,
Acid.
acid.
ma>
Org
VIII
276-293,
Mobile
liquid.
mp
–
plosive!
(mg/kg):
21.5
Ctsuriom
i.
Acra
fall m blood prcs
hypotcnsion, wa
[ndustria
detonators.
Hydr
4816.
ene]-1, I :3,3’-(2H
1,1’,3,3’-tetr0
rrc;
322.27.
C 67.OY
tiosr
of
tion
potassiun
23
of mnhydrin
Chem
211.907
(1
p-Suifophen-
of
( 1894); by the
Th. Zinckc,
A,
Plgmmt),
2.pyrazoli”e
ef af..
C.A.
Clai-
USSR pat. 1,057,-
100,
cmpds:
L.
reduction
of pKuchmbeckcr,
138755q
M.
(1984)
Mukai
e,
a/.,
—
-(3
4814.
from
water.
mp
286”.
2-Hydrzzincrethanol.
sol
in
2-Hydroxyethylhy
draz]nc;
CH2CH1NHNH1.
Lchloroethanol:
(1953),
from
1 )omP
Gcver,
water,
drazinc:
0’Keefe,
CoIorlms,
Omaffora
Prepn
from hydramnc
monoh>dratc
and
Gansser,
Rumf,
HeIv. Chins. Acts 36. 1423
hydranne
monohydratc
and ethylene
oxide
U.S.
front hydraz]nc
and
to Qli”
Malhi~On)
s[$jn”
pat
2,660.607
ethyicnc
sligh; ly
oxldti
Plant
growth
to Eaton Labs.);
(1953
Wit. pat. 776,113
(1957
IIquid.
d
1.11.
Onc
gallon
110-130?
bp~
145- I 53”,
water.
Sol m the lower
Sym
regulant.
Acid.
Iiydrogm
stlckstoffwasscrsf
azide; hydron]tric
of fsaurc
(Gcrma”).
I,
77 ( I 939):
“si”g
stcaric
acid:
the
C,
Gun.
41, 541 (1935).
Prcpn of water
I&r,
Meyer,
2 E/ek/rcxhem.
~d ether SOI”S of hydrazmc
ac]d
W S. Frost
er al,. J. Am.
Chem. Soc 55. 3516 ( 1933). L. F Audrieth,
C. F Gibbs,
b~
CJI.; P W. Schmk
Chemnrr,y vol. I, G
bc
COIIOIJ]
arc u~~d
York,
bc used jnsl=d
~f
S.vn. 2, 37 (l”l~)
2“d
Der, R A
cd,,
I 963)
Slmonaltls,
,n Handbook
o/ Preparative
Inorganic
Brauer.
Ed.
(Academic
Press,
New
J M Zchpp 472.474
GC detennn.
J Chmm
Sci.
14, 493
Consult
fhis serrlon.
A
.6
the
addn
blue
sol
of
color
in
acid
w,lth
a;
Reagentft
USE
acids and similar
d
iodide
I 5;
gas
10%>
In wa!e
sulfide
Iccordlng
Frykholm,
inorg
Iodide.
Colorless
when
or brown
on expc
can bc prevented
phorous
acid ( H31
for some time are
be regenerated
Jr.,
Inorg.
wlt
Syn.
(1976).
ToxLc-
fhe .Vame Index
2,
nor
Dissolves
iodine
bp,w
127”, d 1.7C
acid,
at[acks
Caurlon:
HN,:md W~ 43.03 H 2 34%,N 97.667..
Produced
b>
Sction of sulfur-se acid cm sodium tide:
L. F. Audrieth,
InOrg.
water.
air, preferably
,ISCOUS
~cighs
9.26 Ibs
mp —7U.
bpl,~
Flash PI 22&F
( I06”C)
MISC with
alcohols
Sligh!ly
sol In e[her
4815.
Hydrstzoic
acid;
tr,azolc
acid:
hot
pns
at
;;”~a.:.f,so~n
47%,
Sllghtly
C2H,NIO;mol WI
76.10,C 31,57%,
H 10.60T.,
N 36.8170,
0 21.02T0.
HO&hydroxyethyIhy
Dihydrafc.
reddish-brown
4$17.
Hydriot
water. Marketed
H\/w’n
dls:fl
Prepd
Compreherrsiw
T
isrry vol.
Jones in Compr
Bailar Jr. er af,
mirrors,
W,
pp
ma[enals
81Yc hydrazme
h!”
NajCO,
or gelatin
E
pp
W
57. 360 ( 1979): in isoln of volatllc
ke!onfi.
R6hnert,
Ber. 84.433
(1951); in analysis of
-CC amounts of selcn!um T. Kawashima er al.. Arrcr/
Chirn Acxa 49, 443 ( 1970): e{dern. ib!d. 89, 65 (1977}.
such as Alleghcn!
powerful
reducm~
Insol
In chlorO-
.HISO,.
-
and sodium
hypochlonte
Adams,
Brown,
poudcr
h’
3.6.
(silvering
metals
L V. L.azceva
Tambm
Used in resoln
CarL .l Chem.
Trcibs,
H
F, Gibbs,
as collolds.
bleachlng
278.296
acid:
Arm 330, 1 (1 903):
dralc.
19.57
ethanol,
0.5 to 0.05%
copper,
used to dcc h>.
drogen
pcrot]de
m V-2
type rockets.
M1xturc
w]th
m~l~atlol as propclla”rp.t
WrXlm=..,
~a~h[g
s> n[hest~
and IreaImen!
v.tth
Soly
aq aohr
phcrrylhydrazine-p-sulfonic
‘:”~~r~~~~~~’D~~:~’s”::6:’:’~
—
,Nz:
;.
cpn
m. ~OC, 76,
+ 22.9.
C4H10.
15.38%,
O
Inorganic
of
F.
1981)
J. Org. Chem.
tartratc;
17.04%. Prepn by sulfonation of phcrrylhydrarinc:
USE
for
consmllng
5.53%,
of a sard
depcmtlon
of
aess, P. Rooscrs, Ann.
diazobmzmrcaulfomc
118-1 Iv.
bp~
attacks
gla~s
SICCI or Alleghm!
Clayton,
York,
CCHON103S.
molw’s18B.21. C 38.29% H 4.287.,N 14.68%O 25.50% S
f+
odor
I 03.
H
pH
chc.
agent
as
b!
26.387.,
4813.
4-Hydrazinobmzeneauffonic
Prcpd frJm
followed
–6Y
(two
euccctIcs)
bp,~
Strong
base. very corrosive.
“’Hclman””
C
(PBa5-
mol W! 5006
acid
toxic
Indusrr
U.S. pat. 2.S301,935 (1957 to Merck & CO.).
Needles
alcohol
H,NIO.
ac!lon
delayed
347.
should
agm 1
Mlsmble
fm-rn and ether
Tarrtrate.
Hydrazine
Grat
of
USE:
[email protected] ~
of agncul!ural
Reducing
D}hydrwhlondc
procedures:
~timation of nickel, coba]t and
182.13.
chemical
Owcrt,
yfbydrtinc;
POW der,
bc an!icrpaled
wt
●bout 6 gl iC4Jml.
(Wl!L1n).
I ‘W41
lab
Adams.
hydrogen tartrate: hydrasirre bitartrate.
52.71%.
HZNNH
Crystals,
mp
gas streams
~] Q6e,
under
nntrogm
Fumnng
rcfractlvc
CaUscs
lrn r pason’
cork..
4!h
Revised
(1947);
study:
Review
Patty’s
231.
Hydrazine
4812.
Isydsazirrc
N:O~
mol
wmght.
Rcporf on Carcinogens
Hydrazine Hydrate.
~ ~? Q6~, 0
rubber,
~“ork.
in manuf
antlomdants
HCI
!hc
Manuf
Ige
led
d:
of corn.
(68.5
127
grawmetric
H#-N
hvdra~nc sulfate b)
–51.
47.,
moder-
55 mole-%
,the
p 231
Chcmlcal
spandex
4810.
organic
1.0253:
bp
n pl]&?9.b:#
236”
lnc .
ma> rcawrnabl!
,m safrole:
sol in alcohol,
con(mns
Xc~
LSE
m]cals.
- aJcohol
2.(Y.
d:
gallon
zsrrc are Irnta!ton
of eyes. now and throat.
temporary
bllndness: dwmncss. nausea. derrnallt!s: bums sktn and eyes Set
.%’IOSH Pcwhe! Guide m Chcmwol Hazard, (DH HS NIOSH
W-1 17. IQWJI p 124 Sec ako Patty’s fndusfrm/ H.vgw-rre and
US
To.r/co/ogy,
toi.
2E,
G
D
Clayton,
F
E. Cla!lon.
round.
I m cold,
One
d 1 42
Frccl}
sol jn water,
dlghily
in alcrrhol
Potcntlal
symp!oms
of overexposure
to h!dra.
>Optperonylamlne
I!
1.146;
In mme (mg kg)
H4Nl
2HCI.
a carcinogen
IIN781.
10W)
Rosen
d:$
0.9955
8.38 Ibs.
mp
20fY. bpm~
vman, Rcmfry,
J,
J. App\. Chcm.
113).
d:
Dlacidic base PKf
CriI
!cmp
38W
cr-rt pressure
14 atm.
(~5.):
-tI
05
forms
salIs uvth Jnorganlc
acids.
Hlghl~
Powerful
rcduclng
agent.
Dissol~cs
many
polar
solwtl
Inorganic
wbctanccs
Mist
with water.
methyl.
c!hyl.
prop.
Forms
an
azcmroplc
mtxturc
ulth
yl. mohut}l
alcohols
water,
hcmrr-
vdrv-6 -methyl-
d~s 1011.
conslant
Dipole
momcnl
I 83-1.90.
D1clcctnc
I .46444
(~5-):
51 3.025 kcal (mole.
Laicnt
hc.st of fuwon
(rep).
9760
kcal /mole
(cal.)
latent hc.s! of vaponzatlrm (bp):
[a]# – Scr (c =
218, 238, 298, 3 lb
: 7.8. Freely sol m
m
Contracts
1.024:
( 1947).
80.
cadmium; m the rcfnm-rg of rare merak as arttioxida”t in
aoldcrmg flux for I}ghl mctak as reducing agent in the analpolonium
from @ysis of minerals and slags: in separating
Itsriom; in tests for blood: for datroying fungi and molds; in
Use prcpn of hydrazmc hydrate.
Explodes
dtstn If [races of a}r are present. also affected by uv
Can be stored for years if scdcd in
and metal Ion catalysis.
glass and kep! in a cool. dark place. Flash and fire PI 1MF
(5TC).
h
Ber.
. D.
1994)
u3E:
during
I
Slmons,
109781.
560-606
Colorless
bltng tha~
177
Brown, Org.
2nd ed. ( f941), p 309. Crystal srrrscturc:
SyrL COILvol. I,
Nltta er aL Acfa CKYSL4. 2g9 (19511 Ji%rsaon, Hamilron,
ibid 268.536 (1970). Rctiew of activity and clinical studJ. Gold, Nurr. Corrcer 9, 59-66
ies in cancer cachcxia:
(f9E7).
plates or prisms. d
Orthorhomblc crystals. Glass-like
1.378: Curtis. Jay.
J.Prukl. Cherrr. 39, 39 (1889); d? 2.016.
mp 254”.
%1
in abmst 33 parts watefi freely SOI in hot
watts. Insol in alcohol. pH of 0.2 molar aq sohr 1.3.
Note.’ This substan= may reasonably bc anticipated to be
● carcinogen:
sewnrh Annual Jfepon on carcinogens (PB95Pfciffer.
ity
natul
StrOnl
USE:
Reducing
maceutlds,
dls}n!
analytical
purposes
THERAP
4818.
CAT.
EX
Hydrob
phenyiclhyleneglyc
H 6.59<,
0 14.93
An#
Forst,
Z]nckc,
Chem.
Soc
91, 13
Soc 51, 2163 (192
C. Heath,
Boston
Improved
method
mer:
Collet,
Synrk
before using
this section.
SCRI - Hydrazine Sulfate
m!!i!ml
_—=-.
Page 1 of
2
HYDRAZINE
SULFATE
“...Since
relief
hvdrazine
of a wide sDeCtrum
svmDtorns,
patients
effe~ts...
~rovided
of cancer
it mav be recommended
with end-stage
“... virluallv
side
sulfate
cancer.
for
”
no sign if~cant untowortl
”
GENERAL INFORMATION
——.
_—_
Hydrazine sulfate is an anti-cachexia drug which acts to
reverse the metabolic processes of debilitation and weight loss
in cancer and secondarily acts to stabilize or regress tumors.
Hydrazine sulfate is a monoamine oxidase (MAO) inhibitor
and is incompatible with tranquilizers, barbiturates, alcohol
and other central nervous system depressants. Foods high in
tyramine, such as aged cheeses and fermented products, are
also incompatible with MAO inhibitors. The use of
tranquilizers, barbiturates and/or alcoholic beverages with
hydrazine sulfate destroys the efficacy of this drug and
increases patient morbidity.
The U.S. National Cancer Institute (NCI)-published studies of
hydrazine sulfate (Journal of Clinical Oncology, June 1994),
reported as negative, denied the use of tranquilizers, with the
exception of the short-term use of prochlorperazine
(Compazine). However, under pressure of an investigation of
the NCI studies by the U.S. General Accounting Office
ordered by Congress, the NCI in a subsequently published
paper (Journal of Clinical Oncology, June 1995) admitted to
the widespread use of both benzodiazepine and phenothiazine
tranquilizers, which are incompatible with MAO inhibitors, in
94% of all study patients. Moreover, approximately half of
these patients were given these tranquilizers on a long-term
basis, and some on a continual basis. It was further admitted
by the NCI that concomitant drug use (such as tranquilizers,
alcohol, barbiturates, etc.) was not computerized and patient
http://www,ngen. corn/hs-cancer/
4/29/98
SCRI - Hydrazine Sulfate
Page 2 of 2
records of such drug use were “incomplete.”
—.
There is an abundance of published, positive, peer-reviewed
studies on hydrazine sulfate in the medical literature.
(Abstracts of some of these published studies are given on the
following pages.) These data emanate fi-om major cancer
centers both from the United States (randomized,
double-blind, placebo-controlled studies and single-arm
studies) and Russia (large-scale, multicentric Phase
II-equivalent studies). These data indicate the therapeutic
action of hydrazine sulfate to extend to all types of tumors.
Hydrazine sulfate has been demonstrated to produce only few
and transient side effects. There have been no instances of
bone-marrow, heart, lung, kidney or immune system toxicity,
or death, reported. Hydrazine sulfate has never been
demonstrated to be carcinogenic in humans.
For firther information please have your HEALTH CARE
PROFESSIONAL (no patients or individuals, please) call the
institute.
—
COLLECTION OF ARTICLES IHOW TO CONTACT
SCRI
A collection of articles on Hydrazine Sulfate has been
available on this site since 23 October 1996.
This page is designed and hosted by Next Generation Compu{ev Svstems, and is the
property of the Svracuse Cancer Research Institute. 01996, Syracuse Cancer
Research Institute. All rights reserved.
Last modljied on 21 January 1997.
—
http: //www.ngen.com/hs-cancer/
4/29/98
Page 1 of 1
SCRI - Article List
..—.
ARTICLES
The following is a collection of articles based on published
studies on Hvdrazine Sulfate. You may view the abstract by
clicking on the icon to the left. If the title of an article has no
hyperlink, then that article is not present on this system (you
may still view the abstract).
K!
“Hvdra~ine
Sulfate
/
~~
—
in !luence
on Nutritional
Statusand SLmvival
in
Non-Small-C’ell
Lunq Cancer”
[Journal
of Clinical
V 8:9-15.
Oncolog
19901
“Results
m
of Clinical
ONKOLOGII
“Altcrecl
m
Rccci\ing
Sciences
m
36:721-726.
Metabolism
Metabolism
in Cancer
1984]
“Hvdrazinc
n
D
With
Journal
Colon
cancer
of the Medical
on Abnormal
with
Weight
Tumors
With
ONKOLOGII
Carbohydrate
Loss”
Sehvdrin
40:332-336,
in Cancer
Patients
C’linical
Expcricncc”
[Cancer
With
Research
[Hydrazine
1994]
Weight
[Cancer
Loss:
A
59:406-410,
1987]
~
Profiles
inLate-Stage
CancerPatients
Res~onsiveto
H ydrazine
Sulfkte”
[Nutrition
and Cancer3:13-19,
1981]
“Effect
ofHwh-azineSulF~teon Whole-bodyProtein
Breakdown
Measured bv I K’-LysineMetabolisminLun~~CancerPatients”
[Lancet2:241-244,
1987]
“Anabolic
“Hvdrazinc
m
Brain
[VOPROSY
Sulfate
Sulfate
Patients
of P[lnlary
Placebo-Controlled
in Patients
[American
44:857-861.
m[
[VOPROSY
1995]
of Hydrazine
Sulfatel”
Sulfate”
1990]
Chcmothcrw”
“Influence
“Treal~ment
of Hydrazine
and Mollalitv
310:48-55,
D
—
Evaluation
9:59-66,
Sulfate:
A Current
Pcrs~cctivc”
[Nutrition
and Cancer
1987]
/
“Experience
n
in the advanced
of the treatment
cancer
with
patients”
Sehydrin
(Hydrazine
[Investigative
New
Sulfate,
Drugs
HS)
13:89-97,
1995]
“Use
D
of Hvdrazine
Patients:
E\’aluable
Results
Patients”
Sulfate
in Terminal
or Investigational
[Oncologv
http: //www.ngen.com/hs-cancer/article-list.html
New
32:1-10.
and Pretenninal
DmR
(lND)
Cancer
Study
in 84
K-
1975]
4/29/98
IGM-client? 1653+detail+4 at 130.14.32.43
—_
National
MAIN MESH
SUBJECTS:
—_
ADDITIONAL
MESH
SUBJECTS:
Page 1 of
2
Library of Medicine: IGM Full Record Screen
Use of hydrazine sulfate in terminal and preterminal cancer
patients: results of investigational new drug (IND) study in 84
evaluable patients.
Gold J
Oncology 1975; 32(1) :1-10
76101548
In a series of 84 various evaluable disseminated cancer patients
treated with hydrazine sulfate as a result of a
pharmaceutical-sponsored
investigational new drug (IND)
study, it was found that 59/84 or 70°/0 of the cases improved
subjectively and 14/84 or 17°/0 improved objectively. Subjective
responses included increased appetite with either weight gain or
cessation of weight loss, increase in strength and improved
performance status and decrease in pain. Objective responses
included measurable tumor regression, disappearance of or
decrease in neoplastic-associated disorders and long-term (over
1 year) ‘stabilized condition’. Of the overall 59 subjective
improvements 25 (42°/0) had no concurrent or prior (within 3
months) anticancer therapy of any type. Of the 14 objective
improvements 7 (50°/0) had no concurrent or prior anticancer
therapy. Of the remaining cases in which there was either
concurrent or prior anticancer therapy, improvements occurred
only after the addition of hydrazine sulfate to the treatment
regimen. Duration of improvement was variable, from
temporary to long-term and continuing. Side effects were mild,
comprising for the most part low incidence of extremity
paresthesias, nausea, pruritis and drowsiness; there was no
indication of bone marrow depression.
Hydrazines/ADVERSE
EFFECTS/PHARMACOLOGY/*
THERAPEUTIC USE
Neoplasms/*DRUG THERAPY/METABOLISM
Drug Evaluation
Gluconeogenesis/DRUG
EFFECTS
Human
http: //l 30. 14.32 .43/cgi-bin/IGM-client?
1653+detail+4
4/29/98
Page
IGM-client?l 653+detail+4 at 130.14.32.43
—_
PUBLICATION
TYPES:
LA .NGUAGE:
.—.
—
. —.
❑
Paresthesia/CHEMICALLY
Remission, Spontaneous
JOURNAL ARTICLE
—.
k
p-&*B
~71 oth~r
67
Years
of
2
INDUCED
Eng
order
Documents
2
f+!l
:::’:d~=
..
%4 off
:[email protected]:q
.
———__
http: //l3O. 14.32 .43/cgi-bin/IGM-client?
1653+ detail+4
4129/98
h[tp:/i130.
14.32
.431cgi,..M-elient?28084
+detail
t1
http//l30. 14.32.43fcgi-binTGM-dient?28084
+detailtI
NationalLibraryofMedicine:IGM Full Record Screen
I
E?
TITLE:
Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled
clinical experience.
AUTHOR:
Chlebowski RT; Bulcavage L; Grosvenor M; Tsunokai R; Block JB; Heber
D; Scrooc M; Chlebowski JS; Chi J; Oktay E; et al
SOURCE:
Cancer 1987 Feb 1;59(3):406-10
NLM CIT. ID:
87077829
ABSTRACT:
Hydrazine sulfate was evaluated using 24-hour dietary recalls and body
weight determinations before and after 30 days of either placebo or
hydrazine (60 mg, 3 times/d) oral administration in 101 heavily pretreated
cancer patients with weight lo~After
1 month, 83°A of hydrazine and only
53% of placebo patients completing repeat evaluation maintained or
increased their weight (P less than 0.05). In addition, appetite improvement
was more frequent in the hydrazine group (63°/0 versus 25°/0, P less than
0.05). Although caloric intake was only slightly greater in hydrazine-treated
patients, an increased caloric intake was more commonly associated with
weight gain in patients receiving hydrazine compared with those receiving
placebo (81 YOversus 53Y0, respectively). Hydrazine toxicity was mild, with
71 ‘%0of patients reporting no toxic effects. Hydrazine sulfate circulatory
levels were obtained from a subset of 14 patients who completed 30 days of
treatment, with a single sample obtained in the morning at least 9 hours
after the last dose. Mean maintenance hydrazine sulfate levels, determined
using a spectrofluorometric assay, ranged from Oto 89 rig/ml (mean 45 +/16 rig/ml). These data, which demonstrate an association between 1 month
of hydrazine sulfate administration and body weight maintenance in
patients with cancer, suggest future clinical trials of hydrazine sulfate are
indicated to definitively assess its long-term impact on important clinical
outcome parameters in defined cancer populations.
pl-
MAIN MESH
SUBJECTS:
1 of2
Cachexia/*DRUG THERAPY/ETIOLOGY
Hydrazines/*THERAPEUTIC
USE
Neoplasms/*COMPLICATIONS/DRUG
THERAPY
4129[98
3:13
PM
Chapter
5
HYDRAZINE SULFATE
Hydrazine
sulfate,
a simple,
off-the-shelf
verses cachexia
(ka-KEK-si-a),
two-thirds
of all cancer patients.
chemical,
the wasting-away
This inexpensive
dramatically
re-
process
that kills
drug, with little or
no side effects, also has a clinically documented
antitumor action. It
causes malignant tumors to stop growing, to reduce in size, and, in
some cases, to disappear.
A growing number of cancer patients
diagnosed as terminal have experienced
tumor stabilization
and
remission through hydrazine sulfate therapy.
About half of all patients who take hydrazine sulfate experience
weight gain, restored appetite, extended survival time, and a signifiin pain and suffering. Many patients report an incant reduction
crease in vigor and strength and the disappearance
of symptoms of
the disease, along with feelings of well-being and optimism.
While hydrazine sulfate may not be a sure-fire cancer cure, largescale clinical trials suggest that it affects every type of tumor at every
stage. It can be administered
either alone or in combination
with
cytotoxic chemotherapy
or radiation to make the cancer more vulnerable to these standard forms of treatment,
~~n~
Phase 111trials sponsored b~
the
National
Cancer
Institute.
It
is
a
lvailable
to patients as a ~compas.
ew Drug], ” a designation conferred by
le Food and Drug Administration
on a case-by-case basis, so it is no
~“na’N
longer, strictly speaking, an “unconventional
therapy, ” Yet even
~hough hundreds of patients across the country are using the drug,
it is not widely discussed or disseminated
among practicing physicians and its promise remains largely untapped
twenty-four years
af[er it was first proposed as an anticancer treatment by Dr. Joseph
Gold. Meanwhile, hydrazine sulfate is widely available in the Com-
47
lua3Jad
49 E 8U!1138 aJaM
sju+lud aluos ‘aJoJa.Ia~
“WOPJJAO
‘Sqaam X!Ssu!MollOJ
“I!U JO MOI ,@%HpX)3Xa
P3~OJlS3P
311qM
~dclaqlowaq~
ualjo
luuolluaAuo~
JO passaJdap
Uaaq
SCq ~It>lxOl
SE ‘MOJMXJJ auoq
aluJ[ns
aulzt?Jp~q
‘~JW&
U1 “S30p
JO sl[ao
sEq
sastn
poo[q
uMouq
[email protected]~
‘1
AoJIsap 01 paz!le!aads
OWI s6u!Jds
sv sIIa3
‘SIFKI KVpf
uJersAs eIoqM JnoA ‘paz!u600eJ
lewJouqe
JnOA 6u!uue3s
v JO aJemeun
snoip!su!
‘MoIs
aq~ az!u603eJ
‘vale
pue ‘sasnJ!A
We]suoa
aq 01 anuguos
s]! su!5aq
‘e! Je/3eq
pm~eu
al!qow
AIq6!H
aq] pue
‘Awaue
LLN3JSASeurtu.u!
aA&X?uJ
“aleJa~!loJd
aql
eunum!
JOJ Apoq
JnOA
ue se sIIe3 ~eouect
[email protected]
‘UO!]!J]flU
pue ep!Np
‘sseJ]s
JOOd—SUOSW3J
01 A]!unUoddo
Al!sea uea wa]sAs
aql u! Aep AJaAa UJJOJo] paiwileq
Ja3ue3 o! a3ue]s!saJ
“]pau
alq!ssod
J!aql owl
UI passncmp
‘uo!]oe
s! Apoq u6!eJoJ e se uoos
se t..pns .sJau6!eJojw
Uo Alp3J.JJou s! uJelsAs
noA at!qm sJeaA 10 Jaqu.mu e ~aAo qwoJ6
Ja3ue3
01 sl!e~ Saw!lawos
‘lUauJUOJIAUa Jno u! uo!ytllod
sno!JeA JO! ‘AlaleuniJopJfl
Aaql aJo~aq Luaq] AOJ]Sap pue pa]ap
]nq ‘uosJad Aqlleaq
al]ua6 stApoq aql [email protected]
aurtum!
ue aAeq
6UOJIS e
aJe $Ilaa Jacwe~
leJn]eu s]! pue sJahiod 6u!leaq-\las
~o cap! aq] pJeMol IOOCJ
aJt2 ‘aseas!p
6u!IL16!J
OJqoeoJdde J!eqI u! aAp3SaJ66e aq 01 pau!eJl ‘sue! a!sAqd Ieuo!luem!oa
[empaw aql Aq pauunqs
UOl]e6!]SaAUl q]dap-u!
JO ‘pajn3asJad
asaql q6noy] ‘suJeJ60Jd pa6pa[\-[py
OML ped
sa!deJaq!
ue Inoql!ikf
ISOW
luewqs!lqe~se
‘pOUUJapU03 uaaq aAeq s]uet.uieeJl
st? siua!yd
aunumq
Auet.u Aq pasn aJe
aA!leuJa\le
suo!jdo JO
aaJql eq] ‘ISEJIU03 UI
“le]UaUJ!JadX&I
A[a6Jel u!euJaJ Aaq/ ‘aS!UJOJd JeaJ6 p[oq OJp!es aJe Sa!dt2Jaql
6u!aq Al] UaJJn3 aJe AdeJaqlounww!
paJoldxa
se A[le\o] Isowle
spunlpe
XOPOI.HJOasaqt
aunuml
ellqM
“A.JC16JnSpue ‘uoqe!peJ
pasn IIIIS aJe Aaql
“sasua~ap [emleu
pue leqi-uoa Ieql walsAs
a)eu!w!la
AIKIIJIS IOU q6noq]
-ounww!
sa!deJaql eunum!
%etdeJaqi
JOUJ!e aql
‘AdeJa~10LUE)q3 01
“sJa\uao Jaoueo pue scy-yet u!
xopow.Jo JO suJJo~ ]eJaAaS
s,Apoq aql a]epmu!ls
eAi]euJa]le
osle ‘sa!deJaql
Jaq]o FOW “SIKKI Jeoueo
asoq~Ja~sloq
o]SI
aunumu! aq] JO sued
“Lueql AoJy3ap pue u6!aJo\ se sllao Jecmw az!u
-600aJ ueo warsAs aunt.uuq JnOA U! slle3 Paz!le!aeds
“uoqaalu!
pue Jacme3
~su!e6e allleq aql UI asua~ap ~“ eu!l Jo(euJ siApoq JnOAs! Lua\sAs eunmu!
S31dVH3Hl
sa3mosa~
aql
3N(W’llMl/
—-—.——
OM1
JJEd
I
56
opl16. ... ‘
ers, are your body’s
first line of defense.
natural
killer cells, they proliferate
telltale
substances
ond line of defense
phocytes)
stands
destroy
into
by
against
tumor
eaters”),
ingest
stances
nated
cells.
almost
macrophages
of the tuberculosis
as alternative
malignant
gland,
range
system
T-cc//
in
cells,
created
(Greek
of other
cells
in
them
for
help to orchestrate
“big
vaccine
used
b~G
or prolonged
BCG
stands
remission.
It appears
of
a weakened
for baci//us
/nrerferon
response
k
a family
to viral infection.
/yrrrp/rocytes
yet as
Used by conventional
as well
in treating
injected
directly
into
turned
fever,
into natural
cure when
chills,
and muscle
hairy-cell
H may have limited
approved
swelling,
results
called,
cells in
of macrophages
value
leukemia
industry
and
has reportedly
laryngeal
of other
may
require
of two rare
The FDA
been a failure
it had flu-like
symptoms,
however,
been
by the T-cells,
news media
have
effective
been
was also
as a cancer
disappointing.
in some
as well
chills
patients
hyped
by
breakthrough.
IL-2,
with
as it is
melanoma
as some
mice, TNF causes
its potential
believe
efficacy
is simply
tumor
Burton,
pioneer
the diagnosis
and treatment
Monoc/ona/arrtibodies
fusing
cells. When
a cancer
these
Attached
as “guided
their
missiles”
interferon,
sive,
next cancer
The
treatment.
or suppress
toxins,
the antibodies
Society
Observers
safe,
clinical
of Lawrence
M.D. (Chapter
through
gene-
into the patient’s
only the cancer
monoclonals
serve
they manufacture
stage,
toward
monoclonals—like
to be tremendously
monopoly
freely
touted
expen-
if they
are ever
by the media
that
nontoxic
cancer
in human
twenty
based
power
therapies
beings,
Ph.D. (Chapter
it will
take
immunotherapy]
say this means
results
Burton,
admits
[orthodox
to use its enormous
7), or the biologically
ski, M.D. (Chapter
Ironically,
6).
said to attack
or natural
role of these
the ACS continues
remarkable
therapies
used in
therapy
created
are reintroduced
antibodies
They are frequently
Cancer
treatment.”6
to restrict
patients.
establishment
as the
breakthrough.
American
Meanwhile,
into
being
blood cells with his or her cancer
and TNF—promise
to find the proper
in cancer
white
cancer
immune
antibodies
to the pharmaceutical-medical
used in cancer
why
develop
one of the four blood fractions
Still in the investigative
interleukin-2,
a boon
quantities,
most patients
human
(see Chapter
drugs
drug,
although
the cancer
of cancer
by directing
prey.
in treating
of a nontoxic
bybridomas
Cancer
as a miracle
to melt away. It is currently
arrtibocty,
specific
reactions.”3
vomiting. 5 Injected
are synthetic
to anticancer
malignant
and
upon which
patient’s
bizarre
toxic
in the body in minute
nausea
that TNF,
Treatment
their cell membranes,
their tumors
has spent millions,
duced
and even hallucinations.
produced
produced
effects
requiring
the National
it to the public
cells by destroying
early
of hospitalization
the devastating
presented
factor ( TNF),
Its side
anemia
weeks
of interleukin-2,
used by Lawrence
years
papillomatosis.
rare conditions.
who received
and
interferon
It produces
that they
in 1988, but it has largely
people
and the major
to date,
therapy
synthetic
for use in the treatment
and juvenile
in a number
headaches,
a protein
in 1980,
so severe
is !pproved
trials. Infected
/rrfer/eukin-2,
The
blood
and have toxic side effects.
its use for AIDS patients
in ARC-AIDS
the cancer
by the white
killer cells. Hyped as a wonder
contractions
unit “to survive
57
that IL-2 is highly
SI ~ck, and confusion.
is not clear. Side effects occur :agularly;
observers
cells.
charged
effective.2
may require
died because
body, they manufacture
the production
first synthesized
Today, interferon
forms of cancer,
fatigue,
it was
out to be very expensive
morphine,l
of
(white cells), blocks the growth of tumor cells, and transforms
some lymphocytes
miracle
produced
Some
evident
of the spleen,
bleeding,
had eagerly
tested to determine
splicing,
who discovered
director
and
cancerous
and many
successful
severe
care
this happens
fever
swelling
to Dr. Moertel,
a few patients
that
Research.
It stimulates
in an intensive
After
seems to kill cancer
Ca/rneffe-
remissions
to work well when
of proteins
transfusions,
with IL-2, according
The
strain
with chemotherapy;
particularly
for Cancer
multiple
and became
are major
and not particularly
malaise,
such claims.4
of cancer
was Dr. Lloyd Old, who later became
Institute
chills,
withdrew
One of the researchers
the Sloan-Kettering
fever,
a coordi-
and other forms
potential
include
l~~ies
M. D., of the Mayo Clinic,
expensive,
and sub-
it has also been used to treat lung cancer
BCG’S anticancer
Moertel,
hugely
which
tumors visible on the skin, though
of the diseas~
on. Charles
toxic,
but its drawbacks
Institute,
immunotherapy.
in the treatment
(which
has been
and renal cancer,
Tumor necrosis
works best when combined
melanoma.
(or T-/ym-
(The T’
rnacrophages
A wide
are
sec-
which transforms
to kill cancer cells. Consisting
doctors,
T-cells
blood
it has bro” !ght about some complete
cases of temporary
which
system’s
the
any invader.
bacillus,
Gu&irr)apparently
a solo treatment,
antigerrs,
cells.
white
there are five major types of orthodox
first is f3CG, a tuberculin
stimulates
these
cells,
up the immune
against
Altogether,
blood
the cancer
evade
Specialized
to the thymus
white
that make
attack
because
are carried
T-cells. ) Other
growth.
and virus-infected
for “thymus-derived”
the bone marrow,
and manufacture
cells
theT-cells,
your immune
detected
cancerous
If the cancer
Immune
years
or more.
and influence
that
have
pro-
such as the immune
6) and Virginia
therapy
“many
agents
Livingston,
of .Stanislaw
Burzyn-
2).
Co/ey’s
mixed
bacteria/
vaccine,
which
has perhaps
shown
.-—=
58
options
a greater
cure rate than any other cancer
Dr. William
Coley
Sloan-Kettering
(1862-1936),
researcher,
bacterial
toxins
patients
and cured
successful
of bacterial
his important
amply
since the turn of the century,
today’s
in what they view as merely
Staptrage Lysate, a nonspecific
is legally
staphylococcal
sold today
infections.
doctors
who have
cancer,
herpes,
Relatively
inhaled,
had encouraging
allergies,
inexpensive
injected,
T-1ymphocytes
/eukirr-7, the
Immune
therapies,
destruction
longed
patients
would
whether
supportive
immune
deficiency.
nutrition
have
item.
and chronic
it has been widely used by pragmatic
results
in
asthma,
treating
the natural
multiple
and many
It is known
believe
conventional
from
the
medical
made from staphylo-
other
Staphage
to increase
formation
sclerosis,
conditions.’
Lysate can be
the production
of interferon
or alternative,
in the United
in the
for acute
have received
of the immune
benefit
D.SC,,
and
of
inter-
of interleukin-2.
Many doctors
immune
vaccine
therapy
of
in cal cer
Nauts,
big drug companies
orthodox
through
and
made
Yet, despite
reported
of last resort after patients
often carcinogenic
recovery
Coley
work.
and almost totally nontoxic,
or taken orally.
predecessor
or radiation.
arthritis,
and to induce
as a treatment
bacterial
Unofficially,
a vaccine
an unprofitable
as a specific
unavailable.
ince mechanisms
Helen
vaccines
no interest
cocci,
developed
His daughter,
forward
is totally
New York City surgeon
immune-resis;;
hundreds.
and carried
use
literature
in the 1890s
that activated
has preserved
treatment,
an eminent
are generally
that the prior use of immune-destroying,
treatments
therapy.
system,
lowers
Chemotherapy
and radiation
a patient’s
chances
often accomplishes
can cause
severe,
At any one time, there are thousands
States
undergoing
aggressive
any immune-enhancing
or vitamin
used
toxic chemotherapy
supplementation.
measures
for
the
pro-
of cancer
chemotherapy
who
whatsoever,
even
96-34
c
——.
<
--—
—
=iram
.4 et al. Theuphylline versus
caffe!ne: compxative effecls in treatment of idiop~th!c apnea in the prerenn
infam. J Pediatr, 1987:110636
159 Davis Jhi et al. Use uf caffeine in
infants unresponsive [o theophylline
m apnel of prematurity. Pediatr Pul160 Eisenberg tlG Kang N Stability of
p=:
cmucd caffeine solutions for injectable
/and emend use. Am J Hosp Phwm.
w
19ff4:il:M05
161Eyal F et al. Ammophylline versus
doxapram m idiopmhic apnea of premmunty: z double-blind comrolied
study. Pediau’im. 1985;75:709.
162 Peliowski A, Finer XN. A blinded.
rtrndomlzed. placebo-continiled trial to
compxe Theophylline and doxapram
for {he cremment of apnea of premamrity. J Pedimr. 1990:116:648.
163Bairam A et al. Doxapram for the
!n!tiaf uea[men[ of idiopathic apnea
of prematurity, Bioi !4eonat. 1992:61:
Pediatric
176 Painter MJ. Therapy of ncomtrd WTzures. Clew Clin J Med. 1988.56
(suppl. ):sl?J.
177 Morrison A. Nemmud wiztmes. In:
Pomwmce JJ. Richardwr CJ. @Js.
Neonwology for rhe Cliniumrt. Norwalk: Appkmn & 1+x:
1993:411.
178 Haymond WV. [email protected] in infants and children. Endc~rlnd \fe[ab
Clin .Nonh Am. 1989; 18:22 I
179 Tsang RC. Nemmml magnesmm disturbances. Am J Dis Child. !972;124.
~~~,
lgo ...
. . a.,,,,+pc
... ... . .... mm
. ... c c,.-,..,
, ,, , n..... “.>
J. ..
““..1
.7.
J.,
of treatment prirctlces it>r nemuml .ei zums. J Peritm{ol. 1993;13 107.
181 Painter M.J @ al. Phenob~rhi[d md
diphenylbyckmoin levels in rwrmams
with seizures. J Pedkm. 1978:9?:? 15.
182 Gilman JT et al. Rapid cequenud
phenobarbital wearment of rwonatal
se[zure$. Pediatrics. 1989:S3:074.
183 Desbmukb A et al. Loruep~m tn [he
mwmem of refractory nwm.ualw.
zure.s:a pdot study. Am J Dis Child
209,
1986:140:1042.
164Barrington KJ et A DOse-respcmse
184 McDermott CA et al. Phurmrcokmttrelationsblpof doxapramin [be (herapy
!cs of Iorazepam m cnumlly d! neofor cefntcmry idiopathic apnea of prf nates with wlzures. 1 Pidi.ur. 199?;
mamnty Pediwncs. 1987;8022
[20:479.
165 Tay-Uyboco J eI al. Climcd .md pbys185 Cd Pet al. Valprow md e!timcy. KJkiolog!cal response> to prolonged nmoici(y. and phmmwoktne[tc% In rteondes
gasuic admjni$rr.wmn of doxapmm for
with inwxmbk seizures. Mmolugy.
apnea of prematurity, Biol Xeomt[e.
1988:38:467.
199[,59:190.
186 Fischer JH d d. Phenobwtxml mmn166 Papile LA. Centmf nervous sysrem
[en.mce dow reqwremems in treating
dkmrbances. part four penventnculwneonatal se]zut-es.%mdog~
198I:3 1:
in[ravcnwicular hemorrhage. In: Fwm1042.
mff AA, Mmun RJ, eds. NeOnmd187 Painter W et d. Phenobtiwd
md
Perina[d Medicine: Diseases of the Fephenytoin in neormcal seizures: metabrns and Infcmt. 5th cd. St. LOUIS:Mosby
olism and tissue dismbutnm. NeuroiYear Bcwk; 1992:719.
Ogy. 1981:31:1107.
167Papile LA, Brmm BS IV. lmracranid
188 Rosen TS. [nfam of wldicted mothers.
hemorrhage penventricular. intmvenIn: Fanaroff AA. Wrun RJ. cds .Veouicularbemonbage.
tn:Pomerance JJ,
nmal-Pennmal Medicine: D#se.ases of
Richardson CJ, eds. Neona[ology for
the Fetus and Infant. 5[b ed. SC.Lou]>:
tbe Clinician. Norwalk: Appleton &
Mosby Year Buuk. 1992:574.
lang~ 1993:425.
189 Finnegan LP, Weiner SM. Dmg wi[h168 VOlpeJ.). Inwaventricrdz hemomhage
dmwal in the neomttc. In: Mcrcnste!n
and brain injury in the premature inGB, Gardner S1. eds. Handbwk of
fant: neuropathology aud pathogenesis.
Neonaml Imcnsive Cmc %d cd. St.
Clin Perinatol. 1989; 16:361.
Louis: Mosby Year Bnok: 1993.40.
169 hlinarcik C.J Jr, BeachY P- Neuml190 Levy M, Spino M. Neoniwi wl[hogic disorders. [n: Merenstein GB,
dmwal syndrome: assumted drugs md
Gardner S1. eds. Handbook of Neophammcological management. Phwnatal lmenssve Cxe, 3rd ed. St. Louis:
maco[bemp y. 1993; 13:202.
Mosby Year BcuK [993:430.
191 Doberczak TM et al. Neonttal opime
170 Volpe JJ. Intrwenrriculor hemombage
abstinence syndrome in term and preand brain inJury in he premature interm infmms. J Pediarr. 1991:118:933.
fant: d!agnosm prognos~s, and preven192 Zelstm C et al. Neonatal narcortc ttJ[ion. Clin Pennmol. 19!39;[6:387.
dkwon: comparative effecrs of mwer171 Lamp KC, Reynolds MS. Indometh.
naf intake of heroin and me[hadone. .V
acm for prevention of neonatal intraEngl J Med. 1973.289:1216.
venmcuiar hemorrhage. DICP, Ann
193 Gt-eenglass E.J. The adverse effecls of
Phannacother. 1991;25:1344.
crwune on tbc developing human. In:
172 ,Mc”t LRetal.
Low-do= indomechaYatfe SJ, Armrdz JV. .4s. Pediwic
cin ond prevention of intmven[ricxdar
Pharmacology: Tfmmpeut!c Pnnclpks
hemorrhage: a mulricenter randomized
m Pram!ce. Philadelphia. !$’B SiMUT[nal. Pecfimrics. 1994;93:543.
dws; 1992:598.
173 Vulpe JJ. Brain inJurycaused bymlra194 %uspeil DR. Hamel !3C. Cccum anti
vemrIculx hemorrhage: M mdometbmfam behawor. J J)ev Behm Pediwr.
acm [he dver bullet for preven[wn’
1991:12.55.
Pedimncs. 1994:93.673.
195 Kandall SR, Gmlner 13[. L.i[e pre.
174 Rust RS. Vtdpe JJ. Neonwdseizures.
semwo” Ot drug w!thdrm~d sympk: Dcdson WE. Pellock JM. CIJ5.Petoms m rwwboms. Am 1 Di. Child
dimnc Epilepsy Diagnosis and Ther1974:1?7:58.
apy. New York: Demos: 1993: J07.
196 Finnegan LP et al. !vlima$emenrof ne175 Mizrahi EM. Consensus and comroonmal nwouc abmnence uulizmg a
versy m [he chnicd management of nephenobwbmd loading doe me[hwl
onatal 5eizures. Clin Penmttol. I989:
NM] Inst Drug .Abuse Res Monogr Ser.
16:485.
i979;27:247.
[97 Amerhn
Committee
Academy
nn Drugs.
nf
Pediatrics,
%mmol
drug
wichdr~wol, Pedimrics 1983:72:895.
I’M) W’ijburg FA et nl. Morphine m m
mx-epileptlc drug in neonatal ~bwinence syndrome, A&r P~edi.ur Sumul.
1991;80:875.
199 Hill RM, Desmond Mhl. Mwm:emm-n of the narcotic withdrzwd syndrome in tbe neonate. Petfia[r Clin
Nonh Am. 1963:10:67.
200 Stark AR et al. Muscle relwxion in
mechamcdly ventilated infrets. J PeJifilr,
I979:94:439.
201 Crone RK. Favorito J.Tk effecrs of
p~ncuronmm bromide on infhnts with
hydine membmne diseme J Pedimr.
1980:97:991.
202 Buck ML. Reed
.MD. Use of nondepulwrzmg neuromuwukw blocking
agents in mcchmicdly wnriktkd palmms. C!in Pfunm 1991; ltl.12.
203 Carlo WA et al. Assisted venrilmion
and dK compl icatimts of respiratory
distress. In: Fmwoff AA. Mwtm RJ.
eds. Neonzrtal-Pennwd Mc&ine: Da>CWS of the Fetus .mtf Infant. 5rh d.
St. Louis: Mmby Yeu Booh: !992:
827.
m.kTaylor P. .Agems acung M the neuromu.scuku Junction md ~uronomic xwtglia. I“: Gilmln AC e[ d.. mk. G,xd-
mm md Gi hmm’s The [email protected]!.
cd B.MISof Thw+mmc,. 8!h ed. NW
York Pergammn Press; I9%3:I66.
205 BennettEJ et al. Pmummium id the
neunate. Br J Arxwth. !975:47.75.
206 Gretnough
A et id. Investigation
of
effects of pamlysis by pancumnium
on heart rate varmhiliry, blind pressure
md fluid bidmcc. Acts Pacdkm Scrod.
198%78:829.
207 Cabal LA et d. Cardiovascular and
catechoiamrne change~ after dm!nismrion of pancuronium in Jiswesscd
neunmes. Pediatrics. 198X75:28-!.
208 Piotrowski A. Comparison of mmrrium and pancuronium m mechmically
ventilated nenmues. Intensive Care
Med. 1993; 19:401.
209 American Academy of Pediatrics.
Cummmeeon fetus and newborn. commmee on chugs. section on anesthesiology. section on surgery. Nmnatd anesthesia. Pedimics. 1987:80446.
210 Anand KM. Hickey PR. Pain and m
effecls in cbe human neonate mif fern>.
N Engl J .Mcd, 1987;317:1321.
211 Shapiro C. Pm! in the nennme: assessment and mrewemion. Nmmwd
Netw. 1989:8;7,
(he
212 Goldberg R.?J
elal.
Detcceion of seizure xtiwty in rhe paralyzed neonate
using conmwus mnnitorin~. PediN.
tiCS,1982:69:583.
213 Zenk KE. Przcticd pharmacology for
rhe chnwmrr carinE for the newbum. [n:
Pomerartce JJ, Richardson Cl. eds.
Neonamlo~y for [be Clinicixn. XorwW: Appkmn & Lange: 1993:59.
214 Roth B et al. Anolges ia ond scdauon
m neonatal in[enslve care using fcnmn>I b> connnuous infusion. Dev
Phm-rtwol Ther. 199I;171?1.
215 Xorton SJ. Aim effects of morphine
and fenumyl mdgcsm: a rc[rospective
smdy. Nenrmml %w, 198tk7:?.5.
216 .Amoid JH et al Changes m the pharmauxkynamic rebponse m Wmmyl in
neonates during conunuous infusion. J
Pedia[r. 199 l; 119:639.
TheraPY
217 Katz R et al. Prospective study o“ tie
occurrence nf withdr~wd in criticaf[y
ill children who recci>c fcnmnyl by
cnmmtmu$ !nfubion. Crtl Care Med.
1994:22:763.
218 Lane JC et al. Movement disorder af.
ter wlihdrowrd of fenmnyi infusiom J
Pdimr. 1991;1 19:649.
219 Anand KJS, ..imold JH. Opioid tol-”
mtnce and dependence m infants @
children. Cri{ Care Med. 1994;2?:334.
Watling SN[. DMVJ JF. Prolonged pa. I
mly.sis in inrensive cwe unit patients af.
ter the use of neuromuscular blocking
zgenw: .r review of [he literature. Crit
Cwe MeIJ. 1994:22:884.
,:
Anyebuno MA. Rowmfeld CR. Chloral hydrate toxicity in a term infmt.
Dev Phwrnacol Thu. 1991;17:1 16.
Mayem DJ e: al. Chloral hydrate dk.
miliOn fOo~)win: single-dO= adminismmion m critically ill neonates and
children. WY Phirrmacol ‘fler. 1991;
16:7[.
Mtyers DJ et al. Scdttive/hypnotic
effects of chlm-d hydrate i“ the “enine: tnchloroe[hanol ur parent dreg?
DCVPhmmtcol T&. 1992; 19:141.
Nahata 31C. Hippie TF. Pediatric
Dmg Fonnukuiom. hf cd. Cincinnati,
OH: Harvey Whimey Books; 1992. .~
Blumer JL. Reed MD. Prmciplcs of
nconwrl pbmnutcology. In: Yaffe SV,
ArmIda IV, mls. Pedimric Pharmacology: Therapcurtc Principles in Practice.
Md CL Phdadclphix WEJ Saundem”;
199?: [64. [68.
Ernst JA et al. OsmolaJiry of sub
srances used in the imensive care nursery. Pediwics. 1983:72:347.
WMte KC. Harkavy KL. Hypertonic
formula resulting fmm added oral medicmions. Am J DIS Child. 1982;136:
:,+
:
931.
American
Academy
of
Pediatrics,
ingrediems in phornmcemical prcducrs.:
Pediwics. 1985:76 :63S.
229 Glasgow AM et al. HyWruwnoldity in
small infants due to propylene gfycol.
Pediatrics. 1983;72:353.
i
230 Bafistrwi\VF et al. Lessons from the
E-Fcrol tragedy. Pediatrics. 198678:
503.
Kumar A et al. The mystery [email protected]
ens: sweeteners, flavorings, dyes, and
pmmvalives in mmfgesiclantipy
mtic,
amihis;ammeldecongcstant. cough md
cold. mrtdimhed. md liquid tbcopbylline preparmions. Pediatics. 1993;
9 I:917,
232 Nahata MC. Immvenous infusion cOn(Liions: impliutions t’or phannaCOtiCommittee
on Drugs.
a‘Inactive”
ne[k monitoring. Clin Pharmacokinet.
1993;24:221.
233 Roberts RJ. Issues and problems msnciated with drug delivery in Pcdific
Patlen[s. J Clin Phimnacol. 1994;34
723.
23-f ?Jahata ,MC e! al. Effect of infusion
methods on tobmmycm semm cOncen”
[rations m newborn mfmts. J [email protected]
19&t,lfM:136.
235 Painter \fJ et ol. Neonatal [email protected]
PmhW Chn Nonh Arm, 19s6;33:95.
236 Friedman WF. Con$emtaf he~ ‘isCN in infancy and chddhd.
~
Brmmwahl E, ed. Hwr Dise~e: A‘
Textbwk uf Cirrdiovwcul&r M~c~e.
.$th cd. Philmfeld) ia. WB [email protected]’%
1992:S93.
. .. ...-. _
Reprktted with permission
NOTICE
~H~~MATERIAL,MAYBE PROTECTED BY
(:OFVRIGtiT
LAM) (TITLE !7, U.S. CODE)
_—_
Hydrazine
througtt
Me
Copyright
Clearance Center
Sulfate in Cancer Patients With Weight Loss
A P/acebo-Contro/ledClinical Experience
ROWAN
T. CHLEBOWSKI,
RAYNELLE
MICHELLE
MD, PHD,* LINDA BULCAVAGE,
TSUNOKAI,
SCROOC,
ENGIN OKTAY,
BS,*
RD,t
JEROME
JOAN
MD,5 STEVE
B. BLOCK,
MN, RN,* MARY
S. CHLEBOWSKI,
AKMAN,
GROSVENOR,
MD, ” DAVID HEBER,
MD,$ JOCELYN
MD,” AND ISHRAT
RD. MS,t
MD, PHD,$
CHI, MD,”
ALI, MD$
Hydrazine sulfate was evaluated using 24-hour dietary recalls and body weight determinations before and
after 30 days of either placebo or hydrazine (60 ma 3 times/d) oral administration in 101 heavily pretreated
cancer patients with weight loss. After 1 month 83% of hydrazine and only 53% of placebo patients
completing repeat evaluation maintained or increased their weight (P < 0.05). In additiom appetite improvement was more frequent in the hydrazine group (63% versus 25%, P < 0.05). Although caloric intake
was only slightly greater in hydrazine-treated patients, an increased caloric intake was more commoniy
associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81%
rersus 53%, respectively). Hydrazine toxicity was mild, with 71% of patients reporting no toxic effects.
Hydrazine sulfate circulatory levels were obtained from a subset of 14 patients who completed 30 days
of treatmen~ with a single sample obtained in the morning at least 9 hours after the last dose. Mean
maintenance hydrazine sulfate Ievelq determined using a spectrofluorometric assay, ranged from O to 89
rig/ml (mean 45 * 16 rig/ml). These da% which demonstrate an association between 1 month of hydrazine
sulfate administration and body weight maintenance in patients with cancer, suggest future clinical trials
of hydrazine sulfate are indicated to definitively assess its long-term impact on important clinical outcome
parameters in defined cancer populations.
Cancer59:4OG$10, 1987.
-.—
W
iS cofi~~
in this population. 14 rf this h~thesis
velopment
and k associated
with an adverse
amelioration of the abnormal carbohydrate metabolism
could provide a therapeutic approach to the adverse outprognosis. 1-3Although
intensive caloric support now can
come associated with cachexia development in the cancerbe provided such patients, clinical trials evaluating caloric
provision alone have not reported improved outcome for
bearing host.
We previously demonstrated that hydrazine sulfate is
chemotherapy-treated
populations with advanced canmetabolically active, improving the abnormal glucose
cer.44 As a result, consideration of potential mechanisms
tolerance and reducing the increased glucose production
underlying the development of weight loss in the cancer
rates seen in cancer patients with weight loss.’ J We now
population has led to development of alternative strategies
report clinical observations on short-term hydrazine sulfor clinical intervention in these patients. Altered glucose
fate use in a cancer population with weight loss using a
metabolism is a common metabolic abnormality in cancer
patients with weight IOSS,7-’3and it has beensuggested prospective placebo-controlled study design.
EIGHT
LOSS commonly
that the inappropriate
metabolism
___
I
leads
accompanks
activation
to futile
of pathways
cycling
and
cancer
opment
de-
of glucose
cachexia
Nlaterials
andNlethods
devel-
From the UCLA School of Medicine. Department of Medicine, ●Division of Medical Oncology and tClinicat Research
Center,
HarberUCLA Medical Center, Torrance. and the *UCLA School of Medicine,
Department of Medicine, Division of Clinical Nutrition, and the
$Southem California Pemranente Medical Group, Los Angeles, California.
Supported in part by Grant CA37320 from the National Cancer Institute, NIH: Grant RD- [63 from the American Cancer Society, and
Grant RR-00425 (General Ctinieat Research Center) from the NfH.
Address for reprinw Rowan T. Chlebowski, MD, PhD, Division of
Medical Oncology, Harbor-UCLA Medical Center, 10(X3West Carson
Street, Torrance, CA 90509.
Accepted for publication September 9, 1986.
406
The criteria for inclusion in this trial were: a diagnosis
of advanced cance~ weight loss greater than 1070 from
usual body weight: absence of severe hepatic or renal dysfunction (bilirubin greater than 3 mg/dl and/or creatinine
greater than 2 mg/dl); and normal mental status. Patients
with a known history of diabetes mellitus or those receiving corticosteroid therapy were ineligible. Patients with
ascites or clinically significant edema were not entered to
avoid confounding weight determinations. Patients were
entered either prior to receiving systemic chemotherapy
or when a new systemic therapy program was initiated
_
1 3
HYDRAZINE
SULFATE
IN CANCER
for disease progression, Measurable disease parameters
were not required, and concurrent chemotherapy was
permitted. Both initial and repeat assessment of all study
parameters, however, were conducted at least 2 days before and 4 weeks after chemotherapy administration.
After informed consent was obtained, patients underwent an initial assessment of nutritional parameters, including caloric intake as described below. Patients subsequently were treated with capsules containing hydrazine
sulfate (60 mg) or placebo which were prepared by Anabcslic,Inc. (Irvine, California). Hydrazine sulfate was given
under [ND 17, 671 from the Food and Drug Administration (FDA) (obtained by Dr. Chlebowski). All institutional requirements for human subjects review were
met. The treatment program consisted of an escalating
schedule of capsules containing either hydrazine sulfate
or placebo until the full dosage of 60 mg, 3 times/d given
before meals, was reached beginning on the 8th day. This
program was based on the extensive Russian experience.’5
Patients were contacted weekly to assess compliance and
kept daily compliance diaries. The validity of daily compliance diaries was checked against intake based on returned prescription bottles. Following 30 days of either
agent, the assessment of body weight, caloric intake, and
ther parameters was repeated.
During the initial and repeat evaluation, all patients
received determination of bcdy weight measured on the
same printing scale; anthropometncs, including tricep
skinfold thickness, mid-arm muscle circumference, and
serum albumin; caloric intake using a 24-hour dietary
recall history obtained by nutritionists and computer analyzed to give protein, carbohydrate, fat, and energy contents of the diet. Expected
caloric
intake
was normalized
for each patient by weight based on a calculated recommended daily allowance (RDA). Toxic et%cts of treatment
and influence on appetite were determined by questionnaire.
In a subset of 14 patients, blood samples for hydrazine
sulfate circulatory levels were obtained as a morning sample taken at least 9 hours from the last oral dose following
30 days of treatment. Hydrazine sulfate levels were measured using a de finedlb’L7spectrofluorometric assay in
which reaction of hydrazine sulfate with dimethylaminobenzaldehyde produces a colored derivative. Fluorescence was subsequently determined in an Aminco Bowman (Silver Spring, MD) spectrophotofluorometer with
an excitation wavelength of 466 nm and emission wavelength of 546 nm.
All patients were given defined, uniform dietary coun“–L selling bawd on nutritional status at entry to insure comparability of dietary information available to patients on
hydrazine or placebo treatment. The nutritional guidelines
all patients were provided with were designed to duplicate
a routine clinical diet~ assessment that would be ex$ Petted to be a component of a cancer patient’s standard
“i: ‘:{
CACHEXIA
TABLE
1.
“
Chlebon’ski
407
et al.
Charactenstks
of Cancer
ydmzine Sulfate or Placebo
Pretreatment
H
Patients
Receiving
Treatment received
Hydrazine
—
71
Number entered
Placebo
30
Age in years
Median
Range
56
32-77
59
36-77
Sex (’%Male)
61%
65%
46
13
4
2
3
I
15
4
3
3
I
2
1
I
Disease type
Lung
Colon
Other breast
Esophagus
Nasopharyngeal
Hepamcellular
ovarian
Prostate
:
Performance score
(Oor 1)
(~ or 3)
14%
86%
23%
77%
Nutritional status
% Weight loss (mean)
17%
14%
Caloric intake
>90% of RDA
<90’%of RDA
39%
61%
41%
59%
3.4
3.3
78%
74%
Albumin gm/dl (Mean)
Concurrent chemothempy
RDA: recommended daily allowance.
clinical management. Enteral tube feedings or parenteral
nutritional support was not given any patient while on
study.
A totalof101 patients with advanced cancer underwent
initial evaluation. Sixty-one consecutive patients (including all 30 patients given placebo and 31 given hydrazine)
were randomly assigned treatment in a double-blind fashion with treatment assignment based on published random-number tables. An additional 40 patients received
hydrazine sulfate and represented a consecutive series of
patients seen in the Clinical Research Center meeting ent~ criteria for the trial. Statistically significant differences
between hydrazine and placebo groups relative to pretreatment clinical factors were sought using chi square
contingency table analyses and Student’s / test. The statistical differences between hydrazine and placebo treatment were determined using the two-group t test.
Results
A total of 101 patients with a variety of advanced cancers underwent initial evaluation. Patients receiving hydrazine sulfate or placebo were comparable with respect
to tumor type, age, sex, performance score, nutritional
parameters and chemotherapy experience (Tables 1 and
2). The compromised nutritional status of the study POP-
CANCER February
1 1987
408
CooCurrent Chemotherapy of Cancer Patients Receiving
Hydrazine Sulfate or Ptacebo According to Disease Type
TABLE 2.
Studv arm
Chemothempy gjven
Hydrazine
Placebo
Vet. 59
observation.
Anthropometrks
wereunchanged
overthe
Caloric
intake
was onlyslightly
30-day studyperiod.
higher
inthehydrazine
treated
population.
When aUpatients
experiencing
anincr~se
in~OriCinhkewereconsidered,
however,
weight
gainWaSseenina signifkzmtly
higher proportion of patients receiving hydrazine sulfate
while increasing caloric intake compared with those who
PVB
increased caloric intake while receiving placebo. The reACCO
sults
using hydrazine sulfate were C1O%IY
comparable in
0
ACO
2
No chemotherapy
the 31 patients entered as part of the randomized trial
when compared with the 40 patients added as a consec4
13
Colon cancer (n)
1
2
utive series. The results for the patienfi receiving hydrazine
5-FU
1
7
5-FU + vitamin K
or placebo who were entered as part of the randomized
2
4
No chemotherapy
trial were: weight maintained or increased, 71% versus
II
12
(n)*
Other disease sites
53%; improvement in appetite, 63% versus 25%; caloric
3
4
No chemotherapy
intake increased, 69% versus 37%; and increased caloric
intake associated with weight gain, 77% Versus 53% for
P cisplatin (Platinoi} A: do~orubicin, (Adriamycin} C: cyclophosphamid~ c: CCNU; O vincristine (Oncovin~ 5-FU: 5-fluorouracil; V
the hydrazine versus placebo patients respectively. In advinblastine; B: bleomycin; 5-FU + tit k 5-tluorouracil plus vitamin K]
dition,
results in groups receiving or not receiving con(Synkavite).
current chemotherapy reflected those obtained in the en● The patients with other disease sites received a variety of regimens
which included cisplatin in 62% and 50% of instances for the hydmzine
tire group.
and placebo group, respectively.
Thirty-five patients with cancer other than small cd
lung cancer (the predominant tumor type studied) comulation is demonstrated
by the 16% average
weight
loss pleted serial evaluation, with 26 receiving hydrazine sulexperienced by the overall population. Of this advanced
fate and nine receiving a placebo. In the lung cancer padisease population with weight loss, 58 patients were able
tients, weight maintenance or increase was achieved in
to complete repeat evaluations aher30 days of treatment
83% of those receiving hydrazine sulfate compared with
(41 were given hydrazine; 17, placebo). Early disease pro33% of those receiving the placebo.
foralmost
aUcases
not
gression and/or death accounted
The short term hydrazine sulfate regimen used in this
havingrepeat
study.
Onlytwo patients
refitsed
repeat trial was well tolerated by study participants. Compliance
evaluation.
forms were returned by 90% of patients who completed
Theinfluence
of30daysofhydrazine
sulfate
orplacebo repeat evaluations, and indicated that 95% of the schedtherapy
on study
parameters
for aU entered patients who
uled dose was taken by the study population completing
underwent repeat evaluation is outlined in Table 3. Weight
30 days of therapy. The mean maintenance plasma hywas maintained or increased in a higher proportion of
drazine sulfate levels obtained from a subset of 14 patients
patients receiving hydrazine sulfate compared to placebo
ranged from O to 89 rig/ml with a mean value of 45 f 16
therapy (83% versus 53%,respectively; P < 0.05).The use
rig/ml. Clinical toxicity of patients receiving hydrazine
of weight loss as a study parameter was not compromised
sulfate was limited largely to mild to moderate nausea
by the development of ascites or significant edema, as this
and lightheadedness with 71% of patients reporting no
did not occur in any patient over the 30 day period of
toxic effects from hydrazine use (Table 4). Treatment was
discontinued for toxic effects in 10’%of patients receiving
hydrazine; while 6’% of patients receiving placebo had
TABLE
3. Influence of 30 Days of Hydrazine Sulfate or Placeboon
Nutritional Status of Cancer Patients With Weight Loss
treatment stopped for “toxic effects.” Significantly, parasthesias or hypoglycemic symptoms were not reported
Hydrazine
Placebo
n=17
n= 41*
by any patient receiving hydrazine in this trial.
Lung cancer (n)
PAccO
.
Weight maintained or
increased (>2.5 kg)
Improvement in appetite
Caloric intake increased
(> 10% over baseline)
[ncmased
caloric
intake
associated
wi[hweight
gain (>2.5 kg)
—
●
t
1
46
15
12
9
2
8
15
4
7
2
83’%t
63%t
53%
25%
51%
37%
Sl%t
53%
,Jumbcr completing initial and repeat study.
0.05 hydrazine compared to placebo group.
P<
Discussion
Short-term administration of hydrazine sulfate was
better than a placebo in maintaining body weight and
improving appetite in patients with advanced cancer in
the current clinical experience. The weight effect apparently resulted from an increase in the effectiveness of the
ingested calories, since a higher proportion of patients
—“’3
Hmwzmm
409
SULFATEm CANCER CACHEXIA “ C’hleboW’.ski
etal.
who increased their caloric intake on hydrazine were able
to maintain or improve their body weight. The association
that we have reported18 between weight maintenance and
improved glucose metabolism in hydrazine-treated cancer
patients suggests that interruption of abnormal metabolic
pathway function may underlie the improved nutritional
status seen with hydrazine sulfate in the current trial. If
this hypothesis can be confirmed, hydrazine sulfate could
represent one of a new class of metabolic/hormonal
agents 19-21directed at influencing the abnormal metabolism seen frequently in patients with cancer.
No prior clinical experience with hydrazine sulfate in
cancer patients has prospectively evaluated caloric intake
or included a placebo control population. Sin~e-ann
studies involving 348 Russian and 84 American patients
with cancer have emphasized subjective parameters. 15’22
In the American experience, Gold22 reported that 70% of
the treatment group demonstrated subjective improvemen~ including increased appetite with either weight gain
or cessation of weight loss, increased strength and improved performance status, or deaeased pain, as measured
by need for analgesics. In the Russian experience,
Gershonovichl ‘s23reported that 50% of patients receiving
.hydrazine sulfate as their sole therapeutic intervention
ieved moderate or marked improvement in cachexia
. ith associated favorable symptomatic effects on appetite
and pain. Not all clinical studies ofhydrazine sulfate have
shown benefit. In three small trials of hydrazine sulfate
(all entering less than 30 patients) where reduction in tumor size was used as a major therapeutic endpoint, little
benefit was reported.2&2b The clinical effects of hydrazine
sulfate on body weight observed in the current study in
conjunction with the metabolic effects of hydrazine that
we reported in 198412now provides a strong rationale for
further studies designed to assess the impact of hydrazine
sulfate on clinical outcome in defined cancer populations.
Surprisingly, thirty-seven percent of weight-losing cancer patients given placebo in this trial increased their caloric intake by more than 10%, and 53% of the placeba
group maintained or increased their body weight over the
1-month observation period. This result in the placebo
population may have been related to the nutritional
counseling that was given in identicd f=hion to patients
on both treatment arms in this study. Placebo controls
clearly are important in trials designed to alter and assess
nutritional parameters in cancer populations.
The study protocol employed in our trial was not designed to assess the influence of hydrazine sulfate on tumor
growth characteristics. The short 30day period of treat‘--ent and entry criteria preclude assessment of hydrazine
Afate influence on this parameter. Almost all of our patients with advanced solid tumors refractory to initial
therapy, however, demonstrated no change in tumor dimensions during the 1-month period of observation.
TABLE
4.
Patient Tolerance of Hydrazine
Sulfate or Placebo Treatment
% of Patients Treated
No toxic effects
Nausea and vomiting
Mild
Mcderate
[email protected]
Treatment discontinued for toxic efkcts
Hydr-azine
Placebo
71%
84%
12%
5%
17%
10%
I~~
O%
6%
6%
The relative lack of toxicity of short-term hydrazine
sulfate administration in a 60 mg 3 times/d schedule to
a large cancer population receiving other concurrent chemotherapy treatment was noteworthy. In the previous
limited clinical experience,15’22’23only one repofl hm emphasized significant toxicity; (khoa and coworkers24 reported a 50’%incidence of polyneuritis associated with
hydrazine sulfate use in a 29-patient experience. In three
tnal+5.22.25
and
the
present
report,
polyneuritis
was
~n
in less than 1% of the more than 500-patient cumulative
experience. The lack of toxicit y in the current experience
can be documented further by the good compliance reported by the patients in their diaries. The latter result is
interesting considering the somewhat wide range of hydrazine sulfate maintenance circulatory levels observed
in the pharmacokinetic component of this trial. However,
these results are consistent with developing phatmacokinetic information regarding the half-time of oral hydrazine sulfate administration. 17These data suggest that
future clinical trials involving hydrazine sulfate should
include determination of chronic circulatory levels to assess hydrazine sulfate bioavailability and permit correlation with metabolic, nutritional and clinical endpoints.
Conclusion
This experience with hydrazine sulfate in an advanced
cancer population points to a potential role for this agent
in maintaining weight in patients with cancer cachexia.
Whether maintenance of body weight under these conditions will be associated with improvement in important
clinical outcome variables and overaU survival will require
future prospective, long-term, placebo-controlled evaluation in cancer populations with less advanced disease
given defined systemic therapy. Such studies in the nonsmall cell lung cancer population are currently in progress.
References
1,DeWys WD, BeggC,lain PT eral Prognostic
effects
ofweight
loss
prior
to chemotherapy in cancer patients. An J Med 1980:69:491497.”
2. Costa G, Lane WW, Vincent RG er al Weight loss and cachexia
in lung cancer. Nu!r Cancer 198l; 2:98-103.
,
410
CANCER
February 1 1987
3. Chle&wvskiRT, Heber D, Blcck JB. Lung canctr cachexia. In GrFCO
FA, cd. Lung Carmr IL The Hague Martinus NijholTPublishers, 1983;
125-142.
4. CIamon G, Feld R, Evans WE, er al. Eff&t of h~ralimentation
on the survival and respon~ totreatment of patients with small cell lung
cancer a randomized trial. Cancer Treat Rep 1985; 69:167-177.
5. Nixon DW. Hyperalimenta!ion in the undernourished cancer patient. Cancer Res 1982; (Supp[) 42:727s-728s.
6. CMelnvski RT. Critical evaluation of the role of nutritional support
with chemotherapy. Cancer 1985; 55:268-272.
7. RotrdertbergCL, Bernhard A, Drehbiel O. Sugar tolerance in cancer.
JA.M4 1919:72:1528-1529.
8. Holroyde CP, Gabuzda TG. Putnam RC er al. Altered glucose
metabolism in metastatic carcinoma. Cancer Res 1975; 35:37 IO-37 14.
9. Waterhorr% C, Jeanpretre N, Keilson J. Ghrconeogenesis from alanine in patients with progressive malignant disease.Cancer Res k979;
39:1968- 19?2.
10. Lundholm K, Edstrom S, Kadberg I et al. GIUCOWturnover, ghsconeogenesis from gJycerol, and estimation of net glucose cycling in
cancer patients. Cancer 1982;50:1142- I I50.
assessment of glucose
1I. Chlebowski RT, Heber D, Block JB.Serial
metabolism in patients with cancer cachexia. C/in Res 1982;3069A.
of
12. Chiebowski RT, Heber D, Richard.wr B, Block JB.influence
hydrazine
sulfate
on abnormalcarbohydmte
metabolism in cancer patients with weight loss. Cancer Res 1984;44:857-861.
13. Chlebowski RT, Heber D. Metabolic abnormalities in cancer patients Carbohydrate metabolism. In: Meguid M, Rudnck S, eds. Surg
Clin North .4m 1986; 66:957-968.
14. Gold J. Proposed treatment of cancer by inhibition of gfucone~
genesis. Oncology 1968; 22:185-207.
15. Gershanotich ML. Clinical effectsof Irydmzine sulfate in patients
with advanced malignant disease. In Filov VA, Evin BA, Gershanovich
_,
I
vol. 59
ML, da. Medical Therapy of Tumors. LeningradUSSRMinistryof
Health, 1983;91-183.
16. Vtckers S, SmarI EIL Simple, sensitive spectrophototluorometric
method for hydrazine in plasma. Anal Chem 1974; 46:138-140.
17.Chlebomlci RT, Dietrich M, Tsunokai R et al. Hydrazine sulfate
clinical pharmacokinetics. Proc Am Amoc Can Res 1985; 26:254.
18. Chfebawki RT,Heber D, Richardson Bet al Association between
improved carbohydrate metabolism and weight maintenance in hydraz.ine
sulfate treated patients with cancer cachexia. Proc Am Soc C/in Once/
1983; 2:C372.
19. Schein PS, Kisner D, HaOer D ef al. Cachexia of malignancy
Potential role of insulin in nutritional management. Cancer 1979; 43:
2070-2076.
20. Burt ME, LOWTY
SF, Gorschboth C er al. Metabolic alterations
in a noncachetic animal tumor system. Cancer Res 1982:42:774-78
21. Lelli
G, Angelelti B, Giarnbiasi ME et al.ThemaboiicetTectof
high dose medroxyprogesterone acetate in oncology. Pharmacol Res
Commun 1983; 15:561-568.
22, Gold J. Use ofhydrazine sulfate in terminal and preterminal cancer
patien~ resrrks of investigational new drug (lND) study in 84 evaluable
patients. Oncoiogy 1975; 32:1-10.
23. Gemhanovich ML,Danova LA, Ivirr BA et al. Results of clinical
study of antitumor action of hydrazine sulfate. Nurr Cancer 1981; 3:4t2.
24. Ochoa M, Wittes R, Knkoff I. Trial of hydrazine sulfate (NSC1500 [4) in patients with cancer. Cancer Chemofher Rep 1975; 59 I I5 I1153.
25. Spemuffi E, Wampler CL RegelsorrW. Clinical study ofhydrazine
sulfate in advarrcd cancxr patients. Cancer Chemofher Pharrrracof1979;
3:121-124.
26. Lemer HJ, Regelwr W. Clinical trial of hydrazine sulfate in solid
tumors. Cancer Trear Rep 1976; 60:959-960.
Oncology32:1-10
(1975)
Use of Hydrazine
Sulfate
inTerminalandPretertninal
Cancer
Patients:
Results of Investigational New Drug (lND) Study in
84 Evaluable Patients
Joseph Gold
Syracuse Cancer Research Institue. Syracuse, NY
—
Key Words. Hydrazine sulfate therapy in advanced cancer patients . Treatment of advanced human cancer with anti-ghsconeogenic drugs , Interruption of cancer cachexia
as a mearrs of cancer chemotherapy . Interruption of ghsconeogenesis as a means of
cancer chemotherapy
Abstract. in a series of 84 various evaluable disseminated cancer patients treated with
hydrazine sulfate as a result of a pharmaceutical-sponsored investigational new’ drug (lND)
study, it was found that 59/84 or 70 % of the cases improved subjectively and 14/84 or
17 % improved objectively. Subjective responses included increased appetite with either
weight gain or cessation of weight loss, increase in strength and improved performance
status and decreaw in pain. Objective responses included measurable tumor regression,
disappearance of or decrease in neoplastic.associated disorders and long-term (over 1 year)
‘stabilized condition’. Of the overall 59 subjective improvements 25 (42 %) had no concurrent or prior (within 3 months) anticancer therapy of any type, Of the 14 objective improvements 7 (50 %) had no concurrent or prior anticancer therapy. Of the remaining cases
in which there was either concurrent or prior anticancer therapy, improvements occurred
only after the addition of hydrazine sulfate to the treatment regimen. Duration of improve
ment was variable, from temporary to long-term and continuing, Side effects were mild,
comprising for the most part low incidence of extremity paresthesia, nausea, pruritis and
drowsiness; there was no indication of bone marrow depression.
.:,
,., >
Hydrazine sulfate has been used as an investigational new drug (IND) for
over 1 year in the treatment of advanced cancer. Its proposed mechanism of
action is as a gluconeogenic blocking agent at the phosphoenolpyruvate
carboxykinase (PEP CK) reaction, attenuating host energy loss as a result of increased
giuconeogenesis in cancer and therefore interrupting the sysrernic cycle of fumor-ene~
gairr-host-erte~
loss (tumor growth-host cachexia) (1, 2). Early
reports indicated that hydrazine sulfate, administered orally to advanced cancer
patients, resulted in marked subjective and objective improvements (3), subjective improvements including increase in appetite, cessation of weight loss and/or
—
.-.
..
2
Gold
weight gain, improved performance status, and decrease in pain; objective irrtprovements included measurable reduction in tumor size and reduction in or
disappearance of neoplastic-associated disorders (effusions, jaundice, etc.). Duration of improvements was reported as variable and side effects, minimal. In
further reports (4), in which hydrazine sulfate was used in conjunction with
conventional chemotherapy in patients with disseminated neoplasia, it was unclear as to which type of therapy resulted in the reported subjective and objective improvements. The present report, undertaken as a pharmaceutical-sponsored IND study and representing a series of 84 evaluable cases of various
terminal and preterminal cancer patients, indicates a high degree of anticancer
activity in patients treated with hydrazine sulfate alone.
Procedures and Protocols
Physician selection. This study was the result of separate inputs of many clinicians –
oncologists as well as others – whose participation was under pharmaceutical [ND sponsorship. As such, this study is designated as ‘uncontrolled’.
Parienf seiecfiorr. Patients with any type of disseminated neoplasia, who no longer
responded to chemotherapy and/or radiation, were considered eligible for hydrazine sulfate
A minimum prognosis
of2 months was recommended.
therapy.
Drug and protocol. The dmg consisted of 100 % purity hydrazine suffate mixed with
an inert starch in capsular form (pharmaceutical IND preparation) for oral administration.
Protocol of drug administration was as follows: 60 mg q.d. X 4; 60 mg b.i.d. X 4; then
60 mg t.1.d. as maintenance. In patients weighing less than 50 kg, dosages were hafved (i.e.,
30 mg q.d. X 4; 30 mg b.i.d. X 4; then 30 mg t.i.d. ). In the event that a b.i.d. schedule
producedsatisfactory
results, this dosage schedule was maintained at the clinician’s discretion. In no event was a singfe dosage ever to exceed 60 mg.
Concurreru anticancer medication. The continuing use of concurrent anticancer medication was acceptable if it was no longer producing a demonstrable anticancer effect by
itself.
Data presentation. A 4-sheet data page rPatient Report Form’) was required to be
completed
by the clinician
during the course of treatment of each patient. These data sheets
included the following information: detailed history, site of tumor and metastasis, prior
treatments (defined in this study as any type of anticancer therapy given w’thin 3 months of
the initiation of hydrazine sulfate therapy; prior treatment data included dates of therapy,
types
and
quantitation),
concurrent
medications,
performance
status
evaluation,
objective
check list, laboratory
data, chnician’s statement of patient evaluation prior to hydrazine suffate therapy, clinician’s sta{ement of evaluation of results of hydrazine sulfate therapy, clinician’s evaluation
of side effects of hydrazine sulfate therapy, and clinician’s signature.
Criren”afor designation as ‘improvement’. Designation of subjective improvements was
made on the bam of improvements indicated in the subjective observations rating check list
tumor
size
and
site
evaluations,
and ~or affirmation
of
section,
a subjective
in
general
subjective
improvement
in
the
Improvement
observation
clinician’s
was
ratings
statement
based
on
and
under
‘clinician
a quantitatively
evaluation’
measurable
or
(number of hours ambubtory, quality of ambulation,
etc.), appeti!e (food intake), we]ght (scale measurement) and pain (quantitative need for
anaigesm). Objective improvements were designated on the basis of measurable reduction in
estimable
parameter
such
as s!rength
. .
,,.
. .,..
3
Hydrazine Sulfate Therapy in Advanced Cancer Patients
t,
tumor size, long-term ( 1 year or more) ‘stabilued condition’ in a previously rapidly growing
neoplasm, and disappearance of or reduction in neoplastic-associated disorders. Each case in
this category was to be supported by related laboratory measurements, where possible.
Criteria for designation as ‘nonevaluable’. Cases weredeleted from evaluation for any
of the following reasons: (a) inadequate prognosis: patient survival of less than 3 weeks;
(b) inadequate drug trial: drug trial of Isss than 3 weeks; (c) insufficient data submitted on
Patient Reprt Form: no evaluation possible, and (d) concurrent treatment with newly
initiated cytotoxic chemotherapy: patient responw nonevaluable.
Results
/
,:.,
Of a total number of 158 cases submitted in the study, 84 were evalttable
and 74 nonevaluable. Of the evaluable cases 14 (17 70) were categorized as
‘objective
only’,
(and subjective)
improvement’,
and25 (30 %) as ‘no improvement’.
Table 1. Categorization
zine sulfate
Site and/or type
of primary tumor
Brain(astro,
gho)
Breast(aU)
Colorectal-gastric
GaUbladder
Hodgkins,stagelV
Liver (primary)
Lung (all)
Melanoma
Neurosarcoma (neck)
ovary (au)
Pancreas
Primary unknown
Restate
Squamous cell (neck)
Testis
Tonsil (palatine)
Urinary bladder, ureter
Uterus (cervix)
Uterus (endometrial)
Total
45 (54 ‘%) as ‘subjective
of evafuable cases in Investigational
Objective
and
subjective
improvements
2
2
2
1
0
0
2
0
0
1
1
0
0
0
0
1
0
1
1
14
improvement
The indicated overall improvement
Subjective
improvement
Onty
New Drug study of hydra-
No
improvement
Total
cases
0
0
2
6
12
2
8
10
0
0
0
0
0
1
1
0
0
0
22
1
2
1
15
3
1
5
8
2
3
1
1
1
3
2
1
45
25
84
11
1
1
3
4
2
1
1
1
2
1
2
2
0
1
3
0
2
0
0
0
2
‘.,
.,.
:
4
Gold
Table11.Nonevaluable
casesreasons
forexclusion from evaluation
Inadequate prognosis
suMval tirrse,weeks
Inadequate drug trial,
weeks on drug
O-1
1-2
2-3
0-1
11
1
11
9
1
8
I
31
1–2
2-3
6
11
1
25
data
New concurrent Total
cases
cytotoxic
chemotherapy
15
3
hwufficient
74
rate was 59/84 cases, or 70 %. Of the nonevaluable cases, 31 (42 %) were included under ‘inadequate prognosis’, 25 (34%) under ‘inadequate drug trial’, 15
(20 %) under ‘insufficient data’, and 3 (4%) under ‘newly initiated cytotoxic
chemotherapy’. Categorization of evaluable and nonevaluable cases is given in
tables I and H, respectively.
‘Improvements’
Improvements were noted in tumors from almost all of the 19 reported sites
of origin. No particular site of origin or tumor type was ‘most susceptl%le’ to
hydrazine sulfate therapy, although the largest number of cases came from colothegeneral incidence of these diseases
rectal and lung carcinoma, which reflects
in the population. The duration of improvement was variable, being reported
from very temporary (1 week) to in excess of 1 year and continuing. It was
possible to obtain follow-up reports in only less than half of the improved cases.
Objective responses, Of the 14 reported objective responses, 7 (50%)
showed measurable tumor regression; 2 of these were accompanied by a disap
pearance of or reduction in neoplastic-associated
disorders (effusions, jaundice,
etc.). An additional 2 (14 %) of the 14 cases were classified as long-term ‘stabilized condition’, both of which represented pretenninal lung cancers whose disease had been rapidly progressive prior to hydrazine sulfate therapy. They are
currently both alive and well 17 and 18 months after initiation of hydrazine
sulfate therapy, respectively; neither are on any kind of concurrent anticancer
therapy. The remainder of the 5 (36 %) cases were classified as objective responses on the basis of amelioration of neoplastic-associated disorders, accompanied by marked subjective improvements. (In this regard all 14 cases showed
subjective improvements.) AH objective responses were also accompanied by
tumor-related laboratory improvements, where measured.
improvements
Subjective responses, A ton] of 45 Cases displayed subjective
only;thisnumber, added to the foregoing14 cases,
gavea combined totalof 59
subjectively
improved cases.48 (81 Y.)of these showed an increase in appetite
.!
. .
5
Hydrazine
Sulfate
Therapyin Advanced Cancer Patients
Table III.
Responseanalysis
in improved cases
No concurrent
or prior
anticancer
therapy
Objective
responws
(50%)
7
Subjective
responses
(40%)
18
Concurrent
ant icancer
(incl.
cytotoxic)
therapy
Concurrent
steroid
therapy
only
3
(21%)
1(7%)
17
5
(11%)
(38%)
Concurrent
steroid
and
prior
cyiotoxic
therapy
Concur- Prior
rent
cytosteroid
toxic
and
therapy
prior
radiation
therapy
Prior
steroid
therapy
Prior
radiation
therapy
Total
cases
1(7 %)
1
(7%)
1
(7 %)
14
1
(2 %)
45
1-
3(7 %)
(2%)
with either weight gain or a cessation of weight loss. 48 (81 %) showed an
by an increase
instrength,
improvement in performance status as measured
-- bulation
orboth.
And 21(36%) showed
a decrease in pain as measured by a
~inuted need for analgesics.
Ongoing concurrent (or prior) anticancer therapy. Various of the improved
cases were treated with either steroids and/or cytotoxic chemotherapy and/or
radiation, prior to initiation of hydra.zinc sulfate therapy, as indicated in
table III. In all these cases the noted improvements occurred affer the addition
of hydrazine sulfate to the therapy. 1ssregard to the objective responses 7 (50%)
of the 14 cases were treated with hydrazine sulfate alone, without concurrent or
prior anticancer therapy of any type, while 7 (50%) of the cases did receive
concurrent or prior anticancer therapy. hr the subjective-only responses, 18/45
or 40 YO of the cases were treated only with hydrazine sulfate, without concurrent or prior anticancer therapy, while 27 of the cases (60 %) did receive concurrent or prior anticancer therapy.
‘No Improvements’
Of the 25 ‘no improvement’ cases 2 (8%) expired within 3–4 weeks after
initia~ion of hydrazine sulfate therapy; 2 (8 YG)had very little information in
tlseir Patient Report Form so that actual categorization became difficult; 9
(36 %) had a drug trial of only 3–4 weeks, and 14 (56%) had concurrent anticancer
therapy which consisted of cytotoxic drugs, radiation, steroids or combinations thereof. In only 5 cases were these foregoing considerations not a factor,
i.e., the patient had MI adequate prognosis and drug trial, had no concument or
prior
anticancer
tient Report
therapy,
and had sufficient
Form to SUppOfl a categorization
information
submitted
on his pa-
of ‘no improvement’.
::’-.‘A.- _
, “-r
...
.’,’
Gold
6
Nonevaluable Cases
The general breakdown of categories of the 74 nonevaluable cases is given
above and in table 11. Of a total of 3 I of these cases excluded from evaluation
because of inadequate prognosis (survival time), 11 died within 1 week of initiation of hydrazine sulfate therapy, 22 died within 2 weeks, and the full 31 died
within 3 weeks. Of a total of 25 additional cases excluded from evaluation for
reasons of inadequate drug triaI, 8 were on drug for only 1 week or Iess, 14 were
on drug for 2 weeks or less, and the full 25 were on drug for 3 weeks or less.
Thus, of the 56 cases excluded from consideration for the foregoing two reatime
sons, 19 had a survival time or drug trial of 1 week or less, 36 hadasumival
ordrugtrial
of2 weeksorless,
andthefull
number– 56– hada survival time
or drug trial of 3 weeks or less.
Side Effects
Side effects were determined on the basis of evahrable cases only and were
in general mild. They comprised: extremity paresthesia (5 70); this condition
was diminished or eliminated by a reduction of dosage and/or administration of
pyridoxine hydrochloride (vitamin Bc) in excess of 25 mg daily; nausea (4 %), in
most cases transient; nontransient nausea was eliminated by a reduction of dosage or withdrawal of medication for a period of several days, then reinstitution
of treatment at lower dosage levels; dty skin or transient pnuitis (3 %); ‘dizziness’ ( 1%); ‘drowsiness’ (1 70); possible thrombophlebifi”s ( 1 Yo) (it was not
known whether this condition was drug-related). The total evaluable cases showing aide effects
numbered
13/84 or an overall 1570. There were no deaths
attributable to hydrrszine sulfate therapy, either in the evaluable or in the nonevaluable cases.
Discussion
It is important that a detailed analysis of a study of this nature include not
only the obviously improved cases as a result of hydrazine sulfate administration, but also the nonirnproved and nonevahsable cases. Such factors as poor
patient and clinician selection as well as inadequate protocol planning, must be
assessed as to their quantitative contribution to the latter two categories.
Nonimproved and Nonevaluable Cases
Lack of proper patient selection, via inadequate patient prognosis and inadequate drug trial, contributed heavily to the large number of nonevaluable and
nonimproved CWS. Minimum protocol-recommended prognosis was 2 months,
yet as many as 3 1/74 or 42% of the nonevaluable cases were so designated
because of a suMval time of 3 weeks or less, while in the nonimproved category
Hydrazine Sulfate Therapy in Advanced Cancer Patients
7
2/25 or 8 % of the cases had a survival time of only 3–4 weeks. In addition, as
many as 25/74 or 34 % of the nonevaluable cases were so designated because of
an inadequate drug trial (3 weeks or less), while 9/25 or 36 % of the nonimproved cases had a drug trial of only 3-4 weeks. Thus, in the nonevaluable
category the number of combined inadequate prognosis and inadequate drug
trial cases totaled 56/74 or 76 %, while in the nonimproved category the number
of combined cases of ‘borderline-acceptable’
survival time and drug trial
(3–4 weeks) totaled 11/25 or 44%. Such large percentages, representing inadequate prognosis and inadequate drug trial, must be attributed chiefly to improper patient selection and not to the occasional misevaluations which arise in any
study.
Lack of proper clinician selection was also an apparent factor in this study,
manifest chiefly in those cases in which too little information was submitted. In
Gold
8
and 40 TO(18/45) of the subjective-only responses were also the result of hydrazine sulfate therapy alone. This constitutes strong pn”mufaciue evidence indicating hydrazine sulfate to be a clinically active anticancer agent in itself. It is
import ant to remember that even in those cases which received concurrent or
prior anticancer therapy, the noted improvements occurred only after the addition of hydrazine sulfate to the treatment regimen. Thus, whether as a sole agent
or in combination with other agents, administration
of hydrazine sulfate to
advanced cancer patients is linked to marked anticancer responses.
Moreover, hydrazine sulfate is apparently not a ‘tumor-specific’ agent, as
can be seen from table 1. Virtually all types of cancer – especially those which
ultimately promote a degree of host cachexia – are apparently susceptible to its
actions. Reports, in addition to those of this study, which have reached this
laboratory, indicate that the spectrum of disease beneficially affected by hydrazine sulfate extends to cancers arising from all organ systems and/or tissues in
the body. The most dramatic responses reported to date have been those with
primary lung neoplasms, although this observation may prove to be premature as
more and earlier cases are reported.
The duration of improvement has been unpredictable, but has generally
been longer in those cases responding objectively (as well as subjectively). Some
of the responses have been of very short duration. But others have been quite
lengthy. To date three cases in this study – two primary lung and one ovarian –
are alive 17, 18 and 21 months after institution of hydrazine sulfate therapy
alone, respectively; all three were previously considered terminal or preterrninal
Preliminary indications suggest that the improvements brought about hy hydrazine sulfate therapy – whether objective or subjective – have been accompanied
by extension in survival time and that the quality of this survival time was high:
patients who had obtained objective response and/or increased appetite, strength
and decreased pain as a result of hydrazine sulfate therapy, were reported to
have been restored to a more positive orientation toward living.
The duration of improvement may also be related to the degree of advancement of the disease. The patients in this study were in general in the very latest
stages of disease, yet there were many improvements, some of which were
marked. However, it is generally regarded that any modality of anticancer therapy has its best chances of success when used early in the course of disease. And
this is probably true of hydrazirre sulfate. There would seemingly be no disadvantage in instituting hydrazine sulfate therapy early in the course of disease,
especially in those cases where the ultimate clinical course is virtually unaffected
by any known therapeutic modality. Moreover, since the toxicity of hydrazine
sulfate is apparently of a low order of magnitude, unlike many of the cytotoxic
drugs whose ‘side effects’ can produm extreme patient discomfort and death, it
would seem prudent to investigate the effect of this drug on early patients,
rather than use it at the very last stages as a ‘resurrective’ type of therapy. If
.-,-
10
Gold
References
,.,.
,*,
I
Oncology 32: 11–20 (197:
1
Gold, J.: Cancer cachexia and gluconeogenesis. Ann. N.Y. Acad. Sci. 230: i03- 110
2
(1974).
Gold, J.:
Inhibition
pyruvate
carboxylase
ofgluconeogenesis
reactions,
as
at the
a means
phosphoenolpyruvate
carboxykinase
of cancer chemotherapy.
and
Oncology 29:
74–89 (1974).
3
4
.
Gold, J.: Use of hydrazine sulfate in advanced cancer patients: preliminary results.
Proc. Am. ASS Cancer Res. 15:83 (1974).
Strum, S.B.; Bierrnan, H.R., and Thompson, R.: Hydrazine sulfate in patients with
neoplasia. Proc. Am. ASS Cancer Res 16:243
(1975).
t
!
Joseph Gold, Syracuse
CancerResearch Institute Inc., Presidential Plaza, 600 East Genesee
Street, Syracuse, NY 13202 (USA)
,+--!-
——.
i
e
d,
,..,
,,y,
{.
>.
B. Chemical Name:
Tri-iodomethane
C. Common Name:
Compound Iodoform Paint, B.I.P.P. Gauze, Bismuth Sub-nitrate and Iodoform Paste
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
(S’cijicatiow)
99.0-100.5%
Assay:
Not less than 99% of CEIL
———.
(Results)
99.01%
E. Information about how the ingredient is supplied:
Fine greenish yellow powder, or lustrous crystals, unctuous touc& characteristic.
Persistent odor, slightly volatile evenm at ordinary temperatures, and distils slowly with
steam.
F. Information about recognition of the substance in foreign
pharmacopoeias:
British Pharrnacopeia 1954
The National Formulary - Volume VII, 1942
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Corbridge, R. J., Djazaeri, B., and Hellier, W. P. Iodoform Paste. Clinical
Otolaryngology,
1995; 20(4): 305-307.
HOIW G. and Fuks, A. B. Iodofom-containing paste (KRI). Pediatric Dentistry,
16(6): 403-407.
-
1993;
H. Information about dosage forms used:
Paste
Paint
Gauze
I.
Information about strength:
10-50% Topically
J. Information about route of administration:
Topically
K
Stability data:
Decomposition at about 120°; decomposition at high temperature with evolution of
iodine.
Decomposes violently at 400F
.-—.=
L. Formulations:
M. Miscellaneous Information:
Page -2-
@“ //47
# 5’%733
CERTIFICATE
OF ANALYSIS
------ ------ ------ -----
——
rPRODUCT:
IODOFORM
RELEASE
#: N
POWDER
LOT
GRADE: PURIFIED
CODE:A925D053
RESULT
-----CONFORMS
DESCRIPTION
YELLOW
2.
Melting
115
3.
Moisture
4.
Residue
5.
Assay
on ignition
:B59901C13
SPECIFICATIONS
------ ------ -1.
point
#
POWDER
deg
c min.
120
deg
C
1.0%
1.0%
max.
<
0.2%
max.
< 0.2%
99.01%
Q
—
ATTENTION:
TONY
HATCHETT
.’+’
Date
Prepared
:09/02/97
Order
:
A. dAZARI
Approved
10540
Our
by
237082
#
Your
PO # 53617
by
/
/’
.–-~HEABOVETESTRESULTS
HAVEBEENOBTAINED BYOURMANUFACTUREWSUPPLIER AND/ORINOURQUALITYCONTROLLABORATORY.
+EDATAISPROVIDED ATTHEREQUEST OFANDFORTHE CONVENIE.NCEOFTHE CUSTOMER AND DOESNOTRELIEVE THECUSTOMER
OFITS RESPONSIBILITYTOVERIFY IT. THIS ANALYSIS IS NOTTOBECONSTRUED
AS AVVARRANTY, EXPRESSED ORIMPLIED.
,/
CHEMICAL NAME .:IODOFORM
MANUFACTURE
LOT
NO.
PURIFIED
:B62949P3Q
PHYSICAL
OUSP—. /BP
SPECIFICATION TEST STANDARD..
TEST
/t4ERcK —— /NF
/MART._/cO. SPECS._.
l)DESCRIPTION.:
YELLOW
~’
POWDER
OR
CRYSTALS;
—.
UNCTUOUS ——.——_.—._
TolJCH; CHARACTERISTIC,
DISAGREEABLE
-—— -——.__...
O~R.
—.
2)SOLUBILITY.:
VERY
SLIGHTLY
SOLUBLE
IN WATER;
1 GRAM
16ML BOILING
ALCOHOL,
10ML CHLcIROFO~,
FREELY
SOLUBLE
IN BENZENE,
ACETONE.
__
K
3)MELTING
POINT.:
MELTS
AT ABOUT
120 DEGREES;
EVOLUTION
OF IODINE.
DECOMPOSITION
DISSOLVES
IN
7.5ML
ETHER,
AT
HIGH
60ML
80ML
COLD ALCOHOL,
IN GLyCEROL;
TEMPERATURE
.———.
WITH
—..
4)SPECIFIC
GRAtiTY.
5)IDENTIFICATION
:
.:
FAILS.:
PASSES.:
cOMKENTS.:
ANALYST SIGNATURE.:
PRIZPACKTEST.:
RETEST.
:
DATE.
DATE. :—
DATE.
:
:
INITIAL.:
INITIAL.:
MATERIAL
Page I of5
SAFETY DATA SHEET
Use your web browser’s “Flack” key to return to previous topic
MATERIAL
Iodoform,
97101
****
SAFETY DATA SHEET
99+%
1.
SECTION
PRODUCT
c~~MIc~,
AND COMPANY
IDENT~IcATION
****
MSDS Name: Iodoform, 99+%
_—.
Triiodomethane
Company Identification:
For
information
For emergencies
For emergencies
Acxos Organics N.V.
One Reagent Lane
Fairlawn, NJ
07410
800-ACROS-01
in North America, call:
in,the US, call CHEMTREC: 800-424–9300
in the US, call CHEMTREC: 800-424-9300
**** SECTION
2 - CO~OslTION,
INFO~TION
ON INGREDIE~S
****
+----------------+--------------------------------------+----------+-----------+
I EINECS#
Chemical Name
cAs#
1%
I
I
l---------------- I-------------------------------------l---------- l----------I 200-874-5
75-47-8
[Iodoform, 99+%
+----------------+--------------------------------------+----------+-----------Hazard Symbols: XN
Risk Phrases: 20/21/22
+**+
SECTION 3 – HAZARDS
EMERGENCY
IDENTIFICATION
****
OVERVIEW
Appearance: Not available.
Cancer suspect agent.
Target Organs: None.
Potential Health Effects
The toxicological properties of this material have not been
investigated. Use appropriate procedures to prevent opportunities
for direct contact with the skin or eyes and to prevent inhalation.
**** SECTION
4 _ FIRsT AID ~lJ~s
**+*
Eyes:
Immediately flush eyes w~th plenty of water for at least
occasionally lifting the upper and lower lids.
15 minutes,
Skin:
Flush
while
Ingestion:
skin with plenty of soap and water for at least
removing contaminated clothing and shoes.
15 minutes
Page 2 of 5
MATERIAI. SAFETY DATA !NIEET
.-.
Do NOT induce vomiting. Allow the victim to rinse his mouth
to drink 2-4 cupfuls of water, and seek medical advice.
Inhalation:
Remove from exposure to fresh air immediately.
Notes to PhysicIan:
Treat symptomatically
and supportively.
+*** SECTION
5 - FIRE FIGHTING
M~Up,ES
●
and then
***
General Information:
7+s in any fire, wear a self-contained
breathing apparatus in
pressure-demand,
MSHA/NIOSH
(approved or equivalent), and full
protective gea~. During a fire, irritating and highly toxic gases
may be generated by thermal decomposition
or combustion.
Extinguishing Media:
Use agent most appropriate to extinguish fire.
Autoignition
Temperature: Not available.
Flash Point: 204 deg C ( 399.20 deg F)
NFPA Rating: Not published.
Explosion Limits, Lower: Not available.
Upper: Not available.
General
Information:
Use proper
in Section
personal
8.
protective
equipment
as indicated
Spills/Leaks :
Clean up spills immediately, observing precautions in the Protective
Equipment section. Sweep up, then place into a suitable container for
disposal.
**** SECTION
—.==
_..
7 - WLING
a,ld STO~GE
+***
Handling:
Wash thoroughly after handling. Remove contaminated clothing and
wash before reuse. Avoid contact with eyes, skin, and clothing. Avoid
ingestion and inhalation.
Storage:
Store ina
cool, dry place. Keep container closed when not in use.
● ☛☛☛
SECTION
8
_
EXPOSURE
CONTROLS, PERSONAL
PROTECTION
****
Engineering Controls:
Use adequate general or local exhaust ventilation to keep airborne
concentrations
below the permissible exposure limits. Use process
or other engineering controls
enclosure, local exhaust ventilation,
to control
airborne levels.
Exposure Limits
+--------------------+-------------------+-------------------+-----------------+
ACGIH
NIOSH
Chemical Name
IOSHA - Final
I
I
I
l ----------------l-------------------- l------------------- l------------------\O.6ppm;
10
Inone listed
Inone listed
i Iodoform, 99+%
I mg/m3
I
I
I
+--------------------+-------------------+-------------------+-----------------+
OSHA Vacated PELs:
Iodoform, 99+%:
0.6 ppm ‘lMl; 10 mg/m3
Personal
Protective
PELs[
TWA
Equipment
Eyes :
Wear safety glasses
is possible.
——=
—
and chemical
goggles
if splashing
Skin:
Wear appropriate protective
prevent skin exposure.
gloves
and clothing
Wear appropriate protective
contact with skin.
clothing
Clothing:
to minimize
to
I
I
MATERIAL
Page 30f5
SAFETY DATA SIIEET
Respirators
:
Wear
(or equivalent)
a NIOSH/MSHA- approved
full-facepiece
airline respirator in the positive
pressure mode with emergency escape provisions.
.——-.
+*** SECTION
9 - PHYSICAL
Physical State :
Appearance:
Odor :
pH :
Vapor Pressure:
Vapor Density:
Evaporation Rate:
Viscosity:
Boiling Point:
Freezing/Melting
Point:
Decomposition Temperature:
Volubility:
Specific Gravity/Density:
Molecular Formula:
Molecular Weight:
AND CHEMICAL
PROPERTIES ****
Not available.
Not available.
None reported.
Not available.
Not available.
Not available.
Not available.
Not available.
@ 760.00mm
Hu
120.00 - 123~00 deg C
204 deg C
freely soluble in benzene
4.oo80g/cm3
CH13
393.72
and acetone
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials, strong oxidants.
Incompatibilities
with Other Materials:
Strong bases - strong oxidizing agents – magnesium - alkali metals.
Hazardous Decomposition
Products:
Carbon monoxide, irritating and toxic fumes and gases, carbon
dioxide, hydrogen iodide.
Hazardous Polymerization:
Has not been reported.
**** SECTION
11 - TOXICOLOGICAL
INFORMATION
RTECS# :
CAS# 75-47-8: PB7000000
LD50/Lc50:
CAS# 75-47-8: Inhalation, rat: LC50 =165 ppm/7H;
47o mg/kg; Oral, rabbit: LD5CI = 450 mg/kg; Oral,
mg/kg; Skin, rat: LD50 = 1184 mg/kg.
Carcinogenicity:
Iodoform, 99+% Not listed by ACGIH, IARC, NIOSH, NTP, or OSHA.
**** SECTION
12 _ ECc)LOGI~
****
Oral, mouse: LD50 =
rat: LD50 = 355
INFORMATION
****
CONSIDERATIONS
****
Ecotoxicity:
Not available.
‘*** SECTION
Dispose of in
RCRA D-Series
RCRA D-Series
RCFA F-Series:
RCRA P–Series:
RCFA U-Series:
Not listed as
13 - DISPOSAL
a manner consistent with federal, state, and local regulations.
Maximum Concentration
of Contaminants: Not listed.
Chronic Toxicity Reference Levels: Not listed.
Not listed.
Not listed.
Not listed.
a material banned from land disposal according to RCRA.
**** SECTION
14 - TRANSPORT
US DOT
No information available
IMO
Not regulated as a hazardous
IATA
Not regulated as a hazardous
INFORMATION
material.
material.
****
Page40f5
MATERIAL SAFETY DATA SIIEET
RID/ADR
.—=_
Not regulated as a hazardous
Canadian TDG
No information available.
***+ SECTION
material.
15 - ~GULATORy
INFO~TION
****
US FEDERAL
TSCA
CAS# 75-47-8 is listed on the TSCA inventory.
Health .SSafety Reporting List
None of the chemicals are on the Health L Safety Reporting List.
Chemical Test Rules
None of the chemicals in this product are under a Chemical Test Rule.
Section 12b
None of the chemicals are listed under TSCA Section 12b.
TSCA Significant New Use Rule
None of the chemicals in this material have a SNUR under TSCA.
SARA
Section 302 (RQ)
None of the chemicals in this material have an RQ.
Section 302 (TPQ)
None of the chemicals in this product have a TPQ.
SARA Codes
CAS # 75-47-8: acute, chronic.
Section 313
No chemicals are repo~table under Section 313.
Clean Air Act:
This material does not contain any hazardous air pollutants.
This material does not contain any Class 1 Ozone depletors.
This material does not contain
any Class 2 Ozone depletors.
Clean Water Act:
None of the chemicals in this product are listed as Hazardous
Substances under the CWA.
None of the chemicals in this product are listed as Priority
Pollutants under the CWA.
None of the chemicals in this product are listed as Toxic Pollutants
under the CWA.
OSHA:
None of the chemicals
by OSHA.
in this product
are considered
highly
hazardous
STATE
Iodoform, 99+% can be found on the following state right to know
lists : California, New Jersey, Florida, Pennsylvania, Minnesota,
Massachusetts .
California No Significant Risk Level:
None of the chemicals in this pIoduct are listed.
European/International
Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: XN
Risk Phrases:
R 20[21/22
Harmful by inhalation, in contact with
skin and if swallowed.
Safety Phrases:
S 24/25
Avoid contact with skin and eyes.
WGK (Water Danger/Protection)
CAS# 75-47-8:
Canada
CAS# 75-47-8 is listed on Canada’s DSL/NDSL List.
This product has a WHMIS classification
of DIB, D2B.
CAS# 75-47-8 is not listed on Canada’s Ingredient Disclosure List.
Exposure Limits
OEL-AUSTRALIA:TWA
0.6 ppm (10 mg/m3). OEL-BELGIUM:TWA
CAS# 75-47-8:.
0.2 ppm (3 mg/m3). OEL-FINLAND:TWA
0.6 ppm (10 mg/m3). OEL-DENMARK:TWA
0.2 ppm (3 mg/m3);STEL
0.6 ppm (1 mg/m3);Skin.
OEL-FRANCE:TWA
0.6 ppm
0.2 ppm (3 mg/m3) . OEL-SWITZERLAN
(10 mg/m3). OEL-THE NETHERLANDS:TWA
D:TWA 0.6 ppm (10 mg/m3). OEL-UNITED KINGDOM:TWA 0.6 ppm (10 mg/m3);ST
EL 1 ppm (2O mg/m3). OEL IN BULGARIA, COLOMBIA, JORDAN, KOREA check AC
GIH TLV. OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGI TLV
**** SECTION
16 – ADDITIONAL
INFORMATION
****
MATERIAL SAFETY DATA SHEET
MSDS Creation
~
Date:
2/01/1996
Page50f5
Revision
#O Date: Original.
The information above is believed to be accurate and represents the best
information currently available to us. However, we make no warranty of
merchantability
or any other warranty, express or implied, with respect to
such information, and we assume no liability resulting from its use. Users
should make their own investigations
to determme
the suitability of the
information for their particular purposes. In no way shall Fisher be liable
for any claims, losses, or damages of any third party or for lost profits
or any special, indirect, Incidental, consequential
or exemplary
damages, howsoever arising, even if Fisher has been advised of
the possibility of such damages.
________________________________________________________________________________
I t: Ic 1. to product information
Iodide/ Iodophores
Ammonium
~~phorous
acid.
added
H,POZ,
to prevent
discoloration
~ kcepmg. Wt ~r
ml abOUI 1.] g. hw=~tible
~lkalis and oxidismg
agents. Stem in well-closed
~Ppered
b[tka.
Protect from light.
!1.
~[c
hydriodic
acid
has
“C in weak combination.
,~ H}dnodic
Acid Syrup.
~ratiorra
Hy&kdic
Hydrmd.
Acid
Dilute
(8. P.C.
hydricdic
flow,
general
properties
II was usually
Symp
~yrup tO 100 ml.
the
acid
of
administered
/949).
10 ml.
Wllh
glass.
S yr.
water
Acid.
5 ml,
and
2 to 4 ml,
~c:n
4576-k
formerly used
iodine and 0.05% sodium nitri(e
but
colour
exccnsively as a wound
dressing
not very effective.
Compound
Iodoform Paint has been used as a
protective covering and [o hold gauze dressings
and radium needles in position.
Bismuth SubnitraIe
and [odoform Paste (BIPP)
has been applied to wounds and abscesses, the
area to be treated being cleaned and smeared
with the paste, Sterile gauze impregnated
with
the paste has also been used for packing cavities
after oral and otorhinological surgery.
is
PresssmtiordJB.I.P.P. Gmz!’ (Roy. Naf. T. IV and E. Hosp.). Sterile
gauze Impregnated wi[h a stcrde paste consisting
O( iodo(orm
[~lnated
Glycerol.
Iodopropylidene
Glycerol.
40%,
bismuth
subnimak
20%.
and
Ii uid
An
P
%l$~~nitratt
mad
‘+
mixture
of iodinated dimera of Iyccrol.
= 258.I.
II contains about 50!% of organkdly
Past. thsm. S ubnit. et ld*~Or$1. iodofornr
2. sterilised
form Paatc. Bismuth subnimate
bmmd mdine.
liquid paraffin
1. by wt. prepared aseptically.
Store in a
CAS – 3634-39-9.
cool place in sterilised
collapsible
tubes. Prolonged
or
A pale yellow Ii uid with a pungent bitter after-taste.
extensive application
may give rise to iodoform
poison?
~bk
in chloro orm. ether, and ethyl acetate. Prowet
ing.
fmm light.
,4dwrse
@etx.
Open leg ulcers m a Malay
child aged
Eflee$s Treatment+ aasd Precautiosss. As for
A&rse
13 months were treated wiih the paste. They healed but
Iodine. p.i162.
oedema and pain increaaal.
After 9 wecka, X-ray examination
showed dense transverse
bands of metallic
bisUses. [email protected]
glycerol
is used, as an expectorant in
muth
deposited
in metaphyseal
growth
areas of long
bronchttls and bron:hlal
asthma In doses of 60 mg four
Krige,
S.
A~r.
med.
J..
1963.37.
1005.
bones.—
H.
N.
~lmcs dady wtth flutds.
~eric
C6H,, 1,0]
UK: Boehrlnger
Ingel-
heim, UK}. Elixir
containing
in each 5 ml icdinated
glycerol 6S3 mg and alcohol
1.25 ml (suggested diluent.
equal parts of glycerol and water).
Other Proprietary
Mucorama
Rectal
(Spain/.
] 954),
Form&te
Tri-iod6.
[email protected]
,[1== 393.7.
CAS —
Pharmacopocirrs.
in Arg., Arsst.. Belg..
Po[., Port.. Rcas., Span.. and Swim.
Iemon-yellow
Shining
what
unctuous to the
cauae
G. S.
wuh mdofomr toxicity occurred In
iodine cmrcerrtrationa
in 2 further
kldof.
loss of iodine.
Practically
irtaoktbie in watec sdubie 1 in 60 of
alcohol, 1 in 3 of carbon
diauiphide,
I in 13 O(
chloroform,
I in 8 of ether, 1 in 100 of glycerol,
I in 35 of olive oil; soluble in other fixed and
vola[ile
oils,
and in flexible collcdion. [ncompsst-
ible
with
alkalis,
oxidising
agents,
lead,
silver.
and mercury
salts. Store in a cool place in
airtight containers. Protect from light.
To cover its odour it may & mixed with coumarin I in 50, or with menthol, phenol, or thymol, or with oils of anise, eucalyptus, geranium,
peppermint,
rosemary, or sassafras, about I or
2%.
Adverse Effects. Symptoms O( systemic toxicity,
as described under Mine
(see P.862), sometimes
occur on prolonged or extensive application
to
wounds, As
a precaution
not more than 2 g
should usually be applied as a wound dressing.
Some persons are hypersensitive to iodoform and
even
an
small
quantities
erythcmatous
applied
locally
may
cause
rash.
which may be fatal. is charac~isoning,
terised
by headache.
somnolence,
delirium.
and
rapid feeble pulse.
Severe
__Uaximum
permiss[cde
atmospheric
concentration
$ ppm.
es.
Iodoform
when
applied
relem.es
sucs
Ond
has
.LO
elemental
a
marked
mucous
Iodine
has a mild
Anaesthetlc
membranes.
when
applied
disinfectant
acuon
It
to
action.
slowly
[he
tlS-
It was
Stability
pamoon
OJ so[utton~
DisiisJectiox
and
t Wcscodvne)
or
H.
J
Derewlcz,
42’%
found
to
in 48
hours
at
Am.
J
Hosp.
Pharm
were
J. J. While
effcc! ivcneaa
negative
used
A.
of
as
surgical
Duncan,
iodophores
and Gram-positive
over
hexachlorophane,
skin
to
provide
activity.
Like
dryness
of
the
18,
8S,
1976,
hand
Surgery
Gyrwc.
rquirc
were
for
to
be
cauac
the
excessive
Med.
Left.,
actwe
against
bmh
bacteria
and
maximum
leas
or alcoholic
m
antibacterial
use,—
were
application
aqueous
persist
could
repeated
Gram-pmitivc
considered
than
not
did
continuing
Iodophorcs
repeated
irritant
with
Gram-
they
iodophorcs
$kin
both
was an advantage
but
and
aga insi
organisms
cumulative,
alcohol,
Gram-rsegalive
They
and
1972.135.890.
Obstet.,
The
was no significant
di ffercncc
infections
when an icdophore
of wound
hexachlorophane
scrubs.—
did
not
effectiveness.
bact.mcidal
solutions
but
leas
of iodine
—
ibid., 1977. 19. 83.
Studies
involving
Ing continuous
infection
95
was superior
preparation.—
For other
tants,
with
Iabour
indicated
wi[h
neceasital-
that
skin dis-
an iodophore
(Prqsrs-
a berrzaikonium
Abmaleish
reports,
CI
chloride
.4rsmhmidogy.
al.,
see Povidone-[odine.
[email protected]$
including
aPPrOV~for
case. swuw
iodophorea,
see The
Order
1978:
No.
of
Diseases
1978
934;
in
C.
disi nfcc-
of
dilution
(Approved
No.
32).
Dis-
as amended
preparations
of milk
in Circular
Fkherics
For
Iasaa
approved
cont~iners
FSH
and Foods,
and
Ministry
8/78,
London,
disinfection
virus.
of Health
Oftice,
for
handling
virus
tbe
fever
Stationery
missible
of
Sla-
HM
1978.
Recommendations
and
list
rate
37).
and disinfecting
Fever, Dcpt
HM
No.
iodophore
is contained
with
Lam
1978:
S1 1979:
Virrn [email protected]
don,
their
of Animals
(S[
proprietary
Office,
contact
and
u~ in Great Britain in foot-and-mouth
dis.
vealcular disease, fowl peat. and tuberculosis
in animals,
list
p.867.
Jams. For a
oa
infectants)
D.
site
to thai
E.
in active
analgesia
46.351.
LJJCS of
(S1
women
epidural
of the cathc:er
uonery
of an dophorc
prc150 ppm
avadable
hours
of skin. There
in the incidence
of A8ricui[urc,
L“scd!iutlons
cnnrmmng
24
brown
were
removed by Washing with soap and water, The
iodophorea described in this section are Povidone-iodine
(see p.867) and Undecoylium
Chloride-Iodine (see p.868).
appliances
Iodophorea are carriers of icdine and arc usually
complexes of iodine with certain types of surfactants with detergent properties. It is possible for
iodine to be taken up in chemical combination by
high molecular
weight
surfactants
and
watcrsoiuble
polymers.
The
surfactanta
may
be
nonionic, cationic, or anionic, but generally the
most efficient
and stable iodophorea are compounds of nonionic surfactants.
Though the iodine in an iodophore is held in
loose chemical combination, part of the iodine is
available
and retains its bactericidal
activity.
Iodophores may solubilise up to 25% by weight
of iodine of which about 80% may be released as
available
iodine when a concentrated solution is
diluted.
Solutions of an iodophore are more stable than
solutions of iodine which lose strength by volatilisation a,+ there is no precipitation
on dilution
of an iodophore solution. The statiiity
of the
majority
is not affected by changes in pH. AS
the available iodine is taken up. the colour of the
solution changes from amber to pale yellow.
Unlike the hypochlormes. soiutions of iodophores
can be formulated with acid and the bactericidal
action of most of them is ennanced by Iowermg
the pH. lncremes in temperature
increase the
baclerlcldll
action
of ioctophores.
but
~bove
330
down with the liberation of iodine.
they break
days and
in
for [he cleansing
persistent, penetrating odour and disagreeable 4578-t
taste. Slightly volatile at room temperature. M.p.
115°; at higher temperatures it decomposes with Iodophores
a few
of iodophores are employed
in
prc-operative
skin disinfection
and for disirrfecting blankets and some instruments.
Stains of
iodophores on skin and natural fabrics may be
A
crystals or powder, sometouch, with a characteristic,
lost their typiml
for
Uses.
Solutions
1977,
K
~wncy
J. Abrahams
and
192.
1968.25,
In
Varnish;
Whilehcad’s
Varnish.
Prepared
from iodofomr
IO g, benzoin 10 g. preparedstorax 7.3 g.
tolu balsam 5 g, and solvent ether IO 100 ml.
standing
35°. Similar
dilutions
without
sodium nitrite were more
s~able and 10s[ 9 2% ~tency
after 3 weeks aI 35”. — R.
dyne)
o.; Iodoform
Fr.. [f.. Jug..
lose 24%
patients following the packin of cavitica with gauze
with Bismu!h #“bnitrate and Iodoform
impregnated
Paste. In a further patiem who received a pack soaked
OComrorccal., J .Lw.Or
R
c~wti54,.
~c
,-
75-47-8.
compatible
and raised
to be the
Miller
and
Compound
Iodoform
Paint
no signs of iodoform
toxicity were observed. It was suggested that Bismuth
Subniwatc
and
Icdofonrt
Paste was satisfactory for
packing
small operative
cavities but for large cavities
F. F.
st:,yem,aak:–+
Compound
lodoform
Paint
,4577.4
(~,p.c.
bismuth
subnitrate
were comdcred
ralher
than the iodofomr.—
W. A.
Br. dent. J., 1968.124.420.
Taylor,
Symptoms
I paiierrt
N9mes
Irsfarrtil
\
Jo-
reactions to dental dressings with Bismulh Subnitra!c and Iodoform Paste occurred in which crystals of
Two
proprietaryPreparmiosaa
orgmidk (We Pharmaccuficals,
after
865
and
Social
precautions
dementia
CI al..
materials
Memorarrcfurrr
in
on
Security.
Lon-
1976.
materials
Gajdusek
of
see
in
from,
medical
patients
(Creutzfcldt-Jakob
New
care
with
of.
trans-
disease).—
Engl. J. Med.,
1977, 297,
1253.
For
the
expaed
me
of
m
icdophorm
smallpox
m the
disinfccuon
s-
Disinfectants,
virus,
of
fabrics
General,
p.548.
Proprietary Preparations
Fsringeta
4 mg
of
alkonium
( Winffrrop,
UK).
miriatalkonium
iodine
dimcthyltctradecy
C21H4ZC111N
=621.9).
each
chloride
contli
(myristyl
For
2 lozenges
benzyi-
chloride-iodine
minOr
ni ng
henz-
chloride:
lammonium
throat. LMse. I or
4 houm not more
Lozenges
iodine
complex;
mfectiOns
to be sucked
Of
slowly
the
every
than 6 in 24 hours.
Steribatb (SrUd~. LX). An
an imlophore
(complexed
antiseptic
solution containing
with a nonoxynol)
and provid-
ing 4.5% of avallablc
iodine:
for addition to the bath.
ava]l able
Vmrodine
(Evarr.r
fungicidal
detergent
uK). i bactericidal
and
conmin{ng ~vailable todine
1.92%
Vanodine,
waler
!4. ml
sachets
w/v (in the form of an iodine-~
loxamer complex
the control of foot infections
[n swimming
and changing
roams
Dilule I bol ,n 100 vol. o!
for USC.
18.7~0) For
baths
solutlon
in
Other Proprietary
SeptoDyne
rL!SA I
.
.
\
!
302
THE NATIONAL
THE NA
170RMTIL.4RY
mixture vigorously.
After the chloroform k been decolorised allow the xnixtmre
to stand for 5 minutes. If the chloroform developa a purple color, titrate further
is erruivsdent
b.
with the iodate rmlution. Each ml. of 0.05 M notnssium iodate —
.--.
.—.
—..
30.55
mg.ofiodochlorhydrnxy
uin(C,H,CIINC)I.”
‘Tablets
[email protected]
% oxyquin Tableta usually available contain the
-
following amount of mdochlorhydroxyquin:
Packaging and storag&Preserve
aitit
‘ixmtainers. -
230 mg. (4 grains).
IodochlorhvdroxvauinTablets
in
. .
IPECAC .4~
Dover’s Powder
tight, IighLr+
Ipecsq
invery
tine
powder . .
Powdered
Opium . . . . .
Lactose, coarsely powdered . .
To make
CATEGORY-kltiPrOtOzoan.
Usum
DOSE OF IODOCHLORHYDROXYQUIK-250
nt&
(approximately
4 grains).
‘lliturate the ingredients
reduced b a very fine, unifor
[email protected]
I
\
i
Iodoform
IODOFORM
CHI,
0
cow,
an
f
CATEGoRY—Diaphoretic.
USUM DOSE—300 mg.
Triiodomethane
—–—-
sad O ium I
ar, requer
up to 400 p.m len # , very slowlj
polarisin hght wnth a stropg disp
of ident J cation are the t-es
I
d-cribed in the U. S. Pharmacc
Packaging and storage-Prea-ewe
era
iubiting
Mol. wt.393,75
(ap;
One usual metric dose contains
Iodoform, previously dried over sulfuric acid for 4 hours, contains
not less than 99 per cent of CHIJ.
“ tion-Iodoform occursas a fine greenishyellompowder,or lustrous crystals.
~e
a pec~iar,
very penetrating,
persistent odor.
Iodofon-n is slightly volatile
ven at ordinary tern fe ratures, and diatila aiowly with stenm.
Orizaba Jalap
Volubility-One
~m. o Iodoform dissolves in about 60 ml. of alcohol, in about 80
ml. of glycerin, in about 10 ml. of chloroform, in about 7.5 ml. of ether, and in
about 34 ml. of olive oil. One Gm. dissolves in about 16 ml, of boiling alcohol.
Iodoforrn is practically insoluble in water to which, however, it imRarts its odor
lpomea is the dried root c
volvulacez).
and taste.
Ipomea yieldsnot lesstho
Melting point-Iodoform
mel~ ta a brown liquid at about 115°, and decomposes
at a higher temperature, e nitting vapors of iodine, poge 691:
LOSS on drying-Dry
Iodoform over sulfuric acid for 4 hours: It loses not more than
1 per cent of its wei ht, page 690.
Residue on ignition— ! odoform yields not more than 0.2 per cent of residue on ignition, paue 711.
about 2 Gm. of Iodoiorm with 5 ml, of
[email protected] matter, acids, and elkalies-Shake
water for 1 minute, and Wer:
the filtrste is colorless and free from bitter taste
and is neutral to litmus.
Assay—Dimolve about 200 m . of Iodoform, previously dried over sulfuric acid for
4 hours and accurately we]g
i ed, in 20 ‘ml. of alcohol in a 500-rnl. glass-stoppered
Erlenmeyer flask. Add 30 ml. of 0.1 N silver nitrate and 10 ml. of nit,ric acid,
stopper the flssk, and set it aside overnight.
.4dd 150ml.ofwawr and 5 ml.of
ferric ammonium sulfate T.S.,and titrate the excess of silver nitrate with 0.1 N
ammonium thiocyanata
Each ml. of 0, I N silver nitrate is equivalent to 13,12
mg. of CHI,.
Packaging
snd storage-Preserve
Iodoform in tight, light-resistant containers, and
avoid excessive heat.
CATEGoRY—Loca]
——___
—
Unground Ipomea occurs as nearl
diameter, and from 1 ta 5.5 cm
wrinkled! and has a tough,fil
ringswti protrudinglight
crushed has a distinct, somewh~
what acrid.
Hiatologg-Ipomea
shows a corky
cells;--an o-uter cortex of swew
made up of thick-walled, tanger
or crystals of calcium oxalate,
ta yellow resinous latex; ringE
alternating with bands of prmv
outside of the wood-wedges,
numerous and distributed thro
surrounding the bundles are r
calcium oxahite crystals.
Powdered Ipomea is pale brown
up to 35 p in diameter, mostly
antibacterial,
,...
I
!9,n
,-
THE
“
.
O
AZ&
FOI{31[JI,ARY
NATIONAL
.
——
Ilxtract the mixc(l [Irugs by pcrd:ttion,
using dihtcd alcohol as the
r:ttc
ncnstmlu[n. nl :tccr:Ltc t Ilrce hours, :UNI IWMWI:ACid a Iwk!r:tlc
this
250cc.ofpcrcolatc
isol~t:ti]lr(
1. ‘1’0
Intil
:L{kl slllli{’it’llt
1000”cc.; or, to l)rclxtrc
[Iistillctl
Infusion
wkl s{dIicicltt (Iistilled
n snlu]lcr quantities.
an(l cxklill)or:Ltlc(Jtlsl\~,
,vater to 1 volume of the pcrcolaLe to ttmke 4 volumes of the Infusion.
NOTE:
Thepercoltiteor
com’cntrntrxl
iikfusion Itmy lx:]mwmwml in
[email protected] containers, but the hlfUsiW Illust not k dispwsal UIIIW iL hus
vat,er to make the product
XWII rcccnLIy
IIIC:LSIIrC
Llw
prcp:wc(l.
Storage—Dislwn*c C~)nll)~~llll(llll(llSi{~ll Of Crlllillll illtigl]t. r(1lll[iill(`lx.
Alcohol content—lrrum or-o II ]~er[:ont, by vohunc, (J CJi,OII.
AvEnAGE
DosE—~[ct.ric,
15 cc.;
Apot.hwariw,
4 flui(lrucllll~s.
IFU?USUM SENNAI CXJ~l MAC NI%lI SU1.FA’1’13
lIIIUSh
HI (J’
SVI]IM
will}
Irrf. Senn. c. Msg. Sulf.
h’l:~~llcsillll~
sldr:l.hg
C!omlrr,lllul lnfuaiol] of .Scl)lln
Serrna . . . . . . . . . . . .
. . . . .
. .
. . . .
. .
Manna . . . . . . . . . . . . . . . . . . . . . . . . . . . .
l’onr
fur
half
umrc.
Wf)
(x-. of
cont:till[xl
Iwili]w
~listillwl
ill :1 suital)lc
w:drr Illmn tlw WIIIII:L, III:lmI:L, :tml
t(I illfusc
VQSW’I, :IINI :dknv Ilw Illixtrirc
:1 shaitwr
an Ilour, INL%+tlw Ii([uid Ihroogll
l)isolve
tll(:lll:lgll~siUllls
lllfilt{!ill
tlwli([lli(i,
:UMI cxprrss
the
:mtl :uhl sullicicnt
distilled winter tlltough tile strainer to n}nkc tlw lnfusiw l]m:wure
until the pro(luct
is rlear.
1000 cc. Yiltcr if nerwwry,
Ti]is prqxwtion
nmst not iw (!ispcliscxi U1ih3seit ims l~en
NOTE:
recently prepared.
Storage-– i)islww’
AvERAGE
111(11+,1)
IIf I%lIlm willl Nlcwwsium S{llfiltr in ti~lltt:ollt~lill~:lx.
LWsE—ik]etric,t
i~c c.;
Apoti~ccaries,
2 IIuiciountwr.
101)( )FOl{lV lJIM
Iodof.
@=!!E9
‘f’riiodonwt h}me
Iodoform, previo~wly (iried over suif~lrk acid for 24 houre, contains
not iew tlmn 99pmcc]]tof
CHI,~ (3!)3.78).
.
221
Description-Iodoform
occurs as n fine lemon-yello\v pmv{lcr, or Iust,rotm crystals.
It hne n pcctllinr, wv-v pcnctrnt.iog, ~~i~tenindor.
l,}tlofwm is di htiv volntile
cvrw nt rmlinnry I l,mpernturw, nn dwtlls slowly with Ihe Ynlrr)r of’ wnt cr.
%lubifity—I{)d(>for!l~ is pmcticull insoluble in wn{er t,n wbirh, ht)~vcvrr, it impnrts
iti odor nnd t.rL.rlr. (hIc Gil). I)[ I{xii)f{)rm di!wdvcs in ni)r)ut (W w?. {Ifnlc{)tli)l, in
about 80 cc. of glycerin, in nbnut 10 cc. of chloroform, in nl){mt 7.5 cc. of cl Iwr
nnd in nbnot 34 cc. of olive oil, nt 25° C. Onc Gm. dirwolvrw in nb~)~it 1{;cc. oI
boiling nlcohol.
Meitfmz
dnt—lrxloform
melts to n brown lirruid nt nbrrut 115° C.. nntl deconlpoe& & n hipjmr tempwnture, emittin
Loss on dryfng-Orc
Gm. of lrxloform fV’n’tirs
rmf nvrw“fnulfurm
‘o(’i’!e”nri~l fnr 24
‘ ho~lrs lmrw
not mnre than 1 r ecnt of its wcigtlt.
r cent of nsh upnn iKnition.
Ash—hrinforrn YIC“r Iis not. more timn 0.2
Colorbr matter, acids, and alkaliea--Sim r -e nbnut 2 Gm. t,f l,,{kjfnrm with 5 cc of
distilLi wntrr f,w (me mioutq nnri fiitcr: tile fiit.rntc is roi(,ricas nn(i free fn,m
hitter [email protected] nnd is nrwtrni to iltmus n rer.
Aaaay-Dissnivc
nixmt, 0.2 tlm. of I rr$ol,,rrn prcviousir (irieri over Roifuric nciti
for 24 hourrr nnci nccurntr+ wei Inxi, in ~0 cc. of n col)ol in n 500 rc. glrrs+
stopircrwi ihicnrncycr
flask. A~if 30 CC. of t.eotil-normui silver nit rnte ntl{i it)
cc. nf nitric nci{i, st.r)i]pcr thr? fhsk, nn(i set it nsifie overnight,.
A(i(i 150 rc. {If
dietiiieri wat.cr nm! h ec. of ferric nmmt)l)ium rwlfnte “r.s., no(i tit,rnte t,iIc cxrrw
of siivrr oit.rate wlt.il tmlt,ibnoromi nlnmtmium tiliorynnntc.
ihirh Cc. of (rWtllIl(wmni Hiivor Ilitrnto is wiuivuivnt to 0.[)1313 (;ln. {1~Cli l$.
Storage—1’rescrvo Inciuform in tigilt wrntnilmrs, profwclcd from Iigllt, nod wv~)i{i
excessive heat.
60 Gm.
120 Gm.
lzoGm.
Magnesium Sulfate . . . . . . . .
. . .
. . .
. . . . .
20 Gm.
Fennel,l)rlliut’(1......
. . . . . . . . . . . . . . .
Distilled Water,:lsl)ll/(io)~
(I[m],lity,
.,
. . . . . ...1000
CC.
‘I’oil]{lk(., . . . . . . .
[e]l]lel,
THE NAT; ONAL FORM UI,AIIY
1 POlfI(l?A
Ipolllc:l.
Orimlm Jnini)
Ipom
lpon]en
is tile {iritwi root” of l]mmrzvr
orizdensis
Moxicon
llrxivnois
Scrunmrrlly
(F:tm.
(,’o)L-
V01V711U(’CZ).
IPtxne:i
yici~is not icss th:lll 15 per crwlt of tlw trrtai resins of II)oIIIw~
and not more than 3 pw cent of acid-insoillbie ,Mil.
Unground
Ipomea-Nenrl~
flnt
transverse
slices, from 2 to 12 cm. in riinmctrr,
and from 1 to lb ml. m thickness; externuily brown, very deepiy rvrinklml;
fracture t.ougl), fibrnux; cut surface si)owing concentric rings with protruding
iigbter-colored fibro-v~cuiar
tnmiles.
Histoiogy-A
corky ln,ver of severnl rows of thin-walled, nnrmw taboinr ceils;
rmtar cortex of scvcmi in~crs of thin-waiirvi cclis; n in-end corticn ( Inycr mruie ui)
of tilick-wniicdf tnngrnh-riiy cinngnt,cd ceils, containing citiwr stnrcb grnins or
crystals of calcium oxniate, and rrumeroue lnr e ceils containing reddish brown
to yellow resinous latex; rings or zones of smal f colisternl tibro-vn,,colnr bundkw,
rdtemnting with bnn{is of imrenchymn;
sieve in semi-cyiinciricaf strnnris outside of the wood wedges; meduliary rnys broad; resin celis numerous and rfistributnd throughout tim pnrrmcilyrnn; tim fmrmrcilymn cr-iis surrourr(iing tho
bundics, moro or ICSScoliaiwxi nmi containing cit.hrx stnrcii or cnicium oxnln(o
crystals.
Powdered
Ipomen-+olor
paie brown to wcnk ydlowi~h rrrnnge; odor (iietinct,
eomewimt aromatic; taste mveet, becoming somewhat acrid; starch grains up to
35 microns in diameter, mostly simple, also 2- to 4-comprnuld, rmti nsunily with
a centrai clef!; caicium oxrdate crystnis numerous, mostiy in roeette nggregnt.rs,
occasimwdiy m rhnmboilcdra, from 10 to 4.5 microns in lengti]; frngmcots of
Page
Database:
Medline
Set
Search
1
2
exp hydrocarbons,
iodoform.tw.
3
4
exp
5
6
7
<1966
Number : 1
to present>
Results
iodinated/
2722
103
8472
safety\
efficacy.tw.
2 and 3
2 and 4
from 6 keep 3-5
108250
0
6
3
<1>
Unique Identifier
96081121
Authors
Corbridge RJ.
Djazaeri B.
Hellier WP.
Hadley J.
Title
A prospective
randomized
controlled
trial comparing
the use
of merocel nasal tampons and BIPP in the control of acute
epistaxis.
.———..
Source
Clinical Otolaryngology.
20(4):305-7,
1995 Aug.
Abstract
A prospective
study was undertaken
to compare the efficacy
of Merocel nasal tampons to BIPP (Bismuth Subnitrate
and
* Iodoform Paste
impregnated
ribbon gauze in the control of
L \ acute epistaxil requiring
hospital admission.
A total of 50
patients presenting
with severe epistaxis was treated with
either merocel nasal tampons, or BIPP. The groups did not
differ significantly
i.n terms of age, sex distribution,
aetiology or severity of the bleed. There was no
significant
difference
in efficacy or patient tolerance
of
either treatment.
It was concluded that Merocel nasal
tampons
should
be considered
effective
in the first
line
treatment
of severe
epistaxis
uncontrolled
by simple
measures.
Their
ease of insertion
makes them suitable
for
use in the accident
and emergency
department
or in general
practice.
<2>
Unique Identifier
94203886
Authors
?-IolanG.
Fuks AB.
Page
Number
Title
A comparison
of pulpeetomies
using
ZOE and KRI paste
primary
molars:
a retrospective
study.
Source
Pediatric
Dentistry.
15(6):403-7,
1993 Nov-Dec.
:2
in
Abstract
Maintaining
a successfully
root-treated
primary molar has
the advantage of preserving
the natural tooth--the
best
possible space maintainer.
The purpose of this study was to
compare the success of endodontics treatment
of nonvital
primary molars using ZOE with that of KRI paste. Of 78
necrotic primary molars, 34 were filled with ZOE and 44
with an iodoform-containi.ng
paste (KRI). The canals were
prepared with files, rinsed with saline and filled with one
of the resorbable pastes, using a spiral Lentulo on a
low-speed handpiece.
A radiograph
was exposed immediately
postoperatively
to observe whether the root filling was
flush, underfilled,
or overfilled.
The effect of length of
fill on the treatment
outcome also was evaluated. Teeth
were examined periodically clinically and radi.ographi.tally
to assess success of the treatment.
Follow-up
interval
varied from 12 to more than 48 months. Overall success rate
was 84% versus 65% for ZOE, which was
for KRI paste
—_
—
-— -.
statistically significant (P < 0.05). Overfilling with ZOE
led to a failure rate of 59% as opposed to 21% for KRI (P <
0.02).
Conversely, underfilling led to similar results,
with a failure rate of 17% for ZOE and 14% for KRI. These
results support the clinical efficacy of root filling with
KRI paste as a treatment option for nonvital primary
molars.
<3>
Unique Identifier
94087045
Authors
von Schoenberg M. Robinson P. Ryan R.
Title
Nasal packing after routine nasal surgery--is it
justified?.
Source
Journal of Laryngology & Otology. 107(10):902-5, 1993 Oct.
Abstract
Ninety-five patients undergoing routine nasal surgery were
enrolled into a randomized, prospective trial to
investigate the efficacy and morbidity of nasal packing.
The patients were randomized to receive a bismuth iodoform
paraffin paste (BIPP) pack, a Telfa pack or no pack.
Patients for septal surgery were randomized between the
Page Number : 3
BIPP and Telfa
groups
only.
They were independently
randomized
to receive or not receive, a silastic nasal
splint for the first post-operative
week. Post-operative
pain levels were analysed using a visual analogue scale.
Mean pain scores were increased 50 per cent by the use of
nasal packs and pack removal, particularly
BIPP which, was
a most painful event (p < 0.001). Reactionary
hemorrhage
occurred in only two patients
(2.1 per cent), both of whom
had packs in situ. Vestibulitis
was unique to the patients
with a silastic splint, who were packed with BIPP,
occurring
in 21 per cent of them. Similarly
septal
perforation
was unique to this group. There was no
significant
difference
in the incidence of adhesions
between the groups which received packs and those who did
not. Routine nasal packing, especially
with BIPP, would
seen difficult
to justify i.n view of the increased pain
levels and increased complications
which occur without any
demonstrable
benefit in the majority of patients.
Therefore
packing should be reserved for cases where there i.s concern
about persistent
hemorrhage.
In these cases Telfa would be
preferable
to BIPP.
.
A. INGREDIENT NAME:
METRONIDAZOLE BENZOAT12
B. Chemical Name:
5-nitro-lH-imidazol- 1-ylethyl benzoate
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
99.54°A calculated as dried basis
E. Information about how the ingredient is supplied:
White or slightly yellowish crystalline powder
F. Information about recognition of the substance in foreign
pharmacopoeias:
The Indian Pharrnacopeia Volume I (A-P) 1985
G. Bibliography of available safety and efficacy data incIuding peer
reviewed medical literature:
Stolze, K. Elimination of Elyzol 25’%Dentagel matrix from periodontal pockets. J Clin
Perioabnto~
1995; 22(3): 185-187.
H. Information about dosage forms used:
Suspension
I.
Information about strength:
400mg- 3 times daily, for 5-10
days
—
J. Information about route of administration:
Topically
K
Stability data:
Melts at about 99-102°
Keep container tightly closed
L. Formulations:
M. Miscellaneous Information:
Page -2-
.—. - ————
-—— .-..-.—.
.- ._.
~-.
r __ -.
——.
..——
,..__:_—_~
.~..,.-
—..
=...
—...————
-...—-
-.—
.,. ...____.=
.-
_.
.
llth
Milan,
——— .—. ..
..
-: _—---—..
... . . -=-.
. -.
—.
...
,
—-. Q:______
—.—
-
.----
..
—
.
_---._A—_.
..=
.
-.
___
.
.-.
. . .. ... ___
-.——-.
..—.
.._.
—----._.
- ~ .. —-——
—-—_
.
.
.
_,
. .
.
.
..=
-.
.-
._
——
e——
..—. —
December
1997
—
2
x
25-kg
Manuf.
drums
date
ANALYSIS
Your
July
:
1997
............3.2.4.3............................................................ ...............................................
..... ......N.O
CERTIFICATE
Oral. No. .........of .....t.h.e ....l..O..t.h .....D.e.c.........l.9.9.7 ............ Our Ref. No . ............?..?..?.. ..... ...... .. ........ . . .. .... . . .. .... .... .... ....
Batch
Quantity
MET RONIDAZ,OLE
MATERIAL
..,...ri.icr.on.i.
Empirical
formula
Molecular
weight
Aspect
—
zed. ... . ... .....
... . ...... ....
B.P.
Specific
....Powder
,.,,...
point
50.
0712
-
.,
rotation .......... .................. .................................. .......................
,..
.
Light absorption,
........
Losson
drying
..............?..1?83%
Residue
on
Chloride
............................................. .. .............. ......................................
ye.llow.ish.
.. ..slig.
Odor
Melting
KG.
I
.
.,.
Taste
.
.. . . .. ..... .................................................
.
. ........rC.yonlZo ?gZ..?g
Color
,BENZOATE
.
.............?.?....- ....!02
\. ..O.? ................. ..... .
Boiling range
...
. ... . ..
Suifata
ignition
a
...0.0398%
................................................ ... ...
.
//
Volubility
practically
freely~soluble
in
Aceton~
in
in.soluble.in
Dichloromethone;
Heavy
water;
metals.
......!$?s5.
..~an
Identification.
.;...
..
A). Melting..
.....99....... 102”C
B ) complies
...~)....- . ......... .. .. ...............
D)
u
[aci.di.ty).
Titer
(As-l)
-...
—.
-.
o.o?.
99.54%
~
. .. ........ .
calculated
PPm
soluble
------------..:
...
pH,,,.,.
20
Related
pa
substances
te
““”’’’””’E)
as
dried
basisr
--- .
...
.
/
/
-
.....................
&
T
,/
i
Analyst
L/’
/3/
?7
-
QUALITY CONTROL REPORT
cHEMICAL NAME. :METRONIDAZOLE BENZOATE POWDER
MANUFACTURE
LOT
NO.
:0712
PHYSICAL TEST
sPECIFICATION
TEST
9T-ARD.;UsP
/BP
——
/[email protected]_/~T._/CO”
‘pEcsO_”
l)DESCRIPTION.:
WHITE
OR
SLIGHTLY
CREAM
TO
YELLOWISH,
CRYSTALLINE
POWDER
OR
FLAKES.
2)SOLUBILITY.:
VERY SOLUBLE IN CHLOROFOW,ALCOHOL; SOLUBLE IN ETHER,INSOLUBLE
IN WATER.
3)MELTING POINT.:
MELTS AT ABOUT 99-102
4)SPECIFIC
GRAyxTY.
degree.
c
:
5)IDENTIFICATION.
:
A)COMPLIES
BY IR SPECTRUM
B)A SOLUTION
PH IS 5.8.
AS
PER
COMPANY
PASSES.:
SPECS.
FAILS.
:
COMMENTS .:
ANALYST
SIGNATURE.:
PREPACK
TEST.
RETEST.
___
:
:
DATE .:
DATE .:
DATE.
:
INITIAL.
:
INITIAL.
:
i
Material Safety Data Sheet
Metronldazoie
Common Name/
benzoate
Trede Name
Manufacturer
SPECTRUM
14422
CHEMICAL
SOUTH
GARDENA,
MFG. CORP.
SAN PEDRO
CALIFORNIA
STREET
Code
M4064
CASU
13182-89-3
RTECS
Not available.
TSCA
Not on the TSCA Ikt.
CI#
Not evailable
90248
Commercial Namqs)
Not available
Synonym
2-Methyl-5-nitroimidazolel-ethanol
Chemical Name
Not available.
~ CASE OF EMERGENCY
CHEMTREC (24hr) 800-424-9300
Chemical Family
Not available.
Emergency phone: (31 O)51LWW3
Chemical
Formufn
benzoate
C13H13N304
Supplier
SPECTRUM QUA1.llY PRODUCTS, INC.
14422 SOUTH SAN PEDRO STREET
GARDEN& CA 90248
-.
Exposrm
Name
CAS #
.
:,stidtih$*:H*atit
,.
.
.
.
. .
.
.
...
STEL (mghd
CEIL (mglnr?
% by Weight
100
Metronldazole benzoate
LD50 Not available
LCKr Not available
00 Ingredients
.”..
(mghd)
13182-893
Metronldazole benzoate
Toxkotogicai Data
TWA
I.ImUa
,.>?
. ........ ,,,,,,,.
ific4ti"m::";;::
:~;
:;::;;;
:i.i.i,i':i;;i..:;
;;ii;
!::i!i::,il::;lii::;
':i;":"
::\i!i;::.;:!ii:.
!;';'9.:;:
i;:'
.I..t.~;;::`
.~,~.,
‘, . j,i:',;;
..
., .,. .. .
.
...<...,
..<.!..!:
.
. . ..
. .. .
Potentiel Acate Hmlth
Effects
Slightiy dangerous to dangerous in case d skin contact (irritant), of eye contact (irritant), of ingestion, of
inhalati+m This product may irritate eyes and skin upon contact
Potential ChrorIic Health
MUTAGENtC EFFECTS Not available.
TERATOGENIC
CARCINOGENIC EFFECTS: Not available
Toxicity of the product tu the reprodudve system: Not available. There is no
EFFECTS: Not available
known effect from chronic exfmsure to this product. Repeated or prolonged exposure is not known to
aggravate medical condition
Eflecfs
WARNING: This product contains a chemical known to the State of California to cause cancer.
Chemical ingredient(s) requlrlng this warning:
NONE
WARNING: Thi8 product containa a chemical known to the State of California
other reproductive harm.
Chemical ingredient(a) requiring this warning:
to cauae birth defects or
NONE
—
,.,
.,.,,..
,,, ,.,,
*ti~doiiU%F+a&
M9Y 26
‘9a
:
lEl:i39
~~
‘
!
‘;
‘“”’””.“: ;!’ ‘:
SPECTRIFl
Q1-lrl I TY
““”’: I
PF!GE. m5
Page Number: 2
benzoate
1 Mefroniriazole
..’,... .
. .
,[email protected] 4..,FifszAls?Measures
I
~~
Check for and remwe any contact lenses. DO NOT use an eye ointment.
Seek medical attention.
Mu Contact
If the chemical got onto the clothed portioI of the body, remove tie contaminated clothes as quickly as
possible, protecting your own hands and body Place the wctim under a deluge shower. If the chemical
touches the victim’s expsed skin, such as the hands. Gently and thoroughly wash the contaminated skin
with running water and non-abrasive soap Be particularly careful to clean folds, crevices, creases and
groin. Cover the irritated skin with an emollient.
[f irritation persists, seek medical attention. Wash
contaminated clothing before reusing.
$erious Skin Contact
Wash wth a disinfectant soap and cwer the contaminated sk.n with an antibacterial
attention.
[srhalation
Allow the victim to rest in a well ventilated area
kious
No addttiinal
Inhdsstion
cream.
Seek medical
Seek [email protected] medical attention
information
hrgesSiors
Remove dentures il any. Have cOnScbU$ person drink several glasses of water or milk. INDUCE VOMITING
by stiiking finger in throat. Lower the head so that the vomit will not reenter the mouth and throat NEVER
give an unconscbus person anything to ingest, Seek medkal attention.
ierious Ingestion
No additional information
,,
..,’’,..
.
.
.
.
.
.
.
.
.
.
.
.
.,.
,,,
.’,.
[ Fiamnrabiiity of the Product
[email protected]@iom
..,,,.”
.,
>.
.,,..
.
..>...’
.<
. ...<
.
.
.
.
.
.,,
,..
. .
.
.
,,
.
. .
.
.
.
. .
. . .
. .
. . .
. .
.
.
...
,,
..:
..
<<(..’
.,
’....
Combustible
Not available
Temperature
Flash points
Not available
Slammabie Limits
Not available.
~ [email protected]* of c~busti~
These products are carbon oxides (CO, C02), nitrogen oxides (NO, N02. ~.)
~ ire Harards in Presence of
Various
Substasws
No specifk information is available in our database regarding the flammability of this product in presence of
various materials.
Explosion Harards in
Pre5eoce of Various
Substances
Risks of explosion of the product in presence of mechanical impact: Not available.
Risks of explosion of the product in presence of static discharge: Not available.
No specific information is available in our datebase regarding the product% risks of explosion In the presence
of various materials.
Fire Fighting Medrn
and Instrudons
SMALL FIRE: Use DRY chemicals, C02, water spray or foam.
LARGE FIRE Use winter spray, fog or foam. DO NOT use water jet.
Special Remarks am
Fire Hamrds
No additional remark.
Special Remarks w
Explosion Harards
No additional remark
hnssli Spill
Use appropriate tools to put the spilled solid in a convenient ‘waste disposal container. Finish cleaning by
spreading water on the contaminated surface and dispose of according to local and regional authority
requirements
,arge Spill
Usa a
Our date base contains no additional information in case of a spill andlor a leak of the product
shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on
the contaminated sutiace and allow to evacuate through the sanitarysystem.
.-=
; : @’&~&g$N&pa&
flFrY 26
‘9a
. .. ,,
lEt:10
:;
,,,,
::
.: , : ,,,,
,,
,:,
.: ~ ,:
,,;: ,,
~~
SFECTRLSI
: ,:
.:::
QI_k% 1TY
.,’:.
.:.,,,
,:
PRGE. E116
I
A.letronidamlebenzoate
Page
,:Se&en7,
@dJ!w4tidswge,..:
1
,.,,,...,:.,,..:.,.:,,..,,..,.,...,..:,,.,,,... ,,,.,
Number:
3
I
... . ................. ,..::,..,.,,.,..,,..,..
Keep away fmm heat Keep away from sources of gnrtkm. Empty containers pose a fire risk, evaporate the
rssidue under s fume hood Ground all equipment con:amin~ material, DO NOT breathe dust. In case of
insufficient vent! latlon, wear sutable respiratory equipment
If you feel unwell, seek medical attention and
show the label when Dossible Avoid contac: with skin and eyes.
Precautions
——
storage
Kee container d
Kee in a cool lace Ground all equipment containing material. Keep container tiahtly
prace Combustible materials should be stored away from extreme
~cool,
Iell-ventilald
“h~nd
awav from strono oxidizina aaents
&
Use process enclosures, local exhaust ventilation, or other engendering controls to keep airborne levels
belcw recommendedexposure limits If user operations generate dust, fume or mist, use ventilation to keep
Enginscrhtg Controls
exposure to airborne contaminants below the expasure limit.
Persrmd Protection
Splash goggles
Lab coat
Dust respirator
equivalent. Gloves (Impewlous).
Personal Protection issCase
Ka Large Spill
Splash goggles. Full suit Dust respirator. Boots. GIOWS. A self contained breathing apparatus should be
Suggested protective clothing might not be sufficient, consult a
used to avoid inhalation of the product
specialist BEFORE handling this product.
Exposure Limits
Not available
......... . . . ... ... .,.,.., . .. .. .. .... . . . . . .. .. .
SectJon9.
,<.
.... ..:. @y#/[email protected],[email protected]@[email protected]
Be sure to use a MSHAfNIOSH
;“ ; ~~, ,’ .;,:’:,; ~,;,,-:j ..4...>
..;;”...:,, .,.,,, :...~!,.’
,.,
solid.
‘hyskal state and
Odor
Not avalable
Taste
Not available.
Color
Not avdable.
Ippesrsnce
—
kiolecular Weight
IH
(1%solnhwster)
Ming
.
275.3
approved
respirator
,., ,....; ,..,
,1,.
,,, .,..,
. ,. ,,,
or
...l :,:
r
Not available.
Not available
Point
Iielttng Point
Not available.
kitical Temperature
Not available
eciftcGravity
Not available.
{apor Pressure
Not available.
/apor Density
Not available
idatility
Not available
)dor Threshold
Not available
Water/Oil Dist. Coeti.
Not available.
onicity (in Water)
Not available
)ispcrsion
Not available.
Properties
Not available.
lolubiMy
. . . .. ..... . . . . ..... . . . .
,,,. ,. . . . . .
I
,.
Stability
The product is stable.
[ssstabitity Temperature
Not available.
Conditions of Instability
No addtional
Inconspatibitity with various
substances
No specific information is available in our database regarding the reactivity of this materiel in presence of
various other materiels.
Corrosivity
Non-cofrosive in presence of glass.
Special Remarks oa
Reactivity
No additional remark.
Special Remarks cm
rorrosfvify
No additional remark
No.
dytneriratioss
u ,,
‘:
...,.
remark.
I
I
,., ,,, ,. ,. .:.,:.
[email protected]*4k
MF/Y 26
’98
10:12
‘ :
‘
~
~
SPECTRUI
QLJWI TY
Page Number:
Mefronidazok benzoate
,.,
‘
.s
S41tiW f 7.”[email protected]@
[email protected]
Ingestion
outes of Entry
:, ::
~-
.:: ,. .,.. .,
. .,.’
.
4
..,’
{
I
Inhalation
I
, oxicity to Animals
LD50: Not available
LC50. Not available
Chronic Effects on Humans
Toxicity of the product to the reproductive system: Not available
Other Toxtc Effects on
Humans
Slightly dangerous to dangerous in case of skin contact (irrbnt),
inhalation
Special Remarks oa
Toxicity to Animals
No additional remark.
Special Remarks oa
Chronic Effects on Humans
No addrbonal remark
Special Remarks oa otiser
Toxic Etkts on Humans
No add~nal
of eye contact (irrffant), of
ingestion, of
+
remark.
---i
:“sg*i2;gcu/*#&m#~;”
.
. . . . . . .,. - . ;,..,.... .. . . . . ..
..
.
..
. .
:::: ::.:
,,,
‘:
.
“ ..
‘
.:’
‘,:
:: :;’.
;
.,:
“
Ecdoxicity
Not available.
BOD5 and COD
Not available.
Products of Biodegradation
These products are carbon oxktes (CO, C02), nitfogen Wtdes (NO, N02...)
Toxicity of the Products
d Biodegradation
The products of degradation are more tOXIC.
Special Remarks omthe
Products of Biodemwiatiors
No additional remark.
:,.
:.
.!:
!
:,
;,,
:
,
I
7
Recycle to process, if possible. Consult your local or regional authorlies
wte Disposal
[derstitkation
I
Not applicable (PIN and PO).
1
Special Provisions
for
Not applicable.
r~~pti
OOT(IUctograms)
@
Federal and State
Regulations
Not available.
Califomia
WARNING: This product contains 8 chemical known to the State of California to cause cancer.
Chemical ingredient(a) requiring thla warning:
Proposition 65
Warnings
I
NONE
WARNING: This product containa a chemical
or other reproductive harm.
Chemical ingredient(a) requiring this warning:
.&
k=
known to the State of Caiifomia
to cauee
birlh defects
NONE
OSHA Hazardous by definition of Hazard Communication Standard (29 CFR 1910. 1200)
, Other Rqpdations
.
MQY 26
’98
[email protected]: 13
S’ECTRUI
LJ_iRi-I TY
Pf%E .018
I
Rge Number: 5
Metronidazo/e benzoate
Other Classifications
WHMIS (Canada)
._
DSCL (EEC)
Not controlled under vVHMIS (Canada)
Not controlled under DSCL (Europe)
Flsmmablrlty
.Wational Fire Protection
HMIs (U.S.A.)
Association (U. S.A.)
,/<’?
He-
)
‘,1
+i.
‘~/
$>
Rmslhlq’
Spcclllc
bud
WHMIS (Canada)
(1’ictograms)
@
DSCL
(Europe)
(Pictograms)
@
TDG (Canada)
(Pictograms)
A
(
@
/
ADR(Europe)
(Pictograms)
ProtectiveEquipment
Gloves (impervious).
*
Lab coat.
w*.
Dust respirator. Be sure to use a
MSHAJNIOSH approved respirator or
equivalent
Splash goggles.
E?
M1183
Mtaiog Number(s)
References
Not available
3tlser Special
~onsi deratkms
No additional remark.
Validated by E. Bs-uU on 9126f!?7.
I Printed 9/30/97.
I
msergency phone: (310)516-8000
Notice to Reader
,..{.mtimdm,w.
.,,,,.
. ... . . .. ,,
PIRY 26
..+, ., : .,,p?m...,..,,
.
. ..
‘9S
ID:14
.. . .. . .
.
: :.
:
,
~~
:
‘:.
SPECTM-FI
‘
,?::
Q1-W I TY
:
. . .:,,,;,:
PRGE.019
—
___
PWY 26
’98
lEi:15
5PIECTMJM QWL I TY
PaGE. a2El
Storage
light.
Store in a well-closed
container, protected from
Preparation.
Methylprednisolone
_.——
Action and
uae
Acetate Injection
Corricosteroid.
1/95
Metoprolol Tartrate
Identification
IJne
6. After
Test A. Jine 4. For’ 18°’ read ‘-180’.
‘residue’ insert’, Appendix II A’.
12/93
Heavy metda
Line 2. For ‘1 ml’ read ’10 ml’.
7/94
100 nd tith 1M hydrochkkc
ad
Examined
between
220 nm and 350 run, Appendix II B, the solution shows
two absorption maxima, at 232 nm and 275 nm. The
spuxj?t abmrkmx at the maximum at 232 nm is 52510
575.
C. Examine by inj+ared absmpion spectrophotomesy,
Appendix II A. The absorption mtodrna in the spectrum
obtained with the substance being examin ed correspond
in position and relative intensity to those its the spectrum
obtained with mctmmAsok bwszsxm EPCRS.
D. Examine the chromatogmms obtained in the test for
Related substances under ukauiokt light Q54 rim]. The
principal spot in the cbromatogra.rn obtained with solution
(2) is similar in position and size to the pMcipal spot io
the chromatogram obtained with solution (3).
E. To about 10 mg add about 10 mg of fi”ncpowder, 1 ml
of maser and 0.3 ml of [email protected]&
ad. Heat on a water
bath for 5 minutes and cool. The solution yields the
reaction characteristic ofpninuy arunusttk amine.s,
Appendix VI.
Add the following statement.
1 gin [email protected]~A~ce
of SOIU~OSSDi=lve
ande and dilute to 10 ad wish the same solvent. The
solution is not more opalescent than nfmna suspenwbn
Preparations
Metoprolol
Metoprolol
Injecdon
Tartrate Tablets
star (f?) to the title.
7/94
the following
Inuavenous Infi,ssion
—
Examine by [email protected] chromatousing stka gel HF2~4 as the
coating substance. Heat the plate at 110° for 1 hour and
allow to cool before use.
So&&n (1) Dissolve 0.20 g of the substance being
examined in aoxmw and dilute to 10 ml with the same
solvent.
Soft&n (2) Dilute 1 ml of solution (1) to 10 ml with
acetone.
Solution {3) Dissolve 20 mg of nwnvnidazoie benzoate
EKXS in acetone and dilute to 10 ml with the same
solvent.
Soksion (4) Dilure 5 ml of solution (2) to 100 ml with
Related
Preparations
Add
Metronidazolc
Acidity Dissolve 2 g in a mixture of 20 ml of dimeshyiand 20 ttd of wow, previously neutralised w-icb
0.02M hydroc~
ad KS or 0.02M soa%un hydnmiz!e VS
wdsoiuubn. Not more thars 0.25 ml
using 0.2 ml of mcthyI
of 0.02M sodktn [email protected] Vs is required to change the
colour of the indicator.
f~
Metronidazole
Add a five-pointed
II,
Appendix N A, and not more intensely coloured than
+mna
solutsbn GYP Appendix IV B, Method II.
substances
grap~, Appendix III&
At
acetone,
Solusion~5) Dihne 2 ml of solution (2) to 100 ml with
C,3H,3N304
&
275.3
13182-89-3
Detlnition MeuonidazoleBenzoate contains not less
than 98.5~0 and not more than 101 [email protected]~ of 2-(2-methy15-nitrcJ- MMtn.idazol- 1-ylethyl berszoate, C13H13N10q,
calculated with refance
to the dried substance.
Characteristics
~t$
or slightlv yellowish~se
-.—.
powder or flakes; pxacucally insoluble in w-,
freely’
6 -inds2h&Wmtha
rsGsoluble in ~,
slightly
soluble in ethanoi (96%); very slightly soluble in ether.
[email protected]&m rutC may be omirsed f
siientsj%ationtestt A, B, D and E am cnnizl OULMenaj5canbntests B, Dand Emaybeomissed :~s&[email protected]
andcarecuniaious.
Identification
A. Mes!ting~”n.q 99” to 102”, Appendix V & Method I.
B. Dissolve 0.1 g in lM hydmchbrsk ad and dilute to
100 ml with the same acid. Dilute I ml of rbe solution [O
ac.?wne.
Soknbn (6) Dissolve 10 mg of metmniaks.zoie EXRS in
acetone and diiute to 100 ml with the same solvent.
Solunbn (7) Dissolve 10 mg of 2-meshyf-5-nsimims&zoiein
acetoneand dilute to 100 rtd with the same solvent.
Sokmbn {8) Dissolve 10 mg of metronsihzoieEKRS and
ok in acetone and dihxe ro
10 mg of 2-methyl-5-nimnhdu
50 ml with the same solvent.
Apply separately to the plate [email protected] of each solution.
Develop over a path of 15 cm using ethyf acaate. Allow tie
plate to dsy in air and examine under ufmzwiokr light
(2’54 rim). In the cbromacograrn obtained with solution
(1) any spot corresponding to metronidazole or 2-merhyl5-nitroimidazole is not more intense than the corresponding spot in tbe chrornxograrns obtained with solutions (6)
and (7) respecriveiy
(0, So/o). Any other seamciuy spot 1s
not more intense rban the spot in the Chromatogmm
and at most one SUA
obtained wir-h soiuuon (4) (0.50/o)
spot M more intense&an thespotinthe cbromarognun
METRONIDAZOLE
Lam on drying : Not more than 0.5 percent, determined
on 1.0 g by drying in an oven at 105°, Appendix 5.8.
Weigh accurately about 0.45 g and dissolve in 10
ml [email protected] acetic acid, add a few drops of I-naphtboi-
Assay :
benzetn
solution
and titrate witn O.IN percb[on’c
@id
until a pale-green colour is produced. Perform a blank determination and make any necessary correction. Each ml
of 0.1 N percblon’c acid is equivalent to 0.01712 g of
cJ-i#Jjoy
Storage : Store in well-closed
light-resistant
con-
zole, transfer to a sintered.glass cmcible and extract with
six quantities, each of 10 ml, of hoc acetone. Cool, add to
the combined extracts 50 ml of acetic anbydn”de, 0.1 ml
of a 1 per cent wiv solution of bn”liiant green in giacia[
acetic acid and titrate with O.f N petcb[on’c
acid to a yel.
Iowish-green end-point. Perform a blank determination
and make any necessa~ correction, Each ml of O.z N
perchfonk acid is equivalent to 0,01712g of CJ-l~50J.
Storage : Store in well-closed, light-resistant containers.
tainers.
*
[
Metronidazole
Metronklazole
Category
Tablets
: Anti-amoebic;
i
Benzoate
Benzoyl Metronidazole
antitrichomonal;
antiCti2CH200CCEH5
giardial.
I
Dose : Meuonidazole. For uichomoniasis,
three times daily, for 7 days.
200 mg
02N
“
CH3
yy II
400 mg three times daily, for 8to
For amoebiasis,
10 days.
C1Ji,3N30+
LMO1.
W[.275,27
three
successive
days Category : Anti-amoebic.
For giardiasis, 2 g daily for
foradults,
1 g daily forchiidren and 400 mg daily for
Dose:Foramoebic
dyse~try,
thee-quivalenc
of400
in&ults.
Usual strengths:
200
mg; 400 mg.
Standards : Metronidazole Tablets contain not kss
than 95.o percent and not more than 105.0 percent
of the stated amount of MetronidazoIe, C&N303.
The tablets may be coated.
Identifkwion
tablets equivalent
ml of [email protected]
: (A) Shake a quantity
of the powdered
to about 0.2 g of Meuonidazole with 4
acid and filter. To the filtme add 10 ml
ofpicn”c acidsohtion and slow to stan’dfor one hour, the
precipitate tier washing with cold water under suction
and drying at 105” melts at about 150°, Appendix 5,11.
(B) Comply with Identification test (B) describes mder Metronidazole, using a quantity of the pwdered tablets equivalent to 10 mg of Metronidazole.
2-Merhyl-5-nitroimidazole : Comply with the test ales.
cribed under Metronidazole, using as solution (1), a solution prepared in the foilowing manner: Shake a quantity
of the powdered tablets equivalent to 0.2 g of Merronidazole with 5 ml of mixture of equal volumes of cblorofonn
and metbyi a[cobo[ for five minutes and filter. The chromatogram obtained with solution (1) may aiso show
spots due to exc.ipients.
Other
stated
requirenwnts
under Tablets.
: Compiy
with
the requirements
mg of rnetronidazole three times, daily, for 5 to 10 3
-Ys.
NOTE -ZOO m~ @~.
mately equivalent to 125 mtz o f met?vttiabzrde.
8
“-
Description: White or cream-coloured
powder, odourles; almost tasteless.
crystalline
Solubillty: Sparingly soIuble in water; soluble in
cb[[email protected], in acetone,and in aicobol @per cent).
Stanckmk :Metrohidazole Benzoate is 2-(2-methyl-5-nitro-imida.zo[-l:yl) ethyl benzoate. It contains not less than 98.0 per cent of C13H,JNj04, calculated with reference to the dried substance.
Identifkation
: (A) The light absorption,
in the range
230 to 530 nm ofa l-cm layerofa0.001 percent w/vsolution in ethyl
alcobof
exhibits a maximum oniy x 309 nm;
exthcthn
at 309 nm, about 0,3, Appendix 5,15A.
(B) It gives the reactions of benzoates,
Melting mnge : Between
Appendix 3.1,
100° and 102°, Appendix
5.11.
pH : Between 5.0 and 7.0, determined in a 2.0 per cent
w/v suspension, Appendix 5.10.
add : Not more than 0.2 per cent,determined by the following method: Dissolve 0.50 g in zs ml
of alcohol and titrate with 0.1 N sodium @dt-oxide. using
Free benzoic
&say : Weigh and powder 20 tablets. Weighaccuruely
3 phenol redsoiution as indicator. Perform a blank determi.
quantity
ofthe powderequivalent
to0.2g ofMeuonida- nation and make any necessary correction. Each ml of
320
—
MORPHINE HYDROCHLORIDE
0.1N sodium bydnzvide
isequivalent
to 0.01221
g of
C7H602.
ReIated substances : Carry out the method for tbinlt+ver cbromatog?wpby, Appendix 5.4.3, using sili6a gel
HF 254 as the coating substance and a mixrure of 8
volumes of chloro~onn and 2 volumes of acetone as the
mobile phase. Apply separately to the plate 10p] ofeach of
three solutions in a mixture of equal volumes of metbjd
alcohol and cblomjonn containing (1) 6.o per. cent Wiv
of the substance being examined; (2) 0.02 percent w/v of
2-rnetbyl-5-nftmimitiole R.S. and; (3) 0.02 per cent
w,h of metmnirk.zzole R.S. After removal of the phe,
allow the solvent to evaporate and examine under an
ultra-violet lamp having a maximum output at about 254
nm. The spots in the chromatogram obtained with
solutions (2) and (3) are more intense than any
corresponding spots in the chromatogram obtained with
solution (1).
Sulphated
ash:
Not more than 0.1
per
cent, Appendix
3.2.7.
LOSSon drying: Notmore than 0.5 w cent, determined
on 1.0 g by drying “in vacuo at 60”,” Appendix 5.8.
Assay : Weigh
accurately about 0.5 g and dissolve in 50
ml of acetone. Add 10 ml of acetic anbydn”de aftd titrate
using
bn’lliant gn?en solution
with 0.1 N pe?tblon’c acid
as indicator.
Perform
a blank determination
and make any
necessary correction. Each ml of 0.1 N percblon”c acid is
equivalent to 0.02753 g of Cl~HuN.434.
Storage: smm
in
well-closed, [email protected]
tdners.
Stan&irds : Morphine Hydrochloride is the trihydrate of the hydrochloride of 7,8-didehydro-4, 5aepoxy- 17-methylmorphinm-3,6 a-dioI, which may
be obtained from opium. It contains not less than
98.0 Percent and not more than theequivalent of
100.5 per cent ofC,TH,~Oj,
HC1,calculated with refkrence to the dried substance.
: (A)Sprinkle a small quantity in powder
form on the surface of a drop of nittic acid; an orange. red
colour is produced.
Idendfkatioa
(B) To a 2 per cent w/v solution add prmzssiunr fen-i.
~anide solution containing 1 drop per ml of~hic cblon’de test-sofutifJ?t; an immcdia[c h]uish-grtxn colour k
produced (distinction from codeine).
(C) Add 5 ml of szdpbu?ic acid to 5 mg m a test tube,
solution, and hv~t
and MM i drop of ftim”cc}d(jn”de[1’.s1
in boiling water for two minutes; a deep blue colour is produced. Add a drop of nitric ucid; the colour changes to
dark red-brown (codeine and ethylmorphine give the
same colour reactions, but dihydromorphine
and
papaverine do not produce this colour change).
(D) Add to about 1 mg of the powdered substance in a
acid containing 1 drop
porcelain dish 0.5 ml ofstdpkric
of fonnala%byde solution. A purple colour is formed
which turns to violet.
(E) Dissolve about 5 mg in 5 ml of wafer, and add 1 ml
1 ml of dilute ammonia
solurion and 1 drop of a 4 per cent w/v solution of copper
sulpbate. A transient red colour develops.
ofbydmgen peroxide solution,
(F) AsohttiOn (1 in 20)
Appendix 3.1.
Morphine Hydrochloride
gives
the tea~ions
of cb~o~&s,
Addity or Alkalinity : Dissolve 0.2 g in 10 ml of freshly
boiled and cooled water zdd 1 drop of nwr~l red soiution. Not more than either 0.2 ml of 0.02iV sodium hydroxide or of 0.02N bydrvcblon”c acid is required to change
the colour of the solution.
spe&3c optical rotation: Between -112” and -115°,
calculated with reference to rhe dried substance and determined in a 2 per cent w/v solution, Appendix 5.12.
Cl-, 3 H20
salts : Heat 0.2 g with sodium bydm”de
on a water-bath fcr one minute; no odour of
xnmonia is perceptible.
&n.mordurn
soiution
Other alkaloids : I’Jotmore than 1.5 percent, calculated
C,;Hl#Oj,
HC1,
3HZ0
Category:
Dose:
Mol.Wt.375.85
Narcodc, analgesic.
10 to 20 mg.
Desdption:
Colorless,
glistening needles or
white crystalline powder; odourless; taste, bitter.
Soluble
inwater;
sparingly
soluble
in
etherand in
afcobol;
practically
insoluble
insohrzt
Volubility:
[email protected]; soluble in glycen”n.
with reference COthe dried substance, determined by the
following method: Transfer 0.5 g to a separator, add 15 ml
of wurer, 5 ml of IVs~iufi
@d~~~e,
~nd 10 ml Of
shake. allow to separste, and transfer thv
cbiomjonn.
chloroform solution co another scparmr. Repeat the
extraction with two fm-ther quantities, each, of 10 ml,
of chio?ufonn. Wash the mixed chloroform solutions
with 10 ml of 0.1 N sodium bydruxide and then with two
successive quantities. each of 5 ml, of water, evaporare to
dryness on a water-bath, and dry the residue to constant
weight at 10Y.
321
E
TITLE:
Elimination
AUTHOR
Stoltze K
AUTHOR
AFFILIATION:
Department of Periodontology, School of Dentistry, Faculty of Health
Sciences, University of Copenhagen, Denmark,
SOURCE:
J Clin Periodontal
of Elyzol 25V0 Dentalgel matrix from periodontal
pockets.
1995 Ma~22(3): 185-7
NLM CIT. ID:
ABSTRACT:
—.
MAIN MESH
SUBJECTS:
-
I of2
“n he..lrcat~of
=~-~hfhisd:v’’’”edfor~
[email protected]
a sus e 10n o~metronld~ole
benzoate (40VO) in a mixture
< of [email protected] mono-o eate (GMO) and triglyceride (sesame oil). M~~r-ni~tiole
4
can be de
~a!
p~ckets 24-36 h afte
aim of the present study was to estimate the period
matrix persistson periodontal pockets after 1 application of EDG. 12
patients were included in the study. From each patient, 1 sample was taken
before and immediately after, and 1,2,3,4,5,6,8,
12 and 24 h after
application. Subgingival scaling followed by absorption of gingival
crevicular fluid with filter paper was used for sampling. The sampling unit
was 1 tooth. Each sample was assayed for the amount of GMO and oleic
acid (a degradation product of GMO) by means of high-performance liquid
chromatography (HPLC) with UV detection. To allow determination of the
GMO dose applied into the pockets and to estimate the recovery rate of the
sampling method, 1 tooth in each patient was selected for sampling as soon
as the gel had set, i.e., about 10 min after application. Only in 1 patient was
a detectable amount of GMO within the pocket revealed 24 h after
application. This amount was approximately 0.5°/0 of the mean GMO dose
applied around 1 tooth. GMO was found no longer than 12 h in the
remaining patients.
Glycerides/ADMINISTRATION
&
DOSAGE/ANALYSIS/*
PHARMACOKINET’ICS
Metronidazole/* ANALOGS & DERIVATIVES/ADMINISTRATION
DOSAGE/ ANALYSIS/* PHARMACOKINETICS
Periodontal Pocket/* METABOLISM
Sesame Oil/ADMINISTRATION
&
DOSAGE/ANALYSIS/*
PHARMACOKINETICS
&
5!5!98 12:48 PM
Q
GREDIE NT NAME:
SIL VER PROTEIN MILD ~
B. Chemical Name:
C. Common Name:
Argentum Creole, Collargol (9CI), Colloidal Silver, Stillargol, Vitargenol, Aust.:
Coldargaq Fr.: Pastab~ Ger.: Coldargaq Ital.: Arscolloid, Bio-Arscolloid, CortiAscolloid, Rikosilver, Rinatipiol, R.inovit Nube.
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay: (after ignition)
(S’[email protected]
(Uesults)
19.0-23 .OVO
19.74’%
—.
E. Information about how the ingredient is supplied:
Browq Dark-Brown,or almost black, odorless, lustrous scales or granules, somewhat
hydroscopic, and is tiected by light.
F. Information about recognition of the substance in foreign
pharmacopoeias:
Aust., Belg., Cz., Fr., Hung., It., and Jpn.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Isenberg, S., Apt, L., and Yoshimuri.
Chemical
preparation
oftheeyeinophthalmic
of mild silver protein solution. Archives of Opthabnology, 1983;
surgery.
II.
Effectiveness
101(5): 764-765.
Apt, L. and Isenberg, S. Chemical preparation of skin and eye in ophthalmic surgery: an
international survey. Opthdmic Surgery, 1982; 13(12): 1026-1029.
—.
.-
used:H--- Information
- about
“-dosage forms
Liquid
L
Information about strength:
1-20%
J. Information about route of administration:
Nasal
Opthahnic
K
Stability data:
L. Formulations:
—
M. Miscellaneous Information:
.—-=
Page -2-
“\. ..---
CERTIFICATE
OF ANALYSIS
----- ----- ------ ----- _PF!ODUCT: SILVER
RELE&”E #: N
PROTEIN
LOT
.
1.
DESCRIPTION
2.
Identification
3.
d 5-l~Y?
MILD
#
GRADE:NFXIII
CODE:D5785
:B61695G18
SPECIFICATIONS
------ --- -_ -- granules
Black
4.
Assay
(after
ignition)
5.
Ionic
silver
6.
Distinction
from
silver
protein
D
Conforms
pass
test
Passes
test
TO pass
test
Passes
test
To
Volubility
RESULT
---.--
19.0
-
23.0%
1 ~%
NO
turbidity
Conforms
To
pass
Passes
strong
test
——
‘b
ATTENTION:
Date
TONY
: 06/23/97
Prepared
10762
—
HATCHETT
/
by
test
CONTROL REPORT
QUALITY
NAt4E. : SILVER
CHEMICAL
PROTEIN
MILD
NF
.4
LOT NO. :C64O51D1O
MANUFACTURE
PHYSICAL TEST
TEST STANDARD.:USP
SPECIFICATION
l)DESCRIPTION
/
/
<4
——/BP
/~RcK
——/NF
/wT._/cO.SpECS._.
.:
BROWN, DARK-BROWN,OR
GPJUWJLES ; SOMEWHAT
ALMOST BLACK,ODORLESS,
LUSTROUS
SCAIIES
HYGROSCOPIC,AND
IS AFFECTED
BY LIGHT.
OR
2)SOLUBILITY.:
FREELY
AND IN
_—-
SOLUBLE
ETHER.
IN
WATER.
ALMOST
ALCOHOL,
CHLOROFORM
GRAVITY .:
5)IDENTIFICATION .:
A)COMPLIES (B) AS PER NF 10th
B)COMPLIES (C) AS PER NF 10th
PASSES.
EDITION
EDITION
1955.
1955.
FAILS .:
:
COMMENTS
.:
ANALYST
SIGNATURE.:
PREPACK
TEST.:
RETEST.
—
IN
3)MELTING POINT.:
4)SPECIFIC
-
INSOLUBLE
:
DATE. :
DATE.
DATE.
:
:
INITIAL.
INITIAL.
:
:
-.
------------------ IDENTIFICATION ------------------NAME: SILVER PROTEIN,MILD
PRODUCT#: 29824-7
CAS #: 9015-51-4
SYNONYMS
(j .&lGENTUM CREDE * COLLARGOL(9CI) * COLLOIDALSILVER *
------------------ TOXICITYHAZARDS------------------—
RTECS NO: VW3675000
SILVER COLLOIDAL
TOXICITYDATA
JPPMAB2,20,50
ORL-MUSLD50:100MG/KG
REVIEWS, STANDARDS,AND REGULATIONS
ACGIHTLV-TWA0,01 MG(AG)/M3851NA85,529,86
MSHA STANDARD-AIR:TWA 0,01 MG(AG)/M3DTLVS* 3,231,71
ONLY SELECTEDREGISTRYOF TOXIC EFFECTS OF CHEMICALSUBSTANCES
(RTECS)
DATA IS PRESENTEDHERE. SEE ACTUALENTRY IN RTECS FOR COMPLETE
INFORMATION.
------------------ HEALTHHAZARDDATA ----------------ACUTEEFFECTS
HARMFULIF SWALLOWED,INHALED,OR ABSORBEDTHROUGHSKIN.
MAY CAUSEEYE IRRITATION.
——__
MAY CAUSE SKIN IRRITATION.
TO THE BEST OF OUR KNOWLEDGE,THE CHEMICAL,PHYSICAL,AND
TOXICOLOGICALPROPERTIESHAVENOT BEEN THOROUGHLYINVESTIGATED
FIRST AID
IN CASE OF CONTACT,IMMEDIATELYFLUSH EYES OR SKINWITH COPIOUS
.-
AMOUNTS OF WATER FOR AT LEAST 15 MINUTES WHILE REMOVING
CONTAMINATED
CLOTHING AND SHOES
IF INHALED, REMOVE TO FRESH AIR IF NOT BREATHING GIVE ARTIFICIAL
RESPIRATION
IF BREATHING IS DIFFICULT, GIVE OXYGEN
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVIDED PERSON IS
CONSCIOUS
CALL A PHYSICIAN
WASH CONTAMINATED CLOTHING BEFORE REUSE
-------------------- PHYSICAL DATA -------------------APPEARANCE AND ODOR
DARK-BROWN OR BLACK FLAKES
------------ FIRE AND EXPLOSION HAZARD DATA ----------EXTINGUISHING MEDIA
WATER SPRAY
CARBON DIOXIDE, DRY CHEMCAL POWDER OR APPROPRIATE FOAM
SPECIAL FIREFIGHTING PROCEDURES
.-.
—.
—.
WEAR SELF-CONTAINEDBREATHTNGAPPARATUSAND PROTECTIVECLOTHING
TO
PREVENT CONTACTWITH SKIN AND EYES,
UNUSUALFIRE AND EXPLOSIONSHAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS.
------------------- REACTIVITYDATA ------------------INCOMPATIBILITIES
STRONGOXIDIZINGAGENTS
PROTECTFROM LIGHT.
ACIDS
HAZARDOUSCOMBUSTIONOR DECOMPOSITIONPRODUCTS
TOXIC FUMES OF:
CARBONMONOXIDE,CARBONDIOXIDE
--------------- SPILL OR LEAK PROCEDURES-------------STEPS TO BE TAKENIF MATERTALIS RELEASEDOR SPILLED
EVACUATEAREA.
WEAR SELF-CONTAINEDBREATHINGAPPARATUS,RUBBERBOOTS AND HEAVY
RUBBERGLOVES.
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOIDRAISINGDUST.
VENTILATEAREAAND WASH SPILL SITE AFTERMATERIALPICKUP IS
COMPLETE.
WASTE DISPOSALMETHOD
DISSOLVE OR MIX THE MATERIALWITH A COMBUSTIBLESOLVENTAND BURN
INA
CHEMICALINCINERATOREQUIPPED WITH AN AFTERBURNERAND SCRUBBER.
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --WEAR APPROPRIATE NIOSI-VMSHA-APPROVED
RESPIRATOR
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE CLOTHING
SAFETY SHOWER AND EYE BATH
USE ONLY IN A CHEMICAL FUME HOOD
DO NOT BREATHE DUST
AVOXD CONTACT WITH EYES, SKIN AND CLOTHING
AVOID PROLONGED OR REPEATED EXPOSURE
WASH THOROUGHLY AFTER WLING
TOXIC
KEEP TIGHTLY CLOSED
LIGHT SENSITIVE
STORE IN A COOL DRY PLACE
TOXIC BY INHALATION, IN CONTACT WITH SKIN AND IF SWALLOWED
IF YOU FEEL UNWELL, SEEK MEDICAL ADVICE (SHOW THE LABEL WHERE
.-
POSSIBLE),
WEAR SUITABLEPROTECTWE CLOTHING,GLOVESAND EYWFACE
PROTECTION.
REGULATORYINFORMATION
20 O’%SILVER COMPOUND
THIS PRODUCTIS SUBJECTTO SARA SECTION313 REPORTINGREQUIREMENTS.
THE ABOVEINFORMATIONIS BELIEVED TO BE CORRECTBUT DOES NOT
PURPORTTO BE
ALL INCLUSIVEAND SHALLBE USED ONLY AS A GUIDE SIGMAALDRICH SHALL
NOT BE
HELD LIABLEFOR ANY DAMAGERESULTTNGFROM HANDLINGOR FROM
CONTACTWITH THE
ABOVEPRODUCT SEE REVERSE SIDE OF INVOICE OR PACKINGSLIP FOR
ADDITIONAL
TERMS AND CONDITIONSOF SALE
—==
SanguinarialSlippeW
is srgyria. a generaf grey diacoloratinn. Silver is used as a colouring agent for some types of confectionery It ia also ud
~ Azgenmm Metallicum in homeopathy.
Numerous salts or compmmds of silver have been employed
for various therapeutic purposes, including silver acetate
(P. 175 I). silver allantoinate and silver zinc alhwaoinate, silver
borate, silver carba-mcc, silver chloride, silver chromate, silver glycerolme, colloidal silver iodide, siIver Iamme, silver
manganite, silver mtrate (p. 1751 ), silver-nylon pnlymers, silver protein (p. 175 1), and silver sulphadiazine (p.273).
A report of reversible neuropathy aaxociatcd with the ahxnrptinn of silwr from an artbropiawy cement. i
1. Vtk H, CIal, Neuropathy caused by silver absorptica from Xthmplasty cement. Lmcc: 1985: i: 872.
Coating catbe:era with silver has been reponed to reduce the
incidcrrcc of catheter- asswi ated bacteriuria 1.2but other smd ies have reported increaxed infection.~
1. Lundchcrg T Prevenuon of catheler-srsocmed urinary-tract
mkctiom by uxcof silver-impregnated catheters. Lmcer 1986,
ki: 1031.
2. Johnran JR, cr ai. Prevention of catheler-associated urinary
tract infections wnh a silver oxide-coaled urinary catheter
cbmcal and microbiologic correlates. 1 lnfrcr Dis I [email protected] 162:
I 145-50.
3. Riley DK, e! a!. A large
randomized cltmcal mal of a silverjmpregna!ed urinary catheter: lack of efficacyand staphylnmccal supcrinfec!ion. Am J Med 1995:98:349-56.
Preparations
Namesof prcpamtions arc listed bclnw; dctils src given in PsrI 3.
Proprie~
Preparations
MIcropw Card.. Tabanil; Ger: Dulcargzmt; Silargettent,
Multi-ingredient
pr+mxtions.
Auzrmf.: Sims-Vsrix Bandagct; Simatziret; Fr: St&ilel T au Cuiwe Argentt; GeK Adsorgsnt: Griinc SalbC ‘Schmidr- N; I/al,: Actisnrb Plus: Ag]piiX
Katodamu Katoxyn; Nova-T. SWm-Nova TT; Spain: Argentncmmo; UK: Acrisoth PIUS.
Austrtd.:
Silver Acetate
w 19-P)
Argenu Aceras.
CH3COOAg = 166.9.
CAS— 563-63-3.
Pharmmrpceios
In
AusL and Hung.
Silver acetate has been used similazly to silver nitrate as a diainfcctarw it has alao been wed in arrtismokmg prepamtions.
g;
s=reparations
areIiwcdbelow details am gwcn in Parr 3.
Namesof preparations
0f8clal Preparations
fJSNF
18: Pharrnaceuucal Glszc.
Siam Benzoin
(273-c)
A balsamic resin from Srym.z fonkirwrrsis (Stymcaceae) and
not more than 10%- of alcohol (90%) -insoluble
matter,
Yellowish-brown to rusty brown compressed pebble-like
team with an ameeable. balsamic. vanilla-like odour. The
tears are separa~ o ve~ slightly aggludnated, milky white
on fracture A
and brittle at ordin~ temfwamres, but
containing
m used similarly to Sumatra bmrzoin
ten used as a preservative and was forration of benzmnated lard.
stcd below; detils arc given in ParI 3.
~Tmcmre. PudophyOum Resin TupI-
s. Canad.: Benrmmspmy+: Cold
~.in: vshm Bdsamicost.
1
,-,
Silver
(53 16.VJ
7
‘-=
i,
107,8682,
i — 7440-22-4.
,armacopoe m. In Swiss
7:53540
2 Gourlay SG, McNcill 11 Amismokmg products. Med J Aurr
1990, 153:699-707.
Preparations
Namesof pmpata[ions are li$ted Irdow: details arc given in Psri 3.
Benjoin du Laos: Benzoe Tonkmensis.
F?ronnocopoeios, in AIM., Chin., Fr., IL, and Swiss. Also in many
pharmacopoeias under the ode benzom and should not be
confused with Sumatra Benzoln. Hung.,Jpn, and US allow both
Siam benzom and Sumatra benzom under the title Benzoin.
k
References.
1. Jensen EJ, er al. Serum concentrations and accumulal]onof silwr m skm during !hrec months’ treatment with an ami.smok.
ing chewing gum conwrmg silver xcclate. Hum Toxicol 191t8:
1
Id is used topically
bt absorbed 10 my
;d with r3remetal
Proprietsv
Preparations
UK. Tabmm!.
Siiver Nitrate
(5321-h)
Elm
1751
Chronic application 10 the conjunctival, mucous surfaces, or
open wounds leads to mgyria, which though dlfficub to treat
is considered to be mainly a cosmetic hazard, see under Silver
(abuve).
Absorption of nitrite following rcductinn of nitrate may cause
metbaemoglohinaemiz
There is afso a risk of electrolyte dis-
turbances.
Treatment of these adverxe effects is symptomatic.
Silver nitrate from a stick containing 75% was applied to the
eyes of a newborn infant instead of a 1% solution. 1 After I
hour there waa a drick purulent secretion, the eyelids were red
and ncdcmatous, and the conjrmctiva markedly injected. The
corneas bad a bluqrey
&dewed appearance with areas of
cored opacification. After treaozzent by lavage and topical
apphca~on
of antibiotics
and hnmauopine
2% there was a
marked unprnvemcnt and after 1 week topical application of
corticnatemids was started. Residual damage was limited to
slight cornea! opacity.
I
Homblass A. Silver nitrate nculaz damage in newlmms JAMA
1975; 231:245.
Phaemacokirretics
Silver nitzate is not readily abxotbcd.
Uses and Administration
Silver nitmte pnsxcsaes disirrfectam properties and is used in
marry counfzies as a 1% solution for the prophylaxis of gonococcal opbthahma nennatorum (see Neonatal Conjunctivitis,
p.151) when 2 drops are instilled into each conjunctival sac of
the neamate. However, aa it cao cause irritation, other agents
are otien used
In stick form it ha bccm czaedas a caustic to desmoy warm and
other small skin growths. Compresses soakedin a 0.5% solution of silver nitrate have hem applied to severe bums to reduce infection. Solutions have also been used as topical
disinfcccamrs and astdngentz in other conditions.
Silver nitzare (Argemum Nltricum; &gent. Nk.) is used in homoeopathic medicine. It is also used in cosmetics to dye eyebrows and eye laabcs in a cozzccmtrstion of not more than 4%.
Cystitis. Comment on silver titrate irrigation having limited
value in ox management of hacmorrhagic cystitis after radiothempy. 1
1. Annnymnus. Hacmorrhagic cystitis after rad)o[herapy. &mc#
19S7: i: 304-6.
Preparations
Namerof preparations arc fisted below,: details arc given in Part 3.
Ok%ciaf Preparadons
USP ?3: Silver NIuste
OphtbaMc
Solution, Toughened Silver
Nkmre.
Proprietary
Prwpsrations
Au$rrd: Hnwe’s Sohniont;
Spain: Argenpaf.
Mcdti-hrgmdierrt
Quitt; Ger: Mova Nitrat; Pluralane:
preparations.
Ausmaf.: Super Bamsh; Spain:
Argenmfenol; SIWL: Grsfco: UK: AVOCA.
Silver Protein
(5322-m)
Albumosesilbec .Argentopmteinum; Argentum Pmremicum:
Procargolum: Proteinato de Placa; Protemato de Pram; Srrong
PrOzargIw%-Ong Protein silver Strong Salver Prmem.
CAS — 9007-35-6 (colloldol silver).
Argenu NItras; Nttrmo de Plau, Nmato de Praca
NOTESynonyms for mild silver protein include: ArgenmproAgN03 = 169.9,
!einum Mite; Argentrcm Vkellinicum; Mild
Protargm; Mi)d
CAS — 776 I-88-8.
Silver ProteirmmSilverNucleinate: Silver Vl[ellin,
Phormocopcwos. In AUSL,Belg., &,, G., Eur., Fr., G.w, Hung.,
~ V]telinaIo de F%ua and Vnelinato de Pram.
Jrm, IL,Jpn, Neth., pofi, SWISS,and US.
klg., G., Fr.,Hun.g,lr_,a”dl~.
Many
those couno?es that are DarThe szandards of Ph. Eur. aDDlvto
,, ( -Phor~copmiasl”&sL,
,.,
of dwse phannacopoem
include monogmphs on mild silver
ues to the Convenuon on the Elabormon of a European Phar.
protein as well ar on colloidal silver.
macopoem see p.xm,
Silver protein xoluhons have antibacterial properties, due to
Colorless or wlme lranspzem crysrals or crystaflme odOurthe presence of Lowconcenuahons of ionised silver, and have
less powder. On exposure to ligh! in the pres-mce nf organic
been used as eye drops and for application to mucous memmatter, silver nitrate becomes grey errgrcy]sh-black.
branes. The nuld form of silver protein is considered to he less
Soluble I in 0.4 of waler and I in 30 of alcohol; IN solubilig
irrira:ing, but less active.
is increased in boiling water or alcohol; slightly soluble m
Colloidal silver which is also a preparation of silver in comether. A solu( ion m waler has a pH of about 5.5.
binauon with protein has also been used top]cally for its antiSilver nitrate is incompatible with a range of substances. Albacterial acliviry.
though it is unlikel y rhat there will be a need to add any of the
interacting substances to silver mrzate solutions considccmg
Preparations
tts current uses. pharmacists should be aware of the potential
Nsnresof prepamtmns are listed below, details art gwen in Pm 3.
for incompatibility, Store m aimghc non-metaflic containers.
Proprietary Preparations
Protecr from light.
.L
F.: S~
The reported yellow-brown discolomtion of samples of sih er
nirzate bladder Imgat]on ( 1 m 10 000) probably arose from
the reaction of the silver nitrate wirh alkab released from rhe
glass bottle which appeazed to b soda-glass. 1
t PSGB Lab Repo” P/80/6 1980
Multi-ingredient
p~parations.
AUSI.: Coldargan, Fr: Pawaba: GeK Coldqant. [ml. k’acolloid: Bio-Arscolloid; Coni-Arscnlloid; Rikosil ver; Rhrmtipiol; Rinowt Nube.
Adverse Effects
of poisonin~ stem from the corrosive action of silSytrzPmnzs
Slippery
ver mtrate and include pmn in the mouth. sialomfzoca, diw111% voml!ing, coma, and convulsions.
A shorr llved minor conjunctivms is common in mfarrts given
silver nirrate eye drops: repeamd use or the use of high concenma[ions produces severe damage and even blindness.
ber actively mazketed
Elm
7L)
(545s-1)
Elm Bark Skppwy Elm Bark Ulmus: Ulmus Fulva.
Phormacopoeim. In US.
The
dried inner bark of Ulmusfulwz (= LT.rubru) (Ulmaceae).
Slippery elm cmrrains much mucilage and has been used as a
demulcem.
Metals and some Metallic Salts
942
Epidermal
rnecrolysis. Based on the treatment
of 10
casex, the following
was suggested as treatment
for toxic
epldermal
necrolysi%
continuous
moist compreaaea
of
sihwr niirate
solution 0.25 to 0.5%, with generous wrapping
to
prevent
excessive
cooling:
daily
electrolyte
eatimationx
and
daily
debridemenc
after
about
the
fourth day the compresses could be replaced by dexamethasone/neomycin
spray followed
by inunction
of WOOI
alcuhols ointment.
A penicillin should be given routinely
and steroids if vasculitis was present.—
P. J. Koblenzer,
Archs Derm., 1967, 95, 608.
Herpes simpk.
Silver nitrate 1% had little effect in
vitro or in vivo against herpes simplex virus type 2.—
V, R. Coleman el d., Anfimicrob.
Ag. Cherrmrher.,
1973, 4, 259. A further study.— F. Shimizu er d., ibid.,
{ 976, /0, 57.
Hpdatid cysts. Intrahepatic
cysts of Echinoroccus
grarrUIOSUSwere treated with excellent results in 20 patients
by freezing
the operation
area then administering
silver
nitrate
0.5% to destroy the smlicca.—
1. Nazarian
and
F. Saidi,
Z. Tropenmed.
Para$ir..
1971, 22. 188. per
Trop. Dis. Bull., 1971, 68. 1356.
Ophthalmia neorrotorrrrn In a study of the incidence of
opbchalmia
rreona!orum
in 220000
births, it was found
that in 92865
caaea where preparations
other than silver
nitrate
were used the frequency
of gonococcal
ophthalmia neonatorum
was 0.07% whereas where silver nitrate
was used the rate was 0.1 %. Silver
nitrate
did not
always
suppress the development
of the amdition
and
seemed no more effective
than other agents.
While
a
drop of l% silver nitrate
solution did no harm,
there
was little evidence that it dld any goud.—
Lmrccl. 1949,
1, 313.
Of the 49 states of the USA
which had made regulations requiring
routine
prophylactic
treatment
of the
eyes of newborn
infants,
22 had s~ilied
silver nitrate
applications:
NO evidenm had keen found to contra-indi.
~Sd&%
n_ary.-P.C.
had
rmdered
local reactions occurred
with penicillin
than with silver nitrate eye-drops. Penicillin
for neonatal
prophylaxis
should. not tts abandoned,
since it did not
(letter), ibid.,
infants.+.
Nathenaon
cmrtammg
1ss than 2% of silver
Treatment
was
nitrate were considered to be ineffective.
effective
if applied
early and prophylaxis
was advised
only in infants whose mothers were known or suapemed
ibid.. 281. See
to be infected.—
E. B. Shaw (letter),
also P. Kober, Medsche Klin.. 1967, 62, 424.
appmr
to Smsltlae
275, 280. Eye-drops
To prevent gonorrhoeal
ophthalmia
neonatomm,
a 1%
solution
of silver nitrate
was instilled
at bkth.
The
chemical
conjunctivitis
caused by silver nitrate
was of
short duration.—
P. Thygeaon, J. Am. med. Am., 1967,
201.902,
Silver
Nitrate Cream. Silver nitrate, 0.5 or 2’%, Xalifin- 15 20%. water to 100%. The cream was stable with
only slight disdoration
when stored for 4 weeks in the
dark at room temperature
at O“ to 4° there was nO
discoloration.-Pharm.
SW. Lab. Rep. P/68/ 15.1968.
Eye-drops
Argenti Nitratis pro Neorratis (Drur. Disp.).
Octdogrsttse
Silver
nitrate
670 mg,
ptaaaium
nitrate
1.2 g, and
Water
for Injections.
9g. I 3 g.
A similar meoaration
is included in F.N. Be/g.
Silver
Nit~t~
Eyerkops (B.P.C. /954). Gutt. Argerw.
poraxsium nitrate 1.33%
Nit.
Silver
nitrate
0.5% w/v,
w/v, in solution
for Eye-drops.
Nerd. P. has 1% w/w with potassium nitrate I% W/W in
Water
for Injections.
Ohsaemta
Utrguerrtm Argerrti Nltratia Compoaiturar.
Compwnd
Silver Nitrate
ointment.
An ointmentwith this title is
included
in several
pharmacopoeias.
It contains
silver
nitrate
1% and Peru balsam 5 to 10% usually in a basis
of yellow soft paraffin
or yellow soft paraffin
and WOOI
fat.
Opbtbslmic SoIutkoaaa
silver Nitrate Ophthalmic solution {U.S.P.). A
of silver nitrate 0.95 to 1.05% in an aqueous
pH 4.5 to 6. It may cun~in
sodium acetate
Store in singledoae
amtainera.
Protect from
Pncumorhorax.
fuily treated
silver nitratq
solution
medium.
as a buffer.
light.
aaaoeiated
and recomsee Adverse
Nitrate Soiutiam (u.S.JV.F.
X11.
Silver Nitrate,
Howe. A solution of
diammirvmilver
nitrate
was prepared
from silver nitrate
704 g, water
245 ml, and strong ammonia
solution
to
dissolve
all but the last trace
of precipitate
(about
contains 28.5 to 30.5% w/w of Ag and 9 to
680 ml).lt
9.7% w/w of NH]. Store in small glaas-stoppered cmrtainerx or in amfndes.
Protect from light.
Tlris solution
has been employed
in ekntal
surgery
to
deposit silver in exposed dentine or to till up small crevices in the teeth. After
the solution had been applied 10
the tooth it was followed
by a reducing agent such as a
10% formaldehyde
solution or eugmol to cause a deposit
of metallic
silver. The solution has also been employed
in the treatment
of fungoua infections of ihe nails.
Solmtio
SWer
For’ reports
on the chemical
conjunctivitis
with instillation
of silver nitrate eye-drops
mendations
for reduction
of the incidence,
Effects (above).
water
earn Tetracairao
Argeaati Nitmtis
nitrate
200 mg, amethocaine
nitrate
99.7 g.
(Nerd. P.).
mg, and
100
d
Spontaneous
pneumothorax
wax su-in 132 patients by pleurmfcsis induced with
repeated pleurode5is was nexxaaary in only
2 patients. It was suggested tha! this therapy should be
used for patients with only small or no .blebs visible on
thoracoscopy,
m with orrl
case.[. Andwaon
and ~.m~~p~-$~~’~~flgl~~~~
54, 230,
creams
continual routine prophylaxis Amrraorrisc81Sikr
Engl. J. Med., 1966,
1965). Ammoniacal
Barsam, New
274, 731. Fewer
Toughened SiIvcr Nitrate (fJ.S.P.). Contains not less than
94,5%
of AgN 0],
the remainder
consisting
of silver
chloride. .%ore in airtight containers,
Protect from light.
solutions
l~~~d~~~~~r~?~e~~~~ea~~~~~id$~?i
gonorrh&a
become
grey
or greyish-black
on exposure
to light.
Freely
soluble
in waten
sparingly
xoluble m alcohol.
Protect from light.
A similar
preparation
is included
in acvcral pharmzcofrocias.
per J. Am.
med.
Ass..
1968.206.
6g [.
Wwnds. Silver nitrate
solution 0.5% was more effective
against
Gram-positive
than Gram-negative
bacteria’
in
the treatment
of nontherma[
war wounds. The solution
did not hinder wound healing or epithelialiaation
of split
thickness
skin mafts.—
J. P. Connors
er al., ArcfIs
Surg.. Chicago. -) 969, 98. 119. per J. Am. med. Ass.,
1969, 207, 580.
Preparations
Mitigated silver Nitrate (B.P. C. 1%8).
Argmti
Nitras
Mitigatus
Mitigated
Caustic;
Argenti
Nitras
Dilutus.
Silver nitrate
1 and potassium nitrate
2. fused together
and sumabl y moulded
for application
as a caustic
to
warts and condylomas.
Protect from light.
A similar
preparation
is included
in several pharmaco-
poeias.
silver Nitrate
(N H2.CS.NHj=
Stain Remover (f?rrir. of IOWU).Thiourea
76.12) 8 g, citric acid monohydrale
8 g.
water to 100 ml. It should be freshly prepared.
Nhite (E.P.). A,rgetrti N itras InduToughened
Silver
ratus; Toughened
Caustic.
Fused Silver Nitrat~
Lunar
Caustic;
Moulded
Silver Nitratq
Stylus Argent!
Nitrici.
Silver nitrate 95 and potassium nitrate 5. fused together
and suitably moulded.
White
or greyish-white
cylindrical
rods or cones, which
5322-m
Silver protein (B.P.C, /%8). Argmtoproteinum:
Strong Protein SiIven Strong Protargin;Argenturn
Prmeinicum; Albumoaeailbw %otargolunu Proteinato de
Plats; Protcinato de Prata.
CAS — 9015-SI-4
Pharmocopoeios.
lrr Arg.. Aust., Belg., Cz.. Fr.. Hung..
Irrd., [ru., If.. Jap., Pol., Port., Roum.. Span.. and Turk.
A brown odourleas hw?rosxooic oowder containing
7.S to
8.5%of
Ag.
‘.
“
Slowly
soluble I in 2 of watec
very slightly
soluble in
alcohol,
chloroform,
and e!ber. A solution
in water
is
neutral to litmus. solutions
may bs prepared
by shaking
the powder over the surface of cold water and allowing
it to dissolveslowly.or by trituraling the powderto a
cr~m with walerand diluting. Solutionsare transpaccnt
and not coagulated
by hear. nor precipitated
by the
addition
of alkali, alkali sulphidcs. alkali salts, or albunon-staining.
Store in airtight
min; they are relatively
containers.
Protect from light.
Adverxe
Effects.
As for Silver
(above).
Uses. Silver protein solutions have antibacterial
proyrties, due to the preamce of low concentrations
of ionised
of
silver, and are used as eyedropa
in the treatment
cmjunctivilis.
Solutions
are relatively
non-irritant
unlcsa
they contain more than 10% of silver protein.
----
Ighly with hot 3 per cent hydroeight of the precipitate so obtained
&
Iodide in tight,
IighLresistant
.TRATE SOLUTION
nmoniacal Silver Nitrate,
Howe
i a solution of silver diammino
:quivalent of not less than 28.5
and not less than 9.0 Gm. and
. . . . . . . . . . .
. . . . ,.,
. . . .
. . . . . . . . .
704 Gm.
245 ml.
680 ml.
. . . . . . . . .
1000ml.
,..
xtar and dissolve it in the puri1 t ‘+~m temperature and add
;e~
. all but the last trace of
his last trace of precipitate from
ion is a clear, colorless, almost odorless
“ected by light.
Its specific gramty is
Jte Solution (1 in 10) responds to the
.af.e, page 6S3.
, Solution add a few drops of forrnalde-
recipitate
mmhm
is immediate] y formed (dti-
nitdes
).
-
1Silver Nitrate Solution (1 in 10) add
filter, add 5 ml. of sadium hydroxide
.itmus blue.
remains free from even a transient blue
tiacal Sliver Nitrate Solution add 3 ml.
~he clear fiftrate teated in a &me on a
of sodium or potassium (distinction jrom
ml. of Ammoniacal Silver Nitrate Soluwater, 10 ml. of diluted nitric acid, and
;rate with 0.1 N ammonium thiocyanate.
is equivalent to 10.79 mg. of Ag.
,ut 1 ml. of .4mmoniacal Silver lNitrate
e sample to a Kjeldahl distillation flask
-
519
THE NATIONAL FORWJLAEY
[ULARY
with 50 ml. of water, and add sufficient of the water to make a volume of 200 rnf.;
add 10 ml. of sodium sulfide T.S. and 20 ml. of a solution of sodium hydroxide (4
in 10). Connect the flask to a condenser, the lower outlet tube of which dips
beneath the surface of 50 ml. of 0.5 N sulfuric acid contained in a receiting flask.
Distil the mixture until about 100 rnI. of distillate has been collected, add methyl
red T. S., and titrate the excess acid with 0.5 N sodium hydroxide.
J3ach ml. of
0.5 N sulfuric acid is equivalent to S.516 mg. of NH1.
The ratio between the percentage of wnmonia and the percentage of silver
closely approximates 1 to 3.16.
Ammoniacal Silver Nitrate Solution in small glaasPackaging and storage-Preserve
stoppered, light-resistant containers, or in light-resistant ampuls.
FOR TOPICAL usE—Mix hnrnoniacal Silver Nitrate Solution with a reducing agent, such as formaldehyde (1 in 10) or eugenol, to deposit
the metallic silver, in a state of fine subdivision, in the desired area of the
tooth.
CATEGORY—~rOteCtiVe
(dental).
Silver Protein, Mild
MILD SILVER PROTEIN
Argentum Proteinicum
Mite
Mild Protargin
Mild Silver Protein is silver rendered colloidal by the presence of, or
combination with, protein. It contains not less than 19 per cent and
not more than 23 per cent of Ag.
Solutions of Mild Silver Protein should be freshly prepared or
Caution:
contain a suitable stabilizer, and should be dispensed in ambeT-coioredbottles!
Description-Mild
Silver Protein occurs aa dark brown or afmost black, shining
scales or grsmules. It is odorless, is frequently hydroscopic, and is affected by
light.
Solubility=Mild
Sifver Protein is freely soluble in water, but almost insoluble in
alcohol, m chlorofow and in ether;
Identiiication—
A: Heat ahout MO mg. of Mild Siiver Protein in a porcelain crucible until all
carbonaceous matter is burned off, warm the residue with 1 mf. of nitric
acid, dilute with 10 ml. ofwater,and add a fewdropsofhydrochloric
acid:
a white precipitate is produced which dissolves in ammonia T.S.
B: Ferric chloride T.S. added to a solution of Mild Siiver Protein (1 in 100)
discharges the dark color and a reci itate is gradually produced.
‘r
F rotein (1 in 100) add a few drops of
C: To 10 mf. of a solution of Mild S1ver
mercurv bicbforide T.S.: a whik precipitate is formed and the supernatant “liquid becomes colorless or nedy SO.
Ionic silver—To 10 nd. of a solution of Mild Silver Protein (1 in 100) add 2 rd. of a
solution of sodium chloride (1 in 100): no turbidity is produced.
Distinction from strong silver protein—Dissolve 1 Gm. of Mild Silver Protein in 10
ml. of water. Add, all at once, 7 Gm. of ammonium sulfate, and stir occasionally
for 30 minutes.
Filter through
uantitative filter paper mto a 50-ml. Neesler
tube, returning the first portions o? the filtrate to the filter, if necessary, to secure
a clear filtrate, and allow the filterand precipitate to drain. Add to the clear
filtrate 25 mf. of a solution of acacia (1 in 100). In a second 50-mL Nessier tube
of water, and add to this solution
dissolve 7 Gm. of ammonium sulfate in 10ml.
25 mf. of the solution of acacia and 1.6 ml. of 0.01 N silver nitrate.
To each tube
Page
Database:
Medline
c1966
Number
:
to present>
<1>
Unique Identifier
83203583
Authors
Isenberg S. Apt L.
Yoshimuri
R.
Title
Chemical preparation
of the eye in ophthalmic
surgery. II.
Effectiveness
of mild silver protein solution.
Source
- Archives of Ophthalmology.
101(5):764-5,
1983 May.
Abstract
Although
a mild silver protein solution
(Argyrol) has been
used for a number of years and is still used by many
ophthalmic
surgeons,
its efficiency
as an antibacterial
agent on the conjunctival has not been scientifically
evaluated
as part of the preoperative
chemical preparation
of a mild silver
of the eye. We studied the effectiveness
protein solution on the conjunctival
flora of 32 patients
in a masked fashion. By bacteriologic
analysis,
the mild
silver protein solution was found to be no more effective
in reducing the number of species and colonies in the
treated eye than in the untreated
eye. While the mild
silver protein solution does stain mucus and other debris
on the eye to facilitate
irrigation,
this study did not
demonstrate
a significant
bactericidal
effect.
f/6L
t’
j 8/
/
G–
<2>
Unique
Identifier
83142687
(1
1
i/
G
—.
Authors
Apt L.
&?
#/
Isenberg
S.
Title
Chemical preparation
of skin and eye in ophthalmic
surgery:
an international
survey.
+ource
Ophthalmic
Surgery.
13(12):1026-9,
1982 Dec.
Abstract
We surveyed 214 ophthalmologists
worldwide
to learn their
methods of preoperative
chemical preparation
of eye and
skin. A 96.8% return rate was achieved. While a wide
diversity
of agents was reported, povidone-iodine
was the
most popular agent applied to the skin. The conjunctival
usually was either ignored or rinsed with a saline solution
by the respondents.
Almost a quarter used mild silver
1
Page Number
protein
(Argyrol) on the conjunctival. Most of the
preparation
is performed
by the physician
rather than the
and pitfalls of the agents
nurse. Review of the advantages
reported should cause the ophthalmologist
to reconsider
these agents for their effectiveness,
spectrum,
and
duration of action.
—
: 2
Reprintedwith pemissio~
through the
Chemical Preparation
of Skin
and Eye in Ophthalmic
Surgery:
An International
Survey
I
Leonard
Apt,
Sherwin
Isenberg,
~o~yr~p!?:
Clearance CSfi:f
NOTICE
THIS MATERIAL MAY 8E PROTECTEDBY
CO?YFMGHTLAW (TITLE 17, U.S. COQE)
M.D.
M.D.
I
I
I
SUMMARY
We surveyed
chemical
214
ophthalmologists
preparation
diversity
of eye and skin.
of agents
was
reported,
the skin. Theconlunctiva
respondents.
I
Almost
I
advantages
reconsider
these
A 968°4
return
of the
agents
agents
for their
orrinsed
prot ~(Argyrol)
rather
reported
effectiveness,
methods
of preoperative
rate was achieved.
ignored
by the physician
pitfalls
their
was the most
m(ld silver
used
IS performed
and
to learn
povidone-iodine
usual lywaselther
a quarter
of the preparation
I
worldwide
popular
applied
with
asaiine
solution
on the conjunctival
than
should
a wide
While
agent
the
cause
spectrum,
nurse.
the
to
by the
Most
Review
of the
ophthalmologist
and duration
to
of action.
I
s
I
Ince
the
have
known
sweat
studies
glands,
ingauze
preoperative
for
Today,
1
carbolic
andlaidon
1875,
and deeper
the skin, wasthefirst
asepsls
96 8%. In order to obtain a representative
half
of the questionnaires
were
sent
surgeons
In hair follicles,
acid In spray
Subsequently,
preoperative
In the course
wsitlng
techniques
The
in
are found
other
of the
layers
form,
or
attempt
at
techniques
operatwe
field
evolved
when
i
Lister’s
antisepsis.
achlewng
have
Eberth
bacteria
and in both the superficial
of the skin. i Joseph
soaked
of Carl
that
reasons
and
rat; onale
many
of training
In ophthalmic
surgery,
lnstltuttons,
oneoften
sees different
in preoperative
main
tradition
different
the
rarely
chemical
given
for
determine
exists,
chotce
To learn
throughout
survey
literature
questions
regimen
world,
Thlsinformatlon
definltwely
about
and
Mexico,
Belglum,
AND
whtch
214 were
malted
answered
!s not found
to
and
to 221 ophthalmologists
and returned
This return
and
question
done
Finally,
the
Department
UCLA
School
of
Ophthahrrology,
of Med{c{ne,
Los
Jules
Angeles.
of
rate IS
Stein
Eye
California
Requests
California
1026
for reprints
Stem Eye Imt)tufe,
90024
should
be addressed
UCLA School
[o Leonard
of Med!c!ne,
second
asked
additional
the duration
face
recetving
of questions
proportion
nurse,
comments
There
was
w
dealt
of the
or other
were
considerable
of agents
duratl
agent. T
preparati
nonphyslcl:
requested
67 5?6 of the
respondents
(as Betadine,
Isodine,
In the preparation,
regimen
used
by a third
solution
alcohol.
The
lactated
Ringer
term
solution,
“rtnse”
product
(Figure
1 ). Half
produc
solution
The
of the
somewhe
(p Hiso Hex) v
hexachlorophene
iodine
was
Includes
of the
used
most
frequ
v
respondents,
on the skin followed
balanced
a
types
1 ) Howev
Septodyne)
in the preparation.
used
the
povidone-lodlne
Prepodyne,
while
in
on the skin (Table
and aqueous
somewhere
of all,
disparity
placed
D,
M
series
what
Los Angeles.
Apt,
the
Germar
concerned
to the skin,
of
by a physician,
povtdone-iodine
Jules
area
by wide
countries
Canada,
asked
half
T
RESULTS
126°4
From
answered
such foreign
Argentrna,
applted
the
The
used by 16.5°6,
Insr)rute,
Japan,
of solutlons
application,
application
was
METHODS
were
from
Great Britain,
and Switzerland
The first
series
of questions
sequence
Questionnaires
were
surgeons
third
of agents
MATERIALS
questionnaires
of
regimen
method
of the
ophthalmic
to
was not intended
the best
percent
known
institutions
and
of ophthalmology,
solutions
intentionally
placed on the conjunctlva,
of application,
and what was used as the rinsing
A sctentlflc
on a spectfic
The survey
are
the preferences
the
a consensus
we undertooka
in theophthalmtc
a certain
surgeons
at academic
private
practitioners
sequence
of the eye
of effectiveness
IS mentioned.
whether
answer
using
impression
ophthalmologists
preparation
or
ophthalmic
prominent
sample,
abo
to well -knov
saline,
by a rtnst
sterile
salt solution,
respondents
used
wa
or slm
a sln
DECEMBER 1982, VOL. 13, NC
,_, .. .. . ..
— ..-. —
TABLE
1
ROUTINE OF CHEMICAL AGENTS
USE DFOR SKIN PREPARATION
[n=196)
Mult, ple Agents
Povldone.
tcdtne
soap
Povldone-lod[ne
–rInSe”
soluttonz
- rinse
Soap
Percent
-
-
150
alcohol
solut!on
Powdone-iodine
= rinse or alcohol
73
Hexachlorophene z alcohol or rinse
- Povldone.lodlne
= alcohol or rinse
73
Soap z rinse = alcohol
40
= rinse
Soap z rinse : Iodine = alcohol
Hexachlorophene
Hexachlorophene
-
Povtdone-lod!ne
Alcohol
rtnse
- rinse
- Povtdone.
Stngle
39
- rinse - Iodine z
-
24
alcohol
15
merthiolate
iod{ne
Agents
-
:1
i
10
Iodine
1.0
Rtnse or Alcohol
FIGURE
Powdone-iodine
325
Iodine 1%
48
Hexachlorophene
43
7ephiran
1. (Apt and Isenberg]
particular
chemical
agent
Percemage
of respondents
using a
on the sktn as part of the preoperative
preparation
29
!Iorhexidene
1%
24
Merfen
1.0
Merthtolate
10
Alcohol
10
10
Don’t know
‘R!rrse
=
so{ut)on,
I
saline
solution,
balanced
sterile
salt solution,
water,
lactated
or similar
,(
30
20
Ringer
product
I
TABLE
10
2
CHEMICAL AGENTS INTENTIONALLY
ON THE CONJUNCTIVAL
(n=206,1
Chemical
——
Normal
Agent
PLACED
0
Percent
Sal{ne
345
= rinse
223
Nothing
267
Argyrol
Balanced
salt solution
53
Betadine
solur,on
24
Neosporin
Ringer
(diluted)
20
= rinse
solutlon
15
10
10
10
10
Chlorhexldine
Sterile
water
Chloramphenlcol
Mercury
b!chlorlde
r-~~farnyc,fl
n Gentamycln
05
mtx
,’! know
8 deferred
)pHTHALMIC
or d!d not answer.
SURGERY
05
05
FIGURE
.-.
z (API
particular
preoperative
and Isenberg)
chem)caf
agent
Percentage
on
the
Of
respondents
conjunct(va
as part
using a
o! the
Primary agent (such as aqueous
iodine, hexachlorophene,
or a povldone-iodine
product) followed
by a rinse or alcohol,
while half used a combtnatlon
of primary agents (Table 1 )
The amount
of time that these
skin varted from
variation
in the
I
.:
preparation
agents
were
applledtothe
second to several minutes
So much
length
of ttme was reported
as to make
one
1027
CHEMICAL
PREP OF EYE
-1
‘/o PHYSICIAN‘/o NURSE
FIGURE
50
50
O
100
3 (Apt and [senbergj.
Relative
proportion
ofph yslc(ans compared
100
0
wlrh nurses performing
preoperative
TABLE
3
dents
preparation
indicated
tlon,
HOW MUCH IS DONE BY PHYSICIAN
RELATIVE TO NURSE
(n==205)
—
preoperative
while
that
29°6
preparation
Sixty-two
the
percent
physictan
reported
that
does
the
physician
and nurse
and Figure
of the resp
the entire
nurse
The rest of the respondents
preparation,
of the eye
prepa
does
the
answered
en
thatt
each do part of the preparatlon(Table
3).
Percent
PhysicIan’Nurse
COMMENT
100%/
98”6/
90°6 ~
620
05
05
10
10
o
2’%
10°6
8006/’ 20°6
75°b,’ 25°6
and senior
the validity
While
preparation
recent
universally
The facial
the forehead,
both
areas
eyellds,
treated
were
were
the cheeks,
information
almost
great
and the
Some
on the
quarter
tlva.
ophthalmic
conjunctival
surgeons
while
of the respondents
Forty-two
saline
solutlon,
sterile
water
antimicrobial
percent
tntentlonally
others
place
simply
nothing
rinse
the
this
solutlons
2). About
properties.
Of the
latter,
mild
silver
topic
different
-
were
on the con)unc
conjuncttva
also
a
with
balanced
salt solutlon,
Ringer solutlon,
or
31?’o
use a solutlon
be,:r!ng
any
only
(Argyrol)
IS by far the most frequently
In general,
more physicians
than
1028
place
do not (Table
protein
used (Figure 2)
nurses
perform
the
saline,
Iodine,
a form
of this
others,
found
then
popular.:
of theoperativeftel,
the
study
Maumenee
had to obtain
surgtcal
scientific
and Mlchler
for sterilizing
five
nurse
ag
n the chemical
a lack of recent
These
wasexhlbltedt
that they did not k
sur’geons
usually
In this
Indtcates
In 1951,
these
has been
tn the ophthalm
subject
In thlssub]ect
replled
chem
of
there
used inpreparatlon
techniques
Interes
comparedfi
the operative
techniques
field
were
soap
either alone or followed
by merthiolate
or aque
and hexachlorophene
and saline followed
byelt
benzalkonium
our survey,
these
use
who
survey,
from
dlsparlty
chosen
nose.
or study
this
satlsf
(96 8°6) also attest
survey.
A lack of Interest
agents
academ~cla
foreigners,
The highly
questionnaires
ophthalrnologtsts
what
Including
ophthalmologists,
Americans
and
ophthalmologists
mention
by the b
enhanced
contacted,
for the eye prior to surgery,
literature
some
was
ophthalmologists
of this
all
To answer
difficult.
survey
ophthalmologists
tory rate of returned
or did not answer
conclusions
of this
of
younger
294
05
Not known
validity
specialists
and general
and nonacademlcians,
29
15
05
05
44
50%’ 50°6
25?.:’
75’%
20°6 80%
15°6/85°6
10?6/’
90”6
0 100%
9 deferred
The
spectrum
chlorlde
about
techniques.
experimentally
or aqueous
iodine
1 1‘% of the respondents
The
advent
{n the 1960s
of
and then
DECEMBER
and alcohol.
still
used on
povldone-rodine,
clinically
1982,
VOL
In the
13, N
APT & ISENBERG
_—L
,70s,
changed
‘-d In fact,
gists
currently
preparation
factant
of the skin
popular
prior
(polyvinyl
that
released
can
But if iodine
Iscomblned
less common
toxictty
to
be
and spores
is more
to the
Ignore
conjunctlva
would
not bear
31 % of the
on the
some
ophthalmologists
growth
controversial
if
debris,
which
used
Importance
one
should
these
chemicals
soap or detergent
place
a vasoconstrtctor
constrlctors
while
to
such
others
such
Vascular
damage
could
Potentially
this
problem
as phenylephrine
as naphazoline
will
will
phene,
act,vl[y
to know
that
a Single
of
appllcatton
OPHTHALMIC
at least dally
SLJRGERy
beglnnlng
Llncoff,
same
operation.
ophthal-
preoperative
and
found
was
implants.
was
contamination
might
not
implants”
In
Kreissig
usually
the
}o They
felt
at the
conjunctival.
ultimately
bathing
did
intra that
site
should
the
the
3
be placed
of
the
incidence
of
4
AE,
after
surgery
ocular
tn Wheeler
1974,
Am J Surg
6
pupil,
Klffney
GTJr,
Chase
more effectwe
bacteria
It IS
8
of hexachloro.
to
Steriltty
of the operatwe
field
Coast O(o?ph(halmol
Soc
AC Povldone-lodtne
PP
asanophthalmic
1966,17434-436
Iodophosphors
and
skin
asepsls
Ann
12312-317
1970,
BA, Stewarr
GT Polyvmylpyrrolldone
-lodlne
an
assessment
of ant[-bacterial
activity ./ Hyg (Carob) 1964,
62509-518
V
Fahmy JA Bacter!al flora in relatlon to cataract extraction
Acra
Browning
conluncttval
1980,58567.575
CW, Llppas J pHlsoHex
Ph ysician’s
L!ncoff
ant} b!o!tcs on the preoperative
Ophtha/mo/
keratttts
Arch Ophfha/mo(
53817-824
Desk
Reference,
Co , 1980,
p 1859
H, Nadel
Infected
10
RC
Trans Pacific
Forum
RC, Ellls
Economics
9
‘i
ii
Saggers
flora
7
Mlchler
Hattaway
Surg
Effec~s of topical
vaso -
I
32172-179
Ophlhalmof
lead to
five to seven days prior
As quoted
surgery
t
I
Maumenee
anttseptlc
and after
the
of anl)septic
I
of the
endophthalmitis.
Arch., Bd 52, 1875
I
infecting
Sterilization
decrease
I
I
deter-
on routine
more emphasis
the
and
scleral
Lincoff,
organism
Perhaps
soap scrubs,
Iavage,
scleral
of
coworkers
chlorarnphenicol,
culture
infected
and
preoperative
rate of infected
ES The development
5
as used by some surgeons,
has I)ttle antlmlcroblal
To be maximally
effect!ve,
hexachlorophene
should
b~l~plled
to
to avoid
of any preoperative
Lincoff
saline
with
their
of tnfection
1955,
IS
eye.
three
1 Eberth C V/rchows
from
not
agalrlsl
in
1951;
dllatton,
Some
dilate
regard
of action
REFERENCES
2
One could
before
with
in
agents
127573-579
either
entry
this could
on the conjunctival
mlnimlze
that
or simple
result
is incised
Hexachlorophene
IS bacterlostattc
and
gram -poslt!ve
than gram -negative
Important
is used,
agent,
activity
duration
including
conjunctival
Infectious
of practical
conjunctival
if the conjunctlva
agents
properties.
inadvertent
of the
Hahn,
the
conjunctival
and other
to avoid
organic
is used
use multiple
as to the efficacy
implants
sterilization
of chemicals
antimicrobial
corneal
!nstlllation
hemorrhage
preparation
the
study,
that
bylrngation,
comments
[f a soap or scrub
another
more
removed
combtnatlons
some
be careful
onto
mucus
and
other
often
In
benzyl-
used
commented
the
is
individual
an extensive
alter
mined
buckle
used,
used antimicrobial
of its antimicrobial
skin,
and possible
is
most commonly
Individuals
different
as powdone-iodine,
soap,
the
drug
who
preparation,
Iavagtng
a later
on
of the
blood,
which
that
powdone-iodine
source
whether
or regrowth
mic preparation,
agent
or permits
exists
preparation
operative
antibiotics
surgery
doubt
significantly
but
their
spectrum.
is incom-
not be placed
In addition,
by
material
Ophthalmologists
epitheliums,’
chloride
on skin.’
not be
be taken
the palpebral
should
inactivated
and cotton
in one study
and
Only
entering
to the corneal
benzylkonium
it, even
is
soap,
Care should
and therefore
with
produced
should
overlap
Some
However,
topical
iodine
then
Alcohol
from
that
reconsider
chemical
debris,
noted
chloride
even
of the
action.
theconjunctiva,
It stains
because
the
contact
should
Irrigation
to surgery.
used
bacteria
Some
are Indicated.
hyperemla,
prior
have
who
because
the
sterilize
direct
effectiveness,
use of an antimicrobial
then can be specifically
reviewing
to
the
was the agent
by those
and not necessarily
In
other
bacteriostatic
of surgery.
was
or
just
a
with
are
In
effects.
it is injurious
its application.
selther
it.
antlmicrob(al
of resistant
on the conjunctival
time
mucus
sterilizes
‘ Argyrol
Argyrol
irrigate
in the days preceding
truly
patible
proper
preparation
of the respondent
been
has
ophthalmologists
hexachlorophene
hexachlorophene
material,
dilute
the
It is effective
merely
may
bacteria
used
or
conjunctival
Q&the
conjunctival
—
—
atter practice
in
Given
time,
two thirds
indicated
agent
viru’tidal
‘
among
significant
reports
problems
It has
konium
corneal
of
the hexachlorophene.
because
found
remove
any
solutions
and
these
preoperative
than
and
Powdone-lodlne
wtro
contact
About
In the conjunctival.
and
in
Immediate
More
presumably
skin
povldone
consensus
conlunctlva
the
Aqueous
the
film
its antimicrobial
to prevent
sur -
state
to
bactericidal
against
at the
The
enhances
used to remove
in this
todine.
activity
magnitude.
minutes
and enough
with
changes
with
concentration
original
is
with
in the elemental
inflammatory
within
fungi
easily
remains
and of lesser
shown
solutions
tictlve
surgery
IS a polymer
for antibiotic
and
would
surgery.
ophthalmolo-
for use In chemical
to ophthalmic
combtnes
cause
eplthelium,
regard
agent
pyrrolidone)
of the Iodtne
Iodine
There
many
that povidone-iodine
fissure
two thirds
been
of
showed
most
properties
IS slowly
techniques
survey
the single
country
Powdone
of
the
this
A, O’Connor
sc[eral Implant
ed
7
P Thechang!ng
Arch Ophrha/rno/
Medical
Oradell,
character
1970,84
of the
421-426
Hahn YS, Llncoff A, Llncoff H, el al infection aher
Implantation
for scleral buckllng
Am J Ophrha/mo/
sponge
1979,
87180-185
1029
‘1
,,
through the Copyright
Clearance Center
NOT!(X
~’
THE IUIATERMLMAYBE PROTECTED8$
COPYRIGHTLAW (TJTM 17, M. CODE)
I
Chemical Preparation
:;
,.>,
..
. .
—
Surgery
II. Effectiveness of Mild Silver Protein Solution
Sherwin Isenberg, MD, Leonard APL MD, Robert Yoshimuri, PhD
● Although
a mild silver protehr solution (Argyrol) hae been used for a number
of years and k still used by many ophthatmk eurgeons, its efficiency as an antibacterial agent on the con]unctJva has not
been scientifically evaluated as part of
the preoperative chemical preparation of
the eye. We studied the effectiveness of a
mild silver protein solution on the corrjunctival flora of 32 patients In a masked
fashion. By bactertologlc analysis, the
mild silver protein solution was found to
be no more effecttve In reducing the
“number of species and cotonles In the
treated eye than In the untreated eye.
While the mild silver protein solution does
stain mucus and other debris on the eye
to facilitate irrigation, thie study did not
demonstrate
a significant
bactericidal
effect.
(Arch Ophthalmol
1983; 101:784-765)
T~apeutic
properties of si]ver and
Its salts were recognized as early
as the Roman Empire period. Jabir
ibn Hayyan Geber, an Arabian physician of the eighth century, initiated
the use of silver nitrate on the eye.’
Carl Siegmund Franz Creolebegan the
prophylactic application of silver
nitrate on the eyes of newborn infants
to prevent gonococcal conjunctivitis in
1SS4. After that, silver nitrate was
used for other ophthalmic disorders,
but it was found occasionally to cause
Accepted
From
Isenberg
for
publication
the Departments
and
Ott
22.1982
of OphthalmoloD
(Drs
Apt) and PatholW (Dr Yoshimu-
ri), Jules Stein Eye Institute
—=
of the Eye in Ophthalmic
and Harbor-UCLA
Medical Center, UCLA Scheel of Medicine.
Reprint requests to the Jules Stein Eye Institute, UCLA Schoel of Medicine, Los Angeles, CA
90024 (Dr Isenberg).
764
Arch Ophthalmol—Vol
101, May 1983
necrosis of conjunctival epithelial
cells and a gray-black color when light
reduced the salt to ita metallic state.
In addition, irritation, scarring of the
conjunctival, corneal opacificatio~
and symblepharon occurred. In an
attempt to reduce these problem%
Albert C. Barnes, MD, and Hermann
Hille, in 1902, developed a combination of silver nitrate and grain protein
(Argyrol)? However, this drug also
caused complications. In 1980, Spencer et al’ reported theclinical and
histopathologic findings in one patient who drank this mild silver protein solution for years and in a second
patient who applied mild silver protein drops to one eye for a long-term
period.
A 20% mild silver protein solution
is available
for topical ocular use in
the United States as a silver nitrate
and gelatin colloid. The drug is available also abroad under a variety of
proprietary
names and formulations.
It is classified in pharmacy textbooks
as a local anti-infective
agent.
The antimicrobial
properties of this
mild silver protein solution have been
questioned for years.”
To our knowledge, there has been no controlled
clinical study proving
the antibiotic
efficacy
of this mild silver
protein
solution as part of the chemical preparation of the eye before surgery. Yet,
in a recent international
survey of
ophthalmologists,
Apt and Isenber~
found that 22% of the respondents use
this mild silver protein solution on the
conjunctival as part of the preoperative chemical preparation
of the eye.
We, therefore,
conducted
a masked
study to investigate
the effectiveness
of this mild silver protein solution as
an antimicrobial agent in the preoperative preparation.
PATIENTS AND METHODS
Thirty-two
patients undergoing ophthalmic surgery were studied. No patient had
received preoperative antibiotic therapy or
had an active infection at the time of
surgery.
All subjects had the identical regimen of
preoperative preparation. Initially, a sterile anaerobic transport swab was applied
to either the inferomwal or irrferotemporal
conjunctival fomix of one eye and a second
swab was applied to the conjunctival of the
same quadrant in the second eye. Twenty
microliters (1 drop) of 20% mild silver
protein solution then was instilled in the
inferior conjunctival fornix of one randomly selected eye. This eye may have been the
eye that was operated on when unilateral
Hexachloocular surgerywas performed.
rophenesoapwas appliedequallytoboth
eyelids, eyelid margins, cheeks, nose, eyebrow, and forebead. The inferior fornix of
the eye into which the mild silver protein
solution had been instilIed was then irrigated with a normal saline solution, while
the other eye had no irrigation. Gauze
sponges moistened in a saline solution
were used to rinse areas bearing hexachlorophene. Next, the quadrant of each inferior conjunctival fornix not previously cultured was cultured with a third and fourth
sterile anaerobic transport
swab. Tbe
choice of which portion of the fornix was
cultured before and after the preparation
was randomly assigned. Nursing personnel
coded each specimen before bacteriologic
analysis. The microbiologist had no knowledge of the exact origin of the specimen.
The swab was washed three times in 0.5
mL of Schaedler’s broth and wrung out by
pressing it along the sides of the tube. The
swab was cultured
in10 mL ofSchaedler’
broth.Bloodand chocolate
agareachwere
inoculated
with 0.1 mL of eluantand
spreadon thesurfaceof the agarwith a
Silver Protein—lsenberg
et al
Table 1.—Mean Number of Colonies and Species of Secterie
Isolated per Subject
.-
Mean * SD
,.
Eye
I
Before
Praparaffon
1S3 f 425
After
Preparation
284 t 571
% of
Increaae
55
Colonies
Untreated
Mild silver protein.trea!ed
231 ~ 6S7
3232
750
40
Species
Untreated
1.06 * 0.s3
1.41 f 0.86
33
Mild sitver orotein-treatad
1.00 * 0,75
1,31 f 0.77
24
Table 2.—Number of Eyes in Whiih Cufture Waa Sterile
No, of Eyes That Ware Stbrlle
Type of Eya
Untreated
Mtldsilver protein-treated
Bafore
Preparation
8
7
glass rod. The bloodagar plates wereincubated for aeven days at 35 “C in an
anaerobic jar with a gas mixture of SO%
nitrogen, 10% carbon dioxide, and 10%
hydrogen. The [email protected] agar plates were
incubated in 5% to 10% carton dioxide at
35 “C. After incubation, the colonies were
differentiated
and enumerated by standard bacteriologic procedures.
—
RESULTS
~ble 1 gives the mean number of
+.,.onies and species per subject isolated from untreated and experimental eyes before and after instillation
of this mild silver protein solution.
Although the number of colonies and
species were greater after the preparation than before in both mild silver
protein solution-treated
and untreated
eyes, in no case was the
increase of actual numbers significant
at the 5% level by Student’s t test. The
difference in the amount of increase
of actual number in the untreated eye
as opposed to the mild silver protein
solution-treated
eye also was not
found to be significant at the 5%
level.
of sterile cultures
The pattern
before and after chemical preparation
of the eye is given in Table 2. Of all the
eyes in this study, only three of the 15
that were sterile before preparation
remained sterile after preparation.
The organisms cultured were diphtheroids, Staph @coccus epia%rmtifis,
Propionibactefiurn
acnea, Candida
albicans, and Kleb.siela SP.
—
COMMENT
‘his mild silver protein solution
ginally was intended to be an antimicrobial asent. The colloidal suspension liberates silver ions that alter the
protein in the bacterial cell wall. It
After
Preparation
4
5
No. of Eyaa
That Remained SIerlle
2
1
also has been sumrested that silver
interferes with e;sential metabolic
activity of bacteria.’ The silver in this
mild silver protein solution ionizes
poorly, and thus causes less irritation
than silver nitrate. However, its germicidal effectiveness is also decreased. Pharmacologist
have written that “colloidal silver preparations
are now in a deserved oblivion.”4
Duke-Elder expressed the opinion
that this mild silver protein solution
has “little bactericidal action since
few free ions are liberated.’” Havener
noted that “Argyrol is one of the
poorest germicides.’” None of these
authors cited a controlled study on
humans to support their assertions.
Despi& these negative opinions,
almost a quarter of the 214 ophthalmologist surveyed in a Iarge international study (with a 96%-response
rate) continue to use this mild silver
protein solution in the preoperative
chemical preparation of the eye.*This
investigation, using detailed bacteriologic analysis, was unable tm verify
that the application of this mild silver
protein solution on the eye in vivo waa
significantly better than an untreated
eye in reducing the number of microorganisms on the conjunctival.
Another property of this mild silver
protein solution contributes to its
popularity. This mild silver protein
solution has the capability of darkly
staining mucus or debris present on
the conjunctival, eyelids, or skin. It
therefore serves as a marker for the
adequacy of the preoperative surgical
preparation of the eye. The surgeon
may then irrigati any remaining
mucus and debris from the eye.
Inde~ in the international survey by
Apt and Iaenberg: many ,respondents
commented that they used it mainly
to distinguish mucus and debris in the
preparation. However, this positive
aspect of the tested mild silver protein
solution must be weighed against our
recent finding that irrigation itself
increases the bacterial flora of the
conjunctival (see p 761).
In the design of this study, it was
decided to irrigate the conjunctival of
the eye receiving the mild silver protein solution as is commonly practiced. The control eye received no irrigation in light of our aforementioned
findings. Thus, any increased degree
of antisepsis obtained by the mild
silver protein solution may be offset
by the increase
in bacterial
flora
engendered by irrigation.
A frequently
cited study of the
effectiveness of the tested mild silver
protein solution and other agents is
that of Thompson et al’ published in
1937. Of the ten bactericidal
agents
they studied, our tested mild silver
had the
protein solution
(Argyrol)
second highest percentage of surviving organisms
after one and
minutes of exposure. Although
investigation by Thompson et al
performed on the conjunctive of
ten
the
was
rabbits, doubta about the tiectiveneaa of
our teaf.ed m.ld siIver protein solution
should have been raised at that time.
On the human Conjunctive%our study
did not find a significant bactericidal
effect of this mild silver protein solution when investigated in a masked
faahion.
References
1. Antieeptica, in The Fowmk’rbns [email protected] H~M
Path&ww
lkmmia,
and
l’h.empeedti vol 7, in Duke-Elder S (ad) [email protected]
C$MUX.
p a%.
2 Schset
St Louis. ~
[email protected] 1=
W Argyrol and a [email protected] in Ari
and Arpymi. New York, Yoeeloff Co, 1960, pp
47-5.3
3, Spenmr WH, Garran LIL Contreraa F, et ak
Endogenousand exogenous ocular and systemic
silver deposition. Truns Ophhalmd sac LX
[email protected]&17t-176.
4. Harvey SC Antiseptics and disinfectant
fungicides, sxtoparaaiticidea, in Gitman AG,
GoodmanIS, Gilman A (eds) TAQPAarmwo&
id Basis r/ Therapeutics, ad 6. New York
Macmillan Publishing Co Inq M&l, pp 976-977.
5. Havener Wl+ Germicides, in Ocrdar [email protected]
ed ~. St LQui% CV Mosby &, 197s,
p 42S,
6. Thompson R ham ML, Khoraxo D. A
laboratory study of some antiseptic with referenw to ocular application. Am J OpM&rrol
lmmlw-lm
7. KingJHj Wadsworth JAC. An At&MOf bhtAo4mitSurgfq, ad S. Philadelphi~ [email protected]; &
~W Publiahera IIIC 1961.DS.
:,
through the Copyright
Clearance Center
Chemical Preparation
NOTICE
~y
THK MATERIAL MAYBE PROTECTED~f
COPYRIGHTLAW (TIT& 17, W, CODE)
of the Eye in Ophthalmic
Surgery
II. Effectiveness of Mild Silver Protein Solution
Sherwin Isenberg, MD; Leonard APL MD; Robert Yoshimuri, PhD
●
Although a mild silver protein SOIW
tlon (Argyrol) has been used for a number
of years and is still used by many ophthalmic surgeons, lta efficiency as an antibacterial agent on the conjunctival has not
been scientifically evaluated as part of
the preoperative chemical preparation of
the eye. We studied the effectiveness of a
mild silver protein solution on the conjunctival flora of 32 patients in a masked
fashion. By bacteriologic
analysis, the
mild silver protein solution waa found to
be no more effecUve In reducing the
number of species and cofoniea In the
treated eye than in the untreated eye.
While the mild silver protein solution does
stain mucus and other debris on the aye
to facilitate irrigation, this study did not
demonstrate
a significant bactericidal
effect.
(Arch
Ophthalmol
1983; 101:764-765)
properties
of silver and
Its salts were recognized as early
as the Roman Empire period. Jabir
ibn Hayyan Geber, an .4rabian physician of the eighth century, initiated
the use of silver nitrate on the eye.’
Carl Siegmund Franz Creole began the
prophylactic
application
of silver
nitrate on the eyes of newborn infants
to prevent gonococcal conjunctivitis in
1SS4. After that, silver nitrate was
used for other ophthalmic disorders,
but it was found occasionally to cause
T~era~utic
Accepced for publication Ott 22, 19S2.
From the Departments of Ophthalmolw
(Drs
Isenbsrg and Apt) and Pathology {Dr Yoshimuri), Jules Stein Eye Institute and Harbor-LTCI.A
Medical Center, UCLA School of Medicine.
Reprint requests to the Jules Stein Eye Institute, UCLA %hcml of Medicine, I-m Angeles, CA
90024 (Dr Isenberg).
764
Arch Ophthalmol—Vol
101. May 1983
necrosis of conjunctival epithelial
cells and a gray-black color when light
reduced the salt to its metallic state.
In addition, irritation, scarring of the
conjunctiv~
corneal opacificatiou
and symblepharon occurred. In an
attempt to reduce these problems
Albert C. Barnes, MD, and Hermann
Hille, in lW developed a combination of silver nitra~ and grain protein
(Argyrol)? However, this drug also
caused complications. In 1980, Spencer et al’ reported the clinical and
histopathologic findings in one patient who drank this mild silver protein solution for years and in a second
patient who applied mild silver pr~
tei~ drops to one eye for a long-term
period.
A 20% mild silver protein solution
is available for topical ocular use in
the United States as a silver nitrate
and gelatin colloid. The drug is available also abroad under a variety of
proprietary names and formulations.
lt is classified in pharmacy textbooks
as a local anti-infective
agent.
The antimicrobial
properties of this
mild silver protein solution have been
questioned for years.” To our knowledge, there has been no controlled
clinical study proving the antibiotic
efficacy of this mild silver protein
solution as part of the chemical preparation of the eye before surgery. Yet,
in a recent international
survey of
ophthalmologists,
Apt and Isenber~
found that 22% of the respondents use
this mild silver protein solution on the
conjunctival as part of the preoperative chemical preparation
of the eye.
We, therefore,
conducted a masked
study to investigate the effectiveness
of this mild silver protein solution as
an antimicrobial agent in the preoperative preparation.
PATtENTS AND METHODS
Thirty-two patienta undergoing ophthalmic surgery were studied. No patient had
received preoperative antibiotic therapy or
had an active infection at the time of
surge~.
All subjects had the identical regimen of
preoperative preparation. Initially, a stmile anaerobic transport swab was applied
to either the inferonasal or inferotemprrsd
conjunctival
fornix
ofoneeyeandasecond
swab was aDDlied to the conhnctiva of the
same quad;~nt in the second eye. Twenty
microliters (1 drop) of 20% mild silver
protein solution then was instilled in the
inferior conjunctival fornix of one randomly selected eye. This eye may have been the
eye that was operated on when unilateral
ocular surgery was performed. Hexachlorophene soap was applied equally to both
eyelids, eyelid margins, cheeks, nose, eyebrow, and forehead- The inferior fornix of
the eye into which the mild silver protein
solution had been instilled was then irrigated with a normal saline solution, while
the other eye had no irrigation.
Gauze
spongesmoistenedin a saline solution
were used to rinse areas bearing hexachlorophene. Next, the quadrant of each inferior conjunctival fornix not previously cultured was cultured with a third and fourth
sterile anaerobic transport
swab. The
choice of which portion of the fornix was
cultured before and after the preparation
was randomly assigned. Nursing personnel
coded each specimen hefore bacteriologic
analysis. The microbiologist had no know[edge of the exact origin of the specimen.
The swab was washed three times in 0.5
mL of Schaedler’s broth and wrung out by
pressing it along the sides of thetube.
The
swab was cultured
in 10 mL of Schaedler’s
broth. Blood and chocolate agar each were
inoculated with 0.1 mL of eluant and
spread on the surface of the agar with a
Silver Protein —Isenberg et al
Table 1.—Mean Number of Coloniis and Species of Bacteria
Ieoiated oar [email protected]
[
Mean t SO
Seforo
Eyo
Cobriea
t--
F
I
Untreated
Mitdsilver protein+reated
Untreated
Mild silver womin-treeted
Prepsratfon
1S3 f 425
231 k SS7
l.oe t 0.s3
1.06 i 0.75
Tabte 2.—Number of Eyea in Whii
After
Preparation
234 * 571
323 k 730
1.41 ~ 0.86
% of
Increase
55
40
33
1.31 * 0.77
24
Cuffura Waa Sterile
I
No. of Eyes That Woro Sterno
Type of Eye
Untreated
htifdsilver Protein-trealed
Before
After
No. of Eyea
Preparation
8
7
Preparation
4
5
That Remained Sterile
2
1
also has beeri suggested thatsilver
interferes with essential metabolic
activity of bacteria.’ The silver in this
mild silver protein solution ionizes
pcdy, and thus causes less irritation
than silver nitrate. However, its germicidal effectiveness is also decreased. Pharmawlogista have written that “colloidal silver preparations
RESULTS
are now in a deserved oblivion.’”
—.
themeannumberof Duke-Elder expressed the opinion
- lble 1 gives
Jnies
andspecies
persubject
iso- that this mild silver protein solution
lated
fromuntreatid
andexperimen-has ‘little bactericidal action since
few free ions are liberated.’” Havener
taleyesbefore
andafter instillation
noted that “Argyrol is one of the
of this mild silver protein solution.
poorest germicides.”$ None of these
Although the number of colonies and
authors cited a controlled study on
species were greater after the prepahumans to support their assertions.
ration than before in kth mild silver
Despite these negative opinions,
protein solution-treated
and unalmost a quarter of the 214 ophthaltreated eyes, in no case was the
mologists surveyed in a large internaincrease of actual numbers significant
tional study (with a 96%-response
at the 5% level by Student’s t test. The
rate) continue to use this mild silver
difference in the amount of increase
protein solution in the preoperative
of actual number in the untreated eye
chemical preparation of the eye? This
as opposed to the mild silver protein
investigation, using detailed bacteriosolution-treated eye also was not
logic analysis, was unable to verify
found to be significant at the 5%
that the application of this mild silver
level.
protein solution on the eye in vivo was
The pattern of sterile cultures
significantly better than an untreated
before and after chemical preparation
eye in reducing the number of microof the eye is given in Table 2. Of all the
eyes in this study, only three of the 15 organisms on the conjunctival.
Another property of this mild silver
that were sterile before preparation
protein solution contributes to its
remained stmile after preparation.
popularity. This mild silver protein
The organisms cultured were diphsolution has the capability of darkly
theroids, Staphylococcus epidermidis,
staining mucus or debris present on
PrOpiOnibactm”um
acnea, Candida
the conjunctival, eyelids, or skin. It
a.lbicanq and Klebtila sp.
therefore serves as a marker for the
COMMENT
adequacy of the preoperative surgical
‘his mild silver protein solution
-—
preparation of the eye. The surgeon
ginally was intended tQ be an antimay then irrigate any remaining
microbial agent. The colloidal suspenmucus and debris from the eya
sion liberates silver ions that alter the
Indeed, in the international surwey by
protein in the bacterial cell wall. It
Apt and Isenbergj’ many respondents
glass rod. The blood agar plates were incubated for seven days at 35 “C in an
anaerobic jar with a gas mixture of 80%
nitrogen, 10% carbon dioxide, and 10%
hydrogen. The chocolate agar plates were
incubated in 5% to 10% carbon dioxide at
S5 “C. After incubation, the colonies were
dMerentiated
and enumerated by standard bacteriologic procedures.
-M
Ophfhalmd-Vd
101, May 19S3
,-
commented that they used it mainly
to distinguish mucus and debris in the
preparation. However, this positive
aspect of the tested mild silver protein
aoiution must be weighed against our
recent finding that irrigation itself
increases the bacterial flora of the
conjunctival (see p 761).
In the design of this study, it was
decided to irrigate the conjunctival of
the eye receiving the mild silver protein solution as is commonly practiced. The control eye received no irrigation in light of our aforementioned
findings. Thus, any increased degree
of antisepsis obtained by the mild
silver protein solution may be offset
by the increase in bacterial flora
engendered by irrigation.
A frequently cited study of the
effectiveness of the tested mild silver
protein solution and other agents is
that of Thompson et al’ published in
1937. Of the ten bactericidal agentk
they studied, our tisted mild silver
protein solution (Argyrol) had the
second highest percentage of surviving organisms after one and ten
minutes of exposure. Although the
investigation by Thompson et al was
performed on the conjunctival of rabbits, doubts shut the effectiveness of
our t.eded mild silver protein solutioit
should have been raised at that time.
On the human conjunctiv~
our study
did not find a significant bactericidal
effect of this mild silver protein solution when investigated in a masked
fashion.
References
1. Antiseptics, in [email protected] Hwc&, P-,
~
and
vol 7,in Duke-Elder S (cd) [email protected]
?’herape.die+
of--..%
~ui% m Moeby CO.I*
p 635.
in Art
2 Schaet W Argyrol and a byprodq
and Arpprd New York Yeaeloff Co, 1S60, pp
47+3.
S.Spencer WH+Garron
LK, Contreraa F, et ak
Endngencw and exogenous ocular and systemic
silver deposition. ?’rana OpMhuhnoI Sac UK
lSfW,100IT1-17s.
4. Hamey SC Antiaeptica and disiafectanta,
fungicides, ectoparaaiticides, in GiIman AG,
GoodmanIS, Gilman A (eds) The Phnrtnacdw
id
B&r & 7?wm&ics, ed 6. New York.
Macmillan Publishing Co k. 1SS0,pp 976-S77.
5. Havener W
Germicidq in fkxlar [email protected] d 4- St Loui& CV Mosby Co, 1S7S,
p 425.
6. ‘1’hompwnR, Iaaaca ML+ Ehoraao D A
Iaboratov study of anme antiwptica with refer-
ocular application. Am J Ophihalmol
[email protected]&
7. Kiw~
Wadawortb JA12 An Atlaa Of @&
fAalmu SwperU, ad S. Philadelpb]& Harper &
Row Publishers Irq 19S1,p S.
& Apt I+ Iaenberg & CbemicaJ preparation of
skin and eye in ophthalmic surge~ An interna19SSJS1O%
tional Urrzy. ophthalmic su~
..
’.,/ >’.-’....:..
[email protected]
ence b
1
I
I
;,
--,
_—_ ,
Chemical Preparation
of Skin
and Eye in Ophthalmic
Surgery:
An International
Survey
I
Leonard
Apt,
Sherwin
Isenberg,
~c~f~~
THIS MATERIAL MAY 8E PFK)TECTEDBY
COPYRIGHTLAW (TITLE 17, U.S. CODE)
M.D.
MD
SUMMARY
We surveyed
chemical
of agents
the skin
Thecon]unctwa
reconsider
Ince
the
have
known
sweat
soaked
Almost
In 1875,
are found
carbolic
wasthefirst
asepsls
other
of the
half
layers
form,
or
attempt
at
techniques
operative
Today,
[n the course
reasons
and
rationale
many
of training
In ophthalmic
Inst!tutlon
s, one often
In preoperative
main
tradltlon
dlfferen[
field
the
rarely
chemical
g!ven
for
ophthalmologists
determine
exists,
choice
survey
literature
quesllons
regimen
world
Thlslnformatlon
deflnltlvely
about
of
and
[o
percent
of the
known
ophthalmic
lSnO[f OIJnd
method
first
to
and
of agents
AND
Quest{ onnatres
which
214 were
METHODS
were
mailed
The
answered
and returned
This return
of
rate is
of appllcatlon,
From
rhe
Deparrrnenr
UCLA School
of
Oph(hJ/mo/ogk’
of Meci(c{fre,
Ju/eS
Los Angeles,
Sre/n
Eye
Calt[orn{a
Requesrs
Cal/fern/a
1026
{or repr,nrs
should be addressed
Sre/n Eye Inst,tu?e,
90024
UCLA School
ro Leonard
of Med(clne
Ap[, M D,
Los Angeles,
hal
by wld
answered
Argentina,
Germar
Canada,
quest!ons
the
area
second
additional
the
series
placed
asked
asked
concerned
to the skin,
of
the durat[on
face
recelvlng
of questions
dealt
duratl
on the conjuncttva,
was used as the rinsing
what
proportion
by a physlclan,
nurse,
comments
of the
or other
were
agent
preparatf
nonphyslcla
requested
RESULTS
There
was
considerable
of agents
dlsparlty
placed
In
the
on the sktn (Table
respondents
used
by 16 5%, and aqueous
126°6
regimen
somewhere
of all,
Iodine
solution
in the preparation
used
by a third
types
1 ) Howet
produ
povldone-lodlne
(as Betadine
Isodlne,
prepodyne,
Septodyne}
In the preparation,
while hexachloroph
ene(p
pov!d~ne-lodlne
Jutes
and
ophthalmology
were
applled
and what
question
used
[nst/ture.
of
Intentionally
67 5% of the
to 221 ophthalmologists
Institutions
of
ab
well -kno
from such forelgncountrles
Japan,
series
application
sequence
MATERIALS
to
and Switzerland
and
Finally,
sample,
sent
at academic
of solutions
done
were
surgeons
appltcatlon,
third
representative
a
practitioners
Belglum.
to
of action.
questionnaires
Brtaln,
The
Most
of the
ophthalmologist
to obtain
surgeons
to
by the
Review
ques!ionnalres
private
was
regtmen
was no\ Intended
the best
the
prominent
solutions
A scientific
on a speclflc
Thesurvey
are
nurse.
ophthalmic
Mextco,
solution
and duration
the
sequence
the eye
the preferences
the
a consensus
we undertooka
answer
To learn
throughout
whether
in the ophthalmic
a cerlaln
of effectiveness
mentioned
IS
or
sees different
preparatlonof
using
impression
surgery,
the
cause
of
Great
vtsltlng
techniques
should
a wide
applied
on fhecon]unctlva
than
spectrum,
While
agent
saline
(Argyrol)
rather
of preoperatwe
popular
96 8“A, In order
surgeons
and deeper
methods
was achieved.
orrinsedwltha
pr~
reported
effectiveness,
in hair follicles,
acid In spray
Subsequently,
preoperative
agents
evolved
when
The
for their
and laid on !heskln,
antisepsis
achlevtng
have
of the
agents
Eberth
ignored
by the physician
pitfalls
their
rate
was the most
used mild silver
is performed
and In both the superficial
in gauze
usual lywaselther
a quarter
to learn
A 96 8% return
pov!done-lodtne
and
bacteria
Llster’s
reported,
[hese
of Carl
that
Joseph
preoperative
for
studies
glands,
of the skin.’
was
preparation
advantages
worldwide
of eye and skin.
diversity
of the
s
ophthalmologists
preparation
respondents.
I
214
The
of the
somewb
Hiso Hex)
used
was
most
frequ
respondents,
on the skin followed
by a rlns[
Includes
sallne,
sterile
wa
“rinse”
solutlon
alcohol
The
lactated
Ringer
term
solution,
product
(Figure
1 ) Half
balanced
salt solution,
of the respondents
used
DECEMBER 1982, VOL
or slm
a sir
3, N
—-
..
,---.
TABLE
--——
1
ROUTINE OF CHEMICAL
AGENTS
USED FOR SKIN PREPARATION
(n=196}
Mulr)ple
Percenl
Agents
Powdone.lodtne
soap – rinse”
Powdone-rodlne
solution
-
Soap - rinse
-
150
: alcohol
Povldone-rod[ne
Hexachlorophene
73
= alcohol
– Povldone-lodlne
or rinse
= alcohol
Soap = rinse z alcohol
73
or rinse
40
= rinse
39
Soap z rinse = Iodfne = alcohol
Hexachlorophene
- rinse
-
}odfne = alcohol
24
Hexachlorophene
- rinse
-
merthlolate
15
Powdone-)odlne
Alcohol
- rinse
Powdone
-
Single
I
solutlon
- rinse or alcohol
—
I
10
– Iodine
ii
“+%
10
Iodtne
Agen~s - Rinse or 41cohol
IGURE
325
Powdone-lodlne
Iodine 1%
48
Hexachlorophe/
43
7ephiran
_.—_,
lorhexidene
7 IAp( and lsenberg)
particular
chemical
agent
Percentage
of respondents
II
using a
‘
on the sk(n as part of the preopera?we
\
29
Om
1
24
10
,tierfen
Merth,ola!e
10
Alcohol
10
10
Don’! know
‘Rtnse
=
soluffon,
saline
balanced
solut(on,
sterile
salr solu!fon,
TABLE
wafer.
iacraled
or similar
Ringer
product
—-—
2
,
CHEMICAL AGENTS INTENTIONALLY
ON THE CONJUNCTIVAL
(n=206)
_-——
Chemtcal
Normal
PLACEO
0
‘!
Percent
Agent
267
Argyrol
:
223
rinse
Balanced
salt solutlon
53
Betadtne
solul,on
24
Neosporln
Idllutedi
20
z rinse
15
solu[lon
Chlorhexldlne
Sler,le
wafer
Chloramphen, col
Mercury blchlortde
F.nramycin
.-——..
~ Gentamycln
SURGERY
——
2 {API and lsenbergj
chemical
preope,attve
agenr
Percentage
on
lhe
of respondents
conjunct(va
as part
us!ng a
of the
preparation
I
primary
10
or a povldone-lodtne
05
while
05
or d!d noi answer
FIGURE
particular
10
10
10
05
mIx
, know
—.
8 de ferreti
PHTHALMIC
I
—
34 !5
Sallne
No!hlng
Ringer
J
agen[
half
{such
used
The amount
as aqueous
product)
a combination
of lime
skin varied from
vartatton
In the
that
Iod!ne,
followed
these
hexachlorophene,
by a rtnse
of prtrnary
agents
agents
were
or alcohol,
(Table
1)
applledto!he
i
,i
one second to several minutes
So much
Ieng!h
of time was repor!ed
as to make
I
*
1027
k’
!%
CHEMICAL
--%
----.-,
PREP OF EYE
1
!
I
u)
1-
tl
a
z
g
0
w
a
“/. PHYSICIAN‘/. NURSE
FIGuRE
O
100
3 (Apt and Isenberg]
50
50
Relat]ve
proporoon
of pfr ysiclans
compared
100
0
with nurses per form(rrgpreoperativ
preoperative
TABLE 3
dents
tlon,
HOW MUCH IS DONE BY PHYSICIAN
REL4TIVE TO NURSE
(n=205)
preparation.
indicated
that
Sixty-two
preparation
percent
the physlclan
29°4 reported
while
epreparatlon
that
nurse
The rest of the respondents
physician
and nurse
and Figure
of the respon -
does the entire
the
J
oflhe eve
prepara
does the en!lre
answered
that the
each do part of the preparation
{Table 2
3).
Percent
PhysicIan ‘Nurse
COMMENT
100”6 /
98°~/
o
620
90°’0
10°6
80°b
20°6
75%
2536
50”0. 50”’0
25°,
75”6
20”b
80”6
15°6
85°6
10%
90°6
100”0
0
No! known
_——
9 deferred
The
05
05
10
10
29
15
05
05
44
206
younger
and senior
the validlty
While
all
recent
universally
The facial
the forehead,
both
areas
mention
eyellds,
were
the cheeks
what
agents
on the
quarter
tlva
conjunctlva
solutton,
water
antlmlcroblal
(Argyrol)
IS
In general,
1028
surgeons
while
of [he respondents
Forty-two
sallne
sterile
.—-..
ophthalmic
percent
Intentionally
others
do not (Table
place
simply
place
nothing
rinse
!he
this
solutlons
2)
About
on the conjunc
conjunctlva
Of the
latter.
by far the mos! frequently
more
physicians
than
mild
used
nurses
silver
different
were
with
protein
(Figure
perform
topic
-
the
of this
a form
found
these
and hexachlorophene
!echnlques
experimentally
five
had to obtain
scientific
were
by merthlolate
advent
of
and then
DECEMBER
soap am
by elthe
and
sttll
r
fiw
or aqueou!
followed
Iodine
agent:
r ~ld [ha
the opera’
and sallne
tht
Th~
interest
compared
techniques
1 106 of the respondents
The
nurse
n the chemical
or aqueous
In the 1960s
not know.
surgical
and Mlchler
or followed
chloride
about
the
for sterlllzlng
: These
was exhlbltedb,
of theoperatlvef(eld
study
Maumenee
chemlca
has been llttl~
that theydld
a lack of recent
todlne,
our survey,
[c
In the ophthalmfr
surgeons
usually
either
benzalkonlum
alone
replled
In this
techniques
~hen popular
subject
In this subject
others,
lndlcates
In 1951,
satlsfac
of
there
used In preparation
saline,
these
2)
use
who
survey,
from
also
a
balanced
salt solutlon,
Ringer solullon,
or
Only
31?’. use a Solutlon
bearing
any
properties
this
disparity
chosen
Some
or study
ophthalmologists
great
and the
nose
The highly
survey
some
Information
almost
sub-
academ~ctans
foreigners
acc
(96 8°6) also attests
questionnaires
A lack of Interest
were
by the broac
Includlng
ophthalmologists,
Americans
and
for the eye prior to surgery,
literature
treated
enhanced
contacted,
ophthalmologists
preparation
05
was
ophthalmologists
of this
To answer
dlfflcult
survey
tory rate of returned
or did no( answer
conclusions
of this
of ophthalmologists
speclallsts
and general
and nonacademlc!ans,
294
——
validity
spectrum
alcohol
Ir
used one o
povldone-lodlne,
clinically
1982, VOL
firs
In lhe earl!
t3, NO 1
. ..
---——
----~——
--——-- ..—
.——-—
——
-——-—
_.
---———
. ..——
APT & ISENBERG
i’
‘,
..
~_
—
I
70s,
changed
‘-’ In fact,
~lsts
the
this
techniques
survey
of
showed
many
surgery.
ophthalmolo-
that povidone-lodlne
is
The
enhances
10 prevent
country
fissure
Povidone
(polywnylpyrrolidone)
properties
two thirds
released
iodine
remains
cause
and Inflammatory
But if iodine
is combtned
been
shown
solutlons
to
be
within
and enough
against
and
There
to the
Ignore
conjunctlva
presumably
31%
of the
on the
ophthalmologists
on. the conjunctival
w,glnal
debris,
which
If
these
chemtcals
skin,
onlo
place
a vasoconstrlctor
others
or scrub
antimicrobial
to avotd
such
IS used,
could
Potentially
mlnlm!ze
thts
problem.
as naphazol~ne
wtll
the
phene,
acllvlly
as used
!ha!
by some
surgeons,
effec!lve,
has Iltlle
Iavage,
and
found
the
bathing
was
implants
not
implants
q In
deter-
routine
1,
intra -
usually
the
Infecting
.’” They
felt
that
the
at the site of the
more emphasis
conjunctwa
might
did
Kreissig
on
contamination
Perhaps
and
scleral
Lincoff,
culture
was
soap scrubs,
chlorarnphenicol,
organism
ultimately
should
be placed
Sterilization
decrease
the
of
the
Incidence
of
endophthalmitis
2
Maumenee
AE, M)chler
after
surgery
ocular
Ktffney
4
of the operative
field
Trans Pac Iftc Coast 0tor5phfha/rno/
Soc
Chase
5
RC
Steril,ty
AC Pov!done-lodtne
Saggers
PP
1970,
BA,
1966,
asanophthalmtc
17434-436
Iodophosphors
and
skin asepsls
Ann
12312.317
Stewarl
GT
Polyv!nylpyrrol
of ant, -bacterial
actlwty
ldone-lodlne
J Hyg (Carob)
an
1964,
62 509-51B
6
Fahmy JA Bacrerlal flora In relatlon to cataract extraction
V
conjunctival
Effects of topical antlbiot!cs on the preoperative
flora
vaso 7
puptl,
8
Acts
Browning
1955,
antlmlcroblal
RC, Ellls
assessment
lead to
Ha[taway
Surg Forum
Ophrha/mo/
from
of hexachloro
GTJr,
antiseptic
not
appllcallon
Lincoff,
of
ophthal-
preoperative
rate of infected
scleral
operation.
coworkers
Eberth C Vwchows Arch.. Bd 52, 1875 As quoted In Wheeler
ES The development
of anttseptlc surgery Am J .Su~g 1974,
of
hexachloroph ene should
af least dal Wbeglnn[ng flvetoseven
days prlorto
To be maximally
be applied
a single
infected
and
preoperative
saline
with
same
of infection
of any preoperative
1
3
either
agalnsl
to know
to
to avoid
1951,32172-179
Hexachlorophene
IS bacterlosta~lc
and IS more effective
gram -posll!ve
than gram -negative
baclerla
II IS
imporlant
three
Hahn,
sterilization
and after
Some
WIII dilate
regard
127573-579
One could
before
tn
agents
REFERENCES
dilatlon,
thts could
with
I
organic
IS used
of action
Lincoff
including
their
the
infectious
eye.
an extensive
implants
conjunctival
that
entry
result
IS incised
as phenylephrlne
buckle
on
or simple
Vascular
activity
as to the efficacy
conjunctival
in
source
of practical
agent,
damage
that
and other
Inadvertent
conjunctlva
corneal
study,
mined
of chemicals
comments
other
often
use multlple
duration
In
benzyl-
used
properties
combinations
and
that
alter
a later
agent
agents
bytrrlgatton,
on the conjunc!iva
to
such
mucus
who
preparation,
Iavaging
operative
IS
removed
if the conjunctlva
hemorrhage
but
commented
the
mic preparation,
significantly
used,
blood,
which
individual
of the
in one study
povldone-~odine
Only
exists
preparation
and
of the
most commonly
doubt
either
of Its antlmicrobtal
[nsttllation
more
IS
their
IS incom-
not be placed
In addition,
by
material
palpebral
epitheliums.”
chloride
on skin.’
inactivated
spectrum,
the
should
Ophthalmologists
of the
Whether
or regrowth
Individuals
If a soap
the
In
or permits
used antimtcrob~al
some
another
preparation
Some
chemical
antibiotics
surgery
entering
not be
be taken
overlap
However,
drug
It statns
be careful
soap or detergent
while
bacteria
d{ fferent
and posstble
constrlctors
to surgery
is
should
to the corneal
benzylkonium
and cotton
produced
Care should
therefore
it, even
reconsider
even
debris,
action
theconjunctiva.
who
because
the
should
dilute
Irrtgatlon
used topical
was the agent
because
as povldone-lodlne,
one
other
bacteriostatic
are tndlcated
h},peremla,
prior
have
Some
the
soap,
should
effectiveness,
use of an antimicrobial
then can be specifically
10 sterlllze
importance
the
a
by those
used
reviewing
used
or
it
antimicrobial
of resistant
and not necessarily
In
mucus
just
of surgery
was
Irrigate
the
may
‘ Argyrol
Argyrol
are
that
and
with
soap,
has
proper
preparation
noted
iodine
chloride
ma~erial,
then
Alcohol
from
it IS injurious
its application.
ophthalmologists
in the days precedtng
on the conjunctlva
time
In
the
tt is effective
merely
truly sterilizes
bacteria
controversial
at the
or
conjunctival
growth
konlum
of the respondents
lndtcated
some
:tive
twothlrds
significant
reports
‘atter practice
solutions
problems
G[ven
time,
among
remove
any
agent
-
contact
viru’tidal
‘
preoperative
than
would
not bear
dtrect
found
Immediate
More
would
these
and
contact
consensus
conjunctlva
the
state and
Povldone-todlne
wtro
It has been
corneal
effects.
hexachlorophene
with
and
hexachlorophene
the hexachlorophene.
because
patible
In the conjunctlva.
powdone
in
surAbout
spores
is more
regard
sktn
the
bactericidal
concentration
fungt
Aqueous
to
magnitude
mlnu!es
w!th
lodlne
activity
changes
with
and of lesser
with
In the elemental
toxicity
eplthellum,
less common
easily
for antibiotic
can
a polymer
IS
combines
of the Iodtne
IS slowly
of
that
of
Its antimicrobial
used to remove
currently
the stngle most popular agent for use Inchemlcal
preparation
of the skin prior to ophthalmic
surgery in this
factant
film
9
ph ystc{an’s
L!ncoff
in fecled
10
1980,
58567-575
kerat{fls
Arch Ophfha/mo/
53817-824
Economics
-
Ophthalmol
CW, L!ppas J pHlsoHex
Desk
Co
Reference,
1980,
H, Nadel A, O’Connor
scleral
[m Plant
ed
7
Oradell,
Medical
p 1859
P The changing
Arch Ophrha(mo/
charac[erof
1970,
[he
84 421426
Hahn YS. L!ncoff A, Llncoff t-, et al Infect Ion after sponge
lmplanta~lon
for scleral buckllng
Arn J Ophrha/mo/
1979.
~‘
87 180-t85
_—_
8
I
i
I
OPHTHALMIC
SURGERy
1029
1
‘1
I
‘
“;
A. INGREDIENT NAME:
MYRRH GUM TINCTURE
B. Chemical Name:
C. Common Name:
Myrdq Gum Myrrh
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
—-_
(Test Description)
pH
Specific Gravity
Alcohol Content
Color
odor
Taste
(Test Results)
6.13
.8352
87.23’%
Brownish Red
Aromatic
Bitter
E. Information about how the ingredient is supplied:
Brownish red clear volatile liquid, with balsarnic-aromatic
odor and bitter taste.
F. Information about recognition of the substance in foreign
pharmacopoeias:
Aust., Belg., CM., Ger., Jap., Neth., Port., Span., and Swiss.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Ti~ J. and Shi, S. Constituents of essential oil of imported myrrh and gum opoponax.
Chung Kuo Chung Yao Chih, 1996; 21(4): 235-237,256.
H. Information about dosage forms used:
Liquid
—
—
I.
Information about strength:
2-5ml
J. Information about route of administration:
Applyto indolent ulcers, sore gums, sore mouth and ulcerated sore throat. Administer
internally as a carminative and externally as a protective.
K
Stability data:
L. Formulations:
See compound formula on page 458 to make 1000mL Please see various lists of
formulations in the file.
M. Miscellaneous Information:
—_
Page -2-
——
CERTIFICATE
Item
Code:
06151
MYRRH
OF ANALYSIS
J
GUMTR
NF XI 1:0. ~
=
TEST
------
DESCRIPTION
---
y~”/$Y<
#?bY?c
Lot #: 6-2049
)bo,~
MINIMUM VALUE
MAXIMUM VALUE
- - - - - - - -- - - - - - - - - - - - - - -- -- - - - - - - - - - - - - - - - - -
G;Gmvlm
6.5
.87
88%
BROWNISH
AROMATIC
BITTER
:82
ALCOHOL CONTENT
83%
COLOR
BALSAMIC/
2
D
0.6
TEST
RESULT
------
------
--
87.23%
RED
?!!!$
I
--- ......
/
QUALITY CONTROL REPORT
74-
CHEMICAL
:MYRRH
NAME.
MANUFACTURE
LOT
No.
GUM TINCTURE
NF
:6-2049
PHYSICAL
SPECIFICATION
TEST
STANDARD
TEST
/MERCK——/NF
.:USP —. /BP
/MART._/CO.SPECS._.
I)DESCRIPTION.:
6
BROWNISH
RED CLEAR
AND BITTER
TASTE.
2)SOLUBILITY.:
INSOLUBLE IN
WATER;
Vo IATILE
MISCIBLE
LIQUID;
WITH
WITH
BALSAMIC-AROMATIC
ODOR
ALCOHOL.
3)MELTING POINT.:
GRAVITY.
4)SPECIFIC
:0.820-O.870.
5)IDENTIFICATION
.:
A)A SOLUTION
PH IS
PASSES.
5.5.
FAILS.
:
:
COMMENTS. :
SIGNATURE.
ANALYST
PRJZPACK TEST. :
RETEST.
:
DATE. :
:
DATE. :
DATE .:
INITIAL.
INITIAL.
:
:
ELI I.lLLY AND -- MYRRH TINCTURE. TTO059
—=
—=
_-
ELI LILLY AND -- MYRRH TINCTURE, TT0059
MATERIAL SAFETY DATA SHEET
NSN: 650500N066420
Manufacturer’s
CAGE: 75602
Part No. Indicator: A
Part Number/Trade Name: MYRRH TINCTURE, TTO059
..== =.=. .=.= =.=. .==. ==== .=== ==== .=== ==== ==== ==== ==== ==== ==== ==== ==== ==== ===
General Information
..=.= ..=.= =. .=. ==.=.= ...== =.= == ===== === =.= =. .====== .= ...== =..== === ..==== ===
Company’s Name: ELI LILLY AND CO
Company’s Street: LILLY CORPORATE CENTER
Company’s City: INDIANAPOLIS
Company’s State: IN
Company’s Country: US
Company’s Zip Code: 46285
Company’s Emerg Ph #: 317-276-2000;800-424-9300
(CHEMTREC)
Company’s Info Ph #: 317-276-2286
Record No. For Safety Entry: 001
Tot Safety Entries This Stk#: 001
Status: SMJ
Date MSDS Prepared: 23AuG90
Safety Data Review Date: 14DEC95
MSDS Serial Number: BZRXL
==.= ==.= =..= =.=. ===. =.== ..== ==== ==.= ==== ==== =.=. .==. ==== ==== ==.= ==== ==== ===
Ingredients/Identity
Information
...= =.== ...= ..== ..== ==== .=== =.== .=== =.== ==== ==== ==== ==== ==== ==== ==== ==== ===
Proprietary: NO
Ingredient: RESIN; (S.E. MYRRH) . LD50:(ORAL,MOUSE)
13.9 ML/KG.
Ingredient Sequence Number: 01
Percent: 6.6
NIOSH (RTECS) Number: 100025ORE
OSHA PEL: N/K (FP N)
ACGIH TLV: N/K (FP N)
--.---------.-------— ---------------Proprietary: NO
(ETHANOL). LD50: (ORAL,RAT) 6.9 ML/KG.
Ingredient: ETHYL ALCOHOL;
Ingredient Sequence Number: 02
Percent: 86
NIOSH (RTECS) Number: KQ6300000
CAS Number: 64-17-5
oSHA PEL: 1000 PPM
ACGIH TLV: 1000 PPM
------------------------------------Proprietary’: NO
Ingredient: FIRST AID PROC:DRINK 1-2 GLASSES OF WATER & GIVE 1-2 TBSPS OF
SYRUP OF IPECAC TO INDUCE VOMIT/GIVE ANYTHING BY (ING 4)
Ingredient Sequence Number: 03
NIOSH (RTECS) Number: 9999999ZZ
OSHA PEL: NOT APPLICABLE
ACGIH TLV: NOT APPLICABLE
-—----—-.----——--------------——-——-Proprietary: NO
Ingredient: ING 3:MOUTH TO AN UNCONSCIOUS PERSON. IMMEDIATELY TPJ+NSPORT TO
MEDICAL CARE FACILITY & SEE MD.
Ingredient Sequence Number: 04
NIOSH (RTECS) Number: 9999999ZZ
OSHA PEL: NOT APPLICABLE
ACGIH TLV: NOT APPLICABLE
===. .=== =.== ==== =.== .=== ==== ==== ==== ==.= ==== ==== ==== ==.= ===. ==== ==== ==== ===
Physical/Chemical
Characteristics
..== ==== =.=. ==.. .=== ==== ==== ==== ==== ==== ==== ==== ==== ==== ==== ==== ==== ------------HYDROALCOHOLIC
SOLUTION; SWEET,
Appearance And Odor: CLEAR, REDDISH-BROWN,
PUNGENT ODOR.
Vapor Pressure (MM Hg/70 F) : SUPP DATA
Specific Gravity: 0.8344
Evaporation Rate And Ref: NOT APPLICABLE
Volubility In Water: MISCIBLE
-----.=.. .=.. .=== ===. .=.= ==== ==== ==== ==== =.== ==== ==== ==== ==== ==== ==== ==.= =-----Fire and Explosion Hazard Data
.==== ===== ===.= =.=== ===== ===== ===== ===== ===== ===== ===== ===== ===== ===== =====
Flash Point: 153F,67c
Page 1 of 3
ELI I.lLLY AND -- MYIUUi TINCTIJRE,
TTO059
Flash Po~nt Method: CC
Extinguishing Media: USE WATER, CO*2, DRY CHEMIcAL, FOAM OR HALON.
Special Fire Fighting Proc: USE NIOSH/MSHA APPROVED SCBA & FULL PROTECTIVE
EQUIPMENT
(FP N) .
Unusual Fire And Expl Hazrds: VAPORS ARE HEAVIER THAN AIR & MAY TRAVEL A
CONSIDERABLE DISTANCE TO SOURCE OF IGNITION & FLASH BACK. FLAMMABLE (FLASH
POINT BELOW 100F, 37.8C) .
.......= ..=== =. === ==== ==== === ===== === == ============= === ===== == ========= === =
Reactivity Data
.—.-.—————---————— .....=..== ....= .=.=. ..==. ....= .....==..= ===.= =..=. ===== ==
Stability: YES
AT NORMAL TEMPERATURES
k PRESSURES.
Cond To Avoid (Stability) :~TABLE
Materials To Avoid: MAY REACT VIOLENTLY W/STRONG OXIDIZING AGENTS, STRONG
ACIDS & BASES.
Hazardous Decomp Products: MAY EMIT TOXIC FUMES WHEN HEATED TO
DECOMPOSITION.
Hazardous Poly Occur: NO
Conditions To Avoid (Poly) : NOT RELEVANT
......==.. ..........===== =.=== ===== ===== ===== ===== ===== ===== ===== ===== =====
Health Hazard Data
—————-.--——————
......=.= =. =.= ======== === === ======= ==== == ===== === ===== ===== =-——---—-—————-—
LD50-LC50 Mixture: SEE INGREDIENTS.
Route Of Entry - Inhalation: YES
Route Of Entry - Skin: YES
Route Of Entry – Ingestion: YES
Health Haz Acute And Chronic: NONE REPORTED, COMPONENTS MAY PRDCE SIGNS 6
OF LG VOLS MAY CAUSE IRRIT
SYMPS AS INDICATED. ETHYL ALCOHOL:INH?L/INGEST
OF RESP TRACT, DROW, NAUS, MUSCLE INCOORD, VISUAL IMPAIRMENT, SLOWED RXN
TIME, SENSORY LOSS, SLURRING OF SPEECH, STUPOR/POSS COMA s DEATH. BASED ON
ANIMAL DATA, MAY BE IRRIT TO EYES & (EFTS OF OVEREXP)
Carcinogenicity
- NTP: NO
Carcinogenicity
- IARC: NO
Carcinogenicity
- OSHA: NO
Explanation Carcinogenicity:
NOT RELEVANT
Signs/Symptoms
Of Overexp: HLTH HAZ:& SKIN. ANIMAL TOX:ACUTE: INGEST:ING
I:ATAXIA, SEV LETHARGY, DECR BRTHG, LABORED BRTHG, HYPOACTIVITY,
ING Z:COMA, ATAXIA, LEG WEAK, REDUCED ACTIVITY,
HYPERACTIVITY.
CLEAR OCULAR DISCHARGE, SALIVATION,
CHROMODACRYORRHEA,
CHROMORHINORRHEA,
VOCALIZING.
INHAL:TNG 2:CORNEAL OPACITY, ATAXIA, REDUCED ACTIVITY, (SUPDAT)
Med Cond Aggravated By Exp: ETHYL ALCOHOL - INGESTION, OF LARGE VOLUMES,
MAY AGGRAVATE CIRRHOSIS OF LIVER, HYPERSENSITIVITY
TO ALCOHOL &
GASTROINTESTINAL
ABNORMALITIES
(PEPTIC ULCERS, GASTRITIS) .
Emergency/First
Aid Proc: EYES:HOLD EYELIDS OPEN & FLUSH W/STEADY, GENTLE
IMMED.
STREAM OF WATER FOR AT LST 15 MINS. SEE OPHTHALMOLOGIST/MD
SKIN:REMOVE CONTAM CLTHG & CLEAN BEFORE REUSE. WASH ALL Expos AREAS OF SKIN
W/PLEN’TY OF SOAP & WATER. GET MED ATTN IF IRRIT DEVELOPS. INHAL:MOVE
(MOUTHINDIVIDUAL TO FRESH AIR. IF NOT BRTHG, PROVIDE ARTF RESP ASSISTANCE
TO-MOUTH) & CALL MD IMMED. INGEST:CALL MD/POIS CTL CTR. (ING 3)
-----——------——---.-———------—————-----——--.=.. ==== ==.= .=== ==== ==== ==== ===--------------------------------------——---Precautions for Safe Handling
and Use
-----.=== ==.. ==== .=== ==== ==== ==== ==== ==== ==== ==== -----——-------—--------——
------------------------------PREVENT FURTHER MIGRATION INTO ENVIRONMENT.
Steps If Matl Released/Spill:
USE ABSORBENT/ADSORBENT
MATERIAL TO SOLIDIFY LIQUIDS. SOLIDIFICATION MAy
NOT SUPPRESS VAPORS. DO NOT VACUUM LIQUIDS. WEAR PROTECTIVE EQUIPMENT,
INCLUDING EYE PROTECTION, TO AVOID EXPOSURE.
Neutralizing Agent: NONE SPECIFIED BY MANUFACTURER.
Waste Disposal Method: MATERIAL IS AN IGNITABLE WASTE UNDER RCRA
REGULATIONS . DISPOSE OF ANY CLEANUP MATERIALS L WASTE RESIDUE ACCORDING TO
APPLICABLE FEDERIKL, STATE & LOCAL REGULATIONS.
UNDER NORMAL USE & HANDLING CONDITIONS, NO
Precautions-Handling/Storing:
PROTECTIVE EQUIPMENT IS REQUIRED.
Other Precautions: NONE SPECIFIED BY MANUFACTURER.
----———--————-————————————— ..==. ===.. ==.=. =..=. ==... ..=== ..=== ===== ===== ==----———————---——————
Control Measures
.....==.=. =...= ==.== ==.== ==.== ..=== ===== ===== ===== ===== ===
Protection: NIOSH/MSHA APPROVED RESPIRATOR OR LABORATORY FUME
-——----——-----—--
Respiratory
HOOD .
Ventilation:
LABORATORY FUME HOOD OR LOCAL EXHAUST VENTILATION.
Protective Gloves: IMPERVIOUS GLOVES.
Eye Protection: ANSI APPROVED CHEM WORKERS GOGGS (FP N) .
Other Protective Equipment: EYE WASH FOUNTAIN & DELUGE SHOWER WHICH MEET
ANSI DESIGN CRITERIA (FP N). BODY COVERING TO PREVENT SKIN CONTACT.
Work Hvaienic
Practices: NONE SPECIFIED BY FUWUJFACTURER.
. .
Pagc20f3
ELI LI1.LY AND -- MYIUZII TINCTURE,
——–
.—-.
TTO059
Suppl . safety & Health Data: VP: 2.3 LB/SQ IN. EFTS OF OvEREXp:LOC IRRIT.
SKIN/EYE:ING .2:RABBIT, IRRIT. CHRONIC:TARGET
ORGAN EFTS:ING 2:CORNEAL 13MG,
ING 2:TERATOGENIC EFTS HAVE INCL GROWTH RETARDATION, IMPAIRED LF.AFWING
ABILITY & EMERYOTOXICITY.
-----———————-—————————
=-—————————- ==== .== __
———————— ===== ==.=. ===== ===== ===== .==== ====
Transportat~on
Data
.=. .=. .....=== ...=. .== =.===.== ===== ===.======= ======== ===== ===== === === =====
......= ...=. ..= ..= =. .======= === ===== =====.========== === == === == ==== ==== === ==
Disposal Data
——-——————---—
———.—-——————- ===== ==... =.=.. .=.=. .....=..== ..=.= .=..= ===.. ===.= ...=. .==== =.
...= .......= .==
. =.==. =.= ===== === =.=== ====. === .== == === ===== === === == === =======
Label Data
.....=.=.==.. ===.=...=========.===========.=========================
=======
Label Required: YES
Technical Review Date: 14DEC95
Label Date: 13NOV95
Label Status: G
Common Name: MYRRH TINCTURE, TTO059
Chronic Hazard: NO
Signal Word: WARNING!
Acute Health Hazard-Moderate:
X
Contact Hazard-Slight:
X
Fire Hazard-Moderate:
X
Reactivity Hazard-Slight:
X
Special Hazard Precautions: FLAMMABLE. MAY EMIT TOXIC FUMES WHEN HEATED TO
DECOMPOSITION. ACUTE:ETHYL ALCOHOL: IRRITATION RESPIRATORY TRACT,
DROWSINESS, NAUSEA, MUSCLE INCOORDINATION, VISUAL IMPAIRMENT, SLOWED
REACTION, SLURRED SPEECH, COMA & POSSIBLE DEATH. S.E MYRP.H:ATAXIA, SEVERE
LETHARGY, DECREASED BREATHING, LABORED BREATHING, HYPO/HYPER ACTIVITY.
CHRONIC:NONE LISTED BY MANUFACTURER.
Protect Eye: Y
Protect Skin: Y
Protect Respiratory: Y
Label Name: ELI LILLY AND CO
Label Street: LILLY CORPORATE CENTER
Label City: INDIANAPOLIS
Label State: IN
Label Zip Code: 46285
Label Country: US
Label Emergency Number: 317-276-2000; 800-424-9300 (CHEMTREC)
Page 3 of 3
or volatile mustard oil. This reaction takes
place at ordinary temperature, and explains the pungent odor and taste of aqueous mixtures of ground mustard.
Description—TheN. F. providesa descriptionof UnUround and
cyanute,
Powdered
Block
.~u-stard
and other seeds or olher fomjn
organic
[email protected]!er
and tests for PurW.
AssaY—A coarsely [email protected]@’
the sinigrin is hydrolyzed. The liberated allyl isothiocyanate 1s dlstilfed, with the aid of alcohol,
excess standard silver nitrate
into a mixture
of ammonia
T.S.
and
solution. The ester combines with
ammonia to form thioainamine [HaNCSNHC @s Iwhich Subsequently
decomposes to allyl cyanamide and hydrogen sulfide, the salver
nitrate forming with the latter a precipitate of silver er.dfide. .4fter
filtering, a portion of the 61trate is acidified with nitric acid and the
SUSTlU8st~dmd silver nitrate solution is mewnsred by titration with
standard ammonium thiocyanate, using ferric ammoruum sulfate es
the indicator. See page 1458.
Uses—It is used as a condiment, stirnulan~
and
men
Brown
emetic; externally, it is ~bef~”ent.
Mustard is prepared as a condiment by the addition of
vinegar, salt, and water, the product is known as GerBoth white and black mustard>
man Prepared Mustard.
are used in making homemade poultices. It is chietly~
used as a counterirritant
in the form of “mustard
plasters,” made by mixing it with varying amounts of
wheat flour and adding su5cient tepid water to make a
paste. It ia occasionally used as a gastric and intestinal
stimulant.
It is an active, although unpleasant emetic,
in a usual dose of 10 Gm.
Dose- UsuaJ, Emetic, 10 Gm.
and stomuchic, Horses
Veterinary Doses--Carminative
and Cattle, 8 to 15 Gm.;
Emetic, Dogs, 4 to 15 Gm. in
warm water.
Mustard
Plaster
having
the formula
CIJI leOz and the latter CITHazOs;
commiphon”nic acid (believed to be present as the ester).
phenols
a-and
a- and fi-heerabomyrrolic acz”ds; theresin
p-heerabomyrrhol;
and heeraboresene.
The volatile oil contains up to X per cent of two
sesquiterpenes,
about 11 per cent of dipentene, d-limonene, 1 per cent of V“m, 0.2 percent of eugeml, up to 1
per cent of cuminic afdehyde, cinnamic aldehyde, and up
to 1 percent
ofm-cresol. Acetic, palmitic, and myvholic
acids are present as esters.
The gum present in the drug has been stated to contain 14 per cent of pentosans, 12 per cent of gdwtan, a
considerable amount of zylan, some araban, and an
oxidizing
enzyme.
Description—The
Powdered
Jfwrh
N. F. Provides a description of VwOUti
and tests for Zdentifkotien and Puri&g.
.“.
!
Uses—Myrrh is used as a local stimulant in diseases !
of the mouth and as an application for sore gums. It
“s administered internally as a carminative
and exro.tec~ive.The volatde od is used in perternallyof as
a p
fumes
tfioriental
type and as a fixative.
Myrrh Tincture N. F.
[Sp.Tintura de Mirra]
(Myrrh, in moderately coarse powder.
To make . . . . . . . . . . . . . . . . . . . . . .
Prepare a tincture
the menstruum.
(
200 Gm.
1000mi.
by Process M (page 375), using alcohol as
Alcohol Content—From S3 to SS per cent of C.ZHsOH.
ad
Storag*Preeerve
in tight, light-resistant cmcainer%
posure to direct sunIight and to excessive heat.
N. F.
and
avoidex-
Uses—A local stimulant application
to indolent
Mustard Paper; Sp. EmpIeeto de Mostaza] T
and ulcerated sore throg.t. ,
Mustard Plaster is a uniform mixture of powdered
U~eT
black mustard, deprived of i~ fixed oil, and a soluti?n ~
of a suitable adhesive, spread on paper, cotton cloth, ~
or other suitable backing material.
Each 100 square
G
PERUVIAN BALSAM N. F.
centimeters of spread plaster contains not less than 2.5
Gm. of black mustard which has been deprived of its
[Peru Balsam; Belsaso of Peru; Indian Balsam: Black Balsam: SP. ;
B&amo Negro; B41samo del Perti ]
fixed oil.
When moistened thoroughly with tepid water and
PeruvianBalsamisobtained
from lfy~ozylon
Pe- ;
applied to the ski:, the Plaster produces a decided
reirz (Royle) Klotzsch @’am. Legumin.we).
warmth and reddenxng of the skin within 5 minutes.
Constituents-This Balsam contains from 60 to 64 !
Hot water would destroy the enzyme myrosin and
per cent of a volatile oil termed cinnamtin and from 20:
would not permit the development
of the volatile
to 28 per cent of resin. The higher the content of vola- “
mustard oil to which the mbefacient
action is due.
tile oil, the greater is the market price of the drug. :
Cinnamein is a mixture of numerous compounds, among
Storage—Preseme in well-closedcontainers, preferably at a temperature not above 35°. Protect it from direct sunlight.
which the following have been identified:
the estera
Uses—A rubefacient. A common substitute for the benzyl benzoate, benzyl cinnumate, cinnamyl cinnamate
and the alcohol Patiol (considered by some
manufactured Mustard Plasters is the mustard poultice (stym.cz”n),
of the home, usually prepared by mixing equal parts of authorities to be identical with the sesquiterpene alcoas ester; free cinnamic acid;
hol nerolidol, C ISH260)
ground mustard and flourj moistening with tepid water
to forma paste, and applying to the skin in a muslin bag. about 0.05 per cent of vanillin; and a trace of coumarin.
[Emplaatrum Sinapie;
Note-Before
it is applied, Mustard
thoroughly moisterwd with tepid water.
Plaster should be
MYRRH N. F.
[Gum Myrrh;SP.
Mirra]
The presence
ofthefollowing
compoundshasalsobeen
claimed:dihydrobenzoic mud, farnesol (a sesquiterpene
alcohol), styrol (phenyZethylene), and a phvtoste~ol. The
resin
consists
ofthebenzoic
and cinnamic
acidesters
ofthealcohol
perwes”notunnol,together
withsomefree
cinnamic
acid.
Myrrh is the oleo-gum-resin obtained from Commi- Description—Peruvian Balsm is a dark brown, viscid liquid. It is
Commiphora
abyssinica (Berg) transparent and appears reddish brown in thin layers. It has an
phora molmol Engler,
aveeable odor resembling vanilla, a bitter, acrid taste, with a perEngler, or from other species of Commiphora Jacquin sistent
It does
after-taste, and is free from stringiness or stickiness.
(Fam.BUrS~weZ).Xfyrrh
yieldsnot lessthan 30 per
not harden on exposure to air.
Specific gravity 1.150 to 1.170.
The
N. F.provides
tests
forPurdU.
&nt,
.-—. of alcohol-soluble &tra&ive.
Solubi~i~eThe
Balsamk nearly
insoluble
h water,butissoluble
Constituents-Myrrh
contains from 27 to 50 per cent
inalcohol,
inchloroform,
and in glacial
acetic
acid,withnot more
s
oluble
in ether and in solvent
thanan
opalescence.
Itk
onlypartly
of resin, from 40 to 60 per cent of gum, from 2.5 to 10 per
hexane.
The resin Storage-Preserve in tight containers and avoid exposure to exce=ive
cent of volatile m“l, and a bitter principle.
contains
a-,6-,and ~-commiphor-ic
~s, thefirst
two
heat.
252
Balsams and Resins
secondswas Posl!ive. a faint blue colour
in
30 seconds was a
truce. msd
no colour was a nega[we result. The sensitivity of ~his test was equivaien[
to the orthotolidine
lest (orthoIolidine
400 mg in glacial
acetic acid).
and the tablet test (Hema[esl). —R. H. Wilkinson and W. A. F. Penfold
(letter),
Lczrrcer. iil 1969.847.
Comment.
–J.
Runcie and T. J. Thomson
(letter),
ibid., 954. See also ibid.. i/1970. 819.
tes[s for occult blood in faeces
The guaiacum resin and 1~~ orthololidine
produced
a high number
of false positive results in normal
infants and
normal
children
eamrg a me~t-containing
die[. A modified
reduced
phenolphthalein
[est g~ve no false posi[ives but was insensitive to blood
dilutions
below
I in >000 —A.
E. A. Ford-Jones
and J. J. Cogswell.
,4rrYr$ Chs. Chi/d/I..
1975.50.238.
PREPARATIONS
AmmorriatedGuaiacum Tkscture (5. P.C. 1949). TInct. Guaiac. Ammon.
Macerate guaiacum resin 20 g wilh strong ammonta solrr[lon 7.5 ml and
alcohol
nutmeg
through
Grraiaeum
(90°b)
70 ml for 48 hours; filter, and dissolve in the filtrate.
oil 0.3 ml and lemon oil 0.2 ml: pour sufficient
alcohol
(90”.)
the filter to produce
100 ml. Dose: 2 to 4 ml.
Tiocture
1934). Tinct.
(B P.C.
resur: prepared by macerating
filtering. Dose 2 to 4 ml.
with
Guaiac.
I in
alcohol
(90”~)
for
5 of
48
guaiocum
hours
and
Guaiacsrm wood (RP. C, 1949). Guaiaci Lignum; Lignum Vitae: Bois
The hearlwood
of Guaiacum ojlcirrafe and of
de Gaiac; Guajakholz.
G. mrcrurrr (Zygophyllaceae).
[t is [he source of, guaiacum
sarsapariila
decocuon.
containing
resin and
Mastic (B. P,C.). Mastiche;
Foreign Phurmucopoctas:
A resinous exudation
Mastix;
IS LO 25”: of guaiacum
resin.
is an ingredient
of compound
Almaciga.
[n AUSI,. Neth., Port., Span,,
and
Swiss.
from cer~ain forms or varieties of Pisracia
Ierrfiscus(Anacardiacwe). Small, hard, yellowish tears with an
aromatic odour and agreeable taste, becoming plastic when
chewed. M.p. 105- to 120’.
[~luble in water: partly soluble in alcohol and turpentine
OIi: soluble 2 in I of chloroform. 2 in I of ether. and in
acetone and benzene.
UseS. Solutions of mastic in alcohol. chloroform, or ether are
used. applied on cotton wool. as temporary fillings for carious
teeth. Compound Mastic Paint is used as a protective covering
for wounds and to hold gauze and radium needles in position.
PREPARATIONS
Mastic Paint (B. P.C.). Pigmentum
Mastiches
Composltum;
Compound
Benzo-mastic;
Mastic Solution.
Mastic 40 g. casior 011 1.25 ml. benzene.
ni[ration
grade of commerce
(BS 135/2:
1963). 10 1013 ml. Store in a
cool place in an airtigh[
container.
This preparation
is inflammable.
Keep away from an open flame.
several foreign pharmacopoeias include similar preparations. usually
an agreeable balsamic odour and
containing 49 to 60”i of balsamic
Insoluble iti water; miscible 1
addition of more alcohol causing
ALLERGICREACTION.of
European
clinics
UKMUCQP_
—
(BP
-.5[0
Gum Mvrrh,-
Br. J. c’krrrr..
1970.83.543.
Uses. Peru balsam has a very mild antiseptic actl
of its content of cinnamic and benzoic acids, Dil&
equal part of castor oil, it has been used as an a]
bedsores and chronic ulcers; m an ointment (12.!
Ointment) it has been used in the treatment o~
prurltus. It is an ingredient of some rectal suppo
for the symptomatic relief of hemorrhoids.
Peru balsam was formerly used as an ointment+‘1
or with sulphur, in the treatment of scabies. bl.
superseded for this purpose by benzyl benzoate. ~
,’
PREPARATION
Ung. Bals. Peml.
Co. ( B..V. F. 1957). Peru Balsam Corn&$
Peru balsam 6. liquefied
phenol
2. cfimphor
1. hydrou
yellow sofl paraffin
to 100.
-$
‘?
Vinylinum
Pol]viisox.
Balsam. Poly(bcrtylvinyl
(Rus. P.):
ether),
Polyvinyl
C,.jH,~O,(C,H
butyl
Ether$
ilO)ts=~
A pale yellow.
viscous liquid
with a characteristic
od~,
soluble m
aboui
0.9 g. Insoluble
in water:
sparingly
methyl alcohol:
miscible with acetone. chloroform.
ether
and vegetable oils.
;)
A syn[betic resin. developed in the USSR M t substitute f.
tt is widely used in the USSR
by external
application.
e
or m a 20”~ oily solution
or as ~n ointmen[,
in the
wounds
and burns and various
skin diseases.
[t is st
bac!eriostatic
action and to promote
tissue regeneration
L.
a[ion. It is also administered
by mou[h in the [re~tmentl
duodenal
ulcers, gastritis.
and colitis.
Dose:
4 to 8 m
4
hours atier the last meal.
5106
‘~d
PREPARATION
Shostakovsky Bslssm( Mede.rpor/,
USSR
rkspoki
Churn
:$
Sandarac (B. P.C. 1949).
L
A resin
AUSI., Belg.. Chil., Ger.. Jap.. ,Veth.. Port.,
[inc[ure
C.). Prep*red by macerating myrrh I m 5 of
5.1.
is included in several foreign pharmacopoeias.
alcohol
Peru Balsam (f I. P,C.). Bals. Peruv.: Peruvian Balsam; Baume
PLrou;
4000 puuerrls subjected
to pate
of males and 7,6~~ of femoles s
4.6”;
reactions to Peru balsam 2.5”0 in soft paraffin, -H,
BricI
Archs Dem.. 1972. /06. 335. See also E, Rudzki and
Bacsme
du San Salvador.
obtained
by
of
~
k
Gum Juniper
Sandaraca:
mcislon
[he
stem
of
Tefracf
(Cupressaceae).
Brittle pale yellow [ears. which do not aggl
chewed.
with o slightly
!erebinthinate
odour
and [aste#
160’. Insoluble
in water:
soluble
in ~lcohol,
amyl alco~
partly soluble in chloroform,
carbon disulphide.
~nd turp
S~ndarac
has been used [n alcoholic
soiutlon.
2 parts of
I of ~lcohol (%1”~). on co[ton
WOOI. as a [emporary filli
[ee[h. It IS used in pill varrrshes find in industrial varnish<
Pill Varnish. A
quicker
(drying.
solution
i,andarac
of sand~rac
I in 2 of ~lcohol~
I in tt”mlx!ure of alcohol (95°L)f
>
Shellac (L3,P.C. 1963). Lacca: Lacca in Tabulis.
Forelgrr Pharmacopoems:
Whi[e
A
du
1
a bitter. acrid, bu
esters.
in I of ttlcoh~
and filter.
An oieo-gum-resin obtained from the stem of Comrniphora
mo[moland possibly other species of Commiphora
(Burseraceae),
Reddish-brown or reddish-yellow tears, with an aromatic odour
and a bitter acrid [aste. It contains 25 to 40’!;, of resin, 57 to
61”;, of gum, 7 to IT’,, of volatde oil. and a bitter principle.
Soluble in water to the extent of about 50’): (forms a yellowish
emulsion on trituration); partly soluble in alcohol; soluble in
alkalis. Store in a cool dry place.
Uses. Myrrh is astringent to mucous
~ ,.
is
es for ~
tie mouth and.
hen taken by mouth it has a carminative action.
A sim!lar
1
Be/g., Bra:., Ch
Pol., Port.. ROU
turbidity; solub
form; partly soluble in ether. glacial acetic at;’
petroleum. Water shaken with the balsam only re
.:,
ofcinnamic acid, Wt per ml 1.14 to 1.17 g.
Toxic Effects. Peru balsam may cause skin sensiti
polyvinox.
-Swiss.
AUSI.,
SIIWJ,
Microscopic Varnish. Mastic 15 g. caoutchouc I g. chloroform 60
ml:
t n .-trg.,
A balsam exuded from the trunk of M.vros.vbt ba
pereirae
(Leguminosae). It is a dark brown. viscori
PROPRIHARY
,Nfyrrh (B. P.C.). Myrrha;
/-%
Phurmucopueim:
Hung., Jap., Jug., IWL,.V..Ncth., Nerd.,
comaining about 3&0 of mastic and with I to 210 of linseed oil
instead of caslor oil,
macerate
F
Foreign
Shellac
resinous
.
1
{n Spun. Jrsp. includes p“ritied
(bleached).
substance
formed
by
a scale
insect,
1
~
(Coccidae). which lives on the sap of the stem$
plants. Pdle lemon-yellow to brownish-orange, !jq
odourless. tasteless. hard. brittle scales. II .o!u~ ‘.
readily soluble in warm alcohol; almost completel
alkali hydroxide solutions and borax solutions,
“
Uses. Shellac is used with cetostearyl alcohol &
1
Myrrh-235
CATEGORY—phaITIMCeUtiCd
gredient
of Aromatic
Rhubarb
UeCe.WitY;
in-
Tincture,
page
313.
MYRRH
Gum Myrrh
Myrrh is the ohm-gum-resin obtained from
[email protected] molmol Engler, Commiphora
abyssinica (Berg) Engler, or from other species
of Commiphora Jacquin (Fare. Bur.serme~),
Unground Mym+t-Unground Myrrh occurs in
rounded or irregular tears or masses of agglutinated tears, moderate yellow to dark or reddish
brown, and more or lees covered with a lighter
colored, yellowish dust. The fracture is waxy,
anular, conchoidal; internally, Myrrh is el~wish or reddish brown, sometimes rnar~ed
with nearly white spots or finee~ oily and translucent at the edgee. Its odor M bafeamic, aromatic, not terebinthinate,
and ita taete is aroma tic, bitter, and acrid.
Powdered Myrrh ia weak yellowish orange to
strong yellowieh brown and conaieta of numerous
angular fragments of resin and gum, a few fragmenta of Iignified tissue, and a very few starch
.rraina.
. .... .
Identi6cation—
A: To a Dortion of Myrrh add nitric acid: a
purplish to viblet coloris produced.
B:
E.qmae an ether solution of Myrrh to
vapors:
a reddish violet color is produced.
C: Tnturate about 1 Gm. of Myrrh with 5
bromine
ml. of water:
a ye~owiah to yellowish brown
emulsion is reduced.
Acid-ineo ruble aah, page 460-Myrrh
yields
not more than5 per cent of acid-insoluble aeh.
Alcohol-aolnbie
extractive,
page 462—Myrrh
yields not leas than 30 per cent of alcohol-soluble
extractive.
cATEGoRY-Protective.
MyrrhTincture
Gompound
MyrciaSpirit
;
i
Myrcia Oil . . . . . . . . . . . . . . . . . . . . .
Orange Oil . . . . . . . . . . . . . . . . . . . . .
Pfmenta Oil . . . . . . . . . . . . . . . . . . . .
Alcohol . . . . . . . . . . . . . . . . . . . . . . . .
Water, a sufficient
quantity,
To make ...................
L-=-.
.’a—
458 —Generol
Tests
t.4AT10NAL
FORMULARY;&
1
TINCTURES
Tkctures
are alcoholic or hydroalcoholic
solutions repared from animal or vegetable drugs
or from $ernical substances.
The proportion of drug represmted
in the
different tinctures is not uniform but varies
according to the established standards for each.
Thctures of otent drugs esentiaily represent
the activity o ? 10 Gm. of the drug in each 100 ml.
of tincture.
This conforms in principle to the
recommendation of the International
Protocol
as adopted at Brussels, and with international
standards. In this grou are most of the tinctures
which are assayed and’ adjusted to standards.
Most of the other tinctuws represent 20 Gm.
of the respective drugs in each 100 ml. of tincture. Compound tinctures are made according to
10~h~&~~~~&~&u~o
be employed for thf
manufacture
of tinctures,
unless otherwise
directed in the individual monographs, are as
follows :
Process P-Carefully
mix tbe ground drug or
mixture of drugs with a sufficient quantity of the
prescribed menstruum to render it evenly and
distinctly damp, allow it to stand for 15 minutes.
transfer it to a suitable percolator, and pack the
drug firmly. Pour on enough of the prescribed
menstruum to saturate the drug, cover the top
of the percolator, and when the liquid is a~JOUt to
‘“w
drip from the percolator, close the lower orifics .
and allow the dru to macemte for 24 hou o;*
for tbe time spec $ ed in the monograph.
If nom
MW.y is directed, allow the percolation ,j~“+
proceeti S1OW1V,
or at the specified rate, gradu]l ~
adding sufficient menetruum to produce 1000 ~~,
of tincture, and mix thoroughly.
“’w: ~
If an assay is directed, collect only 95o rnl.;~
pereolate;
mix this thoroughly, and =y,La
portion of it as directed. Ddute the remair+~;.,
3
with such a quantity of the prescribed menetru~ .m
as calculation from the assay indicates is neciiiw~
eary to produce a tincture that conform to the+p
reacribed standard. Mix well. The rate, ‘M,
.. .. J“
Rowof percolatesis definedon page*.
P Pmess M—Mwrate the dru or mixtu~
4 ~ ,~,.
dru s in a container which can t e closed, @ s .-.
mo $ erately warm place, with 750 ml. of ,@e
-+ ~
rescribed menstruum, agitating it frequenff ’ ;,
~or3daysoruntil
theeoluhlematter
iadisaolv $ ~ .
~~
Transfer the mixture to a filter, and when mti,?,
the liquid haY drained away, wash the residue.ou
the filter with a sufficient quantity of @ ,~,,
prescribed menstruum, combining the filtra ~
t,o rxoduce 1000 ml. of tincture.
Mix .tb&
product well.
Packaging and Storage—Preserve Tmc#
in tight, light-resistant
containers and ,av
txposure to direct sunlight and to excessive Iy
.,,,
Direct Titrations-Direct
titration is the
treatment of a soluble substance, contained in
solution in a suitable vessel, with an appropriate
standardized solution (the titrant), the end point
being determined potentiometricdly
or visually
with the. aid of
. a suitable indicator added at the
.!
ap~~$~~~~~~;dded
from asuitableburet
and
is so chosen, with respect to its [email protected] (normality) that the volume added is between 30 per
cent and 100 per cent of the rated capacity of the
buret. The end point is ap roached directly but
cautiously, and finally t E“e tltrant is added
dropwise from the buret in order that the final
drop added wilf not overrun the end point.
The quantity of the substance being titrated
may be calculated from the volume and the
normality factor of the titrant and the equivalence
factor for the substance given in tbe individual
monograph.
Residual Titrations—Certain
National FormuIary assays re uire the addition of a measured
volume of a vo1 umetric solution, in excess of the
amount actually needed to react with the
~ubstance being assayed, the excess of this
solution then being titrated with a second volumetric solution.
This constitutes
a residual
titration and is known also as a “back titration. ”
The quantity of the substance being titrated may
be calculated from the difference between the
volume of the volumetric solution originally
added and that consumed by the titrant in the
back titration, due allowance being made for the
ree ective normality factors of the two dut.
an$ the equivalence factor for the subti
..eJqgiven in the individual monograph.
In many such assays it ia further [email protected],
be performed,. w.&
a reszilual blunk titration
the required
rocedure is repeated m re
detail except tL t the substince being ~
is omitted.
In such instances, the “w
volume of titrant equivalent to the eubat
being assayed is the difference betweeql
volume consumed in the residual blank titq
and that consumed in the titration with
substance present. The corrected volume;d
tained is used in calculating the quantity’01
substance being titrated, in the same manne~
prescribed in the precechng paragraph-_ ,LA.
~
titrations of some polyvalent cations are POf
by use of reagents with which the catio~~
complexes. The titration of the calcium 10
this means is particularly
advanMgeom
poses. The success of complexometry [email protected]
m large measure upon the indicator ch~
Often, no single indicator is entirely aatisfac~l
Thus a combination of two indicators MSY.
specified where the complexometric metho,<
app!ied in this National Formulary.
Titration in Nonaqueous Soivents—Ati~’ ~
bases have long been defined as subs%~
which furnish,. when dissolved in water, hy~~ “
and hydroxyl Ions, respectively. This defimti~
;,
1;
,i
460
‘1’RYZ
PE4=COP~
,,
..,,.
!!
OF lTm
‘i
which the
water.
02s
have
CompIeh
b~n
~MOIv~,
and
the preparation
with
two
hu~red
a mixture
~~
$jty
~~:.”:
of three volum
alcohol and mw volume of water.
AVERAGE DosE—Mettic,
TINCTURA
2
$
milS-ApOthm&M,30~&se
‘~
LINIOMS CORmcIS
j
“
Tinctue of Lemon Peel
Tr.Limos. co-
{
‘1
i
LEMON PEEL, grated from the fresh fruit, Jve hundred
gmmmes. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .$. . . . . . . .
500 G2
To make one thousati millilitms . . . . . . . . . . IM ~
Pwxwe a Tincture by Type proce~ M (see page 45), -. . . ..~..$’
me drug in one thouean.d mik of alcohol (and completing the ~. .Y- -tiL.u
with alcohol. Use purified cotton as the fl.ltefig m~~.
:4
i
T~CTURA
LOBEL~
Tinctwe of Lobelia
Tr. Lobel.—Lobe&
tinctwaP.L
LOBELKA, in No. 50
powder, one hundred gramms..
To make one thousand mitlilitis
p~pme
a Tincture
~cohol
u the
by Type
Proces
*,
i
.....
100 Gm~\
..
........
P (see page 444),
a
Ming
tiute~
memtm~.
TINC~A
Tinctue
MOSC~
of Musk
i
Tr. Mosck
Musrc,jiv epamws . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . --...........
ALcoJ30L,forty-jive millilihs
. . . . . . . . ......
WAmm, forty-$ve miUilitis . . . . . . . . . . . . . . . . . . . . . . . . ...’
Dnmmm ALCOHOL, a su.citmt quantity,
To make one hundred millilibs.
..........
.
5
Gmi
! 45~
45rn&
100 E&
the musk with the water graduafly added unt~ a smoot~Triturati
mixture is obtained;
transfer this to a bottle ~d ~ow the &Ue
+j I
macerati for twenty-fou
hours; then add the alcohol and macerate the
Tr.Myrrh.
MYRRH,
inmoderately coarsepowder, two
To make one husand
hurzdred
grammes 200Gm.
mWiters
..........
-
1000 roils
Prepare a Tincture by Type Process M (see page 445), using alcohol
m the solvent.
AVERAGEDosE—Metric, 1 roil-Apothecaries,
15 films.
TINCTURA NUCIS VOMICIE
Tincture of Nux Vomica
Tr. Nut. Vom.-Strychni
tinctura P.X.
One hundred roils ofTincture of Nux Vomica yields not less than
0.237 Gm. nor more than 0.263 Cm. of the alkaloids of nux vomica.
~ux
VOMICA, in
No. 40 powder, om hundred grammes. . ..
To make about one thousand milliliters..
...
‘1OOGm.
,1
100Q roils
“,.
Prepare a Tincture by Type Process P, as modified for assayed tine“, ,;
of three VolumesOf alcohol and one
~.~
tures (see page 444), wing a ~xture
volume of water as the menstruu
and adj~ttig
the volue
of the
.,..:
‘,,,, :.ti
....<.
so thateach0~ hu~redm~h COntai~0.25Gm” Qf
.: -“&i
finished Tincture
thear~lOi&ofnuxVornica.
The rateofflowforthepercolate
shouid
notexceed
tendropsperminute.
Assa
y—Ev~porate
100roik
of Tincture of Nwx Vorn& on a water
bath until
it meaeures alwut 10. roils, transfer the evaporated
AVERAGE DOSE—MetriC,
.. .. ... .
.
“::).:
,’
liquid to a separator, and
proceed as directed m the as-say unde~ [email protected]@a~um
page 178, second line of the *aY) bea~ng
~th
modifying the process there “ven by u.wng 5 roils
~i~~~e&~jlledwat,er, in divide$~rtions,
to rinse the
was evaporated and by &so vmg the residue in
sul huric acid V.S. instead of 5 nils.
J$ach mi] of tenth-normal sufphuric acid VS.
36.4 mil&rammes of the alkaloids of nux vornica.
‘‘,:,4
;:+
13ehdonna
Rx&@
~
the wor~ “add 10 @%”
of ammonia water mth a
&h in ~hich the Th~tur~
10 roils of tenth-normal
consumed
correspo.da
8 minims.
.
. 0.5 roil-Apothecaries,
to
.!
.,
f
.>.
,..2 !
~ ‘<
“
,.“
54
AUROTHIOMALIC
THE EXTRA PHARMAC03’=L3
m
to 99 to the equivalent
of 10Y ~
cent of anhydrou
ro the dried
C~H,00.N*AsNa, calculatd wbh ~
the IOSSon
substance, determined by the U.S.P. methcd fnr ~n~
drying srt 105” for 4 hours is 2.5 to 3.5 per cem That of rhe F?. C.x.
by
the
fo[lowhg
contains 24.4 to 24.9 per cent of arsenic, d~
method:
To about 0+ g., accuratelywekh=d, di~olved~ ~~~ =--sdd j ml. of hydmcfdoric acid and 12.5 g. of porassium iodide, heat on a -{CUI1,snd titmte ~rb N/l fI~i~
thim~phste Ond. +
weftdfy about 10 g. of sodium bicarbonate, and orram *
N/10 iodine is equivalent to 04303745 g. of smenic, -k
Znjec2ion of Try$arsamtie
J!SAFFrDAOIL. Them+
fraction, b, 8P to 84° at IO mm., is o tically active and has
a composition cmrewonthng
to CH, E H, CH(CHJ. S.S.CH:CflCH,.—C.
.Ma”nich
and P. Frensenius,Arch. $%wm., B&l., 1936,274, 461, per Qaart. J. Phcwm, 1936, 9, 710,
fu ~ nuout=, auow m
-J w
sw excess: add
>,10 h=
Each ml. of
(B.P.). In & aeskd container is dry
powder containing arsenic, Aa, equivalent m 224 m Z-O per cent, and
nitrogen, N, equivalent to 8.0 to 10.5 per a- rhe stared amount of
“de.
tryparaarnide, determined by the B-P. mew
fsx ~
55
diluted. It yields not more than 50 per cent of alcohol (90 per cent).
insohsble matter and not more than 15 per cent of ash. It contains about
6 co 17 per cent of volatde oil, about 40 to 64 per cent of resin, and about
25 per cent of gum. Pure tear aaafetlda usually contains from 65 to 75 per
cent of alcohol (90 per cent) -soIuble subatancea and 3 to 5 per cent of ash.
That of the N.F.-U.S.A. yields on continuous extraction with alcohol
(95 per cent) not 1:ss than 50 per cent of alcohol-soluble extractive,
calculated on the dried drug, the moisture having been determined by
szeotropic distillation with toluerre, and not more than 15 per cent of
acid-insoluble ash.
Trypamamide (l?.P.). [email protected]~i’[email protected]=:Oj”l. It %n*s
25.1 to 25c5 per cent of arsenic, As, and 9.23 m !+5 ?er cent of mtrogett,
N, both calculated with reference to the subsmnm &i at 105”; the IOSS
on drying is 2’5 to 3.5 per cent. That of the ~~-~. contains arsemc
corresponding
trypatide,
ACID
I
Myrrh (B.P.C.). Itcontains at least 7.0 per cent v/w of volatile oil.
That of the N.F.-U.S.A. yields not more than 5 per cent ofacid-insoluble
ash and at [east 30 per cent of alcohol (95 per cent) -soluble extractive.
AUROTHIOMALIC ACID
Sodium Aurothiomalate (13.P.). Itcontains 445 to 46.0 per cent of
gold, Au, determined gravimetncally, and 10.8 to 11.3 per cent of
sodium, Naj determined gravimetncally aa sodium au[phate, both
calculated wmh reference to the dried substance, the Iosa on drying over
phoaphonrs pentoxide under reduced pressure for 24 hours ia not more
than 2.0 per cent.
Injection of Sodium Awothiorndate
(B.P.). This solution contains
gold, Au, equivsdent to 42.3 to 48.3 per cent of the stated amount of
sodium aurothiomalate, determined gravimetrically aa gold, Au.
Sodium Aurothioaulphate
(B.P.C. 1949). Na,Au(St0,)2,2H20
=
526..5. It may be identified by adding 2 drops of sodium hydroxide
solution and 3 ml. of hydrugen peroxide solution to 3 ml. of a 1 per cent
solution, when a blue colour and a deposit of linely divided gold is
contains 37.0 to 37.6 per cent of gold, Au, determined by the
pmch.reed. It
foUowirrgmethod:
DissoIveO.8 & in 50 d. of wster snd sdd 10 mL of N/l sodium hydmxide and 10 ml. of
hydrogen perunde solution, boil to decomposs die exceM of h drogen peroxide, acidify
with hydrochloric acid snd dtow the precipitate of msdhc gol z to coagulate; $lter, wath
with boiling water, dry, ignite, and weigh the ruidue of gold, Au.
BARBITONE
Barbitone (B.P.). C$HI,03N1= 184.2. No assay is described, but it
has a m.p. of 189° to 192°. Barbital, U. S.P., has a m.p. of 188° to 192°.
~iemafum, P.Don., contains 98.3 to 100.4 per cent of barbitone, determined by Kjeldahl method; each ml. of N/10 hydrochloric acid is equivalent to [email protected] g. of [email protected],,03Nt. An officiaf method for the determination
of barbitone is described in the A. O.A.C. ‘Official Methods of Analysis’,
P. 590. The method
is similar to that of the U.S.P. for Barbital Tablets
(see under Tablets of Barbitone, p. 57J except that the preliminary
extraction with etier is omitted and,, to stssiat in removing the last traces of
chloroform and to obtti a crystalke residue, the residue is repeatedly
dksolved in 2 to 3 mf. of ether and the solvent removed. The purity of the
residue is checked by determining its m.p.
http:// 130. 14.32 .46/cgi-bidIGMdieot?
http://130.14.32.46/cgi... M-dimt?lO9dekil+ll+l
10900+detail+ I
National Library of Medicine: IGM Full Record Screen
lx
TITLE:
[Constituents
AUTHOR
Tian J; Shi S
AUTHOR
AFFILIATION:
National Institute for the Control of Pharmaceutical
Products, Beijing.
SOURCE:
Chung Kuo Chung Yao Tsa Chih 1996 Ap~21(4):235-7,256
NLM
97352277
CIT. ID:
ABSTRACT:
..—
ofessential
oilofimpotied
myrrh andgumopoponax]
and Biological
~
/
6“
The constituents of essential oil in two kinds of Myrrha were analyzed by
GC-MS. Fifteen compounds in Myrrh and thirty-three compounds in
Gum opoponax were identified with their percent contents given. The
main constituent of Myrrh is furanoeudesma-1,3-diene,and the main
constituent of Gum opoponaxis beta-trans-ocimene.
MAIN MESH
Drugs, Chinese Herbal/*CHEMISTRY/CLASSIFICA~ON
SUBJECTS:
Oils, Volatile/CHEMISTRY/*ISOLA~ON & PURIF
ADDITIONAL
ComparativeStudy
MESH SUBJECTS: English Abstract
Mass Fragmentography
Support, Non-U.S. Gov’t
PUBLICATION
JOURNALARTICLE
TYPES:
LANGUAGE:
Chi
REGISTRY
NUMBERS:
O(Drugs, Chinese Herbal)
O(Oils, Volatile)
—_
lofl
5/5/’98 12:01 Ph
---—- —-
A. INGREDIENT NAME;
PHENINDAMINE TARTRATE
B. Chemical Name:
1,2,3,4-Tetrahydro-2-methyl-9-phenyl-2-azafluorene
hydrogen tartrate; 2,3,4,gTetrahydro-2-methyl-9-phenyllH-indeno-[2,lc]pyridinehydrogentartrate.
C. Common Name:
l%epho~
Dal% Nolamine, Melod~
Cerose, Carrhist
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Dry Basis:
(Limits)
98.0°A - 101.5%
@esults)
99.7%
E. Information about how the ingredient is supplied:
—
A white to cream white crystalline powder. Is odorless or almost odorless.
F. Information about recognition of the substance in foreign
pharmacopoeias:
Arg., Br., Ind., Int., and Turk.
British Pharmacopoeia 1993
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Witelq T. J., Canastrari, D. A., and Miller, R. D. The effects of phenindamine tartrate on
sleepiness and psychomotor performance. J. Aller~ Clin Immunol, 1992;90(6 Pt 1): 953961.
Sigidinenko, L. V. Various principles of therapeutic tactics in epilepsy patients during
pregnancy. Zh Nevropatol Psikhiatr, 1984;84(6): 897-899.
.
H. Information about dosage forms used:
Tablets
Liquid
Elixir
Capsules
I.
Information about strength:
25-50mg
J. Information about route of administration:
Orally
K
Stability data:
Melts at about 162-167° with decomposition.
Solutions were unstable above pH 7 and were most stable at pH 3.5-5. Heating could
cause phenindamine to isomerise to an inactive form.
_—–_
L. Formulations:
M. Miscellaneous Information:
—__
Page -2-
,’
-------
-,-——-
-—.——.
- .-
,.
,
. .._. _..
..-
—
.——
—-—
GG -
*.
.
UMm
A
B.
c.
D.
—.
P=-
T-
1.7%
a
must not differ by ~
-
3.0%.
-:
35
3.0 to 4.0
0.115
0.007%
<0.002%
<0.ms %
1.3%
m“
A
o
.
A8ia Bask
NLT
%5 %
gg.o% to 1013 ~
B. w=
/
.
.-”-
‘—
_—
99.6%
99.7%
a--m
QUALITY CONTROL REPORT
NAME .: PHENINDAMINE
CHEMICAL
TARTRATE
LOT NO. :
MANUFACTURE
PHYSICAL
/Bp
TEST STANDARD. “usP
.
——
SPECIFICATION
E
I)DESCRIPTION.
A WHITE TO
a> RLESS .
:
CREAM WHITE
2)SOLUBILITY.
SOLUBLE
IN
PRACTICALLY
:
70 PARTS OF WATER;SLIGHTLY
INSOLUBLE
IN CHLOROFORM
3)kfELTING
POINT.:
MELTS AT ABOUT
4)SPECIFIC
A)COMPLIES
B)COMPLIES
c)COMPLIES
degree
POWDER.IS
WITH
ANALYST
(A)
ODORLESS
DECOMPOSITION.
(96%);
1<
.:
AS
PER
(C)
AS
PER
CO.SPECS.
IR
SPECTRUM
CO.SPECS”
FAILS.
:ABOVE
SIGNATUI=.
TEST
IS
CARRIED
OUT
BY SUPPLIER
CERT.OF
:
ANALYSIS.
DATE.
:
DATE.
DATE.
:
:
SpECSo_.
OR ALMOST
(B) AS PER CO.SpECS.
PFUIPACK TEST.:
RETEST .:
/t4ART._/CO.
SOLUBLE
IN ETHANOL
AND IN ETHER.
.:
COMMENTS.
.-
162-167
/~RcK ——
/NF
GRAvxm.:
5)IDENTIFICATION
PASSES
CRYSTALLINE
TEST
:
INITIAL.
:
INITIAL.
:
05/26/1998
15:46
5162777681
ALFA
CHEM
PAGE
g2
-ALFA “CIEM ‘“
1661
TEL:{576)277-7G/31
TLX: 650487 7992
N. SPUR
DR.
c.
ISIJP,
NY
11722-4325
FAX:(5
16)
277-7687
_——_
-----..
-------
.-- .. ..::==
-_
..
-------------
~~..,.=
.. --?---
-.,
-.
.- ..--=
==Z,XZ=8ZZSEZ=Z
===z===xz===_
----
__-==zy==,y==z
ZZz:::
——
..-
PRY 26
’98
14:E19
5162777681
PRGE . D122
05/26/1998
-.
--
- ----
-
..-
-
,. -., . . --
-
-
5162777681
15:46
-
-
-
-
a--
-
-
-
.
.
-
.
,.
.
---
-
.
-
-
-
--
ALFA
--”
“
.
-
--
.
..”
.-
PAGE
CHEM
.
=
=
=
==
=
=
=
=
=
=
=
=
=
=
==
=
=
=
-
.
--
.
.
.
-
--
-
-
-
-
-
-
-
-
-
~
=
=
E13
-
-
.
“
.
-
-
-
-.
-
-
-
.-
-
-! ~- --. .
-
.——=%=
,.
MRY 26
’98
14:1B
5162777681
PRGE . EiD3
-
-
-
05/26/1998
15:46
5162777681
—=
ALFA
CHEM
PAGE
.
siJ&Jj_:J_:
.5table,
_—-
MRY26 ’98
14:1D
5162777681
PRGE , ~
84
05/26/1998
_—_
15:46
5162777681
ALFA
CHEM
PAGE
-
_—_
. ...
MRY
26 ’98
14:11
5162777681
PQGE . W35
05
05/26/1998
ALFA
5162777681
15:46
PAGE
CHEM
E16
_—_
..
salExu_i23T2> SZ.??ET
Mam&mL
T.%R2’!I%TE
PxQc?u.et; ~~~:(rlfc.~.jr:fs
:= ==-..---------=-
------
.——=
;
.-G,----.
------
. ------
------== ==---..==ss”
-“-- ------. ..---...=
----
---
-
---.==
--
Sxas=ti
======
==..--...
_ ..’ =:===
::Z-”-
.----“
=-wL’=== ==.-.=:>:= ==.==== ===.-==
z=zz r-”--”&-”-,--”.
--..
--
.
====’::
======
_..=s
=S=lz=======g:
.
======
?5$2
5 et 7
----.=7,X == 5==. .-----------
== =2.--=
ZS======zzz:.-
===
:===
=.7=
..,--.-?-.----==
.
.,,..
MFIY
26
’98
14:11
5162777681
PCIGE . BZt6
===
05/26/1998
15:46
5162777681
ALFA
PAGE
CHEM
07
-.
MfIY 26
’98
14:12
5162777681
PFIGE . ~7
05/26/1998
15:46
5162777681
ALFA
PAGE
CHEM
E18
—_
.-
Maim CHHL.M
_———_
_—_
--
M(9Y 26
’98
14s12
5162777681
PFIGE . =
1316
Promethazine
and other Antihistamines
For
6148-y
......
a report
of the usc of methdilazine
of migraine,
i%lethdilazine
(~..S.P.). 10-(l-Met-
iryipyrrolidin- 3-ylmethyl)phenothiazi
C18HION2S=296.4.
CAS—
ne.
containing
1982-37-2.
Pharmacopoeias.
Protect
powder with a characteristic odour. M.p. 83” to 88” with a range of not
more than 2°. Methdilazine 7.2 mg is the equivalent of approximately 8 mg of methdilazine
hydrmhloride. Practically insoluble in watec
soluble I in 2 of alcohol, I in I of chloroform,
and 1 in 8 of ether: freely soluble in 3M hydrochloric acid. Store in airtight containers. Protect
from light.
Methdilazine has actions and uses similar to
those of methdilazine hydrochloride. It is given in
usual doses of 7.2 mg two to four times daily.
A
light tan crystalline
Preparations
Mettsdilszirsc Tablets
hdilazine.
light.
Store
in
(L(S.P.).
airtight
Tablets
containing
cmntairrcrs.
Protect
metfrom
(Wesrwaod,
(U5.P.).
Symp
hydrochloride.
4.1. Store
containing
methdilazinc
containers.
Protect
fromlight.
A
with
in
airtight
6.5
hydrochloride.
Store
Tablets
in airtight
the
Treataneat+ msrl Precaratiom.
—
92058.
l-Methyl-3-[
lmethylthio)ethyl
C)xomcmazine
properties
mazine
J.
1, 392.
wcs thought
further
H.
A.
Forrest
Bone-marrow
er of. (letter),
depression
a
phenothiazinc
dcrviativi
and uses of the amihistamirsca
‘%
Ii
II
‘~~~
(aec p.~~~
1
~
, u’
1....>,@J ‘ ‘ ..
3
to be due to the thiourea
molecule.
rather
cwurred
and
Smith
prvscrst in
CAS — 82-88-2
trials
agranulwytosis
had stopped.—
KIinr & Freruh (letter).
W.
L.
Burland
Lmcet,
Metiamide
ia a histsmirre
with
actions
similar
H2-*ptor
#
hypcracidity
bone-marrow
but
haa
antagonist
to those of cimctidirsc
been
found
to
cause
AJr. med. J., [974. 48, 2253;
bigcsfion.
1974, 11. 307; B.
Br. med. J.. 1974
Thicdlcifason
and K. G. Wormalev.
2. 304; idem, Gut, 1975. 16, 501; “G. L Barbcm
c! al.,
GUI,
1975, 16. 186; J. I. kc.rrbcrg, Ann. intern. Med.,
1976, 84, 212 A. S. MacDonald
et af. (preliminary
communication).
.bscer,
1976, 1, 68; J. M. Hind and T.
1977, 29. 244; O. R.
J. Sutton.
J. Phorm. Phormac.,
and
uaca of mctiamide
R.
Brimblceombe
er al., S.
D, M. Shepherd
et al.,
Griffith
et al.,
Br.
W.
2, 307;
Earlam
(letter),
a
cylatc~
phosp~ates,
were unstable
j
to
K
J. Pharmoc.. 1978, 64, 416P.
Dwde.d
arfcers. References to the usc of metiamidc in
duodenal ulcers: M, Mainardi rr af., New Engl. J.
Med., 1974, 29/, 373; G. J. Mil[on-Thompzon cf af.,
Larcet. 1974, 1, 693: R. E. Pounder ec al., 8r, med. J.,
1975,
Br.. Irrd.: ha., mrrl TwkP
In Arg.,
A white or almost white, almost odourl~.
minous powder with a bitter taste. M.p.’%b’ - w
162”: on further heating it solidifies a~
again at about 168” with decompoa[tion,~
I in 70 of water and 1 in 300 of akobob,~.
tally insoluble in chloroform and ether#J $,
solution in water has a pH of 3.4 to 3.9.:
airtight containers. Protect from light. ‘“
d
Iraeormstibilitv. Irrcomoatibkwith alkalis.aodi-~
deprcszion.
to the action
hornsacopocia.r.
1975, Z.p
of action. It has been
(p. 1303) but a shorter duration
used in doses of 1 g daily in conditions
aascciated with
gastric
569-5$;
(phenindamine);
rare).
reference E. J. Fddman and J. L hcnbcrg,
Further
New ErrgL J. Med., 1976, 29S, 1178.
Uses,
,,-.
@J.
Lon-
1085.
(see p. 1294)
A
Pheiriri~
artra~ Phenindaminium Tar[rate; Phenin&-&
Acid Tart rate. 1.2.3.4-Tetra hvdro- 2-mcthvl-~=.
ibid.. 1975, 2802.
4 cases of metiamide-induced
t~
and
above
oxidising
PH
tmg could
7 and
subarancu.
were
isafab
meat sta
cause phcn
Phrrnrr. .tdn, lY~LIJ:
Adverse Eff~~tmcn~
a
for the antihistamines in gene
Unlike most other antihistamines phefi”~,,.
tartrate mav have a stimtalan
possibility if
after 4 p.m.
insomnia
it should
Allergy. In a modified
‘rcpca[ed-insult’
phenindaminc
was
lartratc
.fmcel.
1975. 2, 779; ibid., 80Z R.
sensitisation
of the skin .—
ibid., 973; J. H. B. Saunderzand K. G.
Derm.. 1966, 47, 393.
round
A.
not’
to
M.
pr
K1igman,..
WormsIcy, fmrcef, 1977, 1, 765.
Zolliager-Ellison
symdromc. References to the usc of
in the Zollingcr-Ellison syndrome: M. H.
mctiamidc
Thompson ●f al. (letter), Larrcel. 1975, 1, 35; L. G.
Halloran ef al. (Ieiter). ibid.. 281; E. R. Smith er al.,
Med. J. Arasr.. [976, 1, 100tl D. M.
Ann. intern. Med.. 1978. 87, 668; J.
Am.
J. HOZP. Pharm.,
1978, 35,
141.
MmrufmXuress
Smtth
Kline & French, UK.
~~
Brompheniraminc
‘Preparations
Pbezrizdsmirsc
RP 6847:
10-( 3- Dimethylamino-2
5.5-dioxide.
c,, H*[email protected]=330.4.
Trimcrzrazine
rympforrrz.
associated
For
with
!he me
Malcatc,
p, 1296.
a
re
of
p
,
Uses. Phenindamine tartrate has the P~~
McCarthy
et al,.
and use.vof the antihistamines (see p.1~5~.Lb
K. Siepler tfal..less potent than promethazine but it;[email protected]
. ::**
generally produce drowsiness and mayn~,~ .=
mildly stimulating. It has a modcd
g~~
choiinergic action.
Phenindamine tartrate is given in do.$e~~
up to thricedaiiy.
.,
6151-p
Oxomemazine.
E.zrrapyraneidal
dyskinesia
indaminc
SS-Dioxide.
.methylpropyl)phenothiazine
~
:‘?M..
Tabkts
tartrate.
They
(8. P.). Tablets
are sugar-coated.
t
~%
to H,-receotor
.
.
than
:1
‘W k..
IS. *
due to met-
References
Migraizre. Methdilazine
4 to 8 mg thrice daily was use‘ul to prevent or reduce the frequency of migraine
attacks.— J. M. Sutherland, Drugs, 1973, 5, 212.
ia
daily.
6153-w
]tbiourea.
for the antihistamines in general, p. 1294.
1962, 188, 803.
‘.” ~
2-(5-met-
As with ail phenothiazine derivatives it should be
when they were taking
promethazine,
being twice the
incidence seen with the other drug. but in spite of this
the patients
generally
preferred
it. —Report
No. 25 of
Procritioner.
the General
Practitioner
Research
Group,
hyrJ’;
a ~
to 10 mg of
equivalent
artrate
metiamide.—
et al.,
there was iittle difference in efficacy for pruritus. but
promethazine was superior to methdilazine in the relief
of hay fever. Drowsinessrecurred in 32% of the patients
Oxomemazine
has been given bo(h as the base and ss’ &
~
chloride
in doses equivalent
to 10 to 40 mg”’~”~
3483P-7#.
metiamide
had
whom 58% had pruritus
and 27% hay fever, were studied over 2 weeks in a double-blind
study designed to
compare
mcthdilazirre
hydrochloride
with promethazine
hydrochloride.
The dose was usually 8 mg of the former
and 20 mg of the latter,
twice daily
in syrup.
Both
and
drugs gave relief
to about
one-half
the patients
s,+.
(%
P?,*;
: :++r~
250”.
M.p.
I I.1 mg is approximately
= 244.4.
1975,
iamide
A
used cautiously in patients with hepatic diseasea.
Uses. Methdilazine hydrochloride is a phenothiazine derivative with the properties and uses
of the antihistamines (see p.1295). It is more
potent than promethazine and generally causes
less sedation. It has a duration of action of 8 to
12 hours. It has serotonin-antagonising and anticholinergic properties.
for the
Methdilazine hydrochloride is given
symptomatic treatment of allergic conditions,
particularly to control pruritus. It may also be
given for pruritus of non-allergic origin. The
usual dose is 8 mg twice daily and may be
increased to 4 times daily if necessary. Children
may be given 300 Yg per kg body-weight daily in
2 divided doses.
A/fqy.
Ninety-six
patients
suffering
from allergy, of
::~*&
“;Ayw
%
Propvietsry Names
(Spccirr. Bc[g.; Spccia, Fr.; S~K
Spccia, Swirz.); lmakol (Rh6rre-Poulerrc, Ger.).
SKF
blockade,—
As
and ether,
6 150-q
hydrochloride.
ClgH10N2S,HCl= 332.9.
CAS — 1229-35-2.
[email protected]
~.
mazine.
Flockhart ).
given
of alcohol, and I in 6 of chloroform; practically
insoluble in ethen soluble in 0.1 M hydrochloric
acid and O.I M sodium hydroxide solution. A 1%
solution in water has a pH of 4.8 to 6. Store in
airtight containers. Protat from light.
bitter
.~;f., -:
dightlY*U ‘% ~
Doxcrgan
cer,
A light tan crystalline powder with a slight characteristic odour. It darkens on exposure to light.
M.p. 184” to 190°. Sohrble I in 2 of water and
a
water:
CAS — 4784-40-1.
Methdilazine bydrcchhrride was formerly marketed in
Great Britain under the proprietary name Dilosyn (Durr-
Methdilazine
Hydrochloride
(u.s.P.). IO(1-MethyIpyrrolidin-3 -ylmethyl)phenot hiazine
[n US.
in chloroform
Crystals,
AdverseEffects. Metiamide may came agranulocytcsis.
Acute rewmible neutroperria occurred in 2 patients
Pharmacopoeias.
soluble
with
in
Oxomemazine Hydrochloride.
C18H11N103S,HC1-366.9.
Proprietary Names
can,
powder
iaaolubk
6152-s
containers.
(U.S.P ).
crystalline
Practically
alcohol;
syrup
alcohol
Dibayn (Alien & Hanburys, Au.rtral.; Allen & Hanburys, Camad.); Tacaryl (Meod Johnron, Au$lral.; Pharmacia. Swed.; Wesnvood. USA):
Taeryl
(Pharmacia,
Denns.).
CQH16N,S2
6149-j
..
155”.
Hydracbfosisk TsbkIs
hylimidazol-4-y
USA).
A white
light.
Metlsdlssirsc
CAS
Adverse
pH 3.3 to
from
Metiamide.
Proprietary Names
Tacaryl
methdilazinc
to 7.5%.
U.S.
In
Malcate, p.669.
see Methysergide
Prepamtions
Metbdilszhrc Hydrochloride
,+
CAS — [email protected]
in the treatment
contslw
. ,Tw
~
“ (Sirrc[air.
UK).
Phenindamirre @
~
-abl.ts
of 25 mg. (Alzo available sSF~
in AusIral,, .S,Afr. ).
.>
%
7
#
1
c
(C LIDIHE
E29
HYOROCHLORIOE
pherayHfriocrrbanate.
xsmolytic agent.
‘CLtOttfE HYDROCHLORIDE. (pa(he,
I-(1 -pherrylcyclofrexy
l)piparidirzehydro-
“FHES4ERIDW4E. I+phenyl-b-ethyf)
befhoxy+renylpip sridine.
“FNENETt4fCtLLlt4
Ff3TASSlfJk$
N. N.O. 1S63.
:[
Alpha-pbenoxyethyl
penicillinpet. Penicillin-152 ~
pet. See: Alperr,Tabs. (Scherirrg)
!!
!myl
oz., 1 pt., 1 gal.
entral nervous system stimulant.
t GERMSCSDAL
50LtfTSOlf6 Tlt4C(Ulmer) Eenzalkorrium Chloride,
1%. Bet. 1 qt. & 1 gal.
See:
●FNEMtNOAAfNE
TARTRATE, U.S. P. ; >
#
or T& U.S.P. 2-kfetbyl-9-pheny
l-2, 3,4,9~
Ebm=ll$l:::;.
aspwm, cfriorpheniramine ●aleate,
WAlsmioom
.-
~
~::fa$ag
~Ascher)
~
:,
W/Chlorp~erapy[idaEine
maleate, phenylpro-
ate 1/6 gr. /dr. Supp. 25 nrg. Box 12s.
Phenergan HCI 6.25 mg. /5 cc. Also
25 reg./5 cc. fJof. 1 pt. Tob.: Phenergan
!.5 mg.6 50reg./Tab. Bet. 100s.
CAN INJECTION.
(Wyeth) Promethazine
/ial (25 reg./cc.) 10 cc.; (50 reg./cc.) 10
. U., I.”V., antihistaminic.
CAN PEDIATRIC.
(Wyeth) Oedro)han HBr 7.5 reg., promethazine HCI 5.o
uidexlract ipecac O. 17 min., pot.
IIsrxlforrate 44 mg. , min. chloroform 0.25
tric acid 60 ❑g., sod. citrate 197 mg. /5
L pt.
\ntitussive.
name recognized as USAN 01 by N. F.,
lr N. N.D.
~
#N=~.
‘
Tab. g Etix. (G. W. Carnrick)
W/DezfroaeUrorphan,
ctrlorphenilamine, ■aieate,
<
pbacrylephrine}Cl,
■enthol.
See: Nelodan, SyIX. (Mayrand)
W/Dextro_~han
HBr, phenylephrine.
‘
<
Sea: Cerose, Pediatric {Ives-Cameron)
W/Phenymne
hydrochloride, caramiphen
etharredlsrrlfonste.
See: Uondrii (tyhitehall Latrs. )
W/Phenylephrine HCI, chloroform, ipecac fidal.,
:iycerin, poL gwiacol sulfonate, sod. citrate,
citric acid. See: Cerose, LA (lves-Cameron) ~
W/Pyrilamine ●alealef chlom ernramine maleate,
c(- phenyiephrtrre. See: Carrh
#
~’ St ~carffone)
~/Suifadimethoxine, N-acetyl-p-aminophenol,
caffeine. See: Uadricidin, C- (Roche)
~
“PNENINDIWE, N.N. 0. 1963.(2-Phenylindame-l,3.Oione;2-Phenyl-1,
3-lndendiorie; ._. .
Phenylindanedion,
Oindevan)
See Oanilone,Tab. (Schieffelin)
Hedulia,Tab, (Walker)
Irrdorr, Tab. (Parke,
Davis)
FNENIODOL.$ee: Iodoalphionic Acid
“PNENIPRAZIHE
HCI.
See Catrmn, Tab. (Lakeside)
“PNENIRAMINE.
l-Phenyl-1423yridy
l)-34i■etfrylaminopropane. (No pharmaceutical form
available. )
~
~
~
T:.
,
r,
0.8.1.
GAf4_~ECTOf4ANT TROCHES.
Pt -- L 5 ●g., ifrecac pew. exL 2.3
Ot.
i sulfonate 162 ❑g. /Troctre.
XOLguaiacolsulfonate44 ng., chloro.
25 mg., citric acid 60 mg., Sod. citrate
./5 IX. Bet. 1 Pt Also avail. w/codeine
>
.,
t
“FNHFORMt
HCf, N. N. D. 1%3. N’-phenathylbigrrarride HCI.
(U.S. Vitamin)
FNE30C14TNOL.
(Parke, Davis) Phenol 2%,
ammonium ichthosrrlfonate, alum & lead plaster.
Use: Antiseptic.
MN HCS, N. N.D. 1963. (Wyeth)
!hazine) N{2’-Oimefhylamino-2’thyl)pherrothiazine
HCL
2%, Tuba 1.12 oz. Lot., Phenergan 2%,
lmine 15%. BoL 4 ez.
25 ●g.) Boa 12s.
,rxtihisbmirric.
)1 srrlfonale 162 reg./Troche. Jar 36s.
expectorant.
GM HYDROCNLORIOE,
N. N.D. 1960.
I.Eapectmr~mt: Phenergan HCI 5 mg.,
cphrine HCI 5 mg., ipecac fldxt. O.17
,,,
PHENETRONWUECTABLE.(Larrrrett)
Cblorpheairamine
●aleate 100 ❑g. /cc. Vial 5 cc.
FNENETSAL,N.N. R. 1948.
Tab. (Winthrop Labs. )
See: Salophaar,
.ZW4ESULFATE,N. N.O. 1%3. Uono.
,xidaseietribitor,beta-phenylethyl.
ne scrllatm. Se.: Nardil (Varner-Chilcoff)
NE. (Wyeth)Pherrergan
4.5 fig., codeine
., ipecacpow.eat. 2.3 ❑g., Pot.
*
:.
‘k
;
Broxil (Be~ham Res. )
Chamipam, Tab. (Squibb)
Oarcil (lfyefh)
Oramcillirr-a (White)
Mazipm, Tab. (Roering)
Ro-Cillin, Tabs. (Rowell)
Samopam, Tab., Pow. (Massesrgill)
Syocilli8, Tab. (Bristol)
nalgesic, anesfhelic.
ETRAZINE 61TARTRATE. Calolie
0.3/Tab. See: Plegine(Ayerst Lab.)
?INE. (NacAllisler) Amphetamine sulfate.
:zpeclorant.
CAN EXPECTDRAHT TROCHES W
W/Codeidephosphate.
-+caf-
Sea: Anteaee, Syr. (Sqeibb)
S/Scepoiamine HBr.
SW Nira-flracane,Tab. (Nion)
●FNENIWMEMALEATE, N. F., N.N. 0.
1.9S3 Tab., ft. F.; Ophfb, Sol., N. F. l-Phenyll-(2$yridyi)-3di
metfryiaaino-prepme maleate.
[email protected]
Se~ iahistma (Upjohn)
Trimefen (Scherirrg)
l/Acetopfrenettdia,
aspirin, phenobarbital,
Iryescyamiae
sraifate, pherrylepfrrine HCI.
See: Pbenapbee Plus, Tab. (Robies)
W/A-moniun chloride, Sod, citrate & chloroform.
W
Trimefoaa, Syr. (Schacing)
W/d-Amphefamirre sulfate, chloroform, ■enthol
1 alcohol.
See: Tuaaate, Syr. ( Pifmao+oere)
W/Dibydrocodeinaax bibrfmte, Pot guaiacoi
sulforrate, Sod. citsate, citric acid & chloroform.
See: Trrsaar, Liq. (Armrrrr)
W/Dikydrocedeieena bitra[trate, ViL C, pyrilamine
meleatepet citrate.
See: Cilra Forte. (Boyie)
W/Oihydrocodeinone bi tratrale, phenyiproparrolamiaa HCI, pyfilamiae ■alaete, ~iyceryl @aiacelate, chlorolom.
[email protected] Tesaamioic EapectoraaL SYP. (SmiffrDarsq)
W/Dibydrocedeiaerrc bifartrafa, pyrilaoime ●aleate,
Ptreqiaqrhriae HCI, pet. gsaiacel-aulfeeate,
cherry flavor.
Sea: Nova-Tusaa, Liq. (Orog Specialties-prams)
W/Doayiamime aeccitrate, pyrilamirre ❑aleate.
Se. Tfidecamine, Tab. (Natioaal}
W/Ephedrima sulfate& ammonium cbioride.
SW Exfeses, Syr. (Sqoibb)
W/Glyceryl gaaiacolate, [email protected] HCI k
codeine phosphate.
See: Robitossirr A-C, Syr. (Robins)
W/Hesparidie, ascorbic acid, fhenylpylamhae
fusarate, pyrilamine malaate, salicyiamide,
caffeine. See: Tripac, Cap. (Person & Covey)
W/Heaperidirr, phenylephrine HCI, mefhapyriiene
HCI, pyrilamine ❑aleale, vit. C, salicylamide,
acetophentidin, caffeine.
S*
Beyfe Citra , Caps. (Boyle)
W/Narcotioe, phenylephrina HCI, chloroform,
●axrtfm1, See: Conar, Liq. (Uassengill)
W/Pheeylephrine HCI.
Sao Isohist, Ophttr. Sol. (Btoemmel)
W~henyleplrrine HCI.
SW: Phenistan, Tab. (ChicagoPharm.)
W/PhenylephrineHCI, acefyl-p-asinephenol,
atropirresulfate.
Sea: TPC, Tab. (TennesseePharm.)
W/Phenylephrine
HCI, metfxapyrilene
HCI, pyrilamine ❑aieate, aspirin, acetophenetidin,
caffeine, Vit. C, hesparidin.
See: Darbacin, Cap. {Crestmed]
W/Pharxyfephrina HCI, pyrilamine o
ascwbic acid. Sea: Corizahi st,
W/Pbanylapfarime HCI, pyrilamine n
■etiapyrilene HCL
SeG Citra H. F., Cap. (Boyle)
W/P!ramyfephfine HCI & A. P. C.
WA. P. C., Cap. (Pitnan-Moore)
See: Novahistine
W/Pbecrylephrirre HCi, chloroform ‘
See: Novahistine, Eliair. (Pitm
WIPharaylprepanoiamine HCI, glyc
See: Daraffaorr, SOL (Grail)
W/Pbenylswepanolamine HCi, pyril
See: Triadaic,
Preps.
WPhenylpropanolamine
pyrilamine
Sac
(Smith-[
HCI,
phen
●aleate.
Symer~en, Elix. (Lemmon)
E/Pfrenyipropanolamine
HCI, phen
pyrilauine aaleate, acefyl-p-aml
Seat Phaeagesic (Dalin)
W/Pyrilamine ■aleate.
See: Triaminic,Tab. (Serith-Oo
V/Pyrilamine maleate, dioxyiamin
Se. Tridecamine, Tab. (Merrel
W/Pyrilamine ■aleate & ❑ethapyri
Sex Incorpehist Tab. (Blue L
Ptitafriat,
Syr. (Columbus)
Pyma limed, Cap. (Testagar)
W/Pyriiamine ●aleate, phenylprop
See: Triailer, Tab. (Lemor)
W/Pyrilamine Italeate, phenylprop
trisalfapyrim idines.
SW. Trisulfaminic,
Prep. (Smit
W/pyrilamine Ualeate & phenyltoh
dihydro~en citrafe.
SW Uultibist, Cap. & Syr. (srr
W/Saiicylamide, acetophenetidin,
ascorbic acid, hesperidin purifit
SW Coryban, Cap. (Roerig)
W/Scopolamine hydrobromide, alum
gei, ethyl aminobenzoate.
k
Daptren, Tab. (Davis h S1
V/Thanylpyramine HCI, pyriiamin[
phenylpropanoiaraine.
See: Histene, Tab. (Paul Ilan[
V/Tyrothricio,
neomycin, benzoc
K.
Nae-T-Cairr, Lozenges (C
W/ViL C, aspirin& aitraiizing ba
k Cehistra, Tab. (Organon)
FNEtflRATAN.(Irwin, Neislu)
tannate15reg./Tab. BoL 100!
Use: Antihistamine.
HBr. 3, 44ihy{
“Pt4ENfSOt40NE
isopropylaminopropiophenone H
SeK Oapanone HBr (Merck, Sh;
FNENISTM.
(Chicago Pharm.)
❑al
10BE., prophenpyfldamine
tab. fJol. 50s, 100s, 1“W ‘
e
.——.
end of the tstrauon, as Lncucaror. nepew
ux
UPCIWUIJ
v----
*
..-
-—
------
..--.
..—
_
.
between the titrations represents the amount of iodine
required. Each ml of 0.05M ti&e
P’S is equivalent ro
5.857 mg of C8H1ZN2,H2S04.
produce 25 ml. To 10 ml add 10 ml of-m&i phosphate
buffir pH 4.0 and 10 ml of 0.0 lM rbdine VS and titrate
immediately with 0.01 M sodium rhzimtdphate VS using
starch mucilage, added towards the end of the titration,
Storage Phenelzine Sulphate should be kept in a wellclosed container and protected flom Iighr.
as indicator. Repeat the operation without the substance
being examined. The difference between the titrations
without the substance being examined. The dilYerence
Preparation
Phenelzine Tablets
Action and use Monoamine
oxidase inhibitor.
represents the amount of iodine-absorbing substances
present. Each ml of 0.01 M sodium thrbsrdphate VS is
equivalent to 0.425 mg of iodine-absorbing substances.
Water Not more than 1.s~o wiw, Appendix IX C. LJse
1.5 g.
Phenethicillin
Potassium
402.5
c~#r~l#N~o~s
132-93-4
Definition PhenethicWn
Potassium is potassium (6R.S9[(2S)-2-phenoxypropionarnido]penicillanate.
It contains
not less than [email protected]/o and not more than 100.5°/0 of
C ~7H~9KN205S,
cafctdateci
anhydrous substance.
Characteristics
with reference
[0 the
A white or almost whiIe powder.
Freely soluble in warn, sparingly soluble in ethanol
-.
(96%); slightly soluble in absolute ethanal and in chlaroform; practically insoluble in ether.
Identification A. The itiamd absmptiors spectrum,
Appendix II A, is concordant with the mfkrence spectrum
of phenethicillin potassium.
B. Dissolve 10 mg in 10 ml of water and add 0.5 ml of
neutral red solutwn. Add sufficient 0.01 M sodium hydroxide
to produce a permanent otange colour and then ~dd
1.0 ml of fwrsidbaase so[utaim. The colour changes rapidly
Assay Dissolve 0.25 g in sufficient water to produce
500 ml and dilute 10 ml to 100 ml with waser. Place two
2-ml aliquots of the resulting solution in separate
stoppered tubes. To one tube add 10 ml of imr&zzob-mercuy reagent, mix, stopper the tube and immerse in a
water bath at 60° for exactly 25 minutes, swirling
occasionally. Remove fkom the water bath and cool
rapidly to 20” (solution A). To the second tube add
10 ml of water and mix (solution B). Without delay
measure the absorbance of solutions A and B at the
maximum at 325 nsn, Appendix II B, using in the
10rnlof
reference ceil a mixrure of2rnlofwaterand
imtdazo~
rsagenrfor solution A and warm for
SOhLbOSL B. Cahdate
d’Lecontent of CITHlg~zO#
from the difference between the absorbance of solutions
A and B, horn the clMerence obtained by repeating the
operation using pheneshiciflin potassium BFCRS in place
of the substance being examined and horn the declared
content of C 17H 1JCF1205S in phenethicdin potassium
BXRS.
Storage Phenethicillin
well-closed container.
Porassium should be kept in a
Labelling The label states (1) the date after which the
materiai is not intended to be used; (2) the conditions
under which it should be stored.
Preparationa
PhenethiciUin Capsules
Phenethicillin Tablets
/
??3
H
Ot..’
Pf
Action and use Antibacterial.
to red.
C. Heat 0.5 g with 10 ml of 5M hydrochbti acid under a
reflux condenser for 4 hours, cool, add a rnixrure of 7 ml
of 5M sodium hydmnde and 7 ml of wawr and extractwith
successive 1O-ml quantities of ether until complete
ether
extracrs
extraction is effected. Washthecombined
witiwaur,filter through anhydrous sodium stdphare and
evaporate the filtrate to dryness. The meln”ngpoinr of the
residue, after recrystallisation horn petroleum spirit (boding
range, 40° to 600), is about 116°, Appendix V A.
D. Ignite. The residue yields the reactions characteristic
of potassium sa.k, Appendix VI.
Phenindamine
Tartrate
o
‘1
;H
HOOC
~
NMe
H
Acidity or alkalinity pH of a 10O/.wjv solution, 5.5 to
7.5, Appendix V L
Specific
optical rotation In a 1“k wfv solution in a
solution containing O.2°/0 WIVof diporassium hydrogen
orrhophasphate ~d O.80/0 WIVOfpotasn”umdihydrvgen
orrhophosphate, +2 17° to + 244°, calculated with reference
to the anhydrous substance, Appendix V F.
—_
Iodine-absorbing
substances
Not more than 3%,
calculated with reference to the anhydrous substance,
when deretmined by the following method. Dissolve
Q&
and enantiorner
c,9H~9N,c4H~o~
411.5
569-59-5
Definition
Phenindarnine Tartrate is (RS)-2,3,4,9teuahydro-2-methyl-9
-phenyl- 111-indeno [2, l-c] pyridine
hydrogen (2 R,3R)-tartrale.
It contains not less than
98.50/. and not more than 101.OO/. of C19H19N,C4H606,
http://igm-06.tdm.nih. gov/cgi-bWGM<limt?
httpl/igm46.dm. tih.g.. .M-client?1090Wdetail+ 1
MAIN MESH
SUBJECTS:
lO9OO+debil+ 1
Histamine HI Antagonists/* PHARMACOLOGY
Psychomotor Performance/*DRUG EFFECTS
.—- -. --- --. ,
http://igm-06.nhn.nih,g.,, M-c1ient?lO9OO*[email protected]+l
http:/&yn-06mlm.nih. gov/cgi-bin/’IGM-elient? 10900+detaiI-
National Library of Medicine: IGM Full Record Screen
<[email protected],....,..:.,:
,,,,,, ~ :::~~eji;:;:
:.
Wmdw :67.7’;+&W“;<::m
“:
w=
la
.~,; ,&#$#:: j ‘,’#$#;
Q=DRQ
,:$” ,8?$F*=2’
.~~~gg~$ *em:%;:?:”:
:,:,.fi~~j~
.~!.m.%%.
.j.,.,.,..:.,,.,,~~~+j:
E!
TITLE:
The effects of phenindamine
performance.
AUTHOR:
Witek TJ Jr; Canestrari DA; Miller RD; Yang JY; Riker DK
AUTHOR
AFFILIATION:
Regulatory and Clinical Development, Richardson-Vicks
& Gamble Company), Shelton, Corm.
SOURCE:
J Allergy Clin Immunol 1992 Dec;90(6 Pt 1):953-61
NLM CIT. ID:
93094481
ABSTRACT:
tartrate on sleepiness and psychomotor
USA (A Procter
Phenindamin~
Hi-receptor antagonist that was developed almost 50
-—
——
years ago, has been associated with both drowsiness and insomnia. Since its
central nervous system profile has not been well characterized, we used a
series of psychomotor tests to conduct two studies. In the first, 12 subjects
received single oral doses of phenindamine (25 mg), diphenhydramini
(5o
mg), terfenadine (60 mg), or placebo in a four-way crossover study.
Psychomotor tests included choice reaction time (CRT), tracking, and hand
steadiness (HS). In the second trial, 15 subjects received single oral doses d
pheninda~
(25a
eudoephedrine (60 mg), phenindamine and
pseudoephedrine, diphenhydramine (50 mg), or placebo in a five-way
[email protected]
Psychomotor tests included CRT, HS, and a task thfi—
divided attention between tracking and reaction time. Introspective
drowsiness was measured in both trials with use of a visual analog scale
(VAS) and the Stanford Sleepiness Scale (SSS). All assessments were made
before and 1,3, and 5 hours after drug administration. In the first triall
diphenhydramine produced significant impairment relative to placebo
—— (p<
‘1).05) in CRT, tracking, and HS tasks and higher SSS and VAS scores. with
peak effect noted at 3hours. Phenindamine did not significantly differ from
placebo or terfenadine, In the second trial. diDhenhvdramine nroduced
~.. _—_. —
slmnticant imDairme]
nt rela-pl~ebo
“(p < 0Q05;in CRT, divided
.
‘attention, HS , and VAS, and SSS, also pealfing at 3 hours. Stanford
Sleepiness Scale scores afte~phenindarnine we~e greater than placebo at 3
less than
diphen
lours (p < 00.5)” but significantly
hydramine (p <
.05).(ABSTRACT TRUNCATED AT 250 WORDS)
A
4-
irv
http://igm-06.nlm.nih. gov/cgi-b~GM*lient?
http//igmJ36.nlm. nih.g. ..M-client? 10900+detail+ 1
MAIN MESH
SUBJECTS:
Histamine HI Antagonists/* PHARMACOLOGY
Psychomotor Performance/*DRUG EFFECTS
Pyridines/*PHARMACOLOGY
Sleep/*DRUG EFFECTS
ADDITIONAL
MESH
SUBJECTS:
Adolescence
Adult
Diphenhydramine/PHARMACOLOGY
Ephedrine/PHARMACOLOGY
Human
Middle Age
Time Factors
PUBLICATION
TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED
—
——.
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Histamine H1 Antagonists)
O(Pyridines)
299-42-3 (Ephedrine)
58-73-1 (Diphenhydramine)
82-88-2 (phenindamine)
10900+detail+
TRIAL
—
...
2of2
5/598
12:19 P
http://igm-06.nlm,
nih.g..
http:/figm-06.nlm,nih. gov/cgi-bin/lGM4ient?
.M-client? 10900+detail+ 1
lO9OO+detail+1
[Various principles of therapeutic tactics in epilepsy patients during
pregnancy]
AUTHOR:
Sigidinenko
SOURCE:
Zh Nevropatol Psikhiatr 1984; 84(6):897-9
NLM CIT. ID:
84276611
ABSTRACT:
LV
Forty-two epileptics were examined during pregnancy. According to the
severity of the paroxysmal symptomatology, the authors identified three
clinical groups: the first included patients with a therapeutic remission; the
second, those with non-convulsive paroxysms; and the third group
comprised patients with convulsive paroxysms. With due regard for
impairments identified in the blood content of neurotransmitters, the
patients received the multiple modali ty treatment, which included vitamins
of group “B”, potassium orotate, antihistamine drugs, the substitution of
chloracon for phenobarbital and benzonal for diphenylhydantoin
sodium;
at the laters=
e of pregnancy the patients were given phenindami~
tartratg. The use of them ultiple modality treatment facilitated the cessation
exacerbation in patients
. of attacks and served as the prevention of ep~tic
during the vestational and D~H*“——–—’
—
MAIN MESH
SUBJECTS:
Anticonvulsants/*ADMINISTRATION
& DOSAGE
Epilepsy/BLOOD/* DRUG THERAPY
Neurotransmitters/* BLOOD
Pregnancy Complications/BLOOD/*
DRUG THERAPY
ADDITIONAL
MESH
SUBJECTS:
Adult
Drug Therapy, Combination
English Abstract
Epinephrine/BLOOD
Female
Histamine/BLOOD
Human
Norepinephrine/BLOOD
Pregnancy
Serotonin/BLOOD
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Rus
REGISTRY
NUMBERS:
O (Anticonvulsants)
O (Neurotransmitters)
50-67-9 (Serotonin)
51-41-2 (Norepinephrine)
51-43-4 (Epinephrine)
51-45-6 (Histamine)
—_
—
.-.
2of2
5/5,98 12:24 pM
http://igm-06.nlm.nih, gov/cgi-bitiGM-elient?
http://igm-06mlm.nih.g... M-client?l O9OO+detiil+l
10900+detail+ 1
National Library of Medicine: IGM Full Record Screen
.-—y=
❑
*~*p,(;;~:.
:\,*jl:@f*qg-””;:.,:””’.
,) : ‘qw.i
#-#,,.,:iG
,6?,..,,,:
‘,y~~; ::
w
#w
““tiwwf$’fi: ‘-- Xmfijm;’”::’;
““’””’
“w:w:z;.’
::: ..:.:::;#*[email protected]:
“[email protected]?’:#?l!i&::“’””’@#Wi#i$F?
.==,:t*[email protected]:Btts :..,’swm*’w”;”’”’”
,.,.......WMZ.
QnD--
E
TITLE:
The structure of phenindamine
AUTHOR
Branch SK; Casy AF; Hussain R; Upton C
AUTHOR
AFFILIATION:
School of Pharmacy and Pharmacology,
SOURCE:
J Pharm Pharrnacol 1988 Jan;40(l):83-4
NLM CIT. ID:
88214661
ABSTRACT:
High-field NMR (13C and lH) studies of phenindamine are reported
which establish structuresof the free base and some of its salts in the
solute condition. The base exists as a mixture of two isomers which
differ in double bond position (9-9a or 4a-9a) while most salts are 9-9a
isomers. The clinically employed tartrate (Thephorin) is exceptional in
being a 4a-9a ene. Salts of both double bond type exist in solution as
mixtures of protonated epimers of variable epimeric ratio, that of the
tartrate in D20 being approximately 1:1.
MAIN MESH
SUBJECTS:
Pyridines/*ANALYSIS
ADDITIONAL
MESH SUBJECTS:
Chemistry
Crystallization
Nuclear Magnetic Resonance
Spectrophotometry, Ultraviolet
PUBLICATION
TYPES:
JOURNAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyridines)
82-88-2 (phenindamine)
..—.
base and salts in the solute state.
University of Bath, Bath, UK.
ARTICLE
—
....
5/598 12:22 PM
—
PIRAC ETAM
B. Chemical Name:
l-Acetamido-2-Pyrrolidinone, Euvicor, Gabacet, Genogris, 2-Ketopyrrolidine-l Ylacetamide, Nootro~ Nootropil, Nootropyl, Norrnabraiq 2-Oxo-Pyrrolidine-Acetamide,
2-Oxo-Pyrrolidin-l -Ylacetamide, Piracet~ Pirazet~ Pirroxil, Pyracetw Pyramep 2Pyrrolidininnoneacetamide, 2-Pyrrolidoneacettide,
UCB 6215
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
i%~y: 99.27%
——_
E. Information about how the ingredient is supplied:
White or almost white crystal powder
F. Information about recognition of the substance in foreign
pharmacopoeias:
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Mondadori, C. Nootropics: Preclinical Results in the Light of Clinical Effects; Comparison
with Tacrine. Critical Reviews~ in Neurobiology, 1996; 10:357-370.
Tallal, U., Chase, C., and Russell, G. Calculation of the Efficacy of Piracetam in Treating
Information Processing, Reading, and Writing Disorders in Dyslexic Children.
Intemationd
Journalpf
Psychophysiolo~,
1986; 4:41-52.
Mindus, P., Cronhol~ B., and Levander, S. E. Piracetam-induced improvement of mental
performance: a controlled study on normally aging individuals. Acts Psychiat. Stand,
1976; 54(2): 150-160.
.—
SimeoL J., Waters, B., and ResnicIq M. Effects of Piracetam in children with learning
disorders. PsychopharmacoLBuil., 1980; 16:65-66.
Stegi~ K. J., The clinical use of [email protected] a new nootropic drug: the treatment of senile
involution. Arzneim-Forsch, 1972; 22:975-977.
Wilsher, C., Atkins, G., and Mansfield, P. Piracetam as an aid to learning in dyslexi%
preliminary report. ~sychcyhwrnacolo~. 1979; 65:107-109.
Wdsher, C., Atkins, G., and Mansfield, P. Effkcts of [email protected] on dyslexic’ reading ability
J. Learn. Disability. 1985; 18:19-25.
Mondadori, C., Petschke, F., and Hausler, A. The Effkcts of Nootropics on Memoty: new
Aspects for Basic Research. Pharmacopsychiatry. 1989; 22:102-106.
YaI, V., Derzhirulq L. P., and Mogilevskii, A. Piracetam-induced changes in the
fictional activity of neurons as a possible mechanism for the effects of nootropic agents.
Neurosci Behav. Physiol., 1996; 26(6): 507-515.
Pepeu, G. and Spignoli, G. Nootropic drugs and brain cholinergic mechanisms. Prog.
Neuropsychopharmacol
Biol. Psychiatry.
1989; 13Suppl: S77-78.
—_
Pilc~ H. and Muller, W. E. Piracetam elevates muscarinic cholinergic receptor density in
the frontal cortex of aged but not of young mice. Psychopharmacology.
1988; 94(l): 7478.
De De~ P. P., Reuck, J, D., and Deberdt, W. Treatment of acute ischemic stroke with
Piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Stroke.
1997; 28(12): 2347-2352.
Di Ianni, M., Wilsher, C. R., and Bla& M. S. The effects of Piracetam in children with
dyslexia. J Clin Psychopharmacol. 1985; 5(5): 272-278.
Wilsher, C. R., Bennett, D., and Chase, C. H. Piracetam and dyslexia: effects on reading
tests. J. Clin Psychopharmacol. 1987; 7(4): 230-237.
Reisber~ B., Ferris, S. H., and Gershon, S. An overview of pharmacologic treatment of
cognitive decline in the aged. Arn J. Psychia~ry. 1981; 138(5): 593-600.
Bartus, R. T., Dew R. L., and Sherrmq K. A. Profound effects of combining choline and
Piracetam on memory enhancement and cholinergic finction in aged rats. Neurobiol
[email protected]”ng. 1981; 2(2): 105-111.
—
Page -2-
.—
O. and Bures, J. Piracetarn-induced fwilitation of interhemispheric transfer of
visual tiormation in rats. Psychopharmaco/oH”a. 1976; 46(l): 93-102.
Buresov~
Dimond, S. J., SCarnmell,R. E., and Pryce, I. G. Some effects of Piracetam (UCB 6215,
1979; 64(3): 341-348.
Nootropyl) on chronic schizophrenia. Psychopharmacolo~.
Dirnond, S. J. and Brouwers, E. M. Increase in the power of human memory in normal
man through the use of drugs. Psychopharmacology. 1976; 49(3): 307-309.
Sar~ S. J., David-Remacle, M., and Weyers, M. Piracetam facilities retrieval but does not
impair extinction of bar-pressing in rats. Psychophannacolo~.
1979; 61(1): 71-75.
Brandao, F., Paula-Barbow M. M., and Cadete-Leite, A. Piracetam impedes neuronal
loss withdrawal after chronic alcohol intake. Alcohol 1995; 12(3): 279-288.
Mindus, P., Cronholp B., and Levander, S. E. Does Piracetarn counteract the ECTinduced memory dysfunctions in depressed patients? Acti Psychiatr. Stand 1975; 52(5):
319-326.
Mondadoori, C., Classen. W., and Borkowski, J. Effkcts of oxiracetam on learning
memory in animals: comparison with piracetam. C/in Neuropharmacol. 1986; 9 Suppl 3
S27-38.
Song, C., Earley, B., and Leonard, B. E. Effect of chronic treatment with piracetam and
tacrine on some changes caused by thymectomy in the rat brain. Pharmacol Biochem.
Behav. 1997; 56(4): 697-704.
H. Information about dosage forms used:
Patients received either 3.3 g of Piracetarn daily or matching placebo syrup. Each dose of
test medication was 5 ml. administered before breakfast and again before the evening
meal. A 5 ml dose of active medication contained 1.65 g of Piracetam. No dosage
adjustments were allowed. The patient’s parents were contacted to review dosage
instructions and to determine whether any adverse effects had been observed.
I. Information about strength:
1.65 g-3.3g
J. Information
about route of administration:
Orally
—
Page -3-
K. Stability data:
.
L. Formulations:
M. Miscellaneous
Information:
See File
—
—-
Page-4--———., -
—
.—
——.
.—-,
>_ ..-.
..Uc — — ..—.
-.
.A
.
-. . ..
___
“~—-
.._.
.—
.G.. _.:.
.
— —..
—
—_—
.—
“-
.
..
. . .
-
-.
— ——
..-_—
.——
-—.
.=-
.-
..
__
.——
..—
— :-__—
—.. — .—. ———
..
- . ~=——
- .--e_——_
;.._ “.—
.:
-—
.
-—.---—
..-
..—
_
—
.——-—- _=—.
:
.—=
-. —...———
.—-..__
.
.—
—--————
-----. .- -—.-=.
.-L.
:._—
.-:.=
—..—.
—. —-—
----——- =.. -----—--—-.
____
——
-.—
~.-
u_——.——
_..
-.
-—.
-. ---
–..
_
..
—.
- .== . _.=_-—=
—.---l
.-..—
-—.
.
——.----=——
“-——
.. .—.—.—
..—
.-—
.-. i\
—.
..—
. .. —.—.
CERTIFICATE OF ANALYSIS
—-..
Coa No: 7777
““‘+
f-
-~
Batch No: 96120006
,
Manufacturing Date: Dee-3, 199
>
Testing Result
4ppearance
dentification
delti.ng Poim
llrity of Solution
kavy Metals
,
whitecrysta,
powder
-
=oslUve
152.5-153.5°C
Clear
<
ksidue On Ignition
A3sson Drying
20ppm
0.02%
0.12%
99.27%)
!YM-
~onforms
marks=
/
—------
Standard
The above Ewing result is per rnanufacmrer’s
‘
inforrnarih&
.
.,,
,
—
—
.—=
,>
.- .——.—
—
...—.-
—.-—
——
=——-.
——= - --—.
--—=-.
_____
CONTROL REPORT
QUALITY
CHEMICAL
NAME. : PIRACETAM
MANUFACTURE
LOT NO. :97060036
PHYSICAL
SPECIFICATION
TEST
STWARD.
:USP
l)DESCRIPTION
.:
WHITE TO OFF WHITE CRYSTALS
CRYSTALLINE
POWDER.
2)SOLUBILITY.
:
VERY SOLUBLE
IN
_—&%_
WATER;
—— /BP
TEST
/mRcK —— /NF
FROM ISOPROPANOL
SOLUBLE
IN
ALCOHOL,
/MART ._/co. spECS._.
OR WHITE
ESPECIALLY
TO OFF
IN
ISOPROPANOL.
3)MELTING POINT.:
MELTS AT ABOUT 151.5-152.5 degree.
4)SPECIFIC
GRAVITY.:
5)IDENTIFICATION .:
A)
COMPLIES
IR
SPECTRUM
AS
PER
COMPANY
SPECS.
FAILS.
PASSES. :
:
COMMENTS
.:
ANALYST
PF!JZPACK TEST.:
RETEST. :
DATE. :
SIGNATURE.:
DATE. :
DATE. :
INITIAL.
INITIAL.
WHITE
:
:
.4=
------------------ IDENTIFICATION ------------------NAME:PIRACETAM
PRODUCT#: P5295
CAS #: 7491-74-9
MF: C6HION202
SYNONYMS
%
*
I-ACETAMIDO-2-PYRROLIDINONE* EUVIFOR * GABACET* GENOGRIS * 2KETOPYRROLIDINE-1-YLACETAMIDE* NOOTRON * NOOTROPIL* NOOTROPYL
NORMABRAIN* 2-OXO-PYRROLIDINEACETAMIDE* 2-OXO-PYRROLIDIN-1-
YLACETAMIDE * PIRACETAM
PYRAMEM *
2-PYRROLIDINONEACETAMIDE
.=W.
* PIRA2ZTAM
* PIRROXIL
* PYRACETAM
* 2-PYRROLIDONEACETAMIDE
*
* UCB 6215 *
------------------ TOXICITYHAZARDS------------------RTECS NO: UX9660500
1-PYRROLIDINEACETAMIDE,2-OXOTOXICITYDATA
PCJOAU23,795,89
IPR-MUSLD50:>10GM/KG
KHFZAN 11(8),132,77
SCU-MUSLD50:12GNVKG
KHFZAN 11(8),132,77
IVN-MUSLD50:10 GM/KG
RPTOAN47,205,84
IVN-CATLD50:10GM/KG
RPTOAN44,22,81
UNR-MAMLD5O:>1OGM/KG
ONLY SELECTEDREGISTRY OF TOXIC EFFECTS OF CHEMICALSUBSTANCES
(RTECS)
DATA IS PRESENTEDHERE. SEE ACTUALENTRY IN RTECS FOR COMPLETE
INFORMATION.
------------------ HEALTHHAZARDDATA ----------------ACUTEEFFECTS
MAY BE HARMFULBY INHALATION,INGESTION,OR SKIN ABSORPTION.
MAY CAUSEIRRITATION.
EXPOSURECAN CAUSE:
CNS STIMULATION
THE TOXICOLOGICALPROPERTIESHAVE NOT BEEN THOROUGHLY
INVESTIGATED.
FIRST AID
IF SWALLOWED,WASH OUT MOUTH WITH WATER PROVIDEDPERSON IS
CONSCIOUS.
CALL A PHYSICIAN.
TNCASE OF SKIN CONTACT,FLUSH WITH COPIOUS AMOUNTSOF WATER
FOR AT LEAST 15MINUTES. REMOVE CONTAMINATEDCLOTHINGAND
—_
SHOES CALL A PHYSICIAN
IF INHALED,REMOVE TO FRESH AIR IF BREATHINGBECOMESDIFFICULT,
—=.
CALL A PHYSICIAN
IN CASE OF CONTACTWITH EYES, FLUSHWITH COPIOUS AMOUNTSOF WATER
FOR AT LEAST 15MINUTES ASSUREADEQUATEFLUSHINGBY SEPARATING
THE EYELIDS WITH FINGERS,CALL A PHYSICIAN.
–—-=
.—-
-------------------- PHYSICALDATA -------------------APPEARANCEAND ODOR
SOLID
------------ FIRE AND EXPLOSIONHAZARDDATA ----------EXTINGUISHINGMEDIA
WATER SPRAY.
CARBONDIOXIDE, DRY CHEMICALPOWDEROR APPROPRIATEFOAM.
SPECIALFIREFIGHTINGPROCEDURES
WEAR SELF-CONTAINEDBREATHINGAPPARATUSAND PROTECTIVECLOTHING
TO
PREVENTCONTACTWITH SKIN AND EYES.
UNUSUALFIRE AND EXPLOSIONSHAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS.
------------------- REACTIVITYDATA ------------------STABILITY
STABLE.
HAZARDOUSCOMBUSTIONOR DECOMPOSITIONPRODUCTS
THERMAL DECOMPOSITIONMAY PRODUCECARBONMONOXIDE,CARBON
DIOXIDE,
ANDNITROGENOXIDES.
HAZARDOUSPOLYMERIZATION
WILL NOT OCCUR.
--------------- SPILL OR LEAK PROCEDURES-------------STEPS TO BE TAKEN IF MATERIALIS RELEASEDOR SPILLED
WEAR PROTECTIVEEQUIPMENT.
SWEEPUP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOID RAISINGDUST.
VENTILATEAREA AND WASH SPILL SITE AFTERMATERIALPICKUP IS
COMPLETE.
WASTE DISPOSALMETHOD
DISSOLVEOR MIX THE MATERIALWITH A COMBUSTIBLESOLVENTAND BURN
INA
CHEMICALINCINERATOREQUIPPEDWITH AN AFTERBURNERAND SCRUBBER.
OBSERVE ALL FEDERAL,STATE, AND LOCALLAWS
--- PRECAUTIONSTO BE TAKENIN HANDLINGAND STORAGE--WEAR APPROPRIATENIOSI-UMSHA-APPROVED
RESPIRATOR
CHEMICAL-RESISTANT
GLOVES, SAFETYGOGGLES,OTHER PROTECTIVECLOTHING
-
MECHANICALEXHAUSTREQUIRED
CAUTION
AVOID CONTACTAND INHALATION
THE ABOVEINFORMATIONIS BELIEVEDTO BE CORRECTBUT DOES NOT
PURPORTTO BE
ALL INCLUSIVEAND SHALLBE USED ONLY AS A GUIDE SIGMAALDRICH SHALL
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
II S61U0 wws
/
o
I
I
alup(tn
I
II s6n.Ju
I
J.Jews
(ulxOdAq-180d)M]nuln
OW
-1’-”
012
08L
OSL
“’ --L—--L-–—L--–-
021
‘
06
–-
09
~
Wlleag
WX~~H
t?o1
Wlpmla
P~N
.—- -’-–—’——
1
T
/
//-
I
ule]aoelfd
aiepclfl
II
,1
s6n~Q JJeWS
901
I
ump3eJld
●
lUCIEXX?Jid
( ,
~6Xld
1
1s
#
Oc
0
ZC
.9s
9s
St
92
11
1,,
I
,,1
“
111
saqMo-J ~
Jaleqiua6JoW ‘ueaa
“:)
II
s6nja pews
Ii
011
a6esoa
.luauIJyduJI
aApyJ803
qdal!da
pUnOJOJd
ioJluo301
%idmexa
]e
[email protected]
.saJo3s
MOi
u!s13aJJa
ap!s
asne3
fieSSaXNI
aAoJduJ!
JO~
ue3
s8nJp
ualJo
s8nJp
m]dailda-!~ue
Sasop
q8iq
uaIJo s+mpa.u
Ilq!qxa
aql
~!]d+da-!jue
asuodsaJ-asop
.JaUUtJW
SAgyJ803
‘saJnz!as
le ‘JSAaMOH
Kuew
‘sasop
f)-paJJ~AU!
aql
~!jdai!da-!]uv
j
II s6nJo J.JeWS
ZL1
I
I
Nootropics: Preclinical Results in the Light of
Clinical Effects; Comparison with Tacrine
k
Cesare Mondadon’
Hoechst Marion Rousse[, CNS Research, P. O. Box 6800, Bridgewater.
NJ 08807+800
ABSTRACT: This review is meant to serve several purposes. FiZ-SLII sumcys tbe prechnical and clinical
profiles of piracetarn-like nootropics. Second. the conditions under wtuch tie nootropics Me active in preclimcal
studies are identified and analyzed with a view to finding a common denominator that could explain the
observed effects. Third. the clinicaI profile is examined, on the one hand to assess wherher these drugs are In
fact active in humans, and on the other to determine how the clioical effects of the nootropics compare with
those of tacrine. Lastly. the clinical data are then further scrutinized to =sess whether the) fulfill the expec(auons based on the preclimcal findings.
KEY WORDS: Noorropics.
responders, nonresponden
INTRODUCTION
—
piracecarn. oxiracetam.
pranuracewrs.
armcaam.
wnne.
prtclinical.
mind. and .Topos. toward. and thus reflects not a
class of chemical structures, but the supposed
effect of these compounds on cognitive processes,
II is consequently inevitable that a cetuin tendency exists to attach this label to all memoryenhancirg substances (for a comprehensive review, see references 3,4).
The present review is devoted entirely to the
piraceta.rn-likepreparations and focused on their
direct nomopic effecu. i.e., the spectrum of effects on the memory of intact animals, rather than
on their mechanism of action. The laner aspect
was the subject of recent reviews.fJ Since it is
impossible to assess the activity of a substance
withou[ recourse to reference compounds, both
the preclinical and the clinical results are discussed on hat bask.
Tacrine,
theonlycompound
registered for the tremm-rentof 41zheimer’s disease. is la-kenas the sole reference drug for comptisons of the c1inic31results.
discovery of piracetam] shook faith in
Paracelsus’ famous axiom, “dosis facit venenum.”
This memory improving substance not only was
devoid of other biological activity but also had no
toxic effects whatever at doses up to grams per
kilogram of body weight. Even today, nearly 30
years after the dkcovery, the “nootropic” class of
substances newly created to accommodate piraceuun sdll splits pharmacologks into hvo camps.
For some, the absence of toxicity indicates a lack
of arty pharmacological action, while others see it
as pointing to a new therapeutic approach. Depending on the observer’s standpoint, either the
“nonresponders in clinical trials testify to the inefficacy of these agents, or the responders bear out
their activity. This controversy has severely hindered genuine scientific progress and has prevented full advantage from being taken of the
therapeutic potential of the nootropics.
Piracetarn islongsince
notthesolerepresenIl. PRECLINICAL EFFECTS
[aIive
ofthis
classlnthemeantimea :rea[
many
THE I’400TROPICS
su-ucrumll~
related
active
compoundshavebeen
- Synthesized.
con fmrung rhe need to assign tie
loomopic~ to a category of their own. The mm
noormp~c dentes from the Greek words noo~.
The
clinical.
OF
357
tion of central nystagmus in the rabbit.’ further
findings made during the past 25 years showed
that i[s main action consists in the improvement
of cognitive functions. The earliest srudies were
concerned with pharmacological modulation of
the amnesiogenic effects of a cerebral electroshock. When Giurgea and $louravieff Ixsuisseb
demonstrated that piracetam reduced the disrupting influence of ~ elec~oshock on [he orien~tion of rats in a water maze, this effect was taken
as an indication that piracetam improved memory
consolidation. Over the years, this antiamnestic
ac[ion of the piracetarn-like preparations has often been confmned. Studies with aniracetarn.’
oxiracetam,s prarniracetarn. and a series of analogues9 all showed a distinct pro[ec[ive action
against [he effect of electroshock on memory.
This rather indirect indication of a nootropic
action was supplemented and reinforced by findings showing a direct memory-enhancing effect.
A great many results emerged from experiments
in avoidance learning. For example, aniracetam
were found to
and piracetarn 10.I I ~d ofiaCetm12
exert direct effects on the acquisition and re[ention performance of rats and mice in both passiveand active-avoidance
paradigms.
Of particulu
value were the results of investigations in which
the preparations were administered immediately
after the learning trial (’post-trial’ ). In such conditions. the animal experiences the lemming situation without Ixing under the influence of the
dmg ~d is likewise u~nrluenced during tie retention test. .Anydemonstrable effect can then be
3.scribed to a direct action of the substance on
memory processes that ou[lasc the learning siruation for some time. Several experiments showed
[hat nootropics can improve the memory under
such conditions.’’”
The learning situations in which pirace[amlike nootropics were~ccive
were not limi[ed to
experiments involving 3voidance behakior. Pramimcetarn had positive effects in a place navigation task;s and was aiso found to improve the
acquisition rate in a 16-armradial maze. e whereby
[he ejfec: related exclusi~ely to reference memory.
not working memo~. A slight. but sigmficant.
effect of prarniracemm was also demon smble in
J delayed alternation ui31’ - .Anir3cet2m Iikwlse
display~ positive etfec:s in ~ mdial m.ue” md 3
H,J(chlng-[0-$ample [es[. 0}loreo~er. :t Am iounci
358
that piracetam and pmmiracetam improved performance in an object recognition
test.:o
.tiiracetam: 1and oxiracetarn22 were obsewed to
hay-eposi[ive effects in a social-recognition test
in rats,
In sum. from the data so far available it can be
concluded that the nootropics exert a distinct
memory-enhancing effect in various learning situations and in different animal species. In most
experiments the acquisition or storage of the information occurred under the inlluence of the
drug and retention was assessed ti”~eran intend
of at least one day. Effects on short-term retention
have been described (e.g.. in a delayed-alternationor delayed matching-to-sample task, and social recognition after short intervals), but these
observations
have not yet been confirmed.
A. Which Memory Processes Are
Facilitated by Nootropics?
The many experimental situations in which
nootropics have been asserted to exert a memo~mhancing action raise the question whether there
is a common denominator underlying all these
effects: such as a similar target process. or whether
even the whole spectrum of activity of the
oootropics is the same. The available evidence
would suggest that their activity spectra are not
identical, but at least very similar. inasmuch as all
dtese preparations improve passive avoidance::;’
and active avoidance, ‘2.3and all of them improle
retention performance. even if administered postrnal.13 The results of studies with post-trd Administration reveal a high degree of concordance:
it has been demonstrated that all four prototype
nootropics—oxirac etam, pirace[am, pramlra cetam, and aniracetam--can enhance memory
even if administered
Up to eight hours at”ter [he
learning trial, Ai”ter an interval of 16 hours. an
effect was no longer evident.13t4 [t can be infemed
that under these conditions
all these drug
~ffecr
a process that outlasts the learning situation by
more than S. but less than 16, hours (3 hypothejls
rela[ive to the process affected IS ~dvanced in
reference 111.The improvement in re[ention performance in 311these experiments was 3sscssed
.uler 24 or 72 hours. i.e . a[ a :lme when the
_nemory content IS gener311y S’dK!pOS~Li [0 \e
.—-*sent in a long-mm form. 1[was further shown
.1the retemion perr-ormanceof mice exposed [o
a learning situation tier receivin~ a single dose
of oxiracemm was distinctly bwer than rha[ of
controls even after one. two, or four months.~b
This finding lent additional support not only to
the assumption [h3i the substances ultimately
impro~’e long-term memory (Llll1storage.
bw
alsotothesupposition
that
after
incenals
of 1to
120daysmemory k based on the same substrate.
AISOin accord with the hypothesis that the
nootropics improve LTNl storage are the responses
evoked by prarniracetamlGand aniracetam’a in the
radial maze, in which solely effects on reference
memory were obsened. Thus, the only effects
remaining to be explained are those noted in the
delayed matching-te$ample test:’ and the improvements seen in the social-mco-tition [est after
a two-hour intend.:
[f these efi-ects hold good
for ail nootropics, the> can be taken as an indication that the facilitation of LTM is jus[ one aspect
of a whole range of activity; if not, they could
indicate differences in the activi~ spectra of the
‘—”ious
nootropics. Many indicanons of differ.es have been obsm’ed. Comparative studies
of pramiracetarn and etiracetarn. for example.
showed that only etiracetarn had effects on memory
retrieval.~7 Moreover. a long list of experiments
indicate quantitative and qualitati~e differences
in the biochemical activity spectrum of piracetarnlike nootropics42&w so that there is hardly cause
to expec[ such drugs to display an identical spectrum of activity.
Thus, the most obvious common feature
of
thenootropics
istheir
capacity to facilitate LTNf
storage. This conclusion is consistent with the
majority of the available preclinical results. Despite the high degree of similari~ in the observed
effects. some experimental findin~s do appear [o
indicate
differences
in the activl? spectra.
B. Effects
Those
of Nootropics
of Other
Memory
Compared
Enhancers
with
the ACE inhibitor capropril. the calcium antagonist
rtirnodipine.and the garnma-aminobutyric acid B
(GABABWceptor antagonist CGP 36742 in ~
passive-avoidanceparadigm ([email protected] I). It was sub
sequendy observed that all these LTM effects were
equally steroid sensitive: i.e., ex~rimenta.lly elevated aldosterone or corlicosterone levels suppressed the effects of aIl these memory enhamel !
to the same extent.n3t The pharmacodynamics of
oxiracer.am.arecoline, CGP 36742. and captopril
were sirrik there was an 8-hour drug-sensitive
window after the learning trial ([email protected] 2). Note that
the memoryahancing effect-sinducedby captopril,
CGP 36742. and the muscarinic cholinergic agonist arecolirte followed almost exacdy the same
pattern as that of oxiracetam, in that they were not
immediately detectable, i.e., not in evidence as
soon as the animals showed si=wsof retention. At
least a further 16-20 hounelapsed befo~ it emerged
(hem 3). This s~tising concordance in the frndings strongly suggests that all four of these drugs
affect the same process.
By analogy with the results obtained with
oxiracetam. it seems reasonable to assume that
the process in question is LTM storage. This conclusion is proposed purely as a possible common
denominator and must not be construed as ar,
exhausti~e description of the activity spectrum.
The totality of the cholinergic effects induced by
physostigrnine activates the btin quite differently from blcdade of the angiotensin-convening enzyme or the effects of piracetam. It is consequently logical that, despite the common effects,
differences in the activity spectm are to be expected, Such differences have been observed in
experimental studies: only captopril facilitated
memory retrieval after a ?-month retention interval: pimcetam did not.~: Piracemrn and pmrniracetam improved performance in an object recognition test.~”whereas physosugmine had no such
effect.~~ In contrast to pramiracetam.’b and
aniracecatn.18phvsostigrnine
had no memo~-en.
hancing effect in radial-maze [es~s--- .T,uJ;.however. be conceded that these results are not derived from,comparative studies.
In summary.
a!l memo~ -enhancing compounds dispiay slmilmlties in [heir acri~iues and
in [he [n[ensi[]esand Jvnamics of [heir efi-ecu [n
LT\l
<x~nmen[s,
::1 e and k:ame
The
ttife;[>
&tec:3bjd
‘Irj\
xe
s[erolc
;~nj]-
3J-ler3 ~arjw of
359
I
,
I
—_
NS
C
,.
I
Nthi CAP SIX CC?
LO
3.0
0.1
c
TIM ARE PHY
3.0
03
03
c
o.a3
PIRPRA.4Ntoxl
100
Ml
100
IM
m#kg p.cJ.
substances on the retention performance of mice in a
FIGURE
1. The effects of various memory-enhancing
passive-avoidance
task. Mice were given footshock for leaving a “safe= small platformin the center 0[ a grid floor.
The spontaneous (%aseline”) Iatencies to step onto the grid were measured. Retention (i.e., the retest latencies)
was assessed
24 hours later. The histograms represent the stepdown
Iatencies in seeonds. Solid columns: baseline
Iatencies; blank columns: retest Iatencies of drug-treated animals; hatched columns: retest Iatencies of the vehicleCGP: CGP 36742 (GABA8 antagonist); THA:
treated controls. NIM: nimodipine; CAP: captopril; STR: strychnine;
NW:aniracetam;OXI: oxiracetam.
tacrrne; ARE: arecdine; PHY: physostigmine; PIR: piracetam; PRA: prarniracetam;
Physostigmine was given orally 30 minutes, all other substances, two hours, before the learning trial. Optimal doses
for memory improvement
were determined
in independent pilot experiments. Prolongation of {!1(’ Iutcst L.kncic+ ~:’I
wmpanson
with the no-shock controls [NS] and baseline Iatencies) indicates learning. Prokmgation of the retest
controls indicates druginduced
memory
Iatencies in comparison with the retest Iatencies of the vehicle-treated
improvement.
N = 25 mice/group.
“2p< 0.05,
●=2p<0.01,
.*W2P< 0.001
(Mann-Whitney
U-test)
___
several
hours.
Thereare,
nevertheless,
experimentalfindings indicating differences in activity spectra both within and between the various groups of
memory enhancers. above all in tests not related
to LTN1.
Ill. THE CLINICAL EFFECTS OF
THE NOOTROPICS
—_
Any attempt to pinpoint common features in
the available clinical data on these compounds
qulckiy runs imo certain problems. One major
di~]culty is due to the he~erogeneity of the patient
populations. Studies have been canied out in prob3ble c~es of Alzheimer”s disea.se.>}s in a mixed
papula[ion of .Uzheimer and mult.iinfarctdementia
patients. ‘- :n multi infwct pauems.’: in patients
with psvchoorg~ic syndrome. -g [n aged volunhtxrs.’q in srudenr-s.~”in epileptic pa[]ents.:’ in
dl >Iexic schoolchddren.:: m patients suffering
from cffe’ctsof expcsure to (organic solvenrs.s:”
360
in victims of head trauma.$5s6 in patients with
Korsakoffs
syndrome,57and even in patients with
artificial pacemakers.58The numbers of patients
in each study ranged from 4%to 289.41Durations
of treatment also varied greatly: for exmple. 9
days,sg4 weeks, 43’s3 months.jw’%’;~{ and up to
1year.:4The Smdydesign
wasvariously open,:[email protected]
single-bIind,436’double-blind, [email protected] parallel with
placebo controls]b39‘I$z or active contro1s,6zd3
crossover.37JJ or enriched:~s even comparisons
with historical controls were used.m
No \ess heterogeneous was the clinical and
psychometric
hsrrumentarium
employedm assesstheeffects.
Besides
neuropsychological
tests
and scales.
psychophysiological
tests
weredso
used. The quality of reporting differed greatly. [n
some studies. the test used is not simply mentioned but described exactly (e.g.. referent? -$0].
whereas in others the sole indication of the nxure
of [he effec[ observed and the methodology applied was the single word mernon.53[n evaluating
the effects. the psychomemc tests wer’e some-
timessupplemented by staff-rated scales~~;some‘-:”nes only staff-rated scaies were used,bf or even
.st the clinician’s global impression was given.fi
‘me study design was entirely adapted codemonstrating the existence of an effect of the preparation in patients.
Surprisingly, at fust glance, scrutiny of the
results of the published clinical srudies reveals
that
themajority (more than 60%) of the reports
are positive; i.e., [he authors conclude from their
findings that the ueatrnent was effective. Villardita
eta.1.,39
for instance, showed that after three months
the 30 patients meatedwith oxiracetam in a doubleblind,
parallel-design
study displayed significant
improvements in 9 of the 18 tests used compared
with their baseline performance before the beginning of treatment. The 30 placebo-treated patienu.
on the other hand. showed no irnpro~ements. and
even performed si=~iftcantly worse in two of the
tests. The positive effects were particularly cleNcut in the Mini Mental State Examination
(MMSE), the Auditory Continuous Performance
Test (ACIT), Rey’s 15 Words Test. the Block
A /Tim
m
1547
I
10.I
~
1
I
o
FIGURE 3. The emergence of the memory facilitation
effect induced by the nootropic oxiracetam (100 mg/
kg), the ACE-inhibitor captopnl (3 mgkg), the musca(0.3 m~g), and the GABABrrnic agonist amoline
raptor
blocker CGP 36742 (1 O mcy’kg). The animals
were
trained
in a passive-avoidance
treated immediately
was measured
at various
hours) after training
cate the drug-induced
aes (in lxreent
thereafter.
situation
Retention
intetvals
and treatment.
prolongation
of the [email protected]
and
performance
(1, 2, 8, 16, or 24
The columns
of the retest
indi
laten-
controls). “[email protected],
better memory. Afl treatments were given intraperitoneally immediately after the learning trial (from Mondadori
et al., Proc. Naff. Acad. W., 91, 2C41, 1994).
I
Icll
FIGURE
m
““”2w0001.Prolonged Iateneies indicate
-2pco,ol,
.——.
.;
Ikl I
2.
The
effects
of various
@mpaunds
on
memory if administered at various intervals after me
learning expeflence. The animals were exposed to me
passive-avoidance
situabon, and after the md!mted mintervals(<10 s~nds,
1, 2, 4, 8, 16 hours) treatedw?tt’
Retest wss
optrmal doses of tie memory enhancers
mdl=te
~e
performed
after 72 hours. The columrs
+roiongat]on
of the retest latmc~es (ir Xrcem of T?
htcle-treatd matched controls). P: ClCn9eC Ialenc:es
,dlcate better memo~ AFE arecdme ~AP CaaIOC-I.
OX I oxnce[arn
“2=0
95
“%-AO:
‘-2M
02:
Tapping Test (BTT), the Mattis Word Fluency
Test, Luria’s Alternating Series, and the lrtstrumental Activities of Daily Living Test (IADL-E).
Senin et al.J6performed a study with aniracetam, using a test battery different from that
applied by Villardita. ALthe end of the 6-month
treatment period the authors found significant
improvements of performance in all 18 parameters assessed. As in ViIlardita’s study, positive
effects were recorded in Rey ’s 15 Word Test.
No[e [hat besides effects on cognitive parameters. these authors also observed distinct effec[s
on behaworal parameters. The 6-month study
with aniracetam performed by Parnetti et al. b;
according
to a similar
desi:n
yielded
practically
in 17 of 18 tests, aniracetam
i,mprovedthe patients’ performance. In this com paratl~e study the activity specuum of aniracetam
III some tests was distinctly different from that
P: pir32et3m. L-nlike aniracetam.
for Instance.
~mic:::m displ~}eti no effec:s in Re>’s 15 Words
~ts[. \n [be Tt>uiou\e Pleron Test. and In the
identic.ti
results:
361
—
Raven Test. According to the Sandoz Clinical
Assessment Gwia[ric (SCAG) Scale, however.
the effects were nearly identical. Bottini et d.w
observed dis[inct effects of oxiracermt in tive of
eigh[ cogni[ive tests. In p~icu]u.
there were
slgnlfican[ posi[iveeffecls on verbs] rluenc~.
similar [o those described by Villardita et al..
and the retention of a short story (after a delay of
10 minutes) was also improved. In the 12-month
study with piracetam conducted by Croisile et
al..!’ indications of a retardant effect of :he drug
on the progress of mental decline were noted: in
the placebo group a significant detenora[ion was
evident at the end of the year in 8 of 14 tests.
whereas in the piracetam group negative results
were recorded in only one test. In comras[ [o the
findings of Senin et al. and Pamerti et al.. direct
comparisons of the performance of placebotreated and piracetam-ueated patients yielded
scarcely any statistically significant results. The
study carried out by Maina et al.’{ in the largest
population samples of all (N = 144 + 145), positive (good to very good) effects of oxiracetam
were recorded in 90 of 145 patients (global evaluation), whereas. according to the mrne criteria.
only 27 of 144 placebo-treated patients were
rated as showing good or very good responses.
Only 51 of 144 patients taking c~iracetarn as
against 107 of 144 receiving placebo were rated
as showing no effect ora pooreffect.
Notethat
the patients in this study, in contrast to those in
the study by Villa.rdita et al.. showed positive
effects in the IPSC-E (lnVentory
oiPsychic
and
SomaticComplaints,
Elderly).
Sta[isticdly
significant
incremes
inthelPSC-Escores
werealso
recorded in the 6-month study performed by
Mangoni et ~.,36 while no ch~ges
were
seen
in
the p[acebo-treated controls.
Itil e[ al.%also reported sigmficant effects of
oximce!am in [he D?5C-E, not in .+lzheimer patients. but in diagnostically less precisely defined
cases of organic brain syndrome 10BS). These
effects were more pronounced than the corresponding effects of piraceum. Such changes in
exerts effects
the IPSC-E Suggestthat o~hce[~
that can be manliest as an mpro~”ement in the
quality of life of the patients. The res Its obtained
by SAem et ~l.’s in their j[ud~ ot’ J ~imilarpatlen[
popukmon
were far less distinct:Jparr irom w
impro~ernen[ in
362
\erbal memo~. or~y the o~erd!
score in the SCAG wassignificantly better (the
IPSC-E was not used). The duration of treatment
in this study was only four weeks. ~Moremodest
still were the clinical effects noted in the study
of piracemrrt performed by Abbuzahab et al.~~in
OBS patients ~geriatric memory): apart from a
slight o~-erall improvement. no relevant effects
were observed. Much more pronounced positive
effects emerged from the investigation by Moglia
et al.’: [n this parallel-design smrly in 21 + 22
(3BS pa[ien[s. these authors showed that oxiracetam induced an overall improvement in cognitive and bettaviord parameters. Particularly notable were [he significant improvements seen in
the Benton Visual Motor Retention test (as also
used by Itil et al.) and in the arithmetical part of
the Wechsler Adult Intelligence Scale (WAIS).
The conclusion that the general well-being of
the patients mated with oxiracetarn had improved
is consistent with the many global clinical assessments, as exemplitled by a 3-month piacebo-controlled
doses
study
of piracetam
aI.47 [n
this
evaluations
study,
in 60 patients
carried
with
two
out by C}!ouinard
the results
of
et
the monthiy
bythenursing
staff
(Nurses Global
Improvement Rating Scale) clearly indicated an
improvement in the patients’ sense of well-being, whereby particular emphasis was placed on
alertness. socialization. and orientation. Ano[her
study by Foltyn et al.,bs showing aniracetam to
have been effective over a duration of four weeks
in N = 30 +30 patients. was based exclusively on
staff ratings.
Noomopics were dso tested for efficacy in
completely different clinical indications. .Mcbm
et al.,% for example. examined prarniracetam in
four patients with headinjt.uiesor anoxia and showed
that the drug exetwi clear-cut effects on immediate
and delayed recall. In patients with pacemakers, in
whom the f~ed heart rate often leads to diminished
cerebral circulation and consequent disturbances of
performance during exertion. piracetam was found
to induce a slight improvement in psychomotor
tests% no cognitive tests were pert”ormed,however. Lna jmd~ in epilep[ic patients withmemoq
disorders.
Aldenkarrrp
t:d.:’obsemedno effects
tier12 weeks.butalIparameters measured revealed a mend favoring o.xiracetam.
In some investigations. comparative evaluations were made of the effects of nootropics. [n
the above-mentioned study. by. hi] et al.,% oxira“cetam
was found [o have a slightly better effect on
cognitive parameters than piracetam, whereas
piracetarn displayed a slightly better antipsychotic
effect than oxiracetam. Although the .=eater efficacy of oxiracetam in regard to cognitive aspects
was cordl-rned in the studies by Gallai e! al.b] and
Ferrero.d: these studies were not camied out under
double-blind conditions and are consequently
not
valid
scientific
evidence. The same
applies to the study conducted by Faisaperla,sz in
which the effects of oxiracetam were compared
with those of deprenyl in Alzheimer
patients.
Here,
both drugs improved the patients” performance
above
baseline levels in a whole series of tests.
deprenyl emergingas themore effective
treatment.Aniracetam was also shown to be slightly
more active than piracetam in the study by Parnetti
et al.6Ln contrasl to the many positive results repined. a 3-month study in Alzheimer patients
performed by Green et ala and using a broad
battery of neuropsychological tests revealed no
signs of efficacy of oxiracetam, either on the basis
— nf group analyses or in individual patients. Siti mrly, a 3-month mid by Hjorther et al.S3with a
very extensive test battery gave no indication of
any effects of oxiracetarn: neither behavioral nor
memoty parameters showed any sikmsof improvement. Note that this trial was done in a special
group of OBS patients, suffering from toxic
encephalopathy following exposure to organic
solvents. In full concordance with these results.
Somnier et al.w detected no signs of efficacy of
aniracetam in such patients. A notable feature of
this study was that Somnier employed a crossover
design. Other crossover rnals have also revealed
no positive effects. Lloyd-Evans et al.ti were
unable to detect any effects of piracetam in a 6month double-blind trial in OBS patients. The 2 x
4-week crossover study with ox~aceram performed by Mo[loy et al.~’ in Alzheimer patients
likewise showed no effects. In none of these crossover riaIs was the first drugplacebo phase evaluadmissible
as
ated separately
sults
further
as a parallel
emerged
from
srudy.
Negative
re-
an enriched-design
— study by Claus et al..~~wh,oconcluded from their
‘-results LJIJt pmmlrace[am
1s ineffective
as a symp[OM~[iC
re~tmen[
rating uw
based
for ,Alzhelmer pa[Ient.:. This
on
tie
scores
Jch Ieveti
h)
IQ
patients
in the Alzheimer’sDiseaseAssessment
Scale(ADAS).
In patients with alcoholic organic
mental disorders also, a srudy conducted by
Fleischhacker
er al.s~ demonstmted
improvement
after treatment
with
no relevant
piracetarn.
Given the existence of srudies with positive
and others with negative results or overall ratings, one question that arises is wha[ “positivr’
or “negative” means to the individual pa[ienls.
As regards the positive srudies. tha[ question has
already been answered, insofar as it was often
mentioned that only a limited number of patients
responded to the treatment (e.g.. reference 41).
Unfortunately. in the clinical srudies with nootro-
pics, only scant information is given about the
frequency of significant therapeutic effects and
the quality of such effects in individual patients.
The fi]ct that. despite many nonresponders. posi[ive overall ratings were still reponed would a[
leas( seem to justify the reverse question of how
often individual responders were present even in
the negative studies. For want of adequate information on responders and nonre-spenders in most
double-blind studies, illustrative data must also
be drawn from the results of open trials. In the
study performed by Claus et al..~: the conclusion
that piracetarn was ineffective was based on the
lack of significant effects in the ADAS in 10
patients. In fact, however, there was al least one
responder with a reduction of more than four
points
h the.ADAS andsignificam
drug-related
improvements
inboththeVisualSelective
RemindingTask (total
and delay)and Logical
Memory Imrnedia[e
Recall.
Theseeffects
were
inevitably
submergedh thecalculations
of the
meansvalues
andstatistical
analysis.
h thestudy
by Baumeletai.$~
also,
wherethedrugeffects
wererated
asven modest.
1 ofthe12patients
showed responses. In thatthecasereports were
described as ~pical. this wz~ a substantial effect
from the viewpoint of the auaIip of life. This
outcome is closely similar m the results of the
open study in six patients b] Dageretal..s9
in
which there %as one definite responder. Irrespective of the ex~ent to which tile cited data were
attributable to drug effects. L~eY demonstrate the
need
for anai> ses of this namre.
it can
nootroplcs
.A!zhelmer
be
concluded
Cdn
e’. oke
p~::en:s.
that
:!e
plrocelam-li~e
sig3:~ic3n[
becomm:
effec[j
mmlicst
on
In
[he
363
I
—-
one hand in cognitive improvements and on the
other in behavioral aspects. The effect appears to
become more marked during prolonged tre~tment.
The various nootropics differ in their acrivity spectra. In general, however, there were only a limited
number of responders. The few efforts made to
characterize this group of patients (e.g., reference
59) were unsuccessful.
IV. COMPARISON WITH THE CLINICAL
EFFECTS OF TACRINE
Any attempt to characterize the clinical effects of the nootropics almost automatically necessitates a comparison with cholinomirnetics. In
contradistinction to the nootropics, cholinergic
substances are used in Alzheimer patients, not
because of their memory-enhancing effects in
animals, but because of the existence of a cholinergic deficit in [hese patients.b9In this respect, the
patient population studied is homogeneous and,
unlike the very mixed populations treated with
noo~opics, includes only (probable) Alzheimer
patients. The group sizes are similar to those in
the nootropic studies. The methodology used is
more nearly uniform but different from that
adopted for nootropics. The following section is
confined to tetrahyciroaminoacridine (THA,
tacrine, Cognexa), a cttolinesterase inhibitor and
the only substance so far registered for the treatment of Alzheimer”s disease.
The fiist study by Summers et al.’0 was conducted in three phases. I-n the first phase, the
tolerability and efficacy of incremental doses of
THA were assessed in 23 patients. THA was
always administered in combination with leci[bin. b-ta second double-blind, crossover phase.
15 of these patients were treated with the best or
highest dose of THA, or with placebo, for thee
weeks. after which the treatments were switched.
OnIy the 12 patients showing a clear-cut response
to THA in the second phase wem on [o receive
long-term
treatment
over periods ranging from 3
to 26 months (enriched design). lk final assessment revealed distincr positive results (global
msessment. onentat]on. Alzheimer deflcic scale,
—.
names kxning test), whereby only pauen~ cksed
as Stages 3-4, but not Stages 5-6. cm!he Relsberg
s~de responded.
364
Most of the subsequent
studies initially failed
to confirm Summers’ results. A crossover study
conducted by Davies et al., ~’ for example, in
which 10 patients were treated for up to four
mon[hs. showed hardly any notable effects of
[he combiiied treatment with THA and lecithin.
Only in 1 of IO tests were positive results recorded. The same results were obtained by Chatellier et al.;: In this crossover study with 67
patients. tacrine (combined with lecithin) was
administered oraily for four weeks. Apart from a
slight improvement in the Physician’s Score, THA
was ineffective. Neither in behavioral scales
(Stockton) nor in cognitive scales (MMSE) were
any effects demonstrable. Similarly, in a crossover mid done by Gauthier et al.73over two 8week treatment periods. the response to THA was
limited to an improvement in the MMSE. Despite
this improvement, the authors rated the effect of
TI-L4 as clinically irrelevant. No effect whatever
was observed by .Molloy et al.74 in a multip[e
crossover
study
with
treatment
periods
of three
nor a detailed analysis of individual patients revealed any
indications of effects.
positive results. on the other hand, were obtained in the trial conducted by Davis et al.~sThe
2 Is patients who had responded to tacrine in a
preliminary crossover phase were subsequently
treated for six weeks in a parallel study. By comparison with tie placebo controls, the tacrine group
showed a slight. but siguiflcant. decrease in mental decline (.~AS co.titive subscale). Two of
the duet quality-of-life assessment scales used
indicated changes in favor of tacrine: Progressive
Deterioration Scale LPDS) and Activities of Daily
Living (ADL ). The changes in the MMSE were
slight and statistically not significant, and the
clinician’s global msessment (CGIC) likewise
failed to detect any effects. In a similar, but more
prolonged ( 12-week) parallei study by FarIow et
al..”bven much the same results were obtained:
the .%D.AScogitive subscale indicated some retardation of cognitive decline. but the MM.5E
Showed no changes. In contrast [o [he srudy by
Davis. however. the physicians’ and caregivers’
global niungs were sigirlcan[ly better. In a crossover j~d~ by Eag:er :[ al ---- in which 468 patients were ~exed for cons[derabiy longer ( 15
~eekj~ iqxi t;h~jein Ylciloy ’j j~d~.-l the MMSE
weeks.
~either’
the overall
evaluation
and the A..fTS (.Abbreviated Mental Test Score),
=-’-~Jtnot the .M3L. revealed an effect of tacrine.
]e effects in tie .MMSEwere consistent with the
findings of Gauthier et al..-: but not with those of
Farlow e[ ai.-s and Davis et al.;s; the absence of
effects in the .sOL were at variance uith the
results obscxed by Davis et al.’s
Recent srudies disclosed the entire range of
possible effe...s. Distinctly positive effects emerged
from a 30-week parallel study by Knapp et al.’a In
this study uiti an initial population of 463 patients.
all three poutcome measures (ADAS cognitive subsca.le. Clinicians’ Interview-Based h-npression. and Final Comprehensive Consensus Impress-
ion) showed significant effects of tacrine. In
addition, positive effects. among others, were demonstrated by the Progressive Deterioration Scale
and the ND lSE. but no[ tie .14DL.The effects
indicated by the MMSE were in agreement wirh
those noted 5> Gauthier e[ al..’~Eagger et ai..n and
Davis et af..-: but contrary to those seen by Farlow
et al.’bwd \lollo)’
et al.74Although consistent with
the findings of Eagger et al.,n the absence of effects in r-he.M3L conflicted with those of Davis e[
--A-’~Exacr,h. the opposite, i.e.. no indications of any
ect whatever, emerged from the srudy by Maltby
et al.79with m initial population of 57 patients and
a 36-week duration of treatment. Neither the Caregivers’ rating-based scales nor the co-gnitivescales
showed sigm of changes. Halfway between positive and negative results lie the findings reported
by Wilccd et al.w In a 2 x 3-month crossover
study in 41 patients these authors noted posiuve
uends in fa~-orof tacrine, but statistically the differences were scarcely significant. In a study with
154 patiems. Wood et al.g] likewise merely obsemed positive uends, but there was no sietificant
effect of tacine in the ovemll group ana.lysls.The
results nevenheless indicate that there were individu~ res~nde~, The same applies [o a 3 x 6week crossover smd~ of Alzheimer patienLsconducted by Gusufsong2 in which there was no
detectable olerall effect. but individual responders
were noted. 1[1s.above all. the enrichment srudies
tha[ coniirm tie exisrence of a subset of responders. althou<I e~en tier tie cmrichmen[ no[ dl
pauents res~nd to the memment. In the hgh[ of
“-ese tindir. ~s m-d m view if the need 10 opimlzt
2 Lhem?>. .1 :s ~Upnslng “ANK’3rCel~an) sff(~ns
have been =xe :0 estahijsh s ~ha.nnxolog]cti.
biochemical, and endocrinological profile t-hat
would serve to identifj likely responders.
To sum up, although there are clear indications that cholinesterase inhibitors do exert clinical effects, it is equally clear that only a certain
number of patients respond to the treatment. “fhe
use of enriched-design studies oiten makes the
propofiion of responders appear larger than it
really is. As with nootropics, longer dura[ions of
therapy improve the chances of evoking demonstrable effects. The psychometric scales and tests
employed
were in most cases not comparable
with those used in the nootropic trials. In the few
studies in which comparable scales and tests
(MMSE,ADL)were used, the effects observed
were of roughly the same maetitude as those
produced by the nootropics. Although the methodology was much more nearly uniform than in
the nootropics studies, there was no test that
yielded consistent:
positive results in all trials.
V, PRECLINICAL EFFECTS OF THE
NOOTROPICS IN THE LIGHT OF
CLINICAL FINDINGS
Beforeconsidering
theextent
towhichthe
clinical
datameet theexpectations
basedon
precl.inicd
findings.
1must stress once again that
the clinical investigations were exclusively aimed
a[ showing whether or not the preparations exerted any therapeutic effects. For that reason a
wide battery of tests was used, comprising both
behavioral aspects and cognitive performance. T%e
somewhat unfortunate efforts of many authors to
make use of data from animal experiments in
explaining the rationale of their srudies and discussing the clinical results should not be allowed
to obscure the fact tha[ neither were the studies
designed to validate the preciinical results, nor
were the clinical results in any u’ay adjusted [o
se~e tha[ purpose,
of the prechnical studies.
In the vast majority
a design was used m which the d.xperimental animals were exposed to the lea-rnin~situation
while
=
under
the Influence
of the drugs
md then [ested
hours later, eitier still. or no
longer. under the inrluenc~ of the drug: In the
;!]n]cal srudies. however, retentlcn ~erT-Orman
Ce
for
‘U’3j
retention
[~s[~~
23
ar[~~
j~ofl-[~~
ln[~~.
~(s,
!.~,,
~]~e~
365
after acquisition or after a lapse of
10 minu[es. The se~eral hours’ delay preceding
the tmergence of detectable memory-facilitating
effects that has been observed in the most recen[
animal experiment5:411 strongly emphasizes the
immediately
crucial importanceCIiallowinglong enough re-
course, that
the clinical effect md the memo~ facilitation
[en[lonintervals,
provided only. of
obsa-ved
in
animals
come
about
by way of the
mechanism. Ula[ the [ong-term memory
[ests used in the clinical studies detected was not
the influence of the substances on long-term storage.but [heir inflwnce
on retrieval from LTM.
i.e.. cm the recall of information acquired while
not under the influence of the drugs. Often, learning capacity was tested before and at the end of
the treatment period: i.e., performance without
the influence of the drugs was then compared
with performance wbile under the acute influence
of the drugs. There is thus still no sound scientific
evidence of the predictive validiry of the animal
procedures. This aspect should be examined in
specifically designed clinical
investi~ations.
The various reprts nevertheless do contain
at least a few allusive remarks consistent with
the expectations based on animal experiments.
In the study with osiracetarn by Dager et al.,sg
same
for example, there is a sentence reading: “although long term recall improved only negligibly. his long term memory storage (learning
capacity) and reco-tition
memory were moderately enhanced. ” Similarly McLean et al.%state
“’Themostdrmaticdemonstration
of improvement
withpm.miraceuun
...occurred in the
selecti~e reminding :est-delayed recall. long term
memory retrieval and long term storage. ” Last.
but no{ least. there are a number of reports concerning the effects of pirace[am in dyslexic children that possibly point to effects on LT?d storage. In a double-blind. placebo-controlled study
bv \Vilsher et al.s~r-hechildren showed greater
f~ciliry in reading and comprehension after a 36week phase of treatment with piracetam. 1[k very
probable that [he improved performance at the
end of the treatment period reflects. no[ m acute
effect on memory re~,cval. but rather an improved
av~iability of the !kinowledgeacquired throughout ‘he duration of Teatment. i.e., long-term re[en[lon of information acquired under d-winlluence of piracetarn. T:IS view IS strongly juppo~~d
that:
366
by the fact that the combination of psychological
training and nootropic therapy proved particularly effective, not only in dyslexic children. but
also in other forms of coguitive underperfor-mance.~3Moreover, it appears very likely that
the effects observed after long-term trestment of
Alzheimer patients might. at least partially. be
based on such effects, too.
However, the many reports on an improvement in noncognitive aspects in individual studies
or patients make it seem improbable that
nootropics act exclusively on LTM storage. [t is
conceivable that the effect comes about via a
modification of general processes that play an
important role in the pefi”ormanceof brain cells.
The improvement in long-term storage would then
be otdy one of the measurable consequences. The
reason for the usually modest extent 0[ the clinicaJ effects could be that the action of the substances is confined to cells that are still functionally competent. But since the individual patient’s
speciilc pattern of functional deficits reflects the
impairment of the neurcmal cirrui(s essenti31 !0
this function, it may be that the aspect mostunpakxl through degeneration also affords the least
room for improvement. This applies equally
10
cognitive
and noncognitive performances. Itis
therefore perfectly conceivable that while measurable effects in one aspect or another
may be
detectable in a [email protected] investigation, these aspects may be of little therapeutic
relevance to the symptoms that are particulady
disabling for the patient.
W. SYNTHESIS AND OUTLOOK
Given the observed o~erall positive effects of
the nootropics and their occasionally quite distinct effects in individual patients. this category
of compounds would appear useful. The results
available so far give no indication that tacrine is
superior to the nootropics, or vice versa. The
effects of these drugs seem to be similar. although
the complication that the double-blind namre m
connection with choiinomimetics is very probably wishiui thinkng (dicrirninative stimulus properties.w side effects, e.g.. reference 7-$)has been
completely left out of consideration, In rhe absence of comparative srudies. the wit assump-
tion that the cholinomime[ics
are more effective
‘-=ost
lilcely reflects [he superfkial plausibility of
Aeunderlying hypothesis rather than the exis[ing
clinical results. Toge[her, the clinical resul[s
present a mirror image of the preclinical profile.
In order to maximally exploit the available
therapeutic possibilities. it would be desirable to
give priority to the characterization of a subgroup
of patients likely to respond to a particular therapy.
The s[eroid dependence of the memory -facilita[ing effect of the nootropics~3J1 opens up a practical possibiIi[y in view of the fact that a ve~ large
percentage of Alzheimer patients have elevated
plasma cortisol concentrations.as
WI acttviry of a serses of cyclic inudes. J. Med. Chern-.
30, 498.1987.
10
Yamadai K.. Inoue, T., TanaJQ .%L,and Futmkava+
T.. Prolongation of Iatencles for passive avoidance
reqxmses in tats created with aniracerarrs or piracetarn.
II
and Petsehke. F., Do piracetam-like
compounds act cenually via peripheral mechanisms?
Pharnrocol.
Behav.. Z?. 645, 1985.
Brain Rtw.. 435, 310, 1987.
by nootropics.
Pqchiarry,
Prog.
Neurop~chopharmacol.
1.
?
-.
Gitqq
C. E., Moyensoons, F., and Emand, .4. A.
A Gaba-related hypothesis on the mechanism of action of the anti-motion sickness drugs, Arch lnr.
Phorrnacodyr.. t66, 379, 1%7.
Giurg+ C. E., The ‘nootropic’ approach to the pharmacology of the integrative activity of the brain, Conditional
R#ex,
8.108,
1973.
3. Friist.t, W. and Ma.itre, L. The famities of cognition
enhancers. Phurtnacopmchtiyv,
4, !$londadori,
of the rmtropics:
implications.
5. Vernoq
22 (Suppi. ), $$. 1989.
C., In search of the mechanism
new insights
L4~e Qi.,
and potential
[J.
.Mondadori. C., Ducre~ T., ad Borkowski, J., How
tong does ‘memoty consolidation” take? New compounds can improve retention prefomnance, even if
admirustered up to 24 hours afier the learning experience, Brain Res., 555, 107, t991.
14.
Yfondadori,
C., Hengerer,
B., Ducre& T., and
Borkowski, J., Delayed emergence of effects of
rnemo~-enhancing
drugs: implications for the dynamics of long-term memory, Proc. NuI1. .4cud. S-t..
91, 2041, 1994.
15. PoscheL B. P. H., Ho, P. ,M, Nintemam F. W. and
Calfahq
.M. J., pharmacologic therapeutic window
of pranriracetam demonstrated m behavior, ELG. and
2
Butler.
D.
E..
Leonard.
D..
Caprathe.
matchmg-m-sarnple
perforBiochem
Behov.. 22, 745, 1985.
an
C! In. .Vturophamuccl
J.
on delayed
mance of monkeys and pigeons. Phannucol.
55, 2171. 1994.
B.
20. Ennaaur,
A..
Cavoy.
[email protected] J.C.d Delacour,
J..
A new one-od test for neurobloiogical snsdies of
21.
>-l
---
J;..
L-Itahen. 1“. J.. Pa\la. \L FL. Hembenson. F. >1..
J. G.. ,Amnes; a-re\ t-Poschel. P. H.. and ~far-rio~
memory m rats. II: effecrs of pincer-am and pramiraceram, Bra/n Res.. 33, 197. 1989.
Peno, A., Terranov& J. P.. WoP. Biuthe, R
.M.. Dantzer. R, and Biziere. IL, Specific nmdulauon of socml rnemon m rats by cholinonumetic and
ncaroplc drugs. by benzodi=epine uweme agoniws,
Pyvchophamracdog}.
bur notby psychostrmulanrs.
97 ---?fj,
1989
Mondadori
C, Lederer
R. and kis gg S1. Delayed
emergence of oxiracetam-induced
facilitauon
of long-
term rnemon
.:
-.
f
9. 19 1986,
aniracetarn
clinical
M. W. and Sorkin, E. M., Piracecarrr
chrome cerebral Impairment.
1I 53, 1985.
16. Murray, C. L. and Fibigcr, H. C. The effect of
pramiiacetarn (CI-879) on the acquisition of a radial
89, 378, 1986.
anrs maze task. Prychophamracology,
17. PoacheL B. P. H. Marriow J. G., and Gluckman,
M. I., Pharmacology of the cognition activalor
Pranuracetarn(CI-879), Drugs. Exp. C/in. Res.. tX,
853, 1983.
W.,
18. !Wartin, P. R., Cumin, R., Aschwanden,
h40reau, J. L., Jencfs, F9 and Haefely, W. E.,
Aniraceram Improves radiat maze performana in rats,
NcuroR~porr.
3, 81, 1992.
H. L. Effects of
19. Pontecorvo, .M. J. and Eva
of action
overwew of lts phannacologlca.1 pro~nies and a re~lew of its ther-apeuuc use in senile cogrurrve disorders, Drugs & .4ging, 1. 17.1991.
6. Giurgq
C. E. and MouravietY-Lesui~
F., Effet
facititateur du piracetarn sur un apprenassage repuuf
chez Ie IX. J Pharrnacol.. 3, 17. 1972.
7, Cumin. R. Banctle, E. F., Gamzu, E., and Haefell,
W. E., Effects of he novel compound ansracetarn ( RO
13-50571 upn Impaired learning wrd memo~ m ro78. 104, 1982.
denu. [email protected][ofl.
8 BanfL S. and Dorigotti, L., Expenmenral beha~ lord srud]es with oxlracetam on different :}ps of
—
Biol.
13, 89, 1989.
single neuron fuing rots, &ericnrrk41,
REFERENCES
-
C.
12. Samorre, .M. and Oliverio, A? Avoidance faciii[alion
This approach
would, of course, be valid only if the memoryenhancing effects seen in preclinical srudies and
tie effect observed in patients comeaboutbyway
ofthesame mechanism.
Thisbrings us back to
the question of [he validity of [he preclinical
models, which urgently need clarifying by clinical trials specifically designed for that purpose.
Biochenr.
Ytondadori,
in f-he scxnd-recognition test In rws.
P-rvcho,ohamuzcoiogy,
]n rews]on. 1996.
Mondador-i.
C., Ducret. T.. and Hausler, A.. El-
:\l[ed
?roilng
com~as[erold [e~e!~ bl~~ ~~ m~mo~ ,~.
sffec”x
of rmwtroplcs
,P.7c7L>Dn&rmuo[ oy\.
10s. ::.
md chol]nomimeucj.
1%1
367
-
24. Mondadori, C., The pharmacology of long-~enn
memory, Eur. Rev., 3, 35, 1995.
25. Kunbara, H. and Tadokoro, S., Facllitaung effect
ofoxiracewrr and piraceram on acquisition of discrete
rwo-way shuttle avoidance in normal rnsce. Jpn. J,
Phmnracol.. 48, 494. 1988.
26. \fondadori,
C., \fijbiw, HJ., and Borkowski, J..
The GABAB
receptor anugonis[
CGP 36742
and che
nootropic oxiracemrn facilitam the formation of longterm memory, BtIhav. Brain Res.. 77.223, 1996.
27. SarZ S. J., Memory retrieval detici~:
etiracecarn,
a noocropic
drug,
aile~ iation by
P~chophannacologY.
68.235.1980.
P- Staubfi. L’.. Kessler, M., and Lynch. G.,
Seleccive effects of aniracemrrt across receptor rypes
and forms of synaptic facilitation
in bippocampus,
Hippocampus,
1, 373, 199!.
29. Spignoli, G. and Pepeu, G. C., Interactions between
2S, Xiao,
oxmcecam.
anhcetam
and scopolamine
301,1990.
33. Errnaceur, A. and ~eliasd,
rmrre and scopolamine
jecl-recognition
Wracoiogy. 109, 321,
34. CroisiIq B., Trillet.
Mauguiere, F., and
tugh-dose piraceram
43,
ease. ,Veurolofl,
35. Claus. J. J., Ludwig,
performances
J.,
and
in ob
1992.
M.. Fondarai. J. Laurent. B..
Billardon, M. Long-(erm and
cremnem of ,Aizhetmer’s dis-
36.
.Yfangoni,
37
G. C.. A double-blind. placebo-comrolled jmd~ with
oxmxemm in demented patumts admmls(ered tie
Luna-Yebmska neuropsychological barrety, f)mg Da
/?<s. 14, 217. 19S8.
}folloy.
D. W,. Guvatt
G., and Brown. G.. Efftcr_s
Filippi,
F., Yfarchetti.
C., SmirTIe.
C., Yfotta.
of 3 ,IC:tMIT cm cognluon,
368
Sq piccolo,
A-
1., De
and Monza,
21, 141, 1989.
Aq [email protected]
Zandrki,
IL
C., Guakieri,
S. COrsico, I& and tigo.
A. Activity of oxmcetarn
in patien~ wItb organic br=zinsyndrome: a neuropsy 9 (S Uppl. ),
chologic3J study, Ch. ,Vexropharmacol.,
3, 73. [986,
43,
B. Ekner, I+ KasukhL.M.Mach%nam
R Kam R J. andDeveaugh-GekJ. Oms-aanarnin
BaumeL
tie ueacment of multi-infti
pqchopiumnacoi.
demenna F’ro~, Veuro-
Biol. Ps?chtmy,
1.i, G)3, 1. W.
Lloyd-Evans. S., Brocl&hurs& J. C., and Pafrner,
.M. IL. Pimceram in cbronrc brain failure, Curr ,Med.
Res Opm.. 6.351, 1979.
45. Saletu. B= Linzrnayer, I_ Griinberger, H. and
Pietscb.manm He Double-blind. placebo-controlled,
mvesclirucal. psychomernc and neurophysiologicd
U.
wicls oxitaceram
in the organic
drome of late life, Neuropqdrobrofogy,
46,
17,
Q.
br-mn syn-
13.44.1985,
and Songar, A..
Ml. T. \L. .Meno~ G. N. ~.%
of oxiaceran , ISF 2.522)in pariems w~h
The MYcx.zs
orgamc kun syndrome Ia double-blind canrrolled jmd~
wirh puacerarn). Drug De-i. Res.. 2.4-$7. 1981
G.. Asmable. L., %ss-chouinard.
.\..
Oli$ier. >1.. and Fontaine. F., Piraceram m elderly
psyctuamc pauents wlti mild diffuse cerebml impair81, 100, [983,
ment. Pvchophanrracolo~.
.Abuzzahab, F, S., Mer-win G. E., Zimrnermann, R.
L.. and Sherman, \[. C- .+ double biind m\estirgtChoum
rson of pmceram
(Noomopll)
vs piacetx
rn genamc
memop. Pharmacop~chmn,
10, 49, 1977,
49. Wsdw
P. CrOnbobn. B. Levander, S. E. and
Schallisrg, D., Piracernm-induced
improvement of
menral ~~-ormance:
~rgmg ms~lduals.
50
jmdy
Scad,
of normally
54.150.1976.
Dimond. S. J, and Brouwers. E. Y. M., Increase in
r-h wwm or’human mcrrmry in normal mm ‘kough
rhe use ~fd.rugj.
behat mur and ~cuklues
a conrrolkd
.4CICp~c.ti
Pnc.tiop&innacology,
49.307.1976.
Serdn. L_.,Abate.
.A.. >[ariN.
:enuodea. ne,uropsy cnolc. y.cd M
1-$. 21-.
—
MogliA
Wieringen, .\.. .Alpherts,
W“.C.. ran Ernde-%m. TV., Haverkon
H. .\.. de
Vries. J- and Meirsardi. H.. Double-blind placebo-
of dmly Iivlng
38.
Neurop~chabkrlogy,
42.
301, 1993.
Chase,
A., Perin,
-!0. Bottini. G.. Vallrar, G.. Cappa. S.. Monza. G.,
Scarpini. E.. Baron. P.. Cbeldi, A. and ScarIato,
pl3ceboG.. Oticeram
in demenaa: a double-blind
concrolled jmd~, ,4cra ,Veuroi. Scam’.. $6, Z?-. [992.
4 [. Yfaina G.. Fiori, ‘L., Torts. R, Fagiani. \L B.,
Ra\izza. L.. Bonavi~ E. Ghiazza, B. Teruzzi, F.,
Zagnoni. P. G., and Ferrario, E., Oxiraceram in the
crearment of primary degenermive and rrrulti-infarct
dementia: a double-blind- placebo-corrmolled jmd~,
tests, Psychophor-
M. D., ,Mohr, E., Giufira. M..
T. N., Nootropic
drugs in
Alzheimer’s diseuie: symptomauc
rreatment wl(h
pranuraceram, Neurolo~, 4 [, 570. 1991.
Blin,
39. Vilfardita. C. Grioli, S.. Lorrreo, C.. Cattmw. C.,
and Parini. J., Climcal srudies with oxhceca.m in
pauenm with Jemenua of .Uzheimer rype md multiin fJrct demen[ia of rnl!d to moderate degree,
,Veurop<,chabiology,
?5. :4. 199?.
rigarions
on rats’
controlled
,Vairopr.chop&z~
K- Effecrs of physoscig-
and radial-maze
~~
(S I>A1’): results of a
mulricsrrtre clirucal srudy. Eur.
ol.. [, 51 I, 1991,
of ,Alzheimer’s
placeb
on behavior
bmn acety Icholjne, Pharwracol. Biochem Behav.,
27, 491, 1987.
30. Pugsley, T. A- Pmschel, B. P. H., Downs, D. A.
Shih, Y.-H., and Gluckman, M. L. Some pharrmco
logical and neurwhernicd properties of a new cogniuon activator agent, pramiraceeam [C1-879), [email protected]??UICO[.
Bui[., 19, 721, 1983.
31. Mondadori, C. Gentsch, C., Hengerer, B. Ducre~
T., Borkowski, J., Racine, A- Lederer, R, and
Hiiusler, A., Preweacment with aldosterone or corti costerone blocks rhe memory-enhancing
effects of
nimodipine, captopril, CGP 37849, and sa-ychnsne in
109, 383, 1992.
mice. Psychopharrrwology,
32. Mondadori, C. and Etiennq P., %mtropic effects of
ACE-inhibitors
in mice, Psychophurmuco/ogy,
[00.
and
-,
Anhaceram (Ro 13-5057) m rhe tremnem of senile
demcnua
m demt=nua. J Cf(n. Erp. Gtronro[..
1992,
G.. Fieschi. C.. Gori, G.. Guala.
G.. ViMardj~
C., ~d pane~,
L..
51.
.Aldenkmrp.
A. P.. ran
neurophy sIoiom -
—
.
cd irtvesugarions WIrh oxncewn
~CGp 21690E) k
pariencs With epilepsy, Neurop~-
64
——__mernom-[mpaired
results
cirobwlo~,
24.90. 1990
C. IL, Benne~
D., Ch32. Mlsher,
C. L
DiIanni.
>L.
Feaga,
L.
Han*
7.
L. J.,
230.19s-.
53
Hjorther, A.. Bro=ne. E.. Jalsobsen.
K..Fi.slnm.
P. and G.yntelberg, F.. Organic brain syndrome
Acfu Neurol.
.Scand., 75,
mated with oxficstam.
54.
Somsder,
271,
1986.
F.E..Ostergaard,
Bruhn. P.. and
}li.kkelsen,
Boysen, G..
.W. S..
B. O.. Aruracetam tested
ps}chosysdrome
af~er long-term
sure to orgamc sol~ m-s. Psychop~~co~ogy(
m choruc
:3.
55.
expo-
Neurop~chobiology,
65.
Wetzelsberger,
D., Cuzzupofi,
Da Costa. R B., Maui. E. R, Pimentel,
S75. 1991.
Fleischhacker. W. W.. Giintber, Y.. BC..
Lieder. F. and Miller. C., Pisacetam in alcoholic
organsc mental disorder a placebo-conrrolkd
study
comparing two dosages, [n! Clin. PPchophorrnacol.,
1, 210.1986.
IL and Imander, S.. A double-blind
58. I+ergren,
study Onshe effects of pmcetam upon perceptual and
psychomotor perfonzsance at vtied heart rates in pariertss treated wwh a.rnficial pacemakers. P~chophrwUICologiu.
39.97. 1974.
S. w bebd.
J. P., Claypd
K.. cM.,
59 ~er.
Bssdec& C. B. and Dumer, D. L.. Oxmcetam in the
meanmenr of primary demerma of be Alzheimer”s
cl.
rype: J small C=
serte.s. Inr. J. Gear.
Psychuzs~, 7,
A cllnlcal
md n:urophyslolcgtcal
nootropIc chmgs IC aat]cn[s wIrh mend
.Y~uro(., 13. 1, 1+1
b:.
—
Falsaperia.
.A.. >forki-f%ti.
Seleg]l]ne
~ersus
llzhelmer-p~
-.
decllne. .4cra
P. A..and Otiani.C..
ox~racctam
~emenn~
[rlal on
[n
Chn. ?he’
patients
oxinc-cramin Alzheirner’sdi~,
Ferrero. E.. C~ncmUec :!lrucd mi ~io~lrmwtm
[n
Ir, suff Iclenc”.
:ne T:cunen: Jr: “-mnic :srebroYMcwaI
:n me tIderi\.
CAT
~~c”
Rfs
~0. 19~. QSJ
\i..
Arch. Neurol..
49,
1135, 192.
69. Davi~ P. and Maloney, A. J. F., Selective loss of
central cbolinergic neurons m aizheirner’s disetse.
LMcet. 2. 1403, 1976.
70.
Sumnre~
Tachiki.
W. K., Majowski. V., Marsh, G, M.,
K.,andWing,A.,Oral
teuahydroamino-
acridine in long tenrs treatment of senile detnerrcm
Alzhelrner Type, N. Engl. ~. .tic~, 315, 1241, t 986.
71. Davies, B., Andrewq
D., StargaQ R, Am- Dq
Tuckwell, V. and Davi& S. Tacrine in Alzheimer”s
disease, Lancer, July 15th. 1989.
72. Chatellier. G. and Lacomblez L Tacrine ([email protected]; TI-L4) and kcrdtin in senile demerroa of the Alzheimer
type: a multicenter
trial, Br-. tied.
J., 300.495,
1990.
73. Gauthier, S. Bouchard, % Lamoutagnei A. Bailey,
P., Bergman, & Ramer, J- Tesfayq Y., [email protected]
M., Bather, Y., Carrier, L. Charbonneau, R,
Clarfiel& W Collier, B., Dastoor, D.. Gauthier. L.
W-main. M. KisseL C. -r,
W, Kushni.r. S..
\k~
H., hiorin, J. Mir. ~- %eirinx ~ and
S- Teoahydroarzunoacxiine-lecirhin cornbmanon treatment In pauerm UItb in[ennedia[e-stage
Suka.
.W.hemser”s disease, IV,Errg/. j. .we~. ~~~. 1272. ~~J
7.$. Molloy. D. W., Guya~
G. H.. Wilson. D. B.. Duke.
R.. Rees. L., md Singer, J., Effect of tesrahydroammoacndine on coemtion. ri.mcnon and beha~nour
In ,41zhelmer’s &se Le. CU. .Wed. .4fsoc. J.. !~.
29,
~lth
11. 3-6. iw
F., ,~aggioni,
262. 1991.
w.
\..
L., Bonaiuto, S., CUCinOtta
Erndnio.
68. Greets. R C., Goldstein, F. C. .AuchW A. P..
Presley, R, ~
S. Van Toyl, L. Green. J..
Hersch. S. Mq and Karp, H. & Treatmenttrial o:
905.1992.
Branconnier,
R J- Cole. J. O. [email protected] E. C..
Spa-a. K. F.. Ghaminian.
S., and De vim D., The
therapeutic efficacy of pramhce urn in AJzhelmer’s
observauons. Pnchophamucol.
disease- prelitnmq
f? U/~.. 19.726.
1983.
61. Gailai. V.. Mazzot’ta. G.. Del Gatto. F.. T$Iontesi,
& >fazzetd. A.. Dominici, P.. and DeUa .Motsica.
M.,
Marini, G., Paeiaroni, E., Pedrazzi, F., Peruza,
M., and Senin, U., Arsiracctam (Ro 13-5057) for the
treatment of senile dementia of .41zheitner type: mSU1[Sof a multicencre clinical study, Demenna. 2
J- Cardoso d’Oli~eim. L., Aranjo Lacerda J. C..
and Gomes. J. D.. A controlled [email protected]
-’
N., A test model for cerebrally acn te
Ther.. 2.261, 1976.
67. Parnetti. L., Btiorelli,
10 I.
PuaceramVSplacebo in d.isordem of consciousness
due to bead injurw. .4craTher.. 4. 109. 1978.
56. XfcLean A., Jr.. Cardena% D. D.. Burgess, D. and
Gasnzu. E., Placekottrrolled
study of prasniracetam
in young males UICbmemory and cognitive problems
resulmgfrom head injury
and anona Brain /rrj., 5,
22, 97, 1989.
Foltyn. P.. Lucker, P. W.. Schnitker, J., and
drugs as demonstrated by the esampie of the twu
suhsmnce aniracetam,.4 rvreim -ForscMLkug Res.. ; 3.
865.1983.
&J. .Macchione. C., Molaschi, F., Fabris, F., and
Ferugiio. F. SW Results with ptracetam in the managemen[ of senile psycho-organic syndromes. Acra
1990.
Ckrington
Chefapy ~ itb oxiracetam in pa-
of long-term
tients wlti dementia of Alzhe[rner type and multrinfarct dementia in comparison with a control .moup.
C. H., CoMo~
HeUgotr. E., Kopleti=
H., OVertv.
1’..
Reader,
M.
J. RtsdeL R G.. and Tallal, P., Piraceum and dyskua: dfeccs on rwding [ests, J. CIIZ Psychophor?nUd..
Parnetti. L., JMecocci.P., Pecrirti, A., Lortgo. .\..
Buccolieri, A., and Senin, U.. Yeuropsychologicsl
-~.
1991.
Davis. K L.. TM, L. J..Gamzu. E.R. Davis.C. S..
W’ool.son.
R. F..Cracon. S. L Drachman. D. +..
Schneider, L. S.. W%i[ehome. P. J.. Hoower. T. 31..
>1OMS. J. C.. Kawas. C. H.. Knoprnan. D. S- EJmt.
369
.
Y. L,, Kumar, V. Doody, R. S. Tacrine Collaborative Study Group. A double-blind. piacebontrolled
multicen[er study of tacnne for Alzheimer’s disease.
,V. Engl, j .Wed., 327.1253, 1992.
76 Farlow, M., GMco~ S. L, Hershey, L. A., Lewis, K.
W. Sadowsky, C. H- and DoIan-Urerio, J., A con-
Alzheimer.s disease. J.4M.4.
?68, 2523, 1992.
77 Eagger, S. MomrL N., Levy, R.. Sahakian, B..
Tacrine in Alzheirner.s Disease. Time course of
trolled oial of raerine in
changes in cogrutive funcrion and practice effeets, Br.
~~Chrilf~, 160.36, 19%.
~.
73
Knapp, M., Knopman. D. S., Solomon. P. R..
Pendlebury, W. W. [email protected] C. S., and Gracon. S. I..
A 30-week randomized controlled trial of highdose
tadrre in pauenc
271.991, 1994.
with AJzheimer’s disease, JAMA.
79. .Waltby, X, Broe. G. A., Creasey,
H., .Jorrm A. F.,
Christensen, H., and Brooks, W. S., Efficacy of
tacrine and lecithin in mild to moderate Alzheimer’s disease: double blind trial. Br. Med. J.. 308.
879. 1994.
80. WiJCoe~ G. K., Surmo~ D. J., [email protected] .34,, Boyle,
Ma ,MuUiga~ L Neubauer, K. A., O’Neill, D., and
—
370
Royston, V. H., An evaluation of the efficacy and
safety of tetrahydroaminoacl idijt{ (“l’)LA)u,ithout lecithin in the treatment of Alzheimer’s disease. .4ge and
,-tg~irrg,
22.316,
1993.
81. Wood, P, C. and Castleden, C, \I,, ,? double-blind.
placebc-controlled. multicentre study of rxrine for
9/8.
A[zheimer’s disease, /nr. ~. Geriarr. Prychmyv.
649, 1994.
L., Physostigmine and tetrahydro82. Gustafson,
aminoacridine rrearrnem of Alzheimer. s diwase, Acra
Neuroi. Sciurd, 149 (Suppi. ), 39, 1993.
83. DeberL W., [nteractton beIwtwt psvcho[cg]cal and
pharmacological rremment m cognitive LmOaifment.
Lfe Sci., 55, ?057, 1994.
CornfeId~
.M.,
andField84. Lockq K. W. Gorney, B.,
ing, Sw Characterization of the discriminati~e stimulus effects of physostigrnine in the rat. 1. Pharrnacoi.
Exp. Ther., 250.241, 1989.
85. Manignord, l?.,Petragf.i4 F., Costa, A., Bono, G.,
Genazzitd, A. U and Nappi, C., Dementia of the
-Alzheimer type and h ypothahrnus piutitaiy-adrenocorrical axis: changes in cerebrospinal fluid- corricotropin releasing factor, and plasma corusoi Ie%els.
Acra Neuro[. Stand.,
81.452,
1990.
‘.4LL’.4TIOX
10CESSI\G.
OF THE EFFIC.+C}’ OF PlR4CET.A.\f
[N’ TRE.4TI,NG INFORJ1.4TION
RE.\DING
.A\D WRITING DISORDERS
IS D} ’SLEXIC CHILDREN
1. L+ ~<LL.AL
CHRISTOPHER
QH+SE.
ttII erstn O( C;,. r<wmJ, Son Dtefo.
Plracetam.
a ntu
r.~up I.-I(fifl}.fl.t
~j~<d ~l~ce”~c,
L
c!a$, of drug t n~k~:r..pl!, [h,wghl
IJ\SIe\Ic bo\s
+11 “$uplec. [s ~e[
below
m,
and memo~
[ruments.
Cumparcd
]ro~ements
aboie
~tng accuraci
~[ed with
Islderatton.
thetr
~kllls were etamlned,
[o {he piaceA-
as comparc~
$Igntftcanil!
mor:
precl~l~
TRODLCTIOS
and readnsj.
corr[rol group.
!abng
(o pl~cctm
ed
m
spelling.
and
Plracctam
Health
Ctwer.
other
rewllng
oi aclm
mg dwl:
I
dosi m half of
(audiwm
one
and one
and visual) and verbal
u nung
as compared
d)d mu sh,nw $taustlcall>
(o [he
b} wluch >Peclfic cognjute
or
were ,Igmflcanll:
si-gnlficm[
comprehension.
enhmced
ab!ll[:.
tab.mg both ra[e
placebo
~remmen(
showed no slgrnflcan! ad~erse reac!lons. These results
\he mech~msm
11“ S.4
>[uLI> The other half of [hc subjects
.>p~fiunllies.
no [email protected] efMll] Onal
language. reading accuracy
In a limed pcnd
and
CA
and wnung abthucs *cre measured usm~ standardized
~~[h Plrace[~m
memo~.
wrr[len
Dleco.
medlcauon and scoring M least
p~:choiroplc
wea[ed
Stin
sI.111$.uas pvcn In a 3.W
placeb+con[rolled
normal Cduco[mnal
language
tmhwduals
Effcctlw
[he
S~H\flTT
Oral Rcodlng TeSI Son-verbal
d and numher~ of words
:mpro.
l-(oleratcd and mcdlcal examirra{mc~
~e!crmlne
no!
on !he Gllmorc
douhlc-blind
lnfel]lgenc.
A-.IreS on measures of Perccpllon.
‘H.mt Ltr. readtng ,W
also
phystcai hcallh.
age ecd:~ den!
R L< RR}
to enhance speclflc cognl[lie
In a 12-w I+..
,’rl[<rI.S
n~r~~l
,h< ‘..II..Wlng
wd
und : Children “s HospIIut
~gtd $-1 ? )ears.
their bascllne
P!racc[am,
were
men[al
~SSELL
J, IIIIJ. CulI/ormti
blems. no neur,~i,~g]ca~ handicaps. j.~ti
, ,<=-
GL}”
or
In wbyXl~
m-d accurac}
Into
group. The medlc2t10n was
encourage fur[her slud> of Plracctam
,L[l$ are affected
and ,Aman. 1975). and impulsivi[y and social beh~vior (Barhle) and Cunmngham.
1980: Conners
and U“crq. 1979). However. studies of educational
abllltles using standardized
reading. spelling and
wthmettc
tests ha~e fmled [o demons[rale
any
s]gn~fican[ differences
[n the performance
of
[re~ted children (Quinn and Rapoport. 1975. Weiss
ev ~1., 19751 or non-h >peracuve
cluidren (GIIIl<w-jd Klein.
1976: ,Aman
Jnd Wern,
m~n-Kleln
1~$2),
This cilscrepan:> bctueen [he drug-induced
lmprotements
In beh~~loral control and [he ~bsence
m~~ be due in
pi ~n~nge in sch~ml-performance
p~r;
d<m~t
rl.iit
:,> [he u~i
[n
‘h<
J.>u:n:d
eoch
clhilci
p~.;.
<!ln;(:.sn,
:?, J!
iht
:S ~~jigned
., C:l MJ!
:he proper
Jnd
!n\t
J,\\.lg?
[,.
:!g~[<)r.
,npr<~ic
. .
J.
—
—
Perf~~rm~nce Scale IQ or a Verbal Scale IQ of 90
~~r m~lr<. ~>h[~lned ul[hin 9 months of [he ini[ial
\ IMt. I j I The\ hd
or <qu~i [o 0,s5.
3 Reading Qucmcnt of less [ban
(-$) English was [heir primap
langu~~c. 15) Informed consen[ was ob[ained from
both p~[uen[ and parent or legal guardian.
(6)
The> had normal audiological and ophthalmological func[l~lnlng. ~?} There was no significant neu ( S ) The} had no severe emoroioglc~l h~nd]c~p.
[]onal dl~[urbance ~s a prima~ symptom. (9) There
( 10) The}
u aS nc~ Stiere educottonal deprivation,
h~d n,? clinlcall} significant Iaboraton
abnormalinc~r ~n> medical
ties.
conditions
which
might
put
I
I
I
I
or interfere ui[h the
a[ additional N
~~fth< SIuif}. ( 11 ) The} had n~>his[o V Of
thd pa;]tn[
conduc:
Slgnlfl. ~n[ adverse
Plrac<:~m.
[heraples u
of effic~c~
mcdic~t]on
concom[[ant
or
an!
reaction
or h~persensitivity
U?
112) They were not “involved in an}
hich m][email protected] ]n[erfere with the e~aluation
and sa(e[}. including: psychos[imulan[
uithln 6 mon[hs of [h< ini[ial \’isit.
drug therapy with ps:chosiimulan[s
drug
Itan[ [herapv
]n~es[lga[lonal
for
emo[ional
disturbance.
ccmcom-
with Tofranil for any indication.
drug therapy wi[hin one monlh of
the Inl[ial visit. or concomi~an[ chronic treatment
with ‘@ronchodilators which have cen[ral s[imulan[
acuw[~
Th~ Reading Quotten[ was calculated as equal
VETHODS
Age x
[o Re~dtng Age x IO(3Z by Chronological
Full Q-al< WISC-R IQ. The Reading Age was
derli ed from [he Accuracy Score of the Gilmore
Oral Reading TesI — Form C. Grade Scores from
[hc Gllmore were converted [o Age Scores using
Table [[ prov]ded in [he Ga[es-!vtclGllop
Oral
Reading Test. Abnormal audiological funcuoning
~as defined as a loss of greater than 20 dB in
in the normal
range
el[her <ar for [MO frequencies
Hz- us]ng pure [ones).
( 500. 1000. 2GQ0. 3000.4000
.Ahnorntil ,lphth~lmologcal
func[lonlng M35 cfefined JS less th~n 20,,’40 correc[ed ~lslon in bo[h
c~~j 3, [ejted b> [he .Amencan Op[ICal E Chart.
signlflc~nr neuroioyc~! handicaps uere defined JS
~n> of [he follovlng: acquired neurological
distJ.e, ;lJ>SICJ1 neurc)l~>gc~l sl~ns w;[h functlontil
imp.il:-, tn[ Jr ~t:zure> ‘Althln [he ia~[ ~ ic~r~. Th<
pJ[ler.
. . n.id
n,l[
re~”e[~ed
.,in[l~ont-ui>Jn[
[her~p{
prl~lr I,, [he Inl[].l! .[<, [
F–i,
.-L-L’-.: ‘IE.If J(:C tT(I{it’,C.l! <~~iu~;],,v,. A<;< m~jc
!,>r
~:
,t~.[
Iv, -, it~:~
I
“1
..
-1-4
b: [he medical
j[aff
follouln~
uju~l
cllnlc~i
pr.J~were
dropped
from
[he j[ud}
[Ice. Four subjec[s
one moved. one suffered from an ~sthm~ J[[aCk
and ~~j [rested wi[h bronchodil~[ors
IIn woia[ion
from (he
wl[h [he pro[ocol) and two were r~rno~ed
SIUCfV due [o medical complica[loris
unrelated M
s[udy medication (both were taking placebo). The
f~c[ [ha[ ~ child was currentl} recei~ing academic
remedial ~sswlxrce or hod recel’. ed ju<h m[oring
in [he p~s[ dicl rror preclude <n[r} Into the j[ud>.
Procedures
[re~tmen[s were r~nPlacebo and Pirace[am
domly divided among 6 groupj of 10 subjem.
each on a double-blind
basis wtth the restriction
that [here be equal numbers of each trea[ment
wi[hin each of [he 6 groups. P~tien[s were then
assigned to one of the 6 groups cm the basis O(
[heir age: that is. 8-year-olds
were wsigned [~~
Group One. 9 years olds [o Group TWO. ~nd j<)
forth. When all the [rea[ment medw~tion had been
used up within a group. the patlen[ was assigned
to the e,uouD with the fewes[ members. Pa[wn[s
received either 3.3 g of Pirace(am cfailv or~
Each dose of test mmfic~ti~n
before bre~kfas[
—— and azaln
b-e
evening meal. A 5 ml dose of x(i~e
of Piracetam. so
@sa.~e adj ustmimts were allowed.
The study consis[ed
of -sits.
.M initial
screening visit usually occurred one we:k prior [o
[he st~rt of [rea[ment. The treatment period was
12 weeks long. with follow-up visl[j ~fter 2 Ueekj.
+[ week J ~nd
(j weeks. and 12 ~eckj of [reatment.
week 9. the patient’s ~arents
were conwted
to
review do;ag;-- mwuctions
: “ ““
and 10 determine
w~ether
anv-.. .adverse effects had been obsemed.
.-.__ .._
At [he initial screening,
pa[i;n[s wire tested [o
l~g
——.
placebo
SYrUp.
was [Jken during
[he second
visl[
and
Jbbre~
ia[ed
phystcol examinations
u erd performed
J( [he jeContf and si~th week visi[s. Observations
for possible mi~erse effects and ~ssejsmen[ of general he~l[h
were emph~sized. Laboratory evaiua[lons were obtained
at [he induc[ion
~isi!.
!he 6-week.
and
the
The l~boratory
tests included
hematology. urinalysis and blood chemistry [o [est
for possible adverse jide-effec[s.
1~-week
visits.
[email protected]
All 6 study cen[ers followed the same protocol
~nd used a common ba[tery of tests [o measure
drug efficacy. In addition.
eoch site conducted
a,ddi[iorjal ‘special studies’. Only the results from
the common test battery and special study conducted at the San Diego site are reported in this
paper. The common test bat[ery Was administered
at the induction
and final (week 12) visits. while
the special study tests ucre given at the induction
~nd week 6 visit. At the San Diego Cenwr. JII
patien( was administered
testing for an individual
by the same tester and took approximately
I ~ h.
Th~sc tests included: the Gilmore Oral Reading
Test — Form C at the initial visit and Form D d[
[he final visit —. Information
for Reading Accuracy. Comprehension
and Rate were included: the
Digit Span subtest of the WISC-R. bo[h digits
forwards and backwards administered
vi~ J tape
recording: the Ga(es-Mc KiHop Syilabica[ion sublest — Form 1 at the induction turd Form 2 at the
1?-week visit: the Wide R~nge Achievernen[ sub[ej[ for Spelling: a 5-rein free-writing sample WJS
taken [o include the to(d number of words. number of words misspelled ~nd the number of occurrences of [he most frequen[lv wn[ten word; [he
Raptd
.Au[omatized
Rudel.
1976):
Yarning
a behavioral
TesI
assessment
(Denckl~
~nd
in [he [e>[-
I
.
I
1
I
z behavior and performance
in evaluating the
ange from the start of [he stud).
In addition
[o these common tests. we conc[ed additional
special studies, Subjects were
en the Repetition
Test. developed by Tailal
~80). with 3 sets of stimuli: (1) non-verbal audi“} tones (75 ms duration). differing in funda :ntal frequency: (2) non-verbal visual nonsense
~pes (75 ms duration):
and (3) audi[ory s[opIsonant
vowel syllables (ha/da)
with 40 ms
ration forman( transitions. The Repetition Test
> been shown to be a highly sensitive measure of
-cep[ual and memon
functioning.
In addition.
s theoretlcall> based cm a model of perception
~ IS comprised of a series of subs[ests designed
Assess levels of perception
and memo~ in a
rarchical manner (see Tallai. 1980. for a detailed
,cription of these procedures).
Four dependent
asures were made on each of the 3 versions of
Repetition Test. Subjects were scored for the
al [email protected] of correct [nals. the number of cor~ :using inters(imulus
intervals (1S1”s) of
) n. .he number of trials using 1S1’s less than
) ms and the number of trials needed to reach
:emon. Improvements
in trials to criterion scored
icate an increased rate of learning stimulus– remse associations.
Increases in scores on trials
h short 1S1’s suggest an impro~emen[ in rate of
wessing
and temporal
sequencing
abilities.
provements in the longer 1S1 scores suggest an
rease in short-term and serial memory.
[O these experimental
perceptual
[n addi[ion
i merno~
tests.
subjects were aiso given [he
\en Tes[ (De Renz
and Vignolo. 1962) to assess
:puve language
comprehension
skills and a
red associa[e visual memon
[es[ designed for
study, In the visual memotw test the [ester
:ructed [he child by savlnsg. ‘ 1 would like to see
\ well vou can remember
different pairs of
:ures. I ‘will show you two pictures. one after
o[her. Tm to remember them as a pair tha[ go
r[her”, Tes[lng [Ciok place In [UO psrts. a iearn and a recall section During the Iearnlng sec ~, chl]dren were presen[ed u][h pairs of pic[ures
were presen[ed
~l[h
ln~ed M a set. children
6 and [hen S pairs. if aicnlld successoJ-+4.
Ied Jll ?~lrs ,~l[hln .I j~:, [hci mo~ed ICI
?< ,11.lner \e: Jnd u<:: [csled [f an~ iaiiure
occurred.
the final [es[Ing uxk
place using the
next Iouest w[: e.g.. fa]lure on set 6. final Les[ing
on set 5. During the lc~rnlng p(}rt]on. children
were presented ulth pairs of pictures. on< after [he
other. until the set was complc[ed, Each pair was
presented for 3 s with an in[ertrial in[enal of two
seconds, After all of the pictures in a se[ had been
presented. [he chtld’s recall abilities were tested In
the following wa}: [he second picture of each pair
was grouped.
mixed and lhcn laid dou n on the
table in front of the cluld. L’sing the same order as
presented In [he learning portion of the test. the
first picture of each p~jr uas presen[eci to [he
child. and hc was asked to find [he plclure tha[
goes u’lth it among [h< pictures laid dolt n on the
uas ccm[able In front of turn. Tnis procedure
had been matched,
tinued
un[ll all pIc[uT?~
Children
were scrored for the [otal number of
correctly matched p]c[ures. Improvements
on [his
test suggest increases in l]su~l learning and recall.
I
I
I
I
1
{
I
1
1
[
RESULTS
From [he initial sampie of 61 childrm. 57 successfully completed
[ht $[ud>. From [his group.
two children had poor compliance during the Ias{
6 weeks of the clinc]al trial period (below 70Z as
measured from [he remalnlng bottled medication).
Consequently,
they were removed from the da[a
analysis leaving 55 ctuldren. 2S from [he plrace[am
treatmen[ group and 27 in the placebo [rea[men[
group.
Table 1 presents [he dcmograph]c
and baseline
characwnstlcs
O( [he Plracelam and placebo treti[ment groups. T-test and ,X: comparisons
be[u<tn
[he two groups showed nc s[gn]fican[ demographic
differences.
\o[e
thsl a ‘mgh percentage
of [he
children were act]ue!> rec::un:
remedl~l lu[orlng
for their reading probiems ica. ’07 ),
Table
[1 ~hou’s [he base!lne
scores (or [he
Plrace[amand piace!w-tre~icd
groups on [he
common [est batten.
\“o\e :h~[ the Gllrnore Oral
Reading [es~ .i ~~ s~,lrtd n :u~ ~a}~ Fir>:. lndl ~ld U.1] r~d(;ln~
and rate wm
3hlil[\
cored
f<~r 3CC’J73C\,
j<:
.nd,
~dmor?h~n>ldfl
hec31J~e b\
~<~~]ng
mt>re <I(lul( ~;;ur~~~ i~,~ :..-,~refi~n,;~.~
m<: ‘~<
[mor(>~ei ,.1: .;:: .e:. ti, :-,n?~,.:;c
~e~~,nz . . . r:’.
I
on [he common
test ba[[er:.
Table III g]ves the baseline scores for [he
Pirxemmand pl~cebo-[rea[ed
groups on [he tx penmental
tes[ b~ttery. T-test comparison>
between groups at baseline again jh~wed no sl:nlfi cant difference on JII bu[ one memure. The placebo
signific~n[iy
b~tt~r
~h~n
IhC
group performed
Pirxetam
group on the Paired %socia[e ~“isu~l
\femon
Tes[ J( baseline (/ = 2.0. P < 0.05). There
groups
11.1
Lb
Ji IJ
[lJ s
!()- ]
1: I
10:>
11:
i) -2
() ()-
-i)
were no o[her baseline differences on lhe e.xperl menta] wsI battery.
TO assessthe effect of drug treatment. the me~n
change from baseline WJS calculated for each jubject on each measure and then a~eraged and compared for each treatment group.
Table IV shows the mean change from baseline
(posttest-pretest
scores) [or each measure in the
common test ba[tery for the Pirace[am and placebo
groups. As seen in Fig. 1 for individual re~ding
scores. the Piracetam group demonstrated
a j[~[l~improvement
over
the placebo
ticidly signifkan[
group (at the P <0.003 level of .Iccuracy) on their
reading
:1
b
___
.—
rate
from
(heGilmore (es:. The Piract[am
.~rouu increased their reading speed by alm~st 8
words per min ( - 10%) whereas [he placebo group
decreased by 3 words per min ( – 4% ). lea~ Ing J
difference of almost 11 words per min between [hi
.—=.
47
!more oral read Ing
31
n.s.
19
n.>
+ccurac} (grade ratlngi
Reading
comprdhenslon
grade
raung]
--
6
n.x.
I
b 774 j
n.s.
n.>.
6646..J
-..IIc+34cKIilop
-.
n.s.
s\llatwc21)on
n.>
rau <ore)
n.5
rcersr 0( spelling errors “
p <0.01
.n colcr b
n.s.
n [email protected]
n.~.
h
n.s.
n
n
‘
objcc[
,BLE
sellne
n.s.
b
III
scores
wrtmmtal
J“or Ilre Prra[ prom wrd pI~cdw
rroup~ ,)~ lht
{t-xl htitlen
PERCENT :X?RECT X UCUDS
f[ name
Plraceram
Pluct’ho
r .Ies(
.-.4
-.
lo.~
12b?
n.>
n,
:.
.,.nt.[wee :t., .: 1:-
. . ,-,. ..
-, .. .
FIR rIIf4JTE
.,
4
-
in reading sped
for [he
xcompanled
by impro~ed
rcdlng
accur~c} acd c~.reprehension.
although
;Imllar g~ins wcrt als~ found in the plxebo group
Jnci. [hu~, canno[ be ~wnbed [o drug effect. There
were no slgnlfic.m[ dlifer<nces between groups on
reading Jccuracy or comprehension.
Composite rexling test scores shown in Fig. 2
clernons[ro[e [h~[ [he-Pi racetam group signific~n[l>
Improfed [hetr <ifec[l~e reading bv 16? during [he
course of [he s[ud\. On bo[h their effec[lte reading
(WO groups.
PirJce[~m
accurwq
plxebo
This incr<ase
group
Uas
~nd comprehension
scores. whereas [he
group decreased on both composi[e reod-
A comparison
lndi~iduai
[hc pl~cebc
group
did incre~se in their reading accurxi
~nd
comprehension
this was accomplished
Jt the eKpense of [heir reading speed which decreased. pr,nduclng very little effeetive change in [heir oierall
reding performance.
The Piracetam group. on [he
o[her hand. not only improved their reoding accuracy and comprehension
but also slmul[~neousl.
uas able [O incre~se [heir re~ciing r~tc. This re re~ding
scores
of
reveals
that
and
although
sul[ed
in significant
gains in their o~er~ll re~dln~
performance.
Fig, 3 shows [hat on [he Free- W’n[[n: Test.
bo[h groups showed an increose in the total number of words written. The P]rxe[~m
~roup Improved
15% uhere~s
[he plxebo
:rouc
jh{>ueC
~~nlv d jl g~ln. ~lthough [his Jiff<renc< AJ> n<:
s[.l[istiCall~ signiiicanl.
—_
composite
The Plr~\ :t~m ::Jup.
how -
—
49
sis[en[ ul; h prctious findings. sho~ing no significant med);al abnormal i[its among the Pirwxmm[r<ated
\Lhjcc:s,
The double-blind
ra[ing of drug
tolerance h} [tie ph}sic:an mdica{ed tha[ Piraceb} tht children (mean rat[am U3S uell-[olerated
Ing=l.1
( z 0.1). 1 excel len[. 4 poor). Except for
the one child who suffered from m asthma attack.
311 the c,kulcfrcn who uerc treated wi[h Pirace[am
rernalncd heal[hi.
I
DISCL’SSIO\
Thc~e :<suIIs confirm su~me of the pre~ious findinings ‘>f ii I]shcr et al. 11964) that Piracetam
!
~
PIRACnAt!
:N = 28)
n
PLACEBG
(h ’27)
Percentage
:CS[ scores)
Jp5
made
of
b}
change
from
basehnc
the
P1racc[am
and
arc shown for the 5-rein
(t-,: r3(t of reodin~ and of writing occurac}.
The ~moun[ of changes found In this presen[ stud}
arc com~arabl< m the resuits obtained by Wilsher.
[n Uilshcr’s $-week s[ud). subjeets irnprcned [heir
creases
[rce-wriung
~pos[test
placebo
rnlnu~
[reatmen[
sample. TtIC mial
lber of words wtl(en
m ~ nun b! each (reatmen~ V~uP
I w_Acperccntageof
spelling
errors
J>
are graphed.
:r. did show sig,nifican[ Improvement
over the
.cebo group in the accuracy of their spelling
<0.008).
The Plracetam
group decreased the
-cen[age of spelling errors (number of crrors~’
a]
words wr-iLten ) by 4% whereas [he placebo
NJp increased
in spelllng errors by over ~’3.
ese figures change. however, if one placebo .ou[-’ subject. who scored well above the resd of the
from [he analysis. Then
)up (83% ). is removed
: placebo group shows only a 4.5% Increase In
Nevertheless.
[he lrends
:L]lng errors ( P < 0.02).
naln the same. Overall. the Plrace[am group no[
I! Increased
[n lhelr wnt]ng speed. but ~lso
prov;d in their spelling accuracy. The placebo
speed. howe\’er. Ma:
~up.s Increase in writing
“>e[b\ ~ddi[lonal spell!ng errors.
Analysls of the mean change from baseilnt
“e[est–pos[tes[
scores) for each measure in [hc
penmental
[es[ ba[[e~
for [he Plracetqm and
icebo groups showed [ha[ [here were no slgnlfi11 differences found between [re3[men[ group<
an\ O( [he experlment~l
percep[u~i, memor\ ~i
)QU.I~C measures gl~en
/
- -P
“ s (r<In-. labora[,~n
e’.tilu~[l(~n~ .1( blotd
<r
htma[~~l,l~’. ~~d unn.1 .SIF ‘Acre coG-
The amoun[ of change found
In [he present 12-ueek $tudy is proportional
m
Wtlsher’s data with a 101 Improvement in reading
ra[e. This finding. seen in the light of Wilsher. s
preilw>
data. $uggests [hat the degree of Pirace[am-induced
lmprovemeni in reading and writing
10 [he
dura[lon of treatment. Howma~ hc rcia[ed
e\ er. lmpro~ emen[ oker time was not assessed
readin:
ra[c
h}
directly
WI]] be
rlKeSjJll
I
!2.
in [hc presen[
to
stud>, Additional
studies
[he effects of dose-
eslatilish
dura[lcln.
The presen[ stud] failed [o confirm Wilsher.s
previous flndtngs of drug-[ reproved reading accumay be due in par!
racy. The ~ack ~f imprcn<rnen[
[o Sc>m<~e~ large placebo responders: In fact. the
Iarges[ trnpro~emen[
In reading accuracy (7’97)
WJS fc~un~ [n J member oi [hc placebo group.
Substan[lal
changes In reading accuracy
ad
comprchens]on
Jbll]t\ occurred over the course of
[he s[utii for rnan~ of [n< d\sl<\lc children tn b,.l[h
[he P;:Jc<:~m- and piacebo-trm[ed
groups. This
UJS s.~mes~hq: Jnexpec[cd as [he reading skills ~~f
94
.
—
[Ime-p<nod.
The placebo- we~ted children did jusl
(h~i. The} mcrwed
the number of words written
Huwwer.
O\er [he:r ori~inal baseline performance,
~$ Was f~wnd [n reading. they made this g~in J( the
expense of something else. in this cme w-i increased number of spelling errors. The dyslexics
cfid
no[
show
this
“ Iose-(o-gain”
pat~>n Piracerajn
[ern. R~dtcr. [hey increwd
both [he number of
M uell .JS decreasing the number or’
spelling errors they made. Even though the only
slgnifican[ difference between groups noted a(
bdsdine uas the number of spelling errors made.
group making more errors than
w lth [he Pir~cetam
words w ri[m
the pldccbo group. by the end of the s(udy this
order u as re~ersed. The Piracetam group made
fewer spelling errors than the placebo group.
their accuracy
and comprehension
over their OC#I nal baseline performance.
Thti[ is. they did ao[
have to lose ground in order to gain ground. T’ney
gained both speed and impro~ecl accuracy ~nd
comprehension
over the course of the ~tud~. The
Jnci
percentages
of SUbJeC[S In the pirace[am
placebo [reatment groups >howing gains ~nd losses
In reading accuracy And rate ~re shown in Fig. 1.
On the untmg
s~mplc Subj<cts were told (IJ
—_
Some of the measures
in the special perceptual.
mcmor> and receptive
language studies suffered
from ceiling effects. as most of the subjects found
these LCSISm be relmively e~sy. indic~tlng ade quaoe perceptual. memory and language abilities
for [heir age. Most of the subjects performed Q(
the wp of the scale on all subtesw of the Repeii[ion Test as well as on all 5 parts of the Token
Test. tndico(ing normal perception and receptl~e
language abdities M the onsei of the study. hence
letiving little room for improvement.
Only 4 wbjw[s sc.wcd ~t least one standard deviation below
[he mem on the Token Test. suggesting thtt Mat-
us e[ ~l”s f1975) language disorder syndrome WUS
38
50
18
n
a
poorl> rtpresen(ed
in this dyslex]c sample. Subjects Jlso <ored highly on perceptual sub[t~ts ot’
J]] 3 Rtpctition Tests. indicating that they h~d no
Jifficul[} m cfiscrimina[ing between the di!~eren[
audi[o~ or ~isual stimuli. A subgroup of 19 jubbetween the
jects dld have difficulty
discriminating
(WO ccmputer-synthesized
speech syllables / ba,
and ., da Z’uith WI ms formmr cracsitions. On the
Repe\lIlon Test however. perhaps due to (he !er>
small >~mpk size. a X:-[est indicated no slgn]fi canl Jlifercnces between Piracetam and plJceb~~
to previous findings
groups on this [est. Contrary
( Dlmond. 19~5: Wilsher et al.. 1979). subjw[~
[Ihing P~rxer2m did not demonslrl[e
jt~li>[!c.111}
jigni(lc~nt
Improvements
in [heir $hor[-[<rm ~nd
>erl~l mcm~lry skills. althou~~ ~ome dlifer<nces
b<[%een non-verbal and verbal stimuli were found
.—==
=- ..
—
I
51
odaht~
of
This pa[[ern of resu[[s calls for a much closer
examination of the differen[ stages of’ memo~ [ha[
may be affected b) Pmce!am.
Fu[urf s[udie>
cffec[s
should examine possible ma[erul-specific
cxfali[>.
subjects
of Pirace[am
~lng non-~ erbal stimuli, treotment
differences
~ln the
) stgnifican[
,rrect
stimulus
series
rec~lled
groups showed
total
number
in the
of
ZUCJIIIW
[he Repetl[l~~n Test. in [he $’ISUJI
on pfaccbo
found it easier [o
cdl the proper sequence of the visual nonsenseaped s[irnuli. as demonstrated
by their improved
ores for [o[al correct trials wi[h long 1S[”s. In
re lntrast. when [ml items could be verbally
:~rsed.
as in the Paired
Associate
visual
Memor}
which used namable
pictures as stimuli. and
e Digit Span subtes[s.
the Pirace(am-trea~ed
oup”s mean final perform~nce
and change from
Iseline was almos[ Iwice that of [he placeh~
2SI.
<Iup on both lests t Fig. 5 ). The difference
bc. den groups. however. was nol sta(lsticall> jlgin el[her case. These trends [ouarci lmfican[
mcdia[ed malerial
-oted memory for ~erball]
lg&st
emon
(mple
:n: ‘.
tha[ ~ significant
Improvement in verbal
scores mlgh[ be realized with a larger
Size. a longer
ciuratlcm
drug
ma!.
or
more
measures.
In addition.
Piracetam’s eff<cl
or} could be media[ed by drug-dosage. A
irger (e.g. 4800 mg/rda} ) dosage migh~ produce
gnificant results. since pre\ious findings used a
osage in this range.
n.
5%-
,:
34
‘5
e
as working
on various memo~
capacity.
rehearsal
components.
strategies.
such
retrie~al.
and recall. In addition. the questions of
retention
dosage-dependent
memory effects should be investigated.
Sub-tec[ selection procedures ma} JISO haw important implications for drug studies wi[h dyslewc
children. Se\eral different subgroups of readingor language-impaired
children. exhibl[ing different
profiles in [he areas of perceptual. memory and
language functions. have been descnbcd I<ee Tallal
and Stark. 1982. for re\iew). Bascilne [est scores
sugges[ [ha[ [he majori[v of re~ding-impaired
1
children participating
in this s[ud) did not ha\-e
significant perceptual.
memory or reeepuve language deficits associated with their reading disability. Thus.
it was difficult
to assess [he potential
[hcrapeu[ic efficac> of Piracetam in [rc~tln~ such
deficits in the present stud}. In order to bet~er
assess Plr~ce[am”s
ability to effec[ perceptual.
memon
or receptive language defictts. It will bc
importan[
[o select a group of reading- or lan guage-impaired
children who shcw signlfican[ deficits in these areas at baseline testing. Comparisons be[ween different subgroups of remiing-lmpalred children. selected on the b~sl~ of specified
behavioral profiles. may be ~n lmp~rtant factor [n
assessing [he effects O( noo[roplls on le~rnlng- and
language-impaired
children.
In
summa~.
Pirace[Jm
appe3rs [o impro~e
verbal fluency. as demonstrated
b\ Incrcwd rate>
of reading and ~n[ing accuroc~. These [rend>
encourJge
a poten[ial role for Plrwetam in [he
ciinicai remedla[lon of dvsleua. al[hcwQh question<
Jbou[ clrug-dos~ge. duration of [re~[mc-n[. poss[hle
In[erac!lon
wi[h o~her remedial proced~res. dliferen[l~l effects on tarious subgroups oi le3rningImpxred children Jnci selec[l\l[\ ~f drug -respon><
remain unJnsuered
Some of these i>jut> ~re being
inve>[lga[ed presen[l}
One findl note of cau[lon
of
JnJl\
talnd
Seiec::tt
Se> pcrf~lrmed,
~.~uld be
iri[trprc?[<d
rC’pll. Jl:,ln
— ~!~tn Ihe number
some
(_)I’!ht..<
oi
:ne
J> :!IJ.7::
:5UI[>
L~h-
,w;urren~e~
!] II J,-.:. u ;“, J dl’:::-
I
!
f
1
I
I
I
!
I
1
REFERE~CES
\mJn.
U.G
I [980} Psychotropic
— a >elecuve
+man,
M G
and
Dtanpam
ChAf
review.
~rug
~ Uarrr
W’eery. f S, f 1982)
and scsere reading
Prichfalm.
learratng
JCI~
Df$ab.
problems
13. 36-46.
Uethylphcntda!e
ret~rdJt(cm.
~
,-fm.
children
and
[>WS O( ~ctivl[y IoA
J
*
R.A.
and
In[cracuons
Cunningham,
C.E.
The
drugs. In R.,M
[email protected]
and
D.J.
ChJdhoad
Denckla.
( Eds. }.
J.S. Wew
Wilq,
%w
U B. 3nd
Ing Jisabth[ws.
——
Rudel.
R.G.
( 19~61
Rap,d
dlfferentla[cd
o~her leam-
8ruin. 85:665-678.
Congress
ad
,!ledtrjrre. 9
Dimond.
Colle$e
o~ Psvchosomattr
16-20.
49:
crf
Ihrough [he use of drugs. Pst chopharmucol-
307-309
h\pcractlve
chddrenq /n/ J
tf<nr. Heu/rh.
R. and Kleln.
effec[s fn Ieamtng dlsablhues
Gtin P~&chwn,
D F
( 1976)
4
182-198
Me[h>lphenldl[c
psychometric
changes, .4rch
MJIIIS,
Vtrb
S
children
Brhac.
French.
\ 9 683-694,
J.H.
and
md young adults
R~pin.
1. (1975} D>sle~la In
[hree Independent
neurops>ch~
of
Pr),h(j-
and Ica-rung
JIs-
Methylphcmfa~e
(n
3: 56-67.
E.K.
11977)
differences
.Sc/errce.
In dose cff~[s
cm lcam-
198” 1274-12-6.
.1. and Agnoh.
A. 1197s)
Drrsgs
Paper
presented
~ .$MJt on
at Tiwrd [n[emauonal
of Congress on Psychosoma[!c
K.J. ( [972)
*
,4r:rreIrrt .Fwch..
Svmmcs,
The
clinical
[he
drug:
.Mcdlc,ne.
Rome.
Park
requtslles
Press.
hdi~o~
disabilities
[n
R.
and C>mmuntcu-
Baltlmorc.
lempord
in ctuldrcn.
percepuon.
BnrIn
pb.OCCSC$ ~nd
brig..
9: 1S2 -198.
profiles of
cluldren with or w~thou[ concorrumnt cv~l
language defiots.
,4nal. Dysle.r(a. 32: 163-176.
.M.E. {1977)
IS
re~dln~
for langu~gc
Lvryuaye
P and Stark. R.E. ~1982) Perceptual/motor
reading-impaired
Thomson.
J new
;n~olu[wn
42: 82-91.
I Ed.). .Von-Speech
Talldl. P ( 1980b}
reading
jenll<
J.L. ( 19721 L’nexpec:A
( 1980a~ Perceptual
P
Pirwe!~.m.
W’
22; 975-977.
Am. J Orrhopwchiarrc,
Scfuefelbuwh
use of
mmtrncrst
J.S. and Rapoport.
Idenufylng
the dyslcxrc chsld. Dvsk.rw
5-12,
L’CB ( 1980)
.Vaovopd
LCB.
Pharmaceuucai
D!\ls,on.
Brus-
sels. Belgium.
G..
Kruger,
E..
DanlclsOn.
C
~nd Elman, \(
( 1975)
Effec{ of Iong-[<rm wea[men( of h~pcrac[we cbidren
mt[h~lphen{da[e.
CLJrr.,~led A~SM J
‘A’erm J“S 11981 I DrU~
wr.,
W’crry.
J,S
JCII\; I>
W,lsher,
and lesrmng
ul(h
I I: 159- ;65.
J. Child Pf)cn.d
PJI[hI-
22: 283-90.
C
<mmr.
and
Hdoptndol
33.655-669
Jockwn. \f D 11980) Fur!hcr e. IJencc for J rel~llonshlp be(w<en memorn access ~nd remflng abll]t> Journal o,( L“ertr
Lwrn
nk.
U’CISS,
Gi(!l<mws-Klem. R. Jnd Klein. D F 119-S} Arc behasloral and
p>>chometnc changes rel~ted m me!h}lphenlda[e. ~reatcd.
Gi[[lcman-Kleln.
Cewone.
Effcc[s
[[sly.
R<r.
S J. and Brouwcrs. E.Y.!vt. ( 1976 I rmproiem<nl
human mtmory
,)qY,
lrrwrmrnonal
{ 1980)
disorder,.
Psychophormacoiogy
cluldren:
voo/rop{c
College
Tallal.
of
M.
Iezmlng
Ps,vchtwy,
and Slemor.
tmn. Um\erslty
471-479.
L.A. { 1962) Th< Token Tes[: .s
recepltve dmurbdnces
m .sphasla.
12
Shor(. Term .Memo~ M ,Man. In!eracrwns w((h <ooanulep(tr
TdlJ1.
‘~utoma[tzct
from
D!mond. S,J 11975) The effects of a rsoo[ropic subwnce on lhe
capact[y for ~erbal memory and ksrrung m normal man.
Thlrtl
G..
fadure.
,Veuropsycho/o,qa.
Renzs. E. and Vignolo.
$cn$i[l~e (CS1 10 de[ca
Disorders o!
Ps,rchrrpatholq:cd
York.
nammg ( R. A..~. I‘ dyslexia
De
[n H.
.Vcwruprrc+.logfa.
Rtsmck.
with
Ing ~nd $ocI.dl beha~lor.
noo(roplc
51-60
C K. wrd Werry. J S. 11979) Pharmacotherjpy.
[ 1972)
R,L.
Squltwi.
C.rllimw. 1. and Marchau. .M. ( ]975} Clinlcal mal of Piracedue IO head Injury
Acru
wm us disorders of consciousness
Qu~b wd
BuII.. 16.65-66.
R.L.
h}perkincuc
and karrr)rr~ Disordered
Chddren. L nl~ersl[y Park Press. Baltlmore.
Barkie}.
R.A. and Jackson.
T.L. t 19?7) Hyperklnews.
autonomsc nervous system actwlty and surnulant drug effects.
J Chl/d P~ychol Psvch,arm. 18: 347-357
Cwtrwrs.
ph~rmucol.
Sprague.
Bakker
( Eds. ). Treatmenr o~ Hvperacmv
4rroesthesJol. Belg.. X
B. ~nd
m chddren
orders. J Operal.
parent-chdd
chsidren ~nd [hew modificaoon
ir( hypcractlvc
by $Ilmulan[
( 1980}
dis~btlitles.
P]rxe[~m
Sprague.
4bnorm. Ch(ld Ps,whol. 5 3S I -569.
B~rkle>,
Ieamtng
J . Wa[ers.
“mpn.
In press.
B. Mkd}. R..+. ( 1977} The effects ,s( \[tIhylphenuJaw
on bancru<
jnd J[[en[lon in hyperklne[lc children.
w]th
!09-118.
Acad.
(n duidren:
4rch
.W,G
Cm. Psvchtu[r.,
A[klns,
G
11975)
,Me!hylphemdale
effects on ~[!enl;on,
rcemo~
~nd
md
32: ‘90-795.
and W.snsfidd,
P ( 1979) f%rJce!am
J.
102
The Effects of Nootropics on Memory:
New Aspects for Basic Research
,.-+
-
6-’
C. Mondadon’, F. Petschke, A. Hausler
Pharmaawical
Research Depanment, CIBA-GEIGY Limited, Bade, Switzerland
NOTICE
THIS MATERIAL MAY BE PROTECTEDlily
CO,+q~G).:T LAW (TITLE 17, U.S. CODE)
Wirkungen der Nootropika auf das Gediichtnis:
Neue Aspekte furdie Grundlagenforschung
summary
.
The mechanism through which nootropics of
the piracetam ~
(i.e., piraeetam itself and its analogues oxiracetam, pramiracetam, and aniramtam) improve memory
is still uncertain. Its elucidation will, however, not only mark
an advance in the treatment of cognitive disorders, but also
shed light on the basic processes of memory storage. Although the great majority of the tindings available so far
seem to suggest cholinergic mechanisms, divergent results
are obtained whenever parallel experiments are performed
with two or more of these compounds.
More recent observations indicate that interactions with steroids take place. All
four compounds are inactive in adrenalectomized laboratory
animals; chemical blockade of the adrenal cortex with
aminoglutethimide
and pretreatment with epoxymexrenon,
a potent minerabcofiicaid
antagonis~
eradiuted
the
I mernory<nhancingeffectof
all foursubstances.
1
I
The
—
elucidation
of biochemical
bases
and the
memory is one of the greatest challenges in neurobiology. It is therefore hardly surprising that every year
hundreds of papers are published dealing with some particular facet of memo~. Our knowledge of the subje~ matter increases almost daily, but more in width than in depth. We now
know of many transmitters, receptors, and modulatom that
play some part in memoty processing: but each new finding is
soon relativized by the realization that it is not generally valid,
but simply sometimes true under certain limiting conditions.
In this field, progress tends to follow the discovery of a new
pharmacological tool, e.g., a new specific receptor blocker or
activator, or an enzyme inhibitor. Consequently, the pre\alent
method in efforts to identify the mechanisms and the neuronal
networks operative in memory processing relies on the testing
of mechanistically specific preparations for potential effects
on memory in animal models. For example, the NNIDAblockers (MK 801, AP5, and AP7) that recently became a~aiiable
encouraged studies of the influence
of NNIDA blockade on
regulation
of
Pharmacopsychiat.
22 ( 1989)
102-106
@ Georg Thieme Verlag Stuttgati
New
(Supplement)
York
Es besteht noch immer keine Gewi13heit dariiber, auf welche Weise die Nootropika des Piracetamtyps
Oxiracetam,
(Piracetam und dessen Analogverbindungen
Pramiracetam und Aniracetam) das Ged5chtnis verbessem.
Die Kkung dieser Frage tirde nicht nur einen Fortschritt
bei der Behandlung kognitiver St6rungen darstellen, sonzugrundeliegendem such die der Ged5chtnisspeicherung
den Vorgiinge erhellen. Obwohl die gro13e Mehrzahl der bisIang ve~ugbaren
Befunde auf cholinergische Mechanismen
hinweisen, werden widerspriichliche Ergebnisse erzieh, sobald parallele Experiment
mit zwei oder mehreren dieser
Verbindungen
durchgeffihrt
werden.
Neuere Beobachtungen scheinen auf Wechselwirkungen
mit Steroiden hinzudeuten: alle vier Verbindungen sind bei adrenalektomierten
Labottieren unwirksam; sowohl eine chemische Blockie- I
rung der Nebennierenrinde
durch Aminoglutethimid
als
such eine Vorbehandlung mit Epoxymexrenon (einem potenten Mineralokortikoidantagonisten)
blockierte die gedachtnisverbessemde
Wkkung aller vier Substanzen.
learning and-lnemory and speculation about the possible involvement of this type of receptor in memory processing ( ,Lforrrket al., 1986). In the meantime, it has become evident that the
responses seen under NMDA blockade only apply in certain
circumstances and to certain processes of memory ( Morrdadotiet al., 1989). llus, while the assortment of transmitters
[email protected] in memory processing increases, that does nothing to
alter the fact that almost every pharmacological manipulation
of the CNS has some influence on certain, though not all,
forms of learning and memory ( Morrdudori, 1987).
The opposite way O( seeking insight into the
processes of memory consis~ in characterizing biochemically
the substances known to affect memo~, and then Attempting
of their biochemical profile
to correlate certain components
with their effect on memory. The memory-blocking effects of
certain antibiotic such as puromycin, anisomycin, and qcloheximide, for instance. inspired a very large number of studies
of the possible relations between inhibition of protein synthesis - scientifically [he most appealing aspect – and memory
(for a review see, for example, Da~ies and Squire, 1984). The
underly~ng mode of action has, however, always remained
conjectural, because these antibiotics exert many other knovn
7%eEflects of Nootropics on Memory: New .4spectsfor Basic Research
l~$ffects (see, for example, F7exner and Goodman, 1975; Rain>Wet al., 1979) and quite probably just as many other unmown effects that might equa[fy well be responsible for the
disturbance of memory, or at least contribute to it. The possibility that the known biochemical efTect under scrutiny may
not be responsible for the observed effect on memory, or that
that effect may be due to the interplay of several discrete effects, must always be taken into consideration, even in studies
using the abovmentioned “specific tools”: failure to do so
makes false conclusions unavoidable.
One practicable and valid approach to the experimental investigation of mechanisms underlying memory
storage, or the regulation of memory storage, maybe afforded
by the piracetam-like nootropics. These are interesting preparations, above all because they exert distinct, positive effects
of memory, yet provoke few or no
on various manifestations
side+ ffects. The fact that they have so far been found to display s~rcely any effects in most of the traditional assays used
in biochemistry laboratories may make them appear all the
more or all the less attractive, depending on the viewpoint of
the observer. If, however, as has already been suggested ( Giurgea, 1973, 1982), they do act specifically on cognitive
processes or on the struuures and mechanisms responsible for
cognitive processes, then the elucidation of their mode of action might represent a very significant advance. The following
remarks, illustrated by a selection of experimental observations, will be concerned with the progress made to date along
––—”’-is
line of research and the possibilities emerging from it.
Neumphmnamlogical
ftiings
The first experimentally demonstrable
effect
of piracetam, the prototype substance, on the CNS was inhibition of central nystagmus in the rabbit ( Giurgea et al., 1967). In
retrospect, however, the vast majority of the experimental preclinical findings seem to be indicative of effects on cognitive
processes, in particular on learning and memory in a vety wide
variety of forms. Piracetam, for instance, diminishes the disruptive effect of a mrebral electroshock on the orientation of
1972).
rats in a water maze ( Giurgea and A40uravieflkruisse,
Many other authors have also observed anti-amnestic effects
of piracetam and related substances: distinct protective effects
against the disturbance of memory following cerebral electroshocks in passive- and active-avoidance tests on mice and rats
were noted by Cumin et al. ( 1982) after treatment with
aniracetam and piracetam, and by Mondadori et al. (1986)
after treatment with oxiracetam
and piracetam.
Sara (1980)
observed similar responses to etiramtam. Buf/er et al. ( 1987)
described anti-amnestic effects of a whole series of piracetam
analogues, including pramiracetam. Numerous observations
have also been made of direct positive effects on learning and
memory: aniracetam and piracetam ( Yamada et al., 1985;
Wo/rhws,
1971 ), etiracetam
(Sara, 1980)
and
and
Bures, 1976), on
in rats ( Wetzel, 1985), on
increased theta power in the hippocampal EEG, and on a reduction in the power of cortical slow waves ( Poschef et al.,
1985).
hemispherical
augmentation
(Buresova
transfer
of paradoxical
sleep
Interesting and biochemically inexplicable observations indime that both piracetam and oxirwetam intensify the anticonvulsive effects of anti-epileptics such as carbamazepine
( Mondadon” et al., 1984; A40ndadori and
Schmutz, 1986; Hawkins and Melhnby, 1986).
B*mical
effects of piraeetamlike mdropics
There are relatively few data available on the
biochemical effects of the piracetam-like nootropics. For a
long time, the observation by Nickof.ron and Wohhuti ( 1976)
that piracetam stimulates adenylate kirtase aaivity was the
sole measured biochemical effect. Woefk ( 1979) then showed
that piracetam
increased
the incorporation
of 32P in
phosphatidylinositol and phosphatidyl chloride in glia cells
and neurons. Grau et al. (1987) reported an increase in glucme
utilization under hypoxic conditions and accelerated recmery
of the EEG. Posche/ et al. (1983) demonstrated that neither
piracetam nor pramiracetam bound to muscarinic cholinergic
receptors; nor did binding occur in a dopamine assay with
haloperidol,
The uptake
of GABA
and
serotonin
was not af-
fected by piracetam or by pramirwxtam.
~gsley et al. (1983)
found no evidence of activity in traditional pharmacological
assays. No effects were detectable on the concentrations of
noradrenaline, dopamine, 5-HT, or 5-HIAA in the cortex or
midbrain of the rat. At very high doses (200 mg/kg i.p.),
piracetam increased stnatal HV without affecting DA levels,
indicating that it augments the turnover of DA. Pramiracetam,
however, did not increase DA turnover. Receptor assays revealed no afllrtity of either piracetam
or pramiracetam
for DA
muscarinic, alpha 1,2- and beta 1,2-adrenergic, 5-HT1-, 5receptors. On
HT2-, GABA adenosine, and benzodiazepine
the other hand, it was shown ( l%gsley et al., 1983; Shih and
Fbgsley, 1985) that pramiracetam increased high-affinity choline uptake into hippocampal
synaptosomes. The effective
doses were 44 and 88 mgikg i.p.: neither higher nor lower
doses were active. Surprisingly enough, piracetam at 100 and
300 mg’kg and aniracetam between 10 and 200 mgikg both
had no effect on high-affinity choline uptake. These results
with pirace(am are slightly at variance with the observations
reported by Peda/a et al. ( 1984). These latter authors found
that both oxiracetam
and piracetam
high-affinity
uptake
choline
pus, The discrepancy
determinations.
oxiracetam
,J40ndadon et al., 1986) were found to exert direct effects on
--acquisition and retention performance in rats and mice in pasve- and active-avoidance
paradigms:
pramiracetam
in.ieased Ihc acquisition rate in a 16-armed radial maze ( .Jfurra,i’
and Fibiger, 1986) and in a place navigation test (Morns maze)
( Pow%elet al., 1985): positive effects ofaniracetam were demonstrated in matching-to-sample tests ( Ponrecowo et al., 1985).
All these findings are supplemented and indirectly supponed
by observations of a facilitating etTect of piracetam on inter[
l%armacopschiat. 22 (1989)
The
exerted
positive effects on
in the rat cortex and hippocammay have been due to the timing of the
above
cholinergic
effects
are
supple-
Pepeu ( 1986) which
demonstrated that oxiracetam prevented the decrease in the
acetylcholine content of the cortex and hippocampus induced
b: cerebral electroshock treatment (piracetam was inactive).
show
Further
obsemations
that
piracetam
reduces
scopolamine-induced
amnesia (Pierce}’ et al., 1987) and, according [o one interesting report (Pdch and Mii!ler, 1988), ele\ates the muscarinic cholinergtc receplor density in the frontal
cortex of aged rats.
mented
by findings
made
by Spignoli
and
103
104
l%armacopsychiat. 22 (1989)
C. h40ndadori, F. Petschke, A. Hausler
Taken as a whole, this selection of findings
might at first glance give the impression that the piracxtam-like
nootropics act by way of cholinergic mechanisms. This conclusion is all the more plausible because there is a very large
of cholinergic mechabody of literature on the signifimu
nisms in learning and memory (see, for example, Drachman,
1978; Burfu.s, 1980). On closer scfutiny of the available results,
however. it becomes .cdainly. evident that there is not one single
report in which several piracetam-like nootropics tested a-ncurrently have actually been found to prodwx the same eff-.
The observed effects, insofar as they have been studied,
are not common to all nootropics (Shih and Rigsley, 1985;
Spigrtoliand Pepeu, 1986). Considering their similarity in
strtmure as well as in their pharmacological profiles of activity
on learning and memory, it seems quite likely (or at least quite
possible) that all representatives
of this class modulate
memory via the same mechanism. Failing any definite evidence to the contrary, this is certainly reason enough to continue the search for one common mechanism of action shared
by all the substances belonging to this class.
Are steroids involved inthemediation
of ooohopie effects ?
—=—=
—
Even if allowance is made for indi”fidual variations dependent on their particular pharmacokinetic% it is still
true to say that whenever neurophannaccdogical
agents are administered systemically the brain is flooded with active substance. One may well wonder what chance there is of improving the performance of such a complex and finely tuned
organ by so crude a method. On the other hand, there are indications pointing to the existence of endogenous physiological mechanisms
that can, under certain circumstances,
heigthen the performance of the memory: flash-bulb memories (see e.g. Brown and Ktdik, 1977), i.e. abnormally sharp recollections of certain events mostly associated with highly
emotional states, are a good example. If such mechanisms do
in fact exist, then they obviously desetve to be regarded as
potential targets for pharmacological
interventions. [n this
contexL account must also be taken of the possibility that the
selective physiological activation of certain neuronal mechanisms in the brain proceeds via peripheral mediators. Nor can
one simply dismiss the further possibility that the memory
facilitation induced by nootropic drugs may come about
through modulation of such processes. Since the pituitaryadrenal axis plays a significant part in emo[ional states, it
seemed important to find out whether piracetam-like nootropics retained their activities in adrenaleetomized animals. lltey
did not: oxiracetam,
piracetam,
[email protected], and prashowed
no memory +mhancing
effects
in
mi racetam
adrenal e~omized mice ( Mondadori and Perschke, 1987). A
series of
further studies proved that the blockade of their activities was not an effect of dosage: even significantly higher
..
doses of the nootropics were ineffective after adrenalectomy
( A40mfadori, Ducret and Pefschke, 1989, in press); Accordingly, the next question was whether the products of the
adrenal medulla or of the cortex are the critical components in
the activity of nootropics. To answer that question the animals
were pretreated with aminoglutethimide,
which is an inhibitor
of several cytochrome-P450 -mediated hydroxylation steps in
steroid biosynthesis in the adrenal cortex: e.g. 18-hydroxylation of corticosterone (i.e. aldosterone biosynthesis), sidechain cleavage (i.e. conversion
of cholesterol to preg-
nenolone), and 1I-hydroxylation
(i.e. glucocorticoid
biosynthesis) (for a review see San(en et al., 198 I ). Exactly as
adrenalectomy,
rendered
the
four
this pretreatment
piracetam-like nootropics inactive. .-%ninoglutethimide itself
had no effects on the retention performance of the mice. These
data provided the first indication of the involvement of products of the adrenal cottex in the mediation of the effects of the
piracetam-iike nootropics. It must be conceded that aminoglutethimide is not entirely devoid of effects on the adrenal
medulla: increases in catechohnine
levels have been obsemed (Duckworth and Ki(abchi, 1971). To exclude this possibility, mice were pretreated with epoxymexrenon.
Pretreatment with this specific mineralomrticoid
antagonist (de [email protected] et al., i 987) gave similar results: the memory enhancing
effects of the piracetam-like
nootropics were completely
blocked; and again the drug itself had no effect on memory.
These findings prove that steroids can play a role in the mediation of nootropic effects. Furthermore, these were the first
pharmacological experiments in which all four prototype substances behaved in exactly the same way. ( Mondadon” et al,
1989, in press)
[t is interesting to note that certain other substances also lose their memory-modulating activities in the absence of the adrenals: e.g. amphetamine and hydroxyamphetamine ( Marrinezet al., i 980) and vasopressin (Borellet al.,
1983). However, the effects of these drugs appear to be dependent on the function of the adrenal medulla.
Although autoradiographic
studies of the mt
brain give the impression that oxkacetam does not readily
penetrate the blood-brain barrier ( Mondadori and Perschke.
1987), the above-mentioned
findings as a whole cannot be
taken as evidence that the piracetarn-like nootropics act peripherally. hongst
various other possible mechanisms (see
also Mondadonand [email protected], 1987), it is conceivable that activation
of steroid
receptors
in the brain may be a prerequisite
for the efficacy of the piracetam-like nootropics; in other
words, steroids may mediate the action of nootropies on
memory. The converse is equally plausible, i.e. that these preparations directly or indirectly modulate the effects of certain
steroids on memory. There is ample evidence to show that
steroids can exert an influence on memory (see for example,
Micheau et al., 1985; Bohus and de Kloef, 198 I). A new facet
emerging from the authors’ experiments is that aldosterone-receptor-mediated
activity may play a part in memory processing or its regulation.
How these effects come about is unclear; but
extrapolation
from findings on the peripheral effects of
steroids discloses a particularly fascinating aspect. It has been
that in various organs steroids affect specific
demonstrated
gene expression by moci ., ii:g the rate 01 [r~nscnption oi J
specific set of genes ( Yamamoto, 1985: Schtit:, 1988). It
would therefore be extremely interesting to know wnemer
pirace[am-like nootropics can exert direct effects on gene trwtscnption, or modulate the action of steroids on gene transa-iption. There are already a number of publicmions on the effects
of steroids on protein synthesis (Arenander and Vullir, 1980:
Elgen et al., 1980; Nes~leret al., 1981; i$fdeu~nicet al., [986).
Since it is known
that protein synthesis plays an important
in the formation
of memory
traces (fora
part
review see Davies and
..
Htarmacopschiat. 22 (1989)
The Eflecn of Nootropics on Memory: New Aspects for Basic Research
that nootropica
1984), it is anceivable
emery via modulation of protein synthesis.
~=-quire,
may improve
The present observations, which suggest that
steroids may be involved in the mediation of the nootropic action of the piracetam derivatives, do not contradict the reported findings on their cholinergic effec?.s, since the possibility that steroids may interact with cholinergic mechanisms
cannot simply be dismissed.
References
macologic 46( 1976)93-102
Butler, D. E.. J. D. Leonard, B. W. Clzprathe. Y. J. L ‘Italierr, M. R.
PaVia, F. M. Hershenson, P. H. Poschel, J. G. Mamotf: Amrresia-=
Reversal Activity of a series of Cyclic lmides. J. Med. Chertsky
30( 1987) 498-503
.umin, R., E. F. Bundle, E. Gamzu, W. E. Haefefy: Effeus of the
Novel Compound Astiracctam (Ro 13-5057) Upon Impaired
harming and Memory in Rodents. Psychopharmacology
78
(1982) IWIII
Davis, H. P., L. R. Squire: Protein Synthesis and Memory: A Review.
518-559
de Gospam, M., U. Joss, H. P. Ramjoue, S. E. U%itebread, H. Haenni,
L. ScJrenkd, M. Biollaz, J Grob. P. W’ieksnd, H. U. W’ehrli: Three
New Epoxy -spironolactone Derivatives: Characterization in Vivo
and in Vitro. J. Pharrn. Exp. Ther. 240( 1987) 65L656
Drachrnann, D..4.: Central cholinergic system and memory. In: Lipton, M. A., A. DiMascio, K. F. Killam (Eds.) PsychophacrnaCOlogy a Third Generation of Progress. Raven press, New York
(1978)651461
Duckworth, W. C,, A, E. Kiiabcht:
glutethimide
(PNMT).
on
Stimulatoty
Effect
Phenylathanolamine-N-methyl
of
Amino-
Transfera.se
Endocrinology 88 (1971) 384-388
Ergen, A. M., M. Marnn, R. Gdberr, G. L.ynch:Charactecization of corSlices. J.
ticosterone-induced Protein Synthesis in Hippocampal
Neurochem.
F7exner,
35 (1980)
598-602
IL-. B., R. H. Goodman: Studies on memory: Inhibitom of pro-
tein Synthesis also Inhibit Catecholamine Synthesis. proc. Nat.
Acad. Sci. USA 72(1975)4660-4663
Gru.-gea, C. E., F. Mouraviefl-hrursse.
Effect Facilitateur du
Piracetam sur un Apprentissage R+p+!tif cher Ie Rat. J Pharma COI.3(1972) 17-30
Gwgea, C. E.: The “ Nootropic” Approach to the Pharmacology -r
the Integrative Activity of the Brain Cond. Reflex 8 ( 1973) 108115
Giurgea, C. E.: The Nootropic Concep[ and Its Prospective lmplica= tions. Drug Develop. Res. 2 ( 1982)441-446
mgea, C. E., F Moyensoons, A. A Emund .4 Gaba-Rela~ed HySickness
pothesis on [he Mechanism of Action of the Antimotion
Drugs.
Arch.
tn[
Pharmacodyr,
Micheau, J., C. De.strade, B. Soranireu-MoumI: Time-Dependent Effects of Posttrainirrg Intt-ahippocampa.l Injections of Cofticosterone on Retention of Appetitive f-earning Tasks in Micz.
Europ. J. Pharmacd. 106(1985) 3946
Mileusrric,R., S. Kanaztir, S. RuzdJi, L. Raki:EfTects of Cortisol TreaIment on Protein Synthesis in Septum and Hippxarrrpus of Rat
brain. Neuroerrdoainology
Proteins in ClonaJ Cultures and
ArenarrrJer,A., J Vaffis:Glial-released
their Modulation by Hydroconisone. Bmin Res. 200(1980)40 I419
Bartru, R. Z: Cholinergic Drug Effects on Memory and Cogrtition in
Animats. Ed. L. W. Poorr ( 1980) 163-180
Bohut, B., E. R. de K/oef: Adrenal Steroids and Extinction Behavior:
Antagonism by progesterone, Deoxycortiassterone and Dexamethasone of a Specific Effect of Corticosteron. Life Sci. 28
(1981)433-440
BoreU, ~., E. R. de K[oet, D. H. G. Vemteeg, B. &#rus: The Role of
Adrenomedu!lary Catecholatnines in the Modulation of Memory
by Vasopressin. Dev. Neurosti. 16 ( 1983) 85-90
Brown, R., J Kufik: Flashbulb Memories. Cognition 5 ( 1977) 73-99
llrwrsowi, O., J. Bures: Pirawtarn-lrrduced
Facilitation of Interhemispheric Transfer of Visual information in Ra?s Psychophar-
Psych. BuII.96(1984)
Hawkim, C. A., J. H. Mellanby: Pitacctam poterstiatcs the antiepilep
tic action of carbamazepine in chronic experimental Iimbic
epilepsy. Acts Neurol. Stand. (Suppl. 109) 74(1986) I I7-121
Marrinez, Jr., J. L., B. J. Vasquez, H. Righter. R. B. Messing, R. A. Jensen. K. C. LAmg. J. L. McGaugh:Attenuation of amphetamine-induced cnhanament of teaming. Brain Res. 195 (1980)433443
166(1967)
379-387
Grau, M., J. L .kforr/ero, J Ba/asch Effect of Piracetam on elcktrocorticogram and Local Cerebml Glucose Lhlmanon in Lhe Rat. Gen.
Phamnac. 18(198 ~}205-21 1
42 ( 1986) 30&3 10
Mondadori, C., M. Schmutz, V. Baltzer: Potentiation of the Anticonvulsant EtTecfs of Antiepileptic Drugs by “[email protected]”; a Poten-
tial New llserapeutic Approach. Acza Neurol. Stand. 69 (SuppL
99)(1984)131-132
Mondadori, C., W. Cksen, J. Borkowski, T. Ducrw, H. Buerki, A.
Schade: Effects of Oxiracztanr on Learning and Memory in Artimitls: Comparison with Piraatam. Clinical Neuropharmacology
9 (Suf)pl. 3) ( 1986) S27-S38
Mondadori, C.: pharmacology of Memory - Sciena or Art? In: Mutschler, E., E. WktterfeldL weinheim, New York (Eds.) Trends in
Medicinal Chemistry (1987). Resented at the Ninth International
Symposium on Medianal Chemistry, Bertin 1986
Mon&dori, C., hf. Schmutz: Synergistic Effects of Oxiracetam and
Drugs. Acts Neurol.
Piracetam in Combination with htiepileptic
Sand.
(Suppl.
109)74
(1986)
113-116
Monabdori, C., F. Petschke: Do Picaatam-hke Compounds AU Centrally Via Peripheral Mechanisms? Brain Res. 435(1987)310-314
Mondadori, C., L. Weiskrrzntz, H. Buefi, F. Perschke, G. E. Fagg:
NMDA Reaptor Antagonists Can Enhance or impair learning
perfotmarsa in Animals. Exp. Brain Res. 75 (1989) 449-456
Mondadm”, C., A. Bhamagar, J. tiwski,
A. H&@r: Involvement
of a steroidaf comptcnts
in the mechanism of acdon of
pirac.etam-like nootropics. Brain Rev, in press
Mondadofi, C., T, Ducrer, F. Petschke: Blockade of the Nootropic AcNootzopics by Adtenaleciomy: an Eff=
tion of Piraatam-tike
of Dosage? Behavioral Brain Research, in Ress, 1989
Morris, R. G. M., E. Anderson, G, S. Lynch, M. Baudry: Selective lmpaimsent of L.eaming arid Blockade of Long-term Potentiation by
an N-methyl -D-aspartate Reaptor Antagonist. AP5. Nature 319
(1986) 774-776
Murray, C. L.., H. C. Fibiger: The effect of Pramicacetam (Cl-879) on
the Acquisition of a Radial ,%-rnMaze Task. psychopharmacology
89 (1986) 378-381
Nestler, E., T. C. Rainbow, B. S. i4fcEwen, P. Greerrgard: Cocticosterone Increases the Amount of Protein I, Neuron-specific
Phosphoprotein. in Rat Hippocampus. Sciena 212 (1981) I 162[ 164
Nickdrorr, V. J., O. L. Wolthuti Effect of the Aquisition-Enhancing
Drug Piracetam on Rat Cerebral Energy Metabolism. Comparison with Naftidrofuryl and Methamphetamine. Biochem. Pharmacol. 25(1976) 2241-2244
Pedam, F., F. Moroni. G. C. Pepeu: Effect of Nootropic Agents on
Brain Cholinergic
Mechanisms Clinical Neurophannawlogy
7
(Suppi. I )(1984)77?
Aercey, M. F., G. D. Vogefsang, S R. Fmnklin, A. H. Tang: Reversal of
scopolamine-induced Amnesia and Aerations in Energy Mctaboiism by the Nootropic Piracetam: Implications Regarding i dentlficat]on of Brain Structures Involved in Consolidation of
Memory traces. Brain Res. 424( 1987) I-9
Rich, H,, W. E ,Mti/[er. Piraceram Elevates Muscarinic Cholinergic
Receptor Density in the Frontal Cortex of Aged but not of Young
Mice. Psychopharmacology 94( 1988) ~4-78
on Delayed
Porr!ecorvo, .W. J. H L Evam Effects of Aniraccfam
Mat~?)ng.{o-Sample
Performan.
? or Monkeys and Pigeons. Pharmacol Biochem Beha\ 22( 1985) 745–752
Poschel, B P H,, J G .Wamorr, ,W I Glucknran Pharmacology of the
Cogniuon Amiiz!or %am]race[am (C I-879J. Drugs Expt[. Clin.
Res lX{12,1L 19g3)853-6-l
Poschel, B P H P M. Ho, F. W’ .4’or/eman, M. J Callahan Pharmacologic
Therapeutic
Window of Ramir-aatam
Demonstrated m
105
106
l%annacopsychiat.
C. Mondadori, F. Petschke,A. Hau.der
22 (1989)
Behavior,
EEG, and Singie Neuron firing Rates. Expcrien[ia 41
(1985) 1153-1156
Pugsley, Z A.. B. P. H. Poschel. D.A. Downs, Y.-H. 5hdr. M. 1. Glucknrarr:some pharmacological and Ncur~hemicai Properties of a
New Cognition Activator Agent, Pramiraatam (C1-879). Psychopharrnacd. Bull. 19 (1983) 721-726
Raikw,
T. C., P. L. Hoffman, L. B. Fhzmer:Studies of Memory: A
Reevaluation in Mice of the Effects of Inhibitors On The Rate of
Synthesis of Cerebral Proteins A Related to Amnesia. Pharrnacol.
Biochem. Behav. 12( 1979)79-84
Sarrren, R. J., E. Sanrojlik. T. J. Worgul: III. Aminoglutethimide. Product
2.
profile.
A
In: San[en,
comprehensive
glutethimide.
Karger,
R. J., I. C. Henderson
guide
to
Bascl (1981
the
therapeutic
(Eds.)
use
Ptrarmanual
of
amino-
) 101-160
S. J.: Mcmow Retrieval Deficits: Alleviation by Etiracctam, a
Nootropic Drug. Psychopharmacology 68 ( 1980) 235-24 I
Shih, Y.-H., T.A. Agsley:The effects of Various Cognitionahancing
Drugs on in Vitro Rat Hippocampai Synaptosomal Sodium Dependent High Aff_mityCholine Uptake. Life sciences 36 (1985)
2145-2152
Spignali, G., G. C. Pepm:Oxiracctam Prevents Eleuroshock-Induced
Decrease in Brain Acctylcholinc and Asnncsia. Eump. J. Pharmacoi. 126(1986) 253-257
Schtitz, G.: Control of Gene Expression by Steroid Homtones. Biol.
Chem. 369(1988) 77-86
Werzc/, W.: Effects of nootsopic drugs on the sleep-waking pattern of
the rat. Biomcd. Biochim. [email protected] 44, 7/8(1985) 1211-1217
Woefk, H.: Effects of Piraatam on the Incorporation of ‘2P into the
Phospholipids of Neurons and Glial Cells Isolated from Rabbit
Cerebral Cortex. Pharmakopsychiat. 12(1979) 251-256
WoWrsiz, 0, L.: Experiments with UCB 6215, A Drug Which Enhanm Acquisition in Rats: Its Effeas Compared with ‘Iltose of
Metamphetamine. Europ. J. Pharrnacoi. 16( 197I) 283-297
Yarnada, K., T. Irroue. hi. Tanaka, T Fundcawa: Prolongation of
Latencics for Passive Avoidance Responses in Rats Treated with
Anira~m
or Piracetam. f%arnraco[. Biochcm. Bchav. 22 ( 1985)
645-648
Yamarnofo, K. R,: Steroid receptor regulated transcription of specific
genes and gene networks. Ann. Rev. Gcnct. 19(1985) 209-252
Sara,
—=
Dr. C. Mondadori
pharmaceutical Research Department
CIBA-GEIGY Limited
Basci
cH402
Switzcrfand
.
Life Extension Foundation Offshore Drugs
Page 120f13
Picamilon appears to be more effective than Hydergine or vinpocetin in
improving blood flow to the cerebral vessels. Picamilon readily crosses the
blood-brain barrier to protect neurons against the effects of diminished
oxygen flow. It also produces cognitive-enhancing effects.
The combination of these effects provides an entirely new method of dealing
safely with several causes of neurological aging. Picamilon is approved as a
pharmaceutical product in Russia, but is reallya vitamin-likecompound
consistingof a niacinanalog (n-nicotinoyl)uniquelybonded to GABA
(gammaaminobutyricacid) When niacinis bound to GAB&it creates a
moleculethat readilypenetrates the blood-brainbarrier to enhancecerebral
and peripheralcirculation,What enables pica.milon to work so well is the
synergism between the niacin and GABA molecules.
Suggested dose: One tablet, two to three times a day
If cognitive enhancing results do not occur in 30 days, double the dose.
Piracetam is a derivative of the amino acid GABA that increases the
sensitivity of receptors in the brain involved in memo~ and learning.
Piracetam is called a nootropic drug because of its ability to enhance the
mind. Studies in both animals and humans have demonstrated that Piracetam
can improve memory, increase attention and cognition, improve spatial
learning, and enhance motor mechanisms, Piracetam is one of the most
popular “smart drugs” that is used to increase intelligence, information
processingability,concentration, memory, and creativity.It has been shown
to harmonize and synchronize the spheres of the brain by anchoring
information within the brain.
.—
Suggested dose: Piracetam should be used in doses ranging from 1600 to
2400 rnga day taken first
thing in the morning.
RET
I\
,-$i
Retin A is a highly publicized vitamin A derivative that stimulates skin cell
renewal, increasing-the creation of youthfil cells at the skin’s surface Retin A
may produce side effects such as minor irritation, People using Retin A
should stay out of the sun and use a sunblock for normal sunlight exposure,
because Retin A increases skin sensitivity to sunlight
—
http: //lef. org/cgi-local/shop
pl/page=ofYshore html
3/10/98
Page 2 of 8
EROWID - NOOTROPICS : PIRACETAMFAQ
I
L----
—_
http. //www erowid com/smarts/piracetarn/piracetam_faq
shtm]
3I1OI98
EROti
Page 3 of 8
- NOOTROPICS: PIRACETAMFAQ
“->.
——.._
—
——__
—
http //wnvw erowid com/smarts/piracetadpiracetam_faq
shtml
3/10/98
EROWID - NOOTROPICS : PIRACETAMFAQ
—
Page 4 of 8
Page 5 of8
EROWID - NOOTROPICS: PIRACETAMFAQ
,.-+
-—–
!
—
http: //www erowid,cordsmarts/piracetam/piracetam_faq
shtml
3/ 10/98
EROWID - NOOTROPICS
----.
PIRACETAM
FAQ
Page 6 of 8
‘
—.
http. //Wwerowidid
corn/smarts/piracetam/piracetam_faq
shtml
3I1OI98
-.-r.
-----
,--
.-
-DA-
. ... ... . .
.“
.
,
w----
# ,
,L..y.
,.r”.
.
. ..-’-.
.“”
~.
“,.”
.
.
.
.
.
“,.”
. . .
.
.
.“
.
.
--
.
National Library of Medicine: IGM Full Record Screen
-
•1
Clmn
nnmnn
E
6
TITLE:
Piracetam-induced changes in the functional activity of neurons as a
possible mechanism for the effects of nootropic agents.
AUTHOR:
Verbnyi YaI; Denzhiruk LP; Mogilevskii
AUTHOR
AFFILIATION:
Physical-Technical Low Temperature
Sciences of Ukraine, Khar’kov.
SOURCE:
Neurosci Bebav Physiol 1996 Nov-Dec;26(6):507-15
NLM CIT. HI:
97173873
ABSTRACT:
Studies were carried out on the effects of piracetam (4-20 mM) on the
electrical activity of identified neurons in the isolated central nervous
system of the pond snail in conditions of single-electrode intracellular
stimulation and recording. Piracetam-induced changes were seen in
60-70% of the neurons studied. Different parameters showed different
sensitivities to piracetam: the most frequent changes were in the action
potential generation threshold, the slope and shape of the steady-state
voltag~current characteristics of neuron membranes, and the appearance
of piracetam-induced
transmembrane ion currents. Nifedipine and
cadmium ions, both of which are calcium channel blockem, generally
reversed or weakened the effects of piracetam on the changes seen in test
cells. This indicates that the effects of piracdam result from its action on
calcium channels; selective changes in calcium channels may determine
which piracetam-inducd
cfkct8 appear at the cehrtar IewL It is
hypothesized that the piracetam-sensitive ceUuiim plasticity mechanisms
may make a significant contribution to its nootropic action at the
behavioral level
MAIN MESH
SUBJECTS:
Lymnaed*PHYSIOLOGY
Neurons/*DRUG EFFECTS
Nootropic Agents/ANTAGONISTS
& 1NHIW*PHARMAC0L0G%
Piracetam/ANTAGON ISTS & INHIB/*PHARMACOLOGY
AYa
Institute, National Academy of
. —-.
..,.
3119812(MF
. .
<
IILIPJI
,—-.
ADDITIONAL
MESH
SUBJECTS:
Animal
Cadmium/PHARMACOLOGY
Calcium Channel Blockers/PHARMACOLOGY
Electrophysiology
Ganglia, Invertebrate/CYTOLOGY~HYSIOLoGY
In Vitro
Membrane Potentials/DRUG EFFECTWPHYSIOLOGY
NifedipineiPHARMACOLOGY
Parietal Lobe/CYTOLOGY/DRUG
EFFECTS
Patch-Clamp Techniques
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Calcium Channel Blockers)
O(Nootropic Agents)
21829-25-4 (Nifedipine)
7440-43-9 (Cadmium)
7491 -74-9 (Piracetam)
El
——
2 oi-2
lJV.
l*.
JL.WJl&gl-UIIU
lWIV1%llGUL
:1701
YWGU1lTJ
non
Onnnn
.31198
1206PM
/
m
L
TITLE:
Nootropic drugs and brain cholinergic mechanisms.
AUTHOR:
Pepeu G; Spignoli G
AUTHOR
AFFILIATION:
Department of Preclinical and Clinical Pharmacology,
Florence, Italy.
SOURCE:
Prog Neuropsychopharmacol
NLM CIT. H):
90139561
ABSTRACT:
1. This review has two aims: firs~ to marshaJ and discuss evidences
demonstrating an interaction between nootropic drugs and brain
cholkrgie mechanisms; second, to dellne the relationship between the
effects on cholinergic mechanisms and the cognMve process. 2. Direct or
—
Univemity of
Biol Psychiatry 1989;13 Suppl:S77-88
indirect evidences indicating an activation of cholinergicmechanismsexist
for pyrrolidinone derivatives including piracetam, oxiracetam, aniracetam,
pyroglutamic acid, tenilsetam and pramiracetam and for miscellaneous
chemical structures such as vinpocetin~ naloxone, ebiratide and
phosphatidylsenne. AU these drugs prevent or revert scopolamineinduced
disruption of several Icatning and memoq paradigms in ●nimal and man.
3. Some of the pyrrolidinone derivatives also prevent amnesia associated
with inhibition of acetylcholine synthesis brought about by hemicholinium.
Oxiracetam prevents the decrease in brain acetylcholine and amnesia
caused by electroconvulsive shock. Oxiracetam, aniracetam and
pyroglutamic acid prevent brain acetylcholine decrease and amnesia
induced by scopolamine. Comparable bell-shaped dose-effect relationships
result for both actions. Phosphatidylsenne
restores acetylcholine synthesis
and conditioned responses in aging rats. 4. The tinbs
through which
the action on cholinergic systems might take place, including stimulation of
the high affinity choline uptak% are discussed. The information available
are not yet sufficient to define at which steps of the cognitive process the
action on cholinergic system plays a role and which are the influences of
the changes in cholinergic function on other neurochemical mechanisms of
learning and memory.
.
1 of2
MAIN MESH
SUBJECTS:
Acetylcholine/* METABOLIS,M
BrainiDRUG EFFECTS/* METABOLISM
Psychotropic Drugs/* PHARMACOLOGY
31098439
PM
=.
ADDITIONAL
MESH
SUBJECTS:
Animal
Receptors, Cholinergic/DRUG EFFECTSM4ETABOLISM
Scopolamine/PHARMACOLOGY
Synapses/DRUG EFFECTWPHYSIOLOGY
PUBLICATION
TYPES:
JOURNAL ARTICLE
REvmw
REVIEW, TUTORIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O (Receptors, Cholinergic)
51-34-3 (Scopolamine)
51-84-3 (Acetylcholine)
.
Balm~
IF,,.:.:
II
:,,,,,
---mqgpwwiv.::.:
.... .xmgii.!
*,.....
. . .. . .. .
.:..::”
:.
-’”
lmw”’d
,,:,~“ ““’y,;’
i:wimw~ ‘““’:::..::::’””:W .W ““’’VYMR?M’
—_
20(2
3 1098439
PM
nup;ll
IJU.
14. X.4
{IGgl.
.IV1+X?II
!4JOY4-aeIW7
nup.{r
1
lJV.
l’i. J4.*
l(G~-uuulu
1v1%11G111!LJu7-
National Library of Medicine: IGM Full Record Screen
-------,
~
TITLE:
Piracetam elevates muscarinic cholinergic receptor density in the frontal
cortex of aged but not of young mice.
k
AUTHOR:
Pilch H; Muller WE
AUTHOR
AFFILIATION:
Psychopharmacological
Laboratory, Central Institute of Mental Health,
Mannheim, Federal Republic of Germany.
SOURCE:
Psychopharmacology
NLM CIT. ID:
88158509
ABSTRACT:
Chronic treatment (2 weeks) with ~
(~~~
~)
eiwatwf m-chofinoceptor density in the frontal cortex ofaged (18 [email protected]
female mice by about ~
but had no efM on m4tolinoceptor
density [n*
frontal cort~ of young (4 weeks) mice. me effect of
—
(Berl) 1988; 94(1):74-8
piracetam on m-cholinoceptor density as determined by the specific
binding of tritiated QNB was not affected by concomitant daily treatment
with either choline (200 mg/kg) or scopolamine (4 mglkg). It is concluded
that the effectof p“~
could explain the
on M&-ptor
~ity
positive effects which have beenreportedfor combinations of cboiinergic
precursor treatment with piracetam on memoq and other cognitive
functions in aged experimental animals and patients and could tio
represent part of the possible mechanism of action of piracetam alon~
—
1 @f2
MAIN MESH
SUBJECTS:
Aging/* METABOLISM
Cerebral Cortex/DRUG EFFECTS/* METABOLISM
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Receptors, Muscarinic/*DRIJG EFFECTS
ADDITIONAL
MESH
SIJBJECTS:
Animal
Atropine/PHARMACOLOGY
Female
Male
Mice
Oxotremorine/PHARMACOLOGY
Quinuclidinyl Benzilate/PHARMACOLOGY
Scopolamine/PHARMACOLOGY
31098440
PM
http://l3O. 14.32 .47/cgi...M<liemt?23694 +detil+ 1
=
2 d-2
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyrrolidinones)
O(Receptors, Muscarinic)
51-34-3 (Scopolamine)
51-55-8 (Atropine)
6581 -06-2 (Quinuclidinyl Benzilate)
70-22-4 (Oxotremorine)
7491 -74-9 (Piracetam)
httpj/130. 14.32 .47/cgi-biflGM<
lient’?23694+detil+
1
w
k
[of3
TITLE:
Treatment of acute ischemic stroke with piracetam. Members of the
Piracetam in Acute Stroke Study (PASS) Group.
AUTHOR:
De Deyn PP; Reuck JD; Debenlt W; Vlietinck R; Orgogozo JM
AUTHOR
AFFILIATION:
Department of Neurology, Middelheim
SOURCE:
Stroke 1997 Dec;28(12):2347-52
NLM CIT. ID:
98074088
Hospital, Antwerp, Belgium.
3 [[98
11.59A\!
ABSTRACT:
==+
MAIN MESH
SUBJECTS:
2ot3
BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with
neuroprotective properties, has beenmported in jdbt stndiea * -e
compromised ~onal
cerebral blood flow in patients with acute strxlke
and~~
seem afier onset, to improve clinical outcome. We performed a
multicenter, randomized, double-blind trial to test whether piracetam
conferred benefit when given within 12 hours of the onset of acute ischemic
stroke to a large group of patients. METHODS: Patients received placebo
or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks
and 4.8 g daily for 8 weeks. The primary end point was necrologic outcome
after 4 weeks as assessed by the Orgogozo scale. Functional status at 12
weeks as measured by the Barthel Index was the major seconda~
outcome. CT scan was performed within 24 hours of the onset of stroke but
not necessarily before treatment. Analyses based on the intention to treat
were performed in all randomized patients (n = 927) and in an “early
treatment” population specified in the protocol as tmtment within 6
hours of the onset of stroke but subsequently redefined as less than 7 houm
after onset (n = 452). RESULTS: In the total population, outcome was
similar with both treatments (the mean Orgogozo scale after 4 weeks:
piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks:
piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9?40(1 11/464)
in the piracetam group and 19.2°%0
(89/463) in the placebo group (relative
risk 1.24, 95V0 confidence interval, 0.97 to 1.59; P = .15). Deaths were
fewer in the piracetam group in those patients in the intention-to-treat
population admitted with primary hemorrhagic stroke. Post hoc analyses
in the early treatment subgroup showed differences favoring piracetam
relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam
60.4, placebo 54.9; P = .07) and Barthei Index scores at 12 weeks
(piracetam 58.6, placebo 49.4; P = .02). Additional analyses within this
subgroup, confined to 360 patients with moderate and severe stroke (initial
Orgogoxa scale score< 55), showed significant improvement on piracetam
in both outcomes (P < .02). CONCLUSIONS: Phweetam did not influence
outcome when given within 12 homa of the onset of acute ischemic stroke.
Post hoc analyses suggest that piracetam may confer benefkwhen given
within 7 hoam of oparticdarly in patients with stroke of moderate
and severe deg= A randomized, placebo-controlled, multicenter study,
the Piracetam Acute Stroke Study H (PASS II) will soon begin.
Cerebral Ischemia/*DRUG THERAPY/MORTALITY
Cerebrovascular Disorders/*DRUG THERAPY/MORTALITY
Neuroprotective Agents/ADVERSE EFFECTS/* THERAPEUTIC USE
Nootropic Agents/ADVERSE EFFECTS/* THERAPEUTIC USE
Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
31198 11.5~A
Za
ADDITIONAL
MESH
SUBJECTS:
Acute Disease
Aged
Aged, 80 and over
Double-Blind Method
Female
Human
Male
Middle Age
Support, Non-U.S. Gov’t
Survival Analysis
Treatment Outcome
PUBLICATION
TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
MULTICENTER STUDY
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Neuroprotective Agents)
O(Nootropic Agents)
7491-74-9 (Piracetam)
—
3of3
311981159AM
----............. .-,-- ..... .
....r. . . ..
....r.
.-”.
.
,.
--.!-
,“
~
-“.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
“
.-.
.-’.
F?’!
---—k-!.
.
TITLE:
The effects of piracetam in children witlmdydeh.
AUTHOR:
Di Ianni M; Wilsher CR; Blank MS; Conners CK; Chase CH; Funkenstein
HH; Helfgott E; Holmes JM; Lougee L; Maletta GJ; et al
SOURCE:
J Clin Psychopharmacol 1985 Oct;5(5):272-8
NLM CIT. ID:
86009005
ABSTRACT:
Following previous research which suggests that piracetam improves
performance on tasks associated with the left hemisphere, a 12-weeL
doubl~blind, placebo-controlled study of deveIopmentaJ dyslexics was
conducted. Six study sites treated 257 dyslexic boys between the ages of 8
and 13 years who were significantly below their potential in reading
performance. Children were of at least normal intelligence had normal
findings on audiologic, ophthalmologic, necrologic, and physical
examination, and were neither educationally deprived ❑ or emotionally
disturbed. Piracetam was found to be well tolerated in this study
populatiomp.~~
~~
q,[email protected]
other effects ‘n r-m
we~ ob~rv~” ~ addition*
~-~s
obsem~ in
those piracetarn-treated patieots who showed relatively poor memory at
term treatment with piracetam may
baseline. It @,,suggested that Ion ,.:*/j,:
.:,;.,,
MAIN MESH
SUBJECTS:
Dyslexia/*DRUG THERAPY
Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
Pyrrolidinones/*THERAPEUTIC USE
ADDITIONAL
MESH
SUBJECTS:
Adolescence
Child
Clinical Trials
Depression/CHEMICALLY INDUCED
Human
Male
Memory Disorders/DRUG THERAPY
Memory, Short-Term
Support, Non-U.S. Gov’t
PUBLICATION
TYPES:
CLINICAL TRIAL
CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O~Pyrrolidinones)
7491-74-9 (Piracetam)
K
310
9X 3.54 PM
~
-m_.
TITLE:
Piracetam antkdyslexia: effects on reading tests.
AUTHOR:
Wilsher CR; Bennett D; Chase CH; Conners CK; DiIanni M; Feagans L;
Hanvik LJ; Helfgott E; Koplewicz H; Overby P; et al
SOURCE:
J Clin Psychopharmacol 1987 Aug;7(4):230-7
NLM CIT. ID:
87308901
&
ABSTRACT:
—_
2 d’3
Previous research has suggested that ~wm “
have
shown improvements in madiag [email protected] memury ad vwbaf’
~tIm9
f-tama-bm
proemkgoflettedihe
#&ulLTwo
hundred twenty-five dyslexic children between the ages of 7
years 6 months and 12 years 11 months whose reading skills were
significantly below their intellectual capacity were enrolled in a multicenter,
36-wee~ doubleblind, placebo-controlled study. Children of below average
intelligence, with abnormal findings on audiologic, ophthalmologic,
necrologic, psychiatric, and physical examinations, who were emotionally
disturbed or educationally deprived and who had rtxently been treated
with psychoactive medication were excluded from the t~~
w=
wcil ~ted,
with no serious adverse clinical orhhmtorydkkta
,.
.
[email protected]
imppvements in
~treated
“
reading aME& &y
[email protected] ‘Iia4t]anlrn?adEig cxm-oa
(Gihnore Oral Reading Test). Treatment effects were evident after 12 weeks
and were sustained for the total period (36 weeks).
MAIN MESH
SUBJECTS:
Dyslexia/*DRUG THERAPY/PSYCHOLOGY
Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
Pyrrolidinones/* THERAPEUTIC USE
*Reading
ADDITIONAL
MESH
SUBJECTS:
Child
Clinical Trials
DoubleBlind Method
Female
Human
Male
Random Allocation
Support, Non-U.S. Gov’t
PUBLICATION
TYPES:
CLINICAL TRIAL
CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyrrolidinones)
7491-74-9 (Piracetam)
,...t’
. . . . . ,~-
.- -~.... c.. .,,../,,,.
,V,
a”
~uw,,
~
,,
..),,,
-----
.
. .
.
.
.“,-~.
. . . . . . . . . -.. . . . . .
,“
!
4“
.
.
.
“L{d
&-y
F?3
=>,
>
An overview of pharmacologic treatment of-*-G
TITLE:
.
@he aged.
Reisberg B; Ferris SH; Gershon S
:::::;”
Am J Psychiatry 1981 May; 138(5):593-600
NLM CIT. ID:
81204750
ABSTRACT:
The most widely known substances that have been investigated for treating
cognitive deterioration in the aged are cerebral vasodilators, Gerovital H3,
psychostimulants, “nootropics,” neuropeptides, and neurotransmittem.
The rationale for the choice of specific agents has shifted as our
conceptions regarding the origins of cognitive decline have changed; we
now know that most cognitive deterioration occurs independently of
arteriosclerotic vascular changes. Substances currently being investigated
because of their effects on brain electrophysiology, on neurohumoral
processes, or on central neurotransmitters show promise.
MAIN MESH
SUBJECTS:
Cognition Disordem/*DRUG THERAPY
ADDITIONAL
MESH
SUBJECTS:
Anticoagulants/THERAPEUTIC USE
Clinical Trials
Comparative Study
Dihydroergotoxine/THERAPEUTIC USE
Human
Hyperbaric Oxygenation
Methylphenidate/THERAPEUTIC USE
Parasympathomimetics/THERAPEUTIC USE
Peptides/THERAPEUTIC USE
Piracetam/THERAPEUTIC USE
Procaine/THERAPEUTIC USE
Support, U.S. Gov’t, P.H.S. Vasodilator Agents/THERAPEUTIC USE
PUBLICATION
TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
REVIEW
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Anticoagulants)
O(Parasympathomimetics)
O(Peptides)
O(Vasodilator Agents)
11032-41-0 (Dihydroergotoxine)
113-45-1 (Methylphenidate)
12663-50-2 (Gerovital H3)
59-46-1 (Procaine)
7491-74-9 (Piracetam)
3 1098406
National Library of Medicine: IGM Full Record Screen
PTITLE:
Profound effects of combining choline and piracetam o~l
~~d
cholinergic function in aged rats.
AUTHOR:
Bartus RT; Dean RL 3d; Sherman KA; Friedman E; Beer B
SOURCE:
Neurobiol Aging 1981 SummeC2(2): 105-11
NLM CIT. ID:
82058347
LJ-
—.
—
I (lf3
3 1[) 983:50
PM
ABSTRACT:
“-=2
MAIN MESH
SUBJECTS:
20t-3
In an attempt to gain some insight into possible approaches to reducing
age-related memory disturbances, aged Fischer 344 rats were administered
either vehicle, choline, piracetam or a combination of choline or piracetam.
Animals in each group were tested behaviorally for retention of a one trial
passive avoidance task and biochemically to determine changes in choline
and [email protected] levels in hippocampus, cortex and striatum. Previous
research has shown that rats of this strain suffer severe age-related deficits
on this passive avoidance task and that memory disturbances are at least
partially responsible. Those subjects given only choline (100 mg/kg) did not
differ on the behavioral task from control animals administered vehicle.
Ra&givu~’@[email protected]~
~qm.*eumtmll
b~~~
M 4 @ven’tb~’pfficetamA5N#16e-’~n
,(MHhg/kg&ackjexbi
bited
rwtention ueorw meverml~btter
thaP
-~:h a second study, it was shown that twice the
dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not
enhance retention nearly as well as when piracetam and choline (100 mg/kg
of each) were administered together. Further, repeated administration (1
week) of the piracetam/choline combination was superior to acute
injections. Regional determinations of choline and acetylcholine revealed
interesting differences between treatments and brain ara Although choline
administration raised choline content about 50°/0 in striatum and cortex,
changes in acetylcholine levels were much more subtle (only 6-100/0). No
significant changes following choline administmtion were observed in the
hippocampus. However, piracetam alone markedly increased choline
content in hippocampus (88°/0) and tended to decrease acetylcholine levels
( 19Yo). No measurable changes in stnatum or cortex were observed
following piracetam administration. The combination of choline and
piracetam did not potentate the effects seen with either drug alone, and in
certain cases the effects were much less pronounced under the drug
combination. These data are discussed as they relate to possible effects of
choline and piracetam on cholinergic transmission and other neuronal
function, and how these effects may reduce specific memory disturbances in
aged subjec~ ~
‘ demonstrate that the effects (of
combming cldine aitll piracetam are quite”il’ifferentBm.n’tlmse o%tained
with either drug alone and support the notion that in order to achieve.
to reduce multipie,
substantial efkacy in aged wbjecta it may be ~
interactive neurochem~ctions
in tie brai+er affbct activity in.
more than one parameter of a defiiient metabolic pathway.
*Aging
Choline/ANALYSIS/* PHARMACOLOGY
Memory/* DRUG EFFECTS
Parasympathetic Nervous System/* PHYSIOLOGY
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHAIIMACOLOGY
310’)8.3”5(1I’h
.
.. .
ADDITIONAL
MESH
SUBJECTS:
Acetylcholine/ANALYSIS/SECRETION
Animal
Brain Chemistry/DRUG EFFECTS
Male
Rats
Rats, Inbred F344
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyrrolidinones)
51-84-3 (Acetylcholine)
62-49-7 (Choline)
7491-74-9 (Piracetam)
—
—
3013
3 1098.350
I’M
....r
.-
.,...
. .
.
. =., . . . . . -. . . . . .
. .
--
“----
.
r-
~.
National Library of Medicine: IGM Full Record Screen
.4
-.
❑
F
6’
—
TITLE:
Piracetam-induced facilitation of interhemispheric transfer of visual
information in rats.
AUTHOR:
Buresova O; Bures 1
SOURCE:
Psychopharmacologic 1976;46(1):93-102
NLM CIT. ID:
76152798
ABSTRACT:
The effiwt of Piracetam (UCB 6215, 2-pyrrolidoneacetamide) on learning
mediated by transcommissural information flow was studied in hooded rats.
Acquisition of monocular pattern discrimination was faster in drug-treated
rats (100 mg/kg, 30 min before training) than in untreated controls.
Subsequent relearning with one hemisphere functiomdly eliminated by
cortical spreading depression showed that the strength of the primary
engram formed under Piracetam in the hemisphere contralateral to the
trained eye remained unaffected but that the secondazy trace (in the
ipsilateral hemisphere) was considerably improved and almost equalled the
primary one (savings increased from 20-30% to 50-60Yo). Learning with
uncrossed optic fibers was unaffected by the drug. [nterhemispheric
transfer of Iateralized visual engrams acquired during functional
hemidecortication was facilitated by Piracetam administration preceding
the five transfer trials performed with the untrained eye open (imperative
transfer). Piracetam was ineffective when the trained eye was open during
transfer trials (facultative transfer). After a visual engram had been
literalized by 5 days of monocular overtraining, Piracetam facilitated
formation of the secondary engram induced by 3 interocular transfer trials.
It is concluded that Piracetam enhances transcommissural encoding
mechanisms activated in the initial stage of monocular learning and in some
forms of interhemispheric transfer, but does not affect the
transcommissural readout. This effect is interpreted as a special case of the
Piracetam-induced facilitation of the phylogenetically old mechanisms of
redundant information storage which improve Iiminal or subnormal
learning.
.
I of 2
310983511
.
- .. ..
. . . .
- -- —.. .
MAIN MESH
SUBJECTS:
Form Perception/*DRUG EFFECTS
Pattern Recognition, Visual/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Transfer (Psychology )/*DRUG EFFECTS
ADDITIONAL
MESH
SUBJECTS:
Animal
Corpus Callosum/PHYSIOLOGY
Discrimination Learning/DRUG EFFECTS
Male
Memory/DRUG EFFECTS
Overlearning/DRUG EFFECTS
Perceptual Masking
Rats
Spreading Cortical Depression
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
.—-_
....r.----.,-,.-,
-........................
“--.
,
.—=
2 01-2
.3 1098.351
PM
.
—.. ..... . . . . . . .-. —.. .
,
.
l?:
--~
TITLE:
Some effects ofpiracetam (UCB 6215, Nootropyl) on ~
sebphrenk’
AUTHOR:
Dimond SJ; Scammell RE; Pryce IG; Huws D; Gray C
SOURCE:
Psychopharmacology (Bert) 1979 Sep;64(3):341-8
NLM CIT. ID:
80057401
ABSTRACT:
A study is described of effects of a nootropic drug on chronic
schizophrenia. The nootropic drugs act on the central nervous system with
the cerebral corterastfkefr ~“
Chronic schizophrenic patients on the
drug showed’improvement in object namiagandin teatawhere the patient
was required to indicate the number of times he had been tapped.
Improvements were also noted inkaming ad ~~
in dichotic
listening the patients showed a reduction in the amount of incorrect verbal
responses producedwere mo_emaMirb
~xnthgam
social behaviour m~These
results suggest some cognitive improvement
Biit little if any change in the disease state of the patient.
MAIN MESH
SUBJECTS:
Piracetam/*THERAPEUTIC USE
Pyrrolidinones/* THERAPEUTIC USE
Schizophrenia/* DRUG THERAPY
ADDITIONAL
MESH
SUBJECTS:
Adult
Chronic Disease
Clinical Trials
Dichotic Listening Tests
Double-Blind Method
Female
Human
Male
Middle Age
Motor Skills/DRUG EFFECTS
Psychiatric Status Rating Scales
Schizophrenic Psychology
PUBLICATION
TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
LANGUAGE:
Eng
<
_
—_
201-2
310983,57
PL1
National Library of Medicine: lGM Full Record Screen
‘--A
_—_
❑
Onn
OOC300
R
G
in ❑ormal man through the use
TITLE:
Increase in the power of human mcsn~
of drugs.
AUTHOR:
Dimond SJ; Brouwers EM
SOURCE:
Psychopharmacology (Bed) 1976 Sep 29;49(3):307-9
NLM CIT. H):
77079535
ABSTRACT:
Nootropyl (Piracetam) a drug reported to facilitate learning in animals
was tested for its et%ct on man by administering it to normal volunteers.
The subjects were @em 3x4 capsules at 400 mg per dayr~n a double blind
study. Each subject learned series of words presented as stimuli upon a
memory drum. No effects were obsemwd after 7 days but aflkr 14 days+
VU’bd h!adnfj
bad [email protected]&
inc!mati
MALN MESH
SUBJECTS:
Memory/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
-.
Female
ADDITIONAL
MESH SUBJECTS: Human
Male
Stimulation, Chemical
Verbal Learning/DRUG EFFECTS
PUBLICATION
TYPES:
CLINICAL TRIAL
CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
LANGUAGE:
Eng
—_
1
of-1
3
1098
.3.5X I’M
=--------
.-.
–- . . . ..
National Library of Medicine: IGM Full Record Screen
•1
-J..
Clnn
Onnnn
—
lx
k
TITLE:
Piracetam facilitates retrieval but does not impair extinction of
bar-pressing in rats.
AUTHOR:
Sara SJ; David-Remacle M; Weyers M; Giurgea C
SOURCE:
Psychopharmacology (Berl) 1979 Mar 14;61(1):71-5
NLM CIT. ID:
79180683
ABSTRACT:
Rats were trained on a continuously reinforced bar-press response for
water reward. Seven days later they were retested for retention, with or
without pretest injection of the nootropic drug, piracetam. [email protected]
animala bad ai-tly
shorter mspomc IaZmcka than [email protected]
admdu~,$,qudti
are iutcqmXed as a fhciitatimofn.$fiad
procw8ea
afler f~
‘She experiment was extended under extinction conditions
and it was found that after three sessions there was a tendency to facilitate
extinction when response latency is used as the extinction index. The
clinical interest of a drug which facilitates the retrieval aspect of the
memory process without impairing extinction is discussed.
MAIN MESH
SUBJECTS:
Conditioning, Operant/*DRUG EFFECTS
Extinction (Psychology )/*DRUG EFFECTS
Memory/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL
MESH
SUBJECTS:
Animal
Male
Rats
Water Deprivation
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
_.=
_—_
Iofl
.
‘r
w!
.-.
.—..
TITLE:
Piracetam impedes hippocampal neuronal loss during withdrawal after
AUTHOR:
Brandao F; Paula-Barbosa MM; Cadetc4eite
u’ AUTHOR
A
Department of Anatomy, Porto Medical School, Portugal.
AFFILfATIC)N:
SOURCE:
Alcohol 1995 May-Jun; 12(3):279-88
NLM CIT. ID:
95367208
ABSTRACT:
In previous studies we have demonstrated that &[email protected]
~
consumption induced hippocampal nenrtmalloss. In addition, we have
shown that withdrawal after chronic alcohol intake augmented such
degenerative activity leading to increased neuronai death in all subregions
of the hippocampal formation but in the CA3 field. In an attempt to
reveme this situation, we tested, during the withdrawal period, the effects
of piracetam (2-oxo-l-pyrrolidine acetamide), a cyclic derivative of
gamma-aminobutyric acid, as there is previous evidence that it might act
as a neuronoprotective agenL The total number of dentate granule, hilar,
and CA3 and CA1 pyramidal celis of the bippocampal formation were
estimated using unbiased stereological methods. We found out that in
animals treated with piracetam the numbers of dentate granule, hilar, and
CA1 pyramidal cells were significantly higher than in pure withdrawn
animals, and did not differ from those of alcohol-treated rats that did not
undergo withdrawaLlltesc dam suggest t4at phxetam treatment
impedq during withdrawa~ the pursuing of amrwul degeneration.
MAIN MESH
SUBJECTS:
Ethanol/*ADVERSE EFFECTS
Hippocampus/*DRUG EFFECTWPATHOLOGY
Neurons/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Substance Withdrawal Syndrome/* PATHOLOGY
ADDITIONAL
MESH
SUBJECTS:
Analysis of Variance
Animal
Cell Count/DRUG EFFECTS
Diet
Male
Rats
Rats, Sprague-Dawley
Support, Non-U.S. Gov’t
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
64-17-5 (Ethanol)
7491-74-9 (Piracetam)
——
—
2of3
3119812:0.3
I
l-z
--’ +f
‘J
TITLE:
Does piracetam counteract the ECT-induced memory dysfunctions in
depressed patients?
AUTHOR:
Mindus P; Cronholm B; Levander SE
SOURCE:
Acts Psychiatr Stand 1975 Jun;51(5):319-26
NLM CIT. ID:
75201625
ABSTRACT:
A double-blind, intra-individual cross-over comparison of the effect of
piracetam on retrograde memory impairment as measured by the KS
memory test battery was performed in connection with second and third
Bi-ECT in 18 patients diagnosed as suffering from depression. The seizure
duration and the post-ECT EGG patterns were examined visually and the
post-ECT confusion time was measured. [email protected] was given orally in the
dose of 4.8 g/day for 3 daya. No significant effects were obtained on memory
scores, electrical stimulus duration, EEG pattern or post-ECT confusion
time. The fmdiqp. mq [email protected]@&.dM
of piracetam
shown h animal ektromnvuslive stimulation (ECS) Mdue to a
~
of the disturbing ~
hypoxk on ~nctiotit
is
concluded that more information is needed as regards the pharmacokinetics
and the mode of action of the drug.
MAIN MESH
SUBJECTS:
Depression/* THERAPY
Electroconvulsive Therapy/* ADVERSE EFFECTS
Memory/*DRUG EFFECTS
Memory Disorders/* ETIOLOGY/PREVENTION & CONTROL
Piracetam/*PHARMACOLOGY/THERAPEUTIC USE
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL
MESH
SUBJECTS:
Adult
Aged
Clinical Trials
Drug Evaluation
English Abstract
Female
Human
Male
Middle Age
Placebos
PUBLICATION
TYPES:
CLINICAL TRIAL
CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
LANGUAGE:
El :
.-
—
2 of2
TITLE:
Effects of oxiracetam on learning and memory in animals: comparison
with piracetam.
AUTHOR:
Mondadori C; Classen W; Borkowski J; Ducret T; Buerki H; Schade A
6-.
.
u’ SOURCE:
Clin Neuropharmacol 1986;9 Suppl 3: S27-38
NLM CIT. ID:
87244092
ABSTRACT:
The effects of oxiracetam and piracetam were compared in learning and
memory tests in rats and mice. In the dose range examined, the two
nootropics were equally active in reducing the amnesia induced by
cerebral electroshock in the mouse. Step-down retention performance,
however, was distinctly improved by oxiracetam but unaffected by
piracetam, no matter whether it was given before or immediately after the
learning trial. Oxiracetam also improved acquisition performance in aged
(24- to 27-month-old) rats in an active-avoidance situation at doses of 30
and 100 mg/kg i.p. whereas piracetmn showed no effect at 100 mg/kg i.p.
MAIN MESH
SUBJECTS:
ADDITIONAL
MESH
_——_ SUBJECTS:
Avoidance hamingPDRUG
EFFECTS
Memo~/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidinea/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Aging/PHYSIOLOGY
Animal
Comparative Study
Drug Administration Schedule
Electroshock
Mice
Rats
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyrrolidines)
O(Pyrrolidinones)
62613-82-5 (oxiracetam)
7491-74-9 (Piracetam)
❑
~
mm-----
-.=
.?of2
3 I098428PM
-.
A. INGREDIENT NAME;
UINACRINE HYDROCHLORIDE
B. Chemical Name:
3-Ctioro-7-m~hoW-9-( l-methylA-tiethyltiobutyltino)wtidine
Dihydrochloride;
Mepacrine Hydrochloride;QuinacriniumChloride
2-CNoro-5-(Omega-Diethyltino-Mph-Methylbu&ltino)-7-Metho~actidine
Dihydrochloride
3-Chloro-9-(4’-Diethylamino-1‘-Methylbutylamino)-7-MethoxyacridineDihydrochloride
6-Chloro-9-((4-(Diethylamino)- 1-Methylbutyl)Arnino)-2-Methoxyactidine
Dihydrochloride
3-Chloro-7-Methoxy-9-(1 -Methyl-4-Diethylaminobutylamino)AcridineDihydrochloride
2-Methoxy-6-Chloro-9-(4-Diethykwnino-l-Methylbutylamino)
c. Common
Name:
Acrichine, Acriquine, Akrichin (Czech), Arichi~ Atabrine, Atabrine Dihydrochloride,
Atabrine Hydrochloride, Atebri~ Atebrine, AtebrinHydrochloride, Chemiochi~ Chinacri~
Chinacrin Hydrochloride, Crinodor~ Dial, Erio~ Italchi~ malaricid~ Mecryl, Mepacrine
Dihydrochloride, Mepacrine Hydrochloride, Methoquine, Acridine Dihydrochloride,
Metochi% Metoqui~ Metoquine, Palacri~ Palu~ Pentile~ Quinacrine Dihydrochloride,
Quinacrine Hydrochloride
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay: 100. 12%
98 yO
E. Information about how the ingredient is supplied:
Bright Yellow, Crystalline Powder. It is odorless and has a bitter taste.
F. Information about recognition of the substance in foreign
pharmacopoeias:
—
Pharmacopoeias. In Arg., Belg., Br., BraZ., Eur., Fr., Ger., Hung., Ind., It., Mex., Neth.,
Nerd., Pol., Rus., Span., Swiss., Turk., and U. S.
-
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
H. Information about dosage forms used:
Tablets
L
Information about strength:
loomg” - 900mg
J. Information about route of administration:
Orally
K. Stability data:
—
Melting Point: 257 C (DEC)
Incompatible with alkalis, nitrates, and oxidizing agents.
L. Formulations:
M. Miscellaneous Information:
Page -2-
t
.—
.-.
:. .-.
\
.-
.-’
-.
.
---
.
1.
.
2.
6. {a)
5afch
NO.
(b)
(o)
& RCSULTS OF AHALYsls
ASper
Date of
Eqiry
JUNE
2002
‘
fi,~J,
J
.5ul ubllj
L
ty
.—.
:
D
:
.
At:%-iin (;: :
:
!.
:
o
;,
-
. .
Tha onfniurr]s in reppecrof l~a tas[s carried UULand man!ionad above.
SEP
24
’97
.—=
-.
==,
----.
..-.
.7
09:14
PQ6E .002
/
—.-.--=
.——.
~
,
- -.
.. ___
~:~-._L
.
.
. . ..
.—. . .,..————-
---..
-
. .
—-=--
—- -.
-...:
---
— -._=
_-.:~
~--
-..——
. —---
—--A——-.
—-...
.—-.
—
-----
—
~ _<
-.
.+:,
-- ---- -.’
... . ..— ~,..
.. . .
.—
. - ._
=.
.—
..
...
-4.
...
—.
_..
.---.’.-.
—________
. . ..—
-.-.
.
-.-=
--
—.
-.,
.—
---
,.
-
-:---=--=;—-=—-—-—.==-
-
.-.
–---.—
=--
.-,.,_._.
. .. . .
---. —-- -p+=--- .-=
-,,
___
- %:.:-;
.-- ..., .
:=:---
‘–-”--.:. ~.-—~
–=:-
. ._-._=
-
u. ~..,_
-. .. .
“-~
QUALITY
—
—.
—
CHEMICAL
NAME. :QUINACRINE
MANUFACTURE
LOT
CONTROL REPORT
HYDROCHLORIDE
USP
NO. :025
PHYSICAL
SPECIFICATION
TEsT
l)DESCRIPTION
~
BRIGHT
TASTE .
2)SOLUBILITY.
3)MELTING
MELTS
/NF — /MART. —
:Usp — /Bp_/~RcK_
/CO.==-.
.:
YELLOW,
sPARINGLY
sTmARD.
TEST
CRYSTALLINE
POWDER.
IS
ODORLESS
AND
HAS A BITTER
:
SOLUBLE
IN
WATER;
soLUBLE
IN
ALCoHoLS
POINT.:
AT
ABOUT
250
DEGREES
WITH
DECOMPOSITION.
—. —
4)SPECIFIC
GRAVITY.
5)IDENTIFICATION
.:
A)COMPLIES
(A) As
B)COMPLIES
(C) As
C)A SOLUTION
1 IN
PASSES.
PER
PER
100
IR spECTR~
Usp xxII”
Usp xXIIO
HAS A PH ABOUT 4.5.
FAXLS .:
:
COMMENTS .:QUINACRINE
ANALYST
SIGNATURE.:
PREPACK
TEST.
RETEST
:
.:
DIHYDROCHLORIDE
IS
ALSO
KNOWN AS
QUINACRINE
DATE.
DATE. :
:
INITIAL.
DATE. :
:
INITIAL.
:
HCL.
:
—
.
—
------------------ IDENTIFICATION ------------------PRODUCT #: 22299-2
NAME: QUINACRINE DIHYDROCHLORIDE HYDRATE,
98°h
CAS #: 69-05-6
MF: C23H30CLN30
SYNONYMS
ACRICHINE * ACRIQUINE * AKRICHTN (CZECH) * ARICHIN * ATABRINE *
ATABRINE DIHYDROCHLORIDE * ATABRINE HYDROCHLORIDE * ATEBRIN *
J
C[
t
@(
ATEBRINE * ATEBRTN HYDROCHLORIDE * CHEMIOCHIN * CHINACRIN *
CHINACRIN
HYDROCHLORIDE *
2-CHLORO-5-(OMEGA-DIETHYLAMINO-ALPHA-METHYLBUTYLAMINO)
-7-METHOXYACRIDINE DIHYDROCHLORIDE *)
3-cHLoRo-9-(4’-DIETHYLAMrNo1‘METHYLBUTYLAMINO)-7-METHOXYACRIDINE DIHYDROCHLORIDE *
6-CHLORO-9-((4(DIETHYLAMINO)- 1-METHYLBUTYL)AMINO)-2-METHOXYACRIDINE
DIHYDROCHLORTDE
*
3-CHLORO-7-METHOXY-9-( 1-METHYL”4-DIETHYLAMINoBuTYLAMrNo)AcRrDINE
.—
DIHYDROCHLORIDE ~CRINODORA * DIAL * ERION * ITALCHIN * MALARICIDA *
MECRYL * MEPACRINE DIHYDROCHLORIDE * MEPACRINE HYDROCHLORIDE *
METHOQUINE ~
C
a [2-METHOXY-6-CHLORO-9-(4-DmTHyLM0-I-METHyLBUTYIJkMIN0)
]
ACRIDINE DIHYDROCHLORIDE * METOCHIN * METOQUIN * METOQUINE *
PALACRIN
bc
* PALUSAN * PENTILEN * QUINACRINE DIHYDROCHLORIDE * QUINACRINE
HYDROCHLORIDE * 866 R,P, * SN 390 *
------------------ TOXICITY HAZARDS ------------------RTECS NO: AR7875000
ACRIDINE, 6-CHLORO-9-((4-(DIETHYLAMINO)-I -METHYLBUTYL)AMINO)-2METHOXY-, DIHYDROCHLORIDE
TOXICITY DATA
ORL-RAT LD50:660 MG/KG
IVN-RAT LD50:29 MG/KG
IUT-RAT LD50: 100 MG/KG
———
ORL-MUS LD50:557 MGKG
IPR-MUS LD50: 189 MG/KG
SCU-MUS LD50:212 MG/KG
JPETAB 91,157,47
JPETAB 91,157,47
UEBA6 16,1074,78
JPETAB 91,157,47
JPETAB 91,133,47
ABEMAV 1,317,41
IVN-MUS LD50:38 MG/’KG
JPETAB 91,157,47
JPETAB 91,157,47
ORL-RBT LD50:433 MG/KG
IVN-RBT LD50:9 MG/KG
JPETAB 91,157,47
JPETAB 91,157,47
IVN-GPG LD50: 14 MG/KG
REVIEWS, STANDARDS, AND REGULATIONS
NOES 1983: HZD X4102; NIS 1; TNF 66; NOS 3; TNE 987; TFE 508
EPA GENETOX PROGRAM 1988, NEGATIVE: SPERM MORPHOLOGY-MOUSE
EPA GENETOX PROGRAM
1988, INCONCLUSIVE:
MAMMALIAN
MICRONUCLEUS
TARGET ORGAN DATA
PERIPHERAL NERVE AND SENSATION (FLACCID PARALYSIS WITHOUT
ANESTHESIA)
BEHAVIORAL (ALTERED SLEEP TIME)
BEHAVIORAL (SOMNOLENCE)
BEHAVIORAL (TOXIC PSYCHOSIS)
BEHAVIORAL (CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD)
VASCULAR (OTHER CHANGES)
LUNGS, THORAX OR RESPIRATION (RESPIRATORY DEPRESSION)
LUNGS, THORAX OR RESPIRATION (OTHER CHANGES)
IMMUNOLOGICAL INCLUDING ALLERGIC (ANAPHYLAXIS)
PATERNAL EFFECTS (SPERMATOGENESIS)
MATERNAL EFFECTS (OVARIES, FALLOPIAN TUBES)
MATERNAL EFFECTS (UTERUS, CERVIX, VAGINA)
MATERNAL EFFECTS (MENSTRUAL CYLCE CHANGES OR DISORDERS)
MATERNAL EFFECTS (OTHER EFFECTS ON FEMALE)
EFFECTS ON FERTLLITY (FEMALE FERTILITY INDEX)
EFFECTS ON FERTILITY (PRE-IMPLANTATION
MORTALITY)
EFFECTS ON FERTILITY (POST-IMPLANTATION
MORTALITY)
ONLY SELECTED REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES
(RTECS)
DATA IS PRESENTED HERE SEE ACTUAL ENTRY IN RTECS FOR COMPLETE
INFORMATION
------------------ HEALTH HAZARD DATA ----------------ACUTE EFFECTS
HARMFUL IF SWALLOWED, INHALED, OR ABSORBED THROUGH SKIN
MAY CAUSE EYE IRRITATION
MAY CAUSE SKIN IRRITATION
TO THE BEST OF OUR KNOWLEDGE, THE CHEMICAL, PHYSICAL, AND
TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY INVESTIGATED
FIRST AID
IN CASE OF CONTACT, IMMEDIATELY
OF
WATER FOR AT LEAST 15 MINUTES.
FLUSH EYES WITH COPIOUS AMOUNTS
—.
IN CASE OF CONTACT,
IMMEDIATELY
WASH SKIN WITH SOAP AND COPIOUS
AMOUNTS OF WATER.
IF INHALED, REMOVE TO FRESH AIR. IF NOT BREATHING GIVE ARTIFICIAL
RESPIRATION. IF BREATHING IS DIFFICULT, GIVE OXYGEN.
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVTDED PERSON IS
CONSCIOUS.
CALL A PHYSICIAN.
WASH CONTAMINATED CLOTHING BEFORE REUSE
-------------------- PHYSICAL DATA -------------------‘&- MELTING PT: 257 C (DEC)
APPEWCE
AND ODOR
YELLOW POWDER
------------ FIRE AND EXPLOSION HAZARD DATA ----------EXTINGUISHING MEDIA
WATER SPRAY
CARBON DIOXIDE, DRY CHEMICAL POWDER OR APPROPRIATE FOAM
SPECIAL FIREFIGHTING PROCEDURES
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES
UNUSUAL FIRE AND EXPLOSIONS HAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS
------------------- REACTIVITY DATA ------------------INCOMPATIBILITIES
STRONG OXIDIZING AGENTS
STRONG ACIDS
MAY DISCOLOR ON EXPOSURE TO LIGHT
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
TOXIC FUMES OF
CARBON MONOXIDE, CARBON DIOXIDE
NITROGEN OXIDES
HYDROGEN CHLORIDE GAS
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
EVACUATE AREA
WEAR SELF-CONTAINED BREATHING APPARATUS, RUBBER BOOTS AND HEAVY
—
RUBBER GLOVES.
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOID RAISING DUST.
VENTILATE AREA AND WASH SPILL SITE AFTER MATERIAL PICKUP IS
COMPLETE.
WASTE DISPOSAL METHOD
DISSOLVE OR MIX THE MATERIAL WITH A COMBUSTIBLE SOLVENT AND BURN
—__
—
INA
CHEMICAL
INCINERATOR
EQUIPPED WITH AN AFTERBURNER
AND SCRUBBER
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --CHEMICAL SAFETY GOGGLES
RUBBER GLOVES
NIOSH/MSHA-APPROVED
RESPIRATOR
SAFETY SHOWER AND EYE BATH
USE ONLY IN A CHEMICAL FUME HOOD
DO NOT BREATHE DUST
DO NOT GET IN EYES, ON SKIN, ON CLOTHING
WASH THOROUGHLY AFTER HANDLING
TOXIC
KEEP TIGHTLY CLOSED
LIGHT SENSITIVE
STORE IN A COOL DRY PLACE
HARMFUL BY INHALATION, IN CONTACT WITH SKIN AND IF SWALLOWED
_—.
WEAR SUITABLE PROTECTIVE CLOTHING.
THE ABOVE INFORMATION IS BELIEVED TO BE CORRECT BUT DOES NOT
PURPORT TO BE
ALL INCLUSIVE AND SHALL BE USED ONLY AS A GUIDE. SIGMA ALDRICH
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT. SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
SHALL
\
,
,~!){)
USITED
ST.\TES
OF.{MERICA
L
Packaging and storage-Preserve
P}Toxylin body
cartons, protected
packmf in
from light.
C.4TEGoRT—Pharmaceutic
Ilecessity
for COLLODtON.
A
Quinacrine
QUIXACRIXE
——
<[
(f?
.
/’
I
-#
HYDROCHLORIDE
...
%Chlom7-metio~-Wl-met
Dfiydrochloride;
l[epawine
r
-.f4-
/
.
Hydrochloride
bvltiethylambobuty
1amino)acn&ne
tiydrochlorlde;
Quimm+nium Chloride
~cH30Wc,
1
]2-,”
C=H30C1Y30
Mol. wt. 50s. 94
yH—CH(CHJ-CH2CH2
CH2-~+(C2H5)2
2HCI 2H90
Hydrochloride contains not less than 98 per cent of
Quinacrine
C,,HmCIN,O 2HC1.?H,O.
E
D&cription4
l-tlaod
uinxrine H.vdroehloride occurs as ~
orTsasand tom a bMer twte.
so~ul
nacme
H ~drochforide
crystalline powder.
diasolvea in about 35 ml. of water.
It ia soluble in alco;ol.
Identification.1:
LIS’
Won
he action of a mixture of nitric
s chiefly of cellulose tetranitrate
,
, mattedmw of filament+ resembling
~ touch. It is ezceedingllj jlammable,
with a luminous flame. When kept in
is decomposed with the evolution of
ue.
xvly but completely in 25 parts of a
f alcohol. It is soluble in acetone md
n these aoiutiona by water.
ut 500 mg. of [email protected],
accurately
id wat.q, and ignite the Pyroxylin at
it the &sh to redness, and cool: not
;m. of Pyroxylin with 20 ml. of water
not have an acid reaction to litmus.
on a steam bath, and dry the residue
of residue remains.
To 5 MI. of a solution of CMinacrine Hydrochloride (1 in 40). add a slieht excess
to orange, oily precipitate of quinacrifie baae is
of ammonia TS.: a yellow
formed which adheres to the wall of the veaad and is soluble in ether.
B: To 5 ml. of a solution of Quinacrine Hydrochloride (1 in 40), add 1 ml. of diluted nitric acid: a yellow crystalline precipitate is formed.
(1 in 40), add 1 ml. of
C: To 5 ml. of a eolution of Quinacrine Hy~oc~oride
mercuric chloride T.S.:
* ‘euow oEw’p’mw
‘owed””
tatA, aciditied
D: The filtrate from the preclpltate,
tamed m M
[email protected]
with nitric acid, responds to the tests for Chlotide,. page 901.
pH—The pH of a solution of Quinactie Hydrochloride (1 m 100) is about 4.5.
Water, page 942-Determine
the wat~r content of Qtirine
Hydrochloride by
@ring at 105” for 4 houm or by the had Fischer method: it contains not less than
6 per cent and not more than S per cent of water.
Residue on ignition, page 9 12—The residue on ignition of 200 mg. of Quinacrine
Hydrochloride is negligible.
Assay—Transfer to a 100-ml. volumetric tlaak about 250 mg. of Quinacrine Hydrochloride. accurate[v w-eig.hed. dissolve it in 10 ml. of water, then add 10 ml. of a
solution” Prepared _by &“aol&g 25 Gm. of sodium acetate” and 10 ml. of glacial
tatwium biacetic acid in water to make 100 ml. Add exactly ,W3ml. of 0.1 N
chromate and watir to make 100 ml., stopper the flaak, mix thoroug E y, and filter
into a &v fiaak, ,rejecting the &t 15 ml. of the filtrate.
through a dry filter ~per
Measure 50 ML of e subsequent @trate mto a glaas+tippwed
tlaak, add 1,5 ml.
“ “
of hydrochloric acid and 20 ml. of
contents gently, and allow tistin&~;%;~%%b~p%?;5~k;~a~
and titrate the liberated iodine with 0.1 ,V sodium thioeulfa~~ adding starch T.S.
as the end-point is neared. Perform a bkmk determination with the same quanti-
,
600
-
tiesof
the same
reagents
PEARMACOPEIA
Raidual ZWahbns,
bichromate is equivalent w 8.482 mg. of C& P ~r
and in the same manner (see
832). Each ml. of 0.1X potium
CINmO 2HCI 2H*0.
Packa~ng
and
stor~ge-P~e
Qubcrine
eontaine.m.
CATEGORY—Anthetintic;
DOSE
OF TEE
r
~ct
R%m.%Y%z%
~WSM bath untif
the
p]etely with the ~d of
pr~d
M directed m
@g
with “then add 10
IS equivalent to S.48~
Packaging and s[orage-
anti protozoan.
—USUAL—SUpptiVe-
HydrocMotide
QUN’ACRINE
Ta&[email protected]:
following amoun~ of q
and DO
CATEGORY
Tablets
HYDROCHLORIDE
(
T.4BLETS
Quinacrine Hydrochloride Tablets contain not less than 93 per cent
107 per cent of tlie Mwled timount of CaaHwCIX~O. 2HC1 2H20.
and not more than
ldentification—
.i:
Powder
colorless.
b
A.ntimalanal-100
mg.
Therapeutierng.
every
6
Antixmdanal and antiprotozoan-200
hours for 5 dwxx, then 100 mg. three tim~ a
day for 6 days.
Anthelminti&500
mg. with 500 mg. of sodium
bicarbonate in a single dose.
Quinacrine
is
moistened With
~tton
Hydrochloride in tight, light-reaiatant
antima)aria~;
IONEM1.
Make the
pls%e]ywith ml-v
[C,1
CI-130/
;,
number of QuinacMe H\droehloride Tablets, equivalent
To about 2.50 mg. of uinncrine hydrochlor~de, and extrwt with two 1&ml.
Portionsof [email protected],%[email protected]~r
mbwtmction.
T05 ml, of the e.tmct
ndd ammonia T. S., and remove the oily precipitate so formed by extraction
with two [email protected] portiom of ether. The water layer, acidified with nitric
acid, responds to the teata for Chloride, page 901.
B: To the remaining portion of the water extract obtained in 2denti~ion
kut A
add 2 ml. of ammonin T.S.: a ~ellow, oilv precipita~ forms. Shake the
mixture with several 10-ml. ptmuons of chloroform untif the water layer is
practically colorless. Evaporate the combined chloroform solutions on a
steam bath in a small beaker, and add to the residue 3 ml. of hot water and
2 ml. of diluted hydrochloric acid, moistening the sides of the b=ker with
the liquid and stirring with a glass rod. .4UOU-to stand for 30 minutes, then
filter, wash the crystals with icwold water until the hmt washing is practically
neutral to litmus, and dry at 1050 for 2 hours: tbe CrySWIB so obtained
respond to Idenlijlatti
tcsb B and C under Quirsoainc Hydrochlortiic,
page 599.
Disintegration-Quinacrine
Hydrochloride Tablets meet the requirements of the
IX.sdegration Tes( jor Tableti, page 936! in not more than 1 hour.
W’eight wmia(ion-Quinamine
Hydrochloride Tablew meet the requirements of the
l~cighi I’atition Test -for Tabls&, page 945.
.4ssay—Weigh a counted number of not less than ?0 Quinacrine Hydrochloride Tab)ew, and reduce them to a fine powder without appreciable low, Weigh accurately
a Portion of !he pwder, eq~yalent to about 200 m . of uinacnne hydrochloride,
and place lt m a separator with 23 MI. of water an !7 3 m of diluted hydrochloric
acid. Extract tbe suspension with two l~ml. portions of chloroform, and wash the
chloroform extracti in a second separator with 10 ml. of water. Dismrd the washed
chloroform, and add tbe water in the second separator to the suspension of tablet
a tsufTicient
L
((&)~z.,s2~2)2
~2~04
QUinidine
Sulfate }
species of Cinchom
Fliickiger (Fare. Rub
Description+
titidbe
:
cohering m masses.
II
w light.
Ita solutions
.,
..
. .
.;
..
Solubility+ne
Gm. of
about 10 ml, of dCOhO
[dentification—
.i : .L,cidify a solution
inK solution ha:
B:
TO s-m).
~:
. -“
D:
Specific
of a SOIL
mine T. S., and
green color due
To:
ml. of aso]u
T. S., and stir n
[email protected] (diatim
Quioidine Sulfatz
rotation.
page
8(
the ar+ydro~
b~~,
Quinid:ne Sulfate m @
;
,.
&
.ri-
Amopyroquine/
ch[orquinc
base. Soluble I in 5 of water: practically insoluble in alcohol, chloroform. ~nd ether.
A 1% solution in water has I pH of 3,5 (0 5,5.
g-w
- quint.
Cyclochm; Haloquine. 4-(7 -Chlor&4lamlno)-2,6-bis( dihexylamlnomethy l)phenol.
CIN40-497.
I.
CAS —
Protect
/4s94-33-3,
from light.
[email protected]
Treattstenr., Precautiorm
Resistmsce.As for Chlorcquine, p.395.
Adverse
A yellow crystailirre
powder with a Lsilter taste. PractiCXIly imsofakk in waten
readily soluble in dilu~e acids:
@ubie
in dilute alkalis. Protect from light.
800 mg
Usaa.Cyckqrinc
lupus
MS
rodcrma.
The
rcqulne,
amodiaquine,
resembles chlorcquine in ita action and
for the wppreasion and
used in the USSR
Itutmmtt of malaria. A dose of XH3 mg has km given
~eekly for the suppression
of malaria
and 300 mg has
been given daily for three days in the treatment
of acute
]ttds.
bean
Hydroxyehlwcquine
daily
deposition
One
patient
64,
267*
to 269*.
Uwa. Diformyldapaone
has been used as an antimalarial
m doses of 4CY3 to 800 mg weekly,
but is given with
chloroqutrxc. primaquine,
or pyrime!hamine,
since it has
no acnon on gametoeytes.
Diformyldapsone
had an
hours.–
W’. Peters, PosI#
a proxtmatc
half-life
of
wtd. J., 1973,49,573.
Diformyldapsone
weeks damsged
of 3.2 g twice weekly
for 4
blood c-ells in 25 subjects
in dsxcs
!he red
Smaller doses did
~. Cucineil ●t al.,
nol
appear
[o cause haemolysls.—
1974. [4. 51.
84
S
J. clirr. Pharmac.,
Walarvk. Di form yidapaone
was cmstdercd
to protect
volunteers more effectively
against [he Vietnam
Sm!th
than against the Chcasorr strain
$~*-” gf P, &ipwtsm
r=
vivax
There
were
no
reports
of
met.
i.
\binaem ia in patients receiving diformyidapsmse
ai
in corrjunctiorr
with chloroquine.—
Clyde. D.F.
Med., 1971, /36. 836, per Trop. Dis. Bull.,
tr ~
.tilit.
Med.. 1970, /3S.
1972, 69. 593. See also Idem. Milit
527.
D, formyldapne
100 to 800 mg weekly given wtth chloru+mv.e alone. or with chlorcqutne
and primaquine.
SUF
pressedthe Smith strain of falcqwum
malaria
in 41 of
45 men and the Brai. su-aln in 9 men. The combination
Jppcarcd LObe more effective than treatmenl with chloroqulnc and primaquinc.
or than pyrimethamine
25 mg
weekly which suppressed
the Brsl, but not [he Smith
Am. J. trop
Med. Hyg..
<tram,D. F. Clyde ●r al,
1971, 20, 1, per Trop. f3is, Euil,,
1971, 68, 1153.
who
with
the
had
of
wem
surgery
chlorcquirxe
and
then
untnl
284
dischar8e
)ne meltlng
~~OO.
JI
about
198”
and
Hydroxychloraqu\ne
3pprox]mately
equwalent
the
o[her
sulphzte
to
77
mg
2
at
of
200 mg
w!th
could
Incidence
5%
in
!07
with
mouth
be
of deepvcin
patients
!6%
followed
discharge.
jn
A
1971,
artcr
The
the
that
reducing
pulmonary
J,
controls.
dnscs
by 400 mg every
—
in
znd
the
emtml-
1, 312.
surgery
hydroxychlomqume
!n 97
3 diwdcd
in
Poatoperatwe
appeared
uscfui
thromtmws
given
premcdication
it
Br. mtd
hydraxy.
or by rejection
From
thrombmts
e! al.
De
w ho u nderof
their
by mouth
hospital.
of decpvcin
F
was
sulphate
doac was
?,4 hours
12 hours after
E. C~r[cr ~nd R. Eban.
1.2 g
before
surgery
Br mrd
dlscusslon$,
see A
S
G
G.rllus
Turpw
-
WR
142490,
(2-pipefidyl)methanoi
hydroc”hlorid~.
C17H16F6NZ0,
HCl=414.g.
CAS
— S3230-10-7
(hydrochloride),
- ‘
(mefloquine];
51773-92-3
Adverse Effects. Epigastric
discomfort
has been
reported after doses of I g, and nausea and dizziness after doacs of 1.75 or 2 g.
Uses. Mcfloquine
hydrochloride
is a 4-quinoIincmethanoi
cmmpound which has schizonticidal
activity
against malaria
parasites.
It is acrive
against chloroquine-rcaistant
falciparum
malaria.
.4fa/arr”a. A preliminary study in 17 subjects of the use
of meflcquine hydrochloride in single 1-g doses aa a
r
hylactic
against
●t
drug-resistant
malaria,—
K,
H
al,, 8ss![, W\d Hlrh Org., 1974,5,.375,
llsirty-five
non-immune
volunt~ra
infected
with 1 of 3
strains of P/avmodisrm Jalciporrcm, 2 of them drug-rcslsrant, were treated with a single oraJ dose of mcftcquine
hydrochloride
0,4, 1, or 1.5
The infection
was cured
in 2 of 12 given 0.4g.
l] o !“ IS gwen I g, and E of 8
gtvsm I.5 g, fn 5 partially-immune
volunteers
infected
with single doses of
with P, viva.v cures were achieved
but infection reappeared in the
0.4 or I g in two.
remaining 3 subiceta and was subse=zuendv cured with
●t a/
chloroquke
and “pvimaquine.—
G. M: Tren’holmc
Science. 1973. IW, 791.
None of 21 volurttcm
heavily infected
with
when given meftoquinc
wedy,
500 mg every
bitten
by
IO
P, jafcipurum
hydrochloride
to 15 mosquitoes
developed
malaria
250 or XX) mg
2 weeks, or 1 g every 4 weeks.
Doses of 250 mg weekly suppreaaed P. viva.s infecuons
during drug administration
bul malaria
tveatmcm ceaacd.—
f3. F. Clyde tI al..
appeared
Antimicrob.
when
Ag
Chemother. 1976, 9.384.
Of 39 patients with chiorcquinc-rcaistant
falciparum
mafaaia,
36 (92%)
were cleared
of infection
with
no
sulfadoxine.
reaucbxnee
zftcr treatmcn[ with quinine,
aod pyrimethamirte,
by the regimen
of A.P.
Hall
(B?.
p.405),
whale
med. J.. 197S, 2, 15: see under Quininel
all of 35 were cleared
by treatment
with quinine
folhydrechloridc
1.5 g
lorvad by a ain81e dose of meffoquinc
received
only
I g).
Side-effects
in 40
(orre ptient
patients
given meftaquin<
were,
abdominal
pain (7),
anorexia
(6), diarrh~a
(6), dizziness
(9),
nausea (3),
vomiting (9), and weakness (3). Side-effects
were m!ni mal or abaevvt if at Ieasl 12 houm elapsed after the last
dose of quininc.—
1977.
A. P. Hail ~1 af., B., reed, J
/, 1626.
Arr#ma/ studies of the amlmslarlal
activities
of 4-quinoIincmethanols
including
mefloquine
and a report of the
US Army Malaria
Research Program.—
L. H, Schmtdt
●t al.. Arrlimicro6.
Ag. Chemo(htr
1978. /3. 1011.
Of
37 patients
with
chlorequlne. resistant
falciparum
malaria
all were radicatly
cured by a single dose of
mefloquine
hydrmhlovi&
1.5 g. Side-effects
(nausea,
vonutmg, diarrhoca,
dizzsncsa. head~ch<)
could probably
be reduced
ciors,— E.
by a formulation
B. Dobcmtyn
et
dcwgncd
af.. 8u1/
tO SIOW ASOrp-
W/d H//h
Org.,
1979. S7, 275.
Aftrdolirm.
Preliminary
s!udy in I sUbJect g!ven a single dose of rnefl~uine
!pdlcated
relatively
rap!d absorp.
tion, cxtcnswc
dutrsbsmon,
and prolonged
chmination
pba.ws. Mcflcqulnc
was reported to be extenslyely
bound
lo plasma proteins and to be concentrated
m erythrrrJ. M. Grindel CI al.. J pharm. Sci.. 1977, 66,
cyms.—
E34.
The
kinetics
of mefloquine
Jarditssef al.. Cl[n. Pharmac.
R. E. Dcs1979, 26, 372.
hydrochloride.—
Thrr.
and
and
J
J
Hirsh.
Drugs,
Br. med
Hlrsh.
1382-g
%dfate
pIaqWSId
U“lnrhrop
35
Plaqucnll
:rr 4u.rl
Iceiand
Irol
OtherProprietap
Erc~uln
sulpnatc
L h’
zDenm
Tk\
2(M me
4U <rr~l
.\<[h
T~blcts
Irc
EcIq
.b,m
Names
‘VOW ‘iwed
contllnlng
su~sr-ioatcd
H\droxvchlorcqu!nc
tii
T~bleu
$ulphatc
B P
Tablets
!3blets
rl’ S P I
Tisblvrs
hydrox>chloroqutnc
JVWIJDIC
Fr
Hydrochloride.
Mepacrine
Hydroxychlomquinv
M
Mefloqssine
( ~ )-Q.12.8-Bls(trifluorometh\[)-~-auinoivll-a.
1974, 1, 94
Preparations
~baul
hydroxy
af..
effective
tarda. —
inJcction
phlcbography
1976,/2, 132. A. G
Bu// 1978, 3/. 183.
forms.
100 mg
an
by
A, E. Carter
The
For
crystalline
~re
tre..l ●t
174.
rrom
and
hvdroxychloroqu!ne
There
— R.
[967,
for scve-
and
Of 565 patients
received
hydroxychloroquine
incldencc
Ism. —
1972.87,
sulphate
mg weekly
culanea
200 mg eight-hourly
observations
TW-IUJ In Br ~nd L’S
taste
rctin~
Ryrsex
I.
IO be safe
porphyria
disorders.
Hydmxychloroquim
with
months
long-term
ft.
W
rep.med
1, Dcrm.,
Er.
con[atn!ng
~owder
been
Thrombo-embolic
rr>): ‘J 7-36--J
adourless
26%
after
—
Hydroxychlorcquine,
~:~..-
white
770 g -r
in
There
given.
1979, 22, 832.
rreatment
Mattes,
J
olmost
J bit[er
Comeal
revcmible
seen in a further
pattcnt
Drsbois. Am. J. Ophtha/,,
in 3 of 99 patlenls
Hydroxychkvroquine
Sulphate
IL?P ,
H)droxychloroquine
Sulfate (L’.S, P ); Oxlchloro:h!n Sulohate: Win
1258-2. 2-l,V-[4-(7.
Chloro4-qutnoljlamino)
pentyi]-,V.e~hy l~rnin6\ethanol
,ulphate.
C ~Hz6ClN10,
HjSO. =433.9.
m
was
chlo-
A second case of probable
hydroxychloroquine.
months.
unul
.e
received
399
1381-V
~i%kmarm
surgery
\,
scle-
and in treating an acute attack a dose of 800 mg
has been used. followed after 6 to 8 hours by
400 mg and a further 400 mg on each of the 2
following days. Children may be given a weekly
suppressive dose quivalent
to 5 mg of base per
kg body-weight,
while for treatment
an initial
dose of 10 mg per kg may be given, following by
5 mg per kg 6 hours later and again on the
second and third days.
In the treatment of giardiasis, the usual dose is
2DD mg thrice daily for 5 days.
Hydroxychloroquine
sulphatc has been used in
the treatment
of polymorphous
light eruptions.
The dose is as for rheumatoid arthritis.
by
,’h
received
had
subsequently
and E, L,
compared
} 1,9-.42.3 ~hydroxych/orrrquJ
?1,
it
with
or
quinine,
or
paticrs~
of
Hydroxychloraquine
wlphatc
has an antimalarial
action slmllar
to that of chloroquine
(see p.396) but it is mainly used in the treatment
and
of systemic and discotd lupus erythematoaua
rheumatoid arthritis. Treatment
is usually started
with about 400 to 800 mg daily in divided doses
with meals and the dose is redcsccd to about 200
to 400 mg when a response occurs. In malaria, a
suppressive dose of 400 mg every 7 days is used.
in
1380-b
mcpacvinc,
retinopathy.
Pmphyriiz
Dlformyidapsonc.
400 to 800 mg with pyrlmcthammc
25 mg. both 8iven weekly,
was considered
to provide
efrcctlve prophylaxes against chloroqui ne-rcsis[ant
P Ja/nparum and aga[nst P. WVU,I. No toxic side-effects were
h(ed
1973. /18,
-Io!ed. — D, F Clyde
cr al . M//if
418, pr Trop. Dis Bull,, 1974. 71, 15
patients
ar-thntis,
not previously
26
dose
UseS.
rai
w[th
weekly
D,form yldapaone
chloroquinc
given
protected 5 of 8 volunteers
agams[ falciparcsm malaria.
Better resulu
were nomd when volunteers
were gwen
dapsone dally with chloroquinc
or chlorcquinc
and prv
J. rmp
Med
maqume
weekly. — D. Willerson,
Am
Hyg,, 1972, 2[, 138, per J Am med Ass.. 1972, 220,
1382.
had
average
LO 94
rheumatoid
in
Arrhn’tis Rheum.,
M.p,
an
4!4 years
to
pat Ienu
toxicily
mcnt
PracticsOy iaaolMv in walen soluble 1 in about 200 of dimelhyl sulphoxidc. h is most stable at pH 6
solid.
in
245.
Ocular
CAS — 6784-23-4.
A crystalline
given
20, persistent in 3. and 3 were IOSI to foiIow.up.
was a rapid rise in irrcidensz after 150 g had &en
pathy was
V. Shearer
l)if~yld~~tte.
DFD; DFDDS: Diformyldiaminodiphcnylsulphone.4.4’-Sulphonylbisformanilide,
C,, H,, N,0,S-304.3.
up
toaus.
occurred
developed
i 379-e
for
erythema
wss
and
Mepacrine
>ulufmtc.
( A~,50 .]va)i~b(e
Swrd
f)ucmvl
as
Denm Fln
Sti!r:
LS.4).
CJnad
Ger
Hydrochloride
,8 P, Eur P I.
Mepacrini Hydrochlorldum;
Acrlnamine:
Quinacrine Hydrachlorlde
(LJ.S P /: Quinacrinium
Chloride; Acrich}num: Antimalarlnae
Chlorhvd ras: Chlnacrtna
6- Chloro-9-{ 4-diethylam\noime!hylbutylam lnol. ?.me[hoxv~cndine
dihydroch Ionde dihyar~[e
C:l H,oCl\lO,
2HCI, 2H:O=51M.9
C.-tS — %389-6
ImePaCrIrreI:
69-oS-6
(dih}dr~[”~lorlde,
unhvdrotl r],
6151-304
/dihvdroch.
/or[de, dih vdro!e I
F(
I
Pharmcrcopcwias
1n Arg., Be/g.. Br Bra:,, Eur., Fr..
Ger., Hung.. Ind., lm., II.. Mcx
.Ye{h .bord., Pol..
Rus., Span.. SWISS, Turk., and L’S
bright yellow odourless crvstallinc powder wilh
a biller tasm. M.p. aboul 2>0’ with slccomposilton Soluble I in 35 to 40 of water: soluble in
.-—=-alcohol:
sltghtly soluble m dehydrated
alcohol:
cry slightly
soluble in chloroform;
practically
Insolubie in acetone and ether. A 2% solution in
/
water has a pf+ of 3 to 5. incompatible
with
alkalis, nitrates, and oxidisinR’ a~ents. Store in
k
alrtlght containers. Protect from hgfit.
A
Iacompmihility
Mepacrinc hydroch Ioridc W*S inconrpatamaranth,
benzylpenwlhn,
sod!
.Iglnatc,
with
For rJse u= of mcpaerine as an anthelmintic, scc A.
Davis,
Drug Treatmtaf
in fntesfinal
Helmmthtases,
GcnevI, World Health Organization,
1973.
sodium
sodium
Gicdiasis.
Mepacnne
100 mg thrirx
daily
dap
was usually cffectivc in the treatment
ible
pharm.
amlnmahcylate,
soshum
Iauryl
sulphatc,
wad
-rtixy.mc[,i,lccllul~.
J.
!htomersal.—
Am.
Ass.. proci, Pharm, Edss, 1952, /3, 6$8,
Adverse Effects. Minor cffccss liable to arise with
ordinary doses are dizziness, headache, and mild
gastro-intestinal
disturbances. Most patients develop a yellow discoloration
of the skin. Large
doses may give rise to nausea and vomiting and
occasionally
to transient mental disturbances. A
few patients
develop chronic dcrmatmca
after
prolonged administration
of the drug; these may
be either Iichenoid, eczematoid, or c~foliative in
type. Deaths from exfoliative dermatitis and from
hepatitis have beers reported. The use of mcpacrine over prolonged
periods may give rise to
aplastic anaemia,
Asiversc effects of intraplcural instillation include
fever and chest pain caused b) the inflammatory
r=ction.
The toxicity arising from prolonged administration has eontribtmd
10 the decline in the use of
mcpacrine in malaria.
Two
ticnta
had smwtdsiom a fcw hosm after the
intcap Yeural
400 mg for
_a“
●dministration
of
mepacrittc
hydrochloride
dcvclopad aratus
rnalignattt effsssions.One
epilepticua ●nd died; the other was successfully controlled with phenobarbitonc intravenously ard phenytoin
by mouth.— t Borda snd M. Krant, J. Am. mad. AIJ..
1%7, 201, 1049.
Mcpacrinc
hydrochloride 100 mg daily had been
‘..ewd
tO CXUSC haemolytic
armemia in CCZtain indivi ssala with a deficiency of ghscose+plsmpbatc dehyd.0 rmase. The rcac!ion was SSOIconsidered cfinically aigm“!lam ussdcrnormal circrsmstxnccs(e.g. in the *bsena
of infection).— E. Beutker, Pharmac. Rev,, 1%9, 2). 73.
A patient with rheumatoid arthnus ircatcd with mepacrine hydrochloride
for about 20 !cars had developed a
blue-black
discoloration
of the hard
palate,
the nail
disap
bcda, and the skin over the $hins. The dour
pearecf when
mepacrinc
was stopped
and reappeared
●I al,, J. Am
when i! was restarted — M. J. Egorin
med. Ass.. t976, 236, 385.
Treatment of Adverse Effects. As
for
Chloro-
quinc, p.396.
Precautions.
[
Mepacrinc
enhances the toxicity of
the tl-amirs~uinoiinc
derivatives such as primaquinc by inhibiting their mctabo[ism.
Mepacnne might interfere with fluorime(ric
catlrnatiorss
Adver$c Drug
of plasma hydrccortisone.—
J. Millhousc,
Rcocr. hd!., 1974, UC., 164,
)
Absorption ●tad Fate.
Mcpacrine is absorbed from
the gastrointestinal
tract and appears in lhc
)!
blood within 2 hours. It bccorncs canccntrated in
Iivcr, pancreas, spleen, and lung, and higher concentrations
occur in red and white blood CCIIS
than in plasma, but it also pcrmcatea into all
body fluids and crosses the placenta.
II has a
biological
half-life
of about
5 days and is
excreted only vcr> siowly in [he urine and faeces.
Mcpacrine hydrochloride wcs bound to serum proteins
in .irro.— G. A Lutty. Toxic. oppl. Phormac
1978,
~(q,
44, 225.
Uses.
~
‘-
daily for 7 days is usually effcctwe.
though
relapses ma} occur. A suggested dose for children is 2.7 mg per kg body-weight thrice dailj.
it has been used for the expulsion of tapeworms:
100 mg M given at intervals of 5 minulcs until a
total dose of I g is reached.
Instillations of mepacrine hydrochloride
or mcsy latc arc used in the symplomattc
treatmcn~ of
neopiastic effusions in the pleura or Pcriloneum
but the treatment
is associated wth a high frequency of toxlC effects.
Mepacrinc
was formerly widely used for
the suppression and trcatmcm
of malaria but it
has been superseded for these purposes by chloroqume
and
other
more
rccen[ly introduced antimalarials.
Doses ranged from
suppression and from 900
g reducing
LO
~
‘aily for treatment
&cr)ne
hydroehlorfd~i!
~scd
in
the
Irca[mcn[
of giardlasis:
100
mg
thrice
... ..- ._. ..,.”_.,_.
_. ___
for
5
to
7
of giardlasis,
althou$h a sc.smndCOurw might be required The dfor chddrcn
under 4 y=ra
old was oncquarccr of the
adult doac—
Br. med. J., 1914, 2, 347.
A 95% cure-rstc
was obtamcd
in giardiasis
after
mast wi~b me
Crinc hydrmhlortdc
100 mg thrice
for 7 days. &ages
in children
were:
under
1
33 mg thrice daily; 1 to 4 yeacs, 50 mg Iwicc daily
8 yars,
50 mg !hricc daily; over 8 years, 100 mg
J. Am. med.
daily, all for 7 days..— M. S. Wolfe,
wcs!daily
year,
410
thrice
Am.,
1975, 233. 1362.
Funher references: G. T Mmme C( al,, New Engl. J.
Med., 1969, 281, 402; Med. L#t., 1976, 18. 39; R. E.
Raizman,
Am. J. dig, Di$., 1976, 2f, 1070.
●
ffassioxs. The value of Iccal instillations
of
mcpaerinc
in corrtrollmg
effsssions in advancd
disseminated ncoplastic
disease was studied in 60 patients.
For
pleural
cffuaion$,
asn initial
dose of 50 to I(KJ mg was
followesf
by 2(X) 10 400 mg daily
for 4 or 5 days;
Ma/igaaar
pat]cnta with ascitcs roxiwd
womcr,
—
Advances
Tech Rep
5er
SIX!! women
aPPil~atlOn.
mepacnrre
water
a
52
further
were
Israngkun
lt’arrs,
tr al..
A local
prqnant
at esch
session
response
followed
su~sful
in
shgh:
The
!ransicnt
4S, 71. per
of
firs~
solution
inJccted
were
injection
A.
[
into
The
il
trca~.
the
hea]lh!
be!ng
trea[ed
[u ICC I( “o
treatment
sometimes
Was
Caused
%durrrl,ra,
446
Lopatin,
Wld Med.,
c
of mcpacr, nc,
repeated
I \ ~ patients
pain —
.4bstr
—
14, 7S.
3 to 6 warts
in)caions
the
97
was
wart,
O: ~
usefulness
was used in the
A 4%
ml,
base of [hc
Iz!c:,
pa(encl
success-rate
1976,
wchnique
in doses Of O. I to 0.2
the
low
[nc
I ~ or
SIC:,!C
4 mon[ns
I]ml!ed
Corstraception,
b:
3 unlla~crai
The
in chiidren
skin al
and
Iridica ted
injection
of warts
treated
uterus.
o:
in 7 ml o;
cxamlnauon
patency
Reg UIat,oc,
1973
were
within
the
suspended
for
tubal
application
ment
sterihsa[lon
available
6
of Ferti lit>
W/d Hlfh Or~ No !2?.
desiring
bilateral
slnglc
Methcds
by cannula
hydrochloride
Of
22 hsd
tr
1966.40,
1966,
Preparattiorss
Mepacrirsc
(BP.)
Tabkta
hydroctr16r[dc~otca
Quiwcrissa
taining
Tablets
conlaln]rtg
mepacrlnc
from ~.
Hydmcbhmidc
mcpacrinc
Tablets
(L’.S.P.J
hydroch=S~orc
m
Tablets
con.
airrighl
con.
tainers.
Proprietary Names
(Win/hrop.
USA),
At.abnne
~n~,
Mepacrme
certain
(May
Canad.);
hydrochloride
wuntria
Atabrmc
~---
under
was
Hydrochlond+
--—-
-.
formerly
!hc proprietary
marketed
name
in
Qulnacr]nc
IS Baker).
100 to 200 mg followed by
to 800 mg daily for 3 to 5 days. The mepacrine was
dissolvd in 10 ml of the effusion fhnd which was then
y evaluated
for 2
rc-inpcd.
Of
33 paticn u cliniall
months or more, objcaivc
control
of the effusion
was
maintained
in 27 for 2 10 26 months.
Fever,
often
for a few
accompanied
by Ieucccytoms and pcrsis[ing
rmmpletion
of :rcatmerm
was
houm 10 10 dafi after
noted in about half the patients — J. E. Ultmann
eJ a/.,
Ccsneer, 1963.16,
283.
400
Thirteen
patients
with neoplaatic effusions
were treated
with mcpacrinc
hydrochloride
in dines of 100 to 2tXI mg
daily by kxal instillations
for pleural cffusiom,
and 200
to 400 mg daily
for ascitea, usually
for 3 m 5 days.
Clinical
benefit with favourablc
objcetivc
changes in all
measurable
critcr]a
of the disease was seen in 9 patients
for periods of up to 27 months, Mild
local toxicity
was
frquent
but hacmatopac!ic
depression
did no; occur.
No consistent
cytolytic
changes of tumour
cells were
obscrwcd and response was attributed
to !hc inflammation and fibrosis
produced — M. R. Dolhngcr
tI rs[,.
Ann in(. m Med., 1967, 66, 249
There was a rcspmse in 8 of 12 patients with malignam
pleural cffusions given mepacnne
by Ins!} nation lsr small
daily doses. and in 19 of 27 given mcpacnrsc as a single
dose Lbrough a thorawtomy
tube. More disturbing
and
serious toxici~y tsrzurred
in the second group,—
E. R
Borja and R. P. Pugh. Cancer, 1973, 3/, 899.
A beneficial
cfrscl
(leas than 500 ml fluid
drawn
at
each plcuroccntcsis
in 3 months)
was achieved
on 9 of
14 occmons
after
the mstiliation
of mcpacnnc
( 100,
200, and 200 mg respectwcly
on 3 occasions in I week).
on 4 of 15 @xaslons
after thiotepa
(20 mg per instilJauon). and on I of 9 cccasions after pleurssccnl~is
alone
Fever and chest pain were Iimi[ing
factors:
mcpasmnc
was suuable if I bc patient’s condition and prognosis was
good;
otherwise
thlotepn
or
pleuruccntesis
were
preferred.—
J. McJcr er a/.. ScIZrcd J resp D/s., 1977.
58, 319.
Further
refcrcnccs
J
A
Hickman
and
M.
C,
1383-q
Mepacrine Mesylate.
Mepacnne
Me;hancsulphona!c
(B.P C /%3).
C11H10CIN10,2CH 1SO)H,H?O-610.2,
CAS — 3/6-05-2
Bright
yellow
Mcpacrinc
(asdsydrous)
odourless
mcaylate
to 100 mg of mepxcnne
water
and
has a pH
1 in
muscular
for
It
injection
360 mg
from
Ilght
has
1 m 3 of
!n ua[er
Solutions
to I hose of
soluble
adm!nisicred
treatment
been
given
should
of [Imc
as it IS more
been
taste
qutvalent
has ac; ions s!milar
but
in the
has
blt!cr
Soluble
for any length
mcs! late
a
A 2% solution
alcohol.
hydrochloride,
h}drochlorid:
dose of
hydrochloride
of
or stored
Mepacrinc
mcpacrnrc
the
36
with
Is approximately
of 3 to 5. Protect
not be heated,
Lkea.
crystals
I 20 mg
b!
of severe
than
jn:ra -
malarta
In 2 to 4 ml
,4
O( Wa!cr
I n!ections,
IL M gwcn
by Intrapleural
jn the treatment
or
of ncoplastic
intrapentoncal
Ins[al]al,on
effuslons.
Prcparatisms
Mepacrine
Mctbancsulphormte
Mcpacrinc
Meaylate
mepacnnt
dtssolvlng,
a sakd
A
(B
stcrllc
P C
/ 963,
solu[lon
mcsylatc
In Water
for In]ect}ons,
prepared
immcdlatel~
before USC, the sterile contents
container
Mepacrme
count rlcs
Soluble
lnjcction
InJecr] on.
In ~’alCr
mcsyl.stc
under
uas
the
for
of
b!
of
lnJectlOnS
formerl>
marketed
propnetar~
name
In
ccrra!n
Qulnacr!nc
(May & s%kfr)
Jones,
Thorax, 1970, ?5, 2.26; M. Lec and D A. Boycs.
Obsml, Gyrwec. Br Commonw., 1971, 78, 843.
J
I 384-p
Pneumorhora.c
A patlcm with cystic fibrous was wea{cd
[or pneumothorax
on the left sldc by Ihe Instillation
of
mepacrlne
hydrochloride
100 mg ]n 15 ml saline into the
!n[raplcural
space on 4 consccutwc days This procedure
was repeated
12 months later for pneumothorax
on the
There *as no recurrence of pneumothorax on
right.
e!ther side before the pa[!cnl died 1 I months after [he
second treatment
after several rclapsea of chronic
pulmrd
monary
dlscase — J Kattwinkcl
<[ a/
J Am
Ass
1973, 226 !57 See also R E Jones znd S T
1976, )30
777
Glammona,
Am J DIS Child,
Tubal occlusion
TMO 104 ml of a 30% aqueous su=.pmsmn of mepacnnc
hydrochloride
Insttllcd
!ransvag!nall~
once In the rmmcd!a[c
cutive
cycles Induced
pc%lmenslrual
tubal
calus!on
phase of 2 conseIn 93% oi 134
pamaquin
(BP
Pamaquinc
Embona[e
D,eth)lamin+
/9f31
Gamctocldum,
Plasmoq.]num,
l-met h>lbutylaml
4,4’-mcthylcncbis(
3.h>droxy-2.
Pamachln,
SN
97 I
no)-6-methoxyqu
8-{4.
\nol\nc
naphthoate)
C,: H,{ X,0,-703.8
CAS — 49/-92-9
(base,
A ~cl)ow
to orange.>ellou
ICr taste
alcohol
Practical}>
d
635-03-?
fcmhonofe!
odourless
insoluble
~wder
In u.a~cr,
u)th
soluble
a b!!
I tn 20
Lscs. Pamaqu!n
nas formerl>
used ]n the trcalment
O(
malaria
bul has heen superseded
b, prlmaqulnc
pho$pha[c
A. INGREDIENT NAME;
SULF ADIMETHOXINE
B. Chemical Name:
(2,6-dimethoxy-pyrimidin-4-yl)sulphailamide
c. Common Name:
Arg.-Lenterap, Denrn.-Sulopla~ Ital. -Bensulf~Chemiosalf~ Crozinal, Deltin, Diasulf~
Diazinol, Dimetossilinia, Fultamid, Ipersulfa, Levisul, hlicromeg~ Neosulfamyd, Redifal,
Risulpir, RitarsulfA Sulfabon, Sulfadomus, Sulfaduran, Sulfastop,
Sulfomikro~Tempodiazin~ Pol.- Madroxine,S. Ml--- Jatsulp~ Lensulph~ Pansulp~
SulfathoA Spain-Dimetox~ Oxazina,Sulf-reten.
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
—
Assay (tit.)
99%
E. Information about how the ingredient is supplied:
White Crystals from Dilute Alcohol
F. Information about recognition of the substance in foreign
pharmacopoeias:
Indian Pharmacopoeia
British Pharmacopoeia 1988
British Pharmacopoeia 1993, VOL I
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Weinstei~ L. A review of sulphadimethoxine. Nw Engl. L Mea! 1960; 263:842.
—
Vree, T. B. Pharrnacokinetics. N1 -glucuronidation and N4-acetylation of sulfadimethoxine
in man. Pharm. Weebl. (Scz), 1990;12:5 1-59.
Marusic~ W, L., Ogrinz E, f., and Hecht. B. Stiety of Sulfadimmethoxine in turkeys
Poultry Science, 1971;50(2):5 13-517.
Marusic~ W, L., Ogrinz, E., and Brand, M. Safety and compatibility of Sulfadimethoxine
in chickens. Poultry Science, 1969;48(1):2 10-216.
Maestrone, G., Thompson, E., and Yeisley, H. Rofenaid at a 0.02V0dose level in feed
was effkctive prophylactically and therapeutically against an experimentally induced
Escherichia coli airsac. The activit of Rofenaid compared very favorable with that of the
aproved dose level of NF- 180. Avian Diseases, 1979;23(3): 682-687.
Porapnev, F. V.and Skuratovic& A. A. Sulfamonomethoxin and Sulfadimethoxin in
patients. Antibiotiki. 1973 ;18(5): 453-456.
Ames, T. R., Casagrand~ C. L.,a nd Werdi~ R.E. Effect of sulfadimethoxine-ormetoprim
in the treatment of calves with induced Pasteurella pneumonia. American Journal of
Veterinary Research, 1987;48(1): 17-20.
H. Information about dosage forms used:
Tablets
—
I.
Information about strength:
500mg
J. Information about route of administration:
Orally
K
Stability data:
Melts at about 201-203°
Storage stabilities (decay half-lives at -20° C) 567 days
Stable in fortified chicken liver and thigh muscle tissues during fi-ozen storage for 1 year at
-20 and -70 “C.
L. Formulations:
M. Miscellaneous Information:
—
Page -2-
.—
—_
Page -3.
.
OF ANALYSIS
CERTIFICATE
Sulfadimethoxine
S0359
Lot# GFO1
CAS# 122-11-2
.
Appearance:
White crystalline powder
Melting Point:
199°C
0
990/0
~-
Assay(tit.):
Clear (0.5/20, acetone)
Volubility:
Sd?Hu
_—.
B
*
qb
—
..
.
..
—
,--
/
-.
.
..
.
.
.
..:..-
.
...’ ..-.
.-’, .”-
.-.
QUALIW
—_
cHEMICAL
CONTROL
. : SULFADIMETHOXINE
=
MANUFACTURE
LOT
NO. :98 F0349
PHYSICAL
SPECIFICATION
TEST
l)DESCRIPTION
.:
WHITE CRYSTALS
~
2)SOLUBILITY
[email protected]
:Usp
FROM DILUTE
/(
3)MELTING
MELTS
/NF
_
/MART.
_
/cO.
SPECS._.
,E
.:
AQUEOUS
SOLUTIONS
OF
SODIUM
CARB-
POINT.:
AT ABOUT
4)SPECIFIC
201-203
GRAVITY.
5)IDENTIFICATION
PASSES.
TEST
_/Bp_/~RcK_
ALCOHOL.
DILUTE
HCL AND IN
SOLUBLE
IN
IN WARM WATER.
ONATE . SOLUBLE
__
REPORT
degree.
:
.:
FAILS .:
:
COMMENTS. :
ANALYST
SIGNATURE.:
PMPACK
TEST.
FUZTEST .:
.
DATE. :
DATE. :
:
DATE. :
INITIAL.
INITIAL.
:
:
.
------------------
IDENTIFICATION
------------------NAME SULFADIMETHOXTNE
PRODUCT #: S7007
CAS #: 122- I 1-2
MF: C12H14N404S
SYNONYMS
ABCID * AGRTBON * ALBON * 4-AMINO-N-(2,6-DIMETHOXY-4-PYRIMIDINYL)
BENZENESULFONAMIDE
* ARNOSULFAN * BACTROVET *
BENZENESULFONAMIDE,
4AMINO-N-(2,6 -DIMETHOXY-4-PYRIMIDINYL)(9CI) * DEPOSUL * DIASULFA *
DIASULFYL * DIMETAZINA *
2,6-DIMETHOXY-4-(P-AMINOBENZENESULFONAMIDO)
PYRIMIDINE * N(SUP 1)-(2,6-DIMETHOXY-4-PYRIMIDINYL)SULFANILAMIDE
*
DIMETHOXYSULFADL4ZINE
* 2,4-DIMETHOXY-6-SULFANILAMIDO-
1,3-DIAZINE *
2,
6-DIMETHOXY-4-SULFANILAMIDOPYRIMIDINE
MADRIBON
* MADRIGID
* MADRIQID
* DINOSOL * DORISUL * FUXAL *
* MADROXIN
* MADROXINE
* MAXULVET
*
-
MEMCOZINE * METOXIDON * NEOSTREPAL * 0MNB30N * PERSULFEN *
RADONIN *
REDmAL * ROSCOSULF * SCANDISIL * SDM * SDM() * s~~
* suLDI~
SULFADIMETHOXIN
* SULFADIMETHOXINE
* SULFADIMETHOXYDIAZINE
SULFADLMETOSSINA
———.
(ITALIAN) * SULFADIMETOXIN
*
*
* 6-SULFANILAMIDO-2,4-
DIMETHOXYPYRIMID INE * SULFASOL * SULFASTOP * SULFOPLAN
SULPHADIMETHOXINE
* SULXIN * SYMBIO * THERACANZAN *
------------------ TOXICITY HAZARDS ------------------RTECS NO: W09030000
SULFANILAMIDE, N(SUP 1)-(2,6-DIMETHOXY-4-PYRIMIDINYL)TOXICITY DATA
NIIRDN 6,386,82
ORL-RAT LD50:>20 GM/KG
ARZNAD 15,1441,65
ORL-MUS LD50:>I0 GM/KG
NHRDN 6,386,82
IPR-MUS LD50:866 MG/KG
NIIRDN 6,386,82
SCU-MUS LD50:791 MG/KG
NIIRDN 6,386,82
IVN-MUS LD50:844 MG/KG
NIIRDN 6,386,82
ORL-DOG LD50:>3200 MG/KG
NHRDN 6,386,82
ORL-RBT LD50:>1 GM/KG
NHRDN 6,386,82
IVN-RBT LD50: 1000 MG/KG
REVIEWS, STANDARDS, AND REGULATIONS
NOES 1983: HZD X2763; NIS 1; TNF 403; NOS 5; TNE4029; TFE 2015
TARGET ORGAN DATA
VASCULAR (BP LOWERING NOT CHARACTERIZED IN AUTONOMIC
*
SECTION)
SPECIFIC DEVELOPMENTAL
ABNORMALITIES (CRANIOFACL4L)
ONLY SELECTED REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES
(RTECS)
DATA IS PRESENTED HERE SEE ACTUAL ENTRY IN RTECS FOR COMPLETE
INFORMATION
------------------ HEALTH HAZARD DATA ----------------ACUTE EFFECTS
HARMFUL IF SWALLOWED, INHALED, OR ABSORBED THROUGH SKIN
CAUSES EYE AND SKIN IRRITATION
MATERIAL IS IRRITATING TO MUCOUS MEMBRANES AND UPPER
RESPIRATORY TRACT
MAY CAUSE ALLERGIC SKIN REACTION
TARGET ORGAN(S)
BLOOD
KIDNEYS
LIVER
FIRST AID
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVIDED PERSON IS
CONSCIOUS
CALL A PHYSICIAN
IN CASE OF SKIN CONTACT, FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES. REMOVE CONTAMINATED CLOTHING AND
SHOES. CALL A PHYSICIAN
IF INHALED, REMOVE TO FRESH AR IF BREATHING BECOMES DIFFICULT,
CALL A PHYSICIAN.
IN CASE OF CONTACT WITH EYES, FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES.
——-.
ASSURE ADEQUATE FLUSHING BY SEPARATING
THE EYELIDS WITH FINGERS CALL A PHYSICIAN
-------------------- PHYSICAL DATA -------------------APPEARANCE AND ODOR
SOLID
------------ FIRE AND EXPLOSION HAZARD DATA ----------EXTINGUISHING MEDIA
WATER SPRAY
CARBON DIOXIDE, DRY CHEMICAL POWDER OR APPROPRIATE FOAM.
SPECIAL FIREFIGHTING PROCEDURES
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES
UNUSUAL FIRE AND EXPLOSIONS HAZARDS
_—_
EMITS TOXIC FUMES UNDER FIRE CONDITIONS
------------------- REACTIVITY DATA ------------------INCOMPATIBILITIES
STRONG OXIDIZING AGENTS
MAY DISCOLOR ON EXPOSURE TO LIGHT
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
TOXIC FUMES OF
CARBON MONOXIDE, CARBON DIOXIDE
NITROGEN OXIDES
SULFUR OXIDES
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS REL.EASED OR SPTLLED
WEAR SELF-CONTAINED BREATHING APPARATUS, RUBBER BOOTS AND HEAVY
RUBBER GLOVES
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
—.
AVOID RAISING DUST
VENTILATE AREA AND WASH SPILL SITE AFTER MATERIAL PICKUP IS
COMPLETE
WASTE DISPOSAL METHOD
DISSOLVE OR MIX THE MATERIAL WITH A COMBUSTIBLE SOLVENT AND BURN
INA
CHEMICAL INCINERATOR EQUIPPED WITH AN AFTERBURNER AND SCRUBBER
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS.
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --WEAR APPROPRIATE NIOSHM4SHA-APPROVED RESPIRATOR
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE CLOTHING,
MECHANICAL EXHAUST REQUIRED.
HARMFUL BY INHALATION, IN CONTACT WITH SKIN AND LFSWALLOWED,
IRRITATING TO EYES, RESPIRATORY SYSTEM AND SKIN.
MAY CAUSE SENSITIZATION BY SKIN CONTACT,
IN CASE OF CONTACT WITH EYES, RINSE IMMEDIATELY WITH PLENTY OF
WATER AND SEEK MEDICAL ADVICE
WEAR SUITABLE PROTECTIVE CLOTHING
DO NOT BREATHE DUST
TARGET ORGAN(S)
BLOOD
KLDNEYS
THE ABOVE INFORMATION IS BELIEVED TO BE CORRECT BUT DOES NOT
PURPORT TO BE
ALL INCLUSIVE AND SHALL BE USED ONLY AS A GUIDE SIGMA ALDRICH
SHALL
-
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
Sulphadiazine Sodium/Sulphadimidine
,5 ~1,
water
to
5 ml.
Dose.
Sulphadiazine,
150
to
~g Fr k8 body-weight daily in four 6-hourly dm~,
~azim T,bkta (B.P.). Tablets containing srdphadprotect from light.
1
#etsfl
Pharmacopoeias.
White
or creamy-white,
ctdourims or almost
odourkss, hygioscopic crystals or powder with a
bitter alkaline
taste. It slowly discolors
and
decomposes on exposure to light: on exposure to
air it absorbs carbon dioxide and becomes less
soluble in water. Sulphadimidine
sodium 1.08 g is
of the
infection,
followed by a dose of
1 g daily. A suggested dose for children is
30 mg per kg body-weight
initially,
followed by
one-half
this amount
review
avadable
of
(both
in
z
&Dlmethoxypyrlmldln-4-yl)sulphanilamide.
,,N,O,S=310.3.
Fr., [t., Jug.. and
Au.stral.,
~
Nerd.
~
[email protected]
TrerstmenGsand Precsssstioasa.As
‘b Sulphonamides, p. 1457.
If side-effectsoccur, suiphadimethoxine has the
&sdvanw&
that
several
days
are required for
k elimmat]on from the body. The Stevens-Johns syndrome has been reported following the use
~ wlphadimethoxine.
~
on the blood. Sulphadimethoxine
bas been
cause haemolysia
in patients
with
haemogloE.
Eeuder,
~ti$.
A Wient
[email protected]
g~nulomatw
reactions
& tba liver and lymph
nodes, with
fever, skin rash,
#cc,
and interstitial
pnersmonitis,
2 days after the
titration
of 2 g of sulphadimethoxine
by mouth.
b made a full spontaneous
recovery within 3 we&s.—
~R. Espiritu et a,., J. Am. med. Ass.. 1967, 202, 98S.
kmcfious.
For the effect
doting protein binding
of
x Chlorpropamide,
p.853.
of sulphadimethoxine
in
sulphony[urea
compounds,
k’ the poasiblc effect
of srdphadimethoxine
~life of tolbutamide,
see Tolbutamide,
p.860.
~.tion
on
is not
see Sulphamethox-
Protect
Tablets
light.
from
Be*gT&(ad.,
Dcrmt..
containing
i+..
the
and Fate. As for Sulphonamides,
sul-
available
aa
as Madribon
Ger.,
[tai.,
Sulfathox:
Spain--
Dimetoxan,
Oxazlna,
Sss1 hadimidine
(B. P.. B.P. Vet,, Eur. P.]. SUIpha ! lmid.: Sulfadimidine;
Sulfadimidinum;
Sulphadimethylpyrimidine,
Sulphamethazine;
Suifamethazine (U.S.P.); Sulfadim.5razine;
SuIfadimezinum; Solfametazina.
Ni-(4,6-Dimethy
[pyrimidin-2- yl)sulphanilamide.
C12H14N402S=278.3.
CAS — 57-68-/.
NOTE. Sulfadimethylpy
rimidine has been used as
a synonym for sulphasomidine (see p. 1483). Care
should be taken to avoid confusion between the two
compounds. which are iaomeric.
Pharmsrcopocios.
In Arg.. Aust., Br., Chin.. Cz.. Eur.,
Fr.. Ger.. Hun ., [rd.. Irrt.. II., Jug., Neth., Nerd., Po[..
Rorsm., Rus., ~wiss, Turk., and US.
White
or yellowish-white,
odour]ess
or
almost
odourless, crystals or powder with a s[ighlty bitter taste.
M.p.
197° to 200”. It darkens and
decomposes on exposure to light.
Ve~ slightly soluble in wate~
soluble 1 in 200 of
boihng watec soiubie 1 in 120 of alcohol. 1 in 30
of acetone, 1 in 600 of chloroform,
and 1 irv
2500 of ethev soluble in dilute mineral acids and
in aqueous solutions of alkali
hydroxides
and
carbonates.
Sulphadimidine
may be sterilised by reducing to
a fine powder, drying at 100”, and heating in the
final sealed containers so that the whole of the
powder is maintained
at 150” for 1 hour; the
sterilised powder is not more than slightly discolored.
Store in airtight containers. Protect from
light.
~hadimethoxine
is readily absorbed from the
Pa-intestinal
tract. After a single dose of 2 g
&blood
cone entrations
are reached
in 4 to 6
after 24 hours are sti]] at
IX, concentrations
half the original value. About 90% of sulh
hdimethoxine
is bound to plasma
albumin.
&t
10% of sulphadimethoxine
in the blood ia
FWrt as the acetyl derivative and rather less as
~ ducuronide. Penetration
into the cerebrospi? fluid is cam.
Wphadime{hixine
is excreted
slowly
in the
.?& about half of a single dose being recovered
a ~ hours; abut 8070 is excreted in the form of
J tdstiveiy highly soluble glucuronide, and about
& as the acetyl derivative.
Sulphadimethoxine
M its acetyl derivative
are poorly soluble in
b.
Mention of changes in dissolution-rate
and equilibrium
volubility
of
the
hydrophobic
drug
sulphadimidine,
brou ht about by the presence of hydrophilic
polymers,
pow “Jone and
carmelloae
sodium,
in the dissolution
Pharm. J.. 1978. 2. 249.
medium.—
& ~dogicsl half-life
of sulphadimethoxine
is variously
~
as 20.2 to 41 hours.—
W, A, Ritschel,
Drug
~1. & c/in, pharm.,
197o, 4, 332.
A study on the formulation
and evaluation
of a sulphadimidine suspension for infants.—
R, N. Nasipuri
and E,
Pharm. J., 1978, 2.258.
0. C)gunlana,
~dimethoxin.
we
tissue in
was
about
73.2%
vitro,— B. Fichtl
* pharmuc., 1978.14.335.
and
bound
H.
to
Kurz.
The
effect
of formulation
absorption
of sulphadimidine
et al., J. Pharrrr.
Oudrzhoom
and compression
tablets.—
M, C.
on
B,
...
4934-d
%lphadimethoxine
is a [ong-actin
~ide, with the general properties o f :$:::
@tides, p. 1458. With usual doses the blood con%tion
of “nConjugated
suiphadimethoxine
Sulphadimidine
Sodium (B. P., B.P. vet.).
Sulphadimid.
Sod.; Sulfadimidine
Sodium;
Soluble Sulphadimidine;
Soluble Sulphamet!tszirr~ Soluble Sulphadimethylpy rimidine.
% ~ maintained
k“ Inmal
dose
CAS
&
L
—.
at
is
50
I
——
to
or
100
2 g,
~g
per
according
ml.
to
the
the
van
Pharrrrac., 1971, 23, 583.
human
Eur. J.
approximately
equivalent
to 1 g of sulphadimidine.
Soluble I in 2.5 of water and 1 in 60 of alcohol.
A 10% solution has a pH of 10 to 1I. Solutions
are most stable at pH 10 to 11; precipitation
of
sulphadimidine
occurs
below
pH 10. Solutions
are steritiaed by distributing
into ampoulea,
replacing the air with nitrogen or other suitable
gas, sealing, and autoclaving, or by filtration into
sterile ampoules in which the air is replaced by
nitrogen or other suitable gas. Incompatible with
acids, iron salts, and salts of heavy metals. Store
in airtight
containers. Protect from light.
see
Other Proprietary
Names
Arg.—Lentera ;
Denm -SulfOplan;
Chemiosalfa, /rozinaL behin, Diasuifa, &\X~##~~
toaailina, Fultamid, lperaulfa, Leviaul, Micromcga,
Neo-
or creamy white, almost odourlcss,
[ pamulph,
@ss, crystalline powder. M.P. 198” to 204”.
&lf-reten
soluble in waten soluble 1 in 200 of
Im slightly
tihol. 1 in 800 of chloroform.
and 1 in 2000 of
&
soluble in dilute mineral acids and in solu~ of alkali hydroxides and carbonates. Protect
4933-f
~ light.
b Zitrtch (an unstable
haemogiobin).—
&rmac. Rsv.. 1969, 2!, 73.
al.,
sulfamyd,
Redifai,
Risulpir,
Ritarzulfa,
Sulfabon,
Sul.
fadomus,
Sulfaduran,
Suifastop,
Sulfomikron,
Tem~
diazina:
Po/.—Madroxinc.
S, A~r.—Jatsulph.
&nsulpha,
~ white,
@to
et
S. A~r., Spain, Swed., Swifz.).
1
122-II-2.
Br.,
of leprosy,
(Roche, UK). Sulphadimethoxine.
Madribors
scored tablera of 5013 m
(Also available
&hadimethoxine.
.%lfadimethoxine: SOL
l&@ssina .Solf?d[rnetossipirimidina. N’-
In
Weinstein
clinical reporrs on su[phadimethoxine.
27tkI Edn, p. 147
phadimethoxine.
#j2-r
~copoems.
Martinda[e
L.
Med..
1960.263.842.
an opinion that sulphadimethoxinc
/+
Preparatiossa
SuIpklhnethoxkreTablets j13.P.J.
‘
.
$!
&–
daily.
sulphadimethoxine.—
suitable for the treatment
ypyridazirre,
p. 1480.
For earlier
&,~~~!~~?r.~~~v?f~u!!~~-ti#z~ne
@raf.).
In Aurt., Br.. lrrd.. Pol.. and Turk.
severity
Preparations
e Per ml~ m ampul~
Of 4 ml. (AIso
~~diazine
sodium m Au$fra[.).
.
,
,SdP
1475
0.5 to
Sadi uos (.MCZY.-4 Baker, UK). Available
a~~cw
Engl. {.
tiprosy.
For
II containing,
the equivalent
Of 2S0 m8 Of, sul-
y
Sodium
C[2HlJN,Na02S=q00 .3,
—
198 I -58-4.
fncompwtibility.
A haze developed over 3 hours when
amiph~na~o]e
sulphadimidine
sodium
was mix~
with
hydrochloride
in sodium chloride
injection.
An immediate
precipitate
occurred
with chlorpromazine
hydrochloride,
promazine
hydrochloride,
promethazine
hydr~
chloride, and a yellow colonr with a precipitate
developing over
3 hours occurred
with
bydrslazine
hydro.
chloride
in dextrose injection
or sodium chloride
injection. An immediate
precipitate
occurred when sulphadimldine sodium was mixed with prochlorperazine
mesyIate in sodium chloride
injection,
but when they were
mixed
in dextrme
injeetion
a haze developed
over 3
228.
hours,–B. B. Riley, J. Hosp. Pharm.. 1970.28,
Adverse
[email protected]
Treatnrearq
and Precautions.
As
for Sulphonamidea, p. 1457.
The Stevens-Johnson syndrome has been reported
after treatment with sulphadimidine.
Sulphadimidine and ita acetyl
derivative
are relatively
soluble in urine; the risk of crystalhsria is therefore slight, but adequate fluid intake is recommended.
Sulphadimidine
sodium should not be given intrathecally or subcutaneously,
intramuscular
injections are painful.
Effects on tlsc blood. A 7-year-old boy developed acute
haemol tic anaemia
following
a total dose of 28 g of
sulpha c?”
Imtdme given over a period of 5 daya. Recovery
occurred after treatment
with blood transfusion,
prednisone, and
penicillin
intramuscularly.
H
rather than a direct baemolytic
action waa %!:%”’:
the cause.— J. L. Grech and E. A. Cachia, Br. med. J.,
1959, 2. 1309.
EJ’@rs on tke hears
A 12-year-old African boy developed a fulminating
skin Ieaion 2 daya after sulphadlmidine therapy
(6 g in 2 days) and acute cardiomyopathy
28 days later. The cardiomyopathy
was considered
most
likely
to be a hyperaerssitivity
reaction
to suIphadimidirre.—
E. T. M. MacSearraigh
and K. M. Patel, Br.
med. J., 1968, 3, 33.
So/nbifity
iu crris.c. The solubilitiea of ssdpbadimidine
and its acetyl derivative
in urine at 37” were 692 and
670 pg per ml respectively at pH 6, 752 and 864 # per
ml at pH 6.4, 833 and 907 M per ml at 6.8, 997 and
1140 ~g per ml at pH 7.2, 1.445 and 1.762 mg Wr ml
at pH 7.6, and 1.793 and 2.16
mg per ml at pH 8.—
L. H, Schmidt
et al., J. Pharmac. exp. Ther., 1944, 81,
17.
Absortrtion mad Fate. As
for Sulphonamides,
p.1458.
Sulphadimidine
is readily
absorbed
from
the
gastr~intestinal
tract and about 60 to 80% is
bound to plasma albumin. It penetrates into the
cerebrospinal fluid, but less readily than sulphadiazine; concentrations of sul hadimidine in body
fluids may be more than ha] f those in the blood.
Abast
40% of sulphadimidine
in the bled
is
present as the acetyl derivative. About 50% of a
dose may be excreted in the urine in 2 days, 70%
being in the form of the acetyl derivative.
A
study
of
tbe
$ulphadimidine.—
kinetics
G.
L.
of
the
Turin
intestinal
e{ af.,
absorption
of
Clirr. Phanvrac,
Ther,. 1966.7.603.
Sulphadimidirre
~bleta,
50% of which dissolved
minutes in vitro, were given to 9 subjects in a
and gave average
serum
concentrations
of
acetylated
suiphadimidine
at 0.5, 1, 4, 10, and
in 1 to 5
3-g dose,
free plus
24 hours
Sulfenazone/Sulphafurazole Diethanolamine
Belg.: Trimmim; Canad.: Coptm: Ovcquinol$; Trisulfamimc;
Fr: Anuima: Gtic: Bisolvommid+: Dihcn-amidt: Niwofuramoin
camp.+: Sagin~mtdt; Spasmc-Urocleti: StennonSutfa-Ozmtrint; Sulfa-Um-T~blinent:
SutbUrotong*:
wdlbpecucepl~: Tri globe; Uroclear;
Urospasmon:
L1ro\pasmon
sine: [Iul. :
Chemiows?; Geomix?: Komhimcx: Oxo$int: S[erinor; Sulfmh’imm: Tibirox; SAfr: Tersulpha+; Triwtpha+: .spain: Bio Hubbcc
Bio Hubber Fuerce; BioHubherSimplet; Bronco A.scp[ilex: Bmncomlcin Bds+; Triglohe: SnwJ.: Tnmm wdfx .SWI: : Uro~pa%mon: L!TA:Neomzmer, Triple Sulfa No. 2.
imicrobial Action
~:
&or
.,
Wphamethox=o,e,
,.,,,.
~hWmacokinetics
Su]phariiazineis re2dilYabsorbed from
intes[lnoi tract. pelk
[he gttstroblood ~oncentratlons
being
~~hed 3 [o 6 hours ufter a single dose; 20 to 55%
~ been reported to be bound to plasma proteins, It
into the ce,rebrosp!nal fluid to produce
~netra[es
~mpeutic concentrations, which maybe more than
Sulphadimethoxine
~f of [hose m the blood, within 4 hours of zdminbmtion bY mouth. fJp [O 40% of sulphitdiazine
in
~e blood is present as the flcetyl derivative.
Sulphadimethoxme
Solfadimetossina:
(riNN).
~UL
50% of a single dose of sulphadiazine gwen
by mouth is excreted in the urine in 2-I hours; 15 to
~
unnzuyexcetiOn Of sutphadi~zi?emd tie [email protected]
CAs —
= 3103.
/22-11-2.
‘
bcrrs.
I. vi-cc TB. e! al. Dctermtnat!on ot
the acetyktor ph.amvpe and
@rmiicol.,netlcs of somewlphonamrdesIn man. C[in Phur.
IW): 5: ?7’$-94.
>f
Sulphadimethoxine
is a long-acting sulphonamide
with propenies similar ro those of sulphamethoxa-
mine
initial
dose is 1 or 2 g, according
the infection. fo=y
to [he severity
a dose of 0.5 to 1 g dai-
Uses and Administration
Iv.
~lphadiazine is a short-acting sulphonamide which
‘
Pharmacotdnetics.
A study of the harnmcokinetics of scdf
fM.Sbeen used similarly to sulphamethoxazole (see
ph~dimethoxine and its mecabolites.
due to S.uSCepri-/A
V,U TB, d, d Phmmacokinetics. N 1.elucuronida[lon and !44D.282) in the treatment of lrtfeCtiOM
ide
It has been used in the treatment
--- ormnisms.
_
orxrrdiosis and lymphogranuloma
b been given for the prophylaxis
of”-
~er in penicillin-allergic
patienrs. For details of
these infections and their treatment see Choice of
Antibiotic, p. 133. Sulphadirczine is also given with
~methamine for the treatment of toxoplasmosis
(see p.612).
la the treatment of susceptible infections sulphadiazine may be given by mouth in usual doses of 2 to
4 g followed by up to 6 g daily in divided doses, [email protected]@r up ro 8 g daily has been suggested for toxo: plasmosis; a suggested dose in children is 75 mg per
g. kg body-weight initially then 150 mg per kg daily in
: divided doses to a maximum of 6 g daily, A concen~~ ~on
in the blood of lt3fI to 150 ~g per”mL is desir-
~,” die. For the prophylaxis of rheumatic fever,
& ptients weighing less than about 30 kg are given
~ nrg once daily, while those over 30 kg may re‘.” CCrve1 g once daily.
“ Sdphadiazine is also given intravenously as the so:
&rt
“’
~’
:
salt. The usual dose is the equivalent
of sul-
~iuine
2 to 3 g initially, followed by 1 g four
daily for 2 days: subsequent trearment is given
& mouth. Children over 2 months of age may be
~~
the equivalent of 50 mg per kg initially,
bwed by 25 mg per kg four times daily.
‘“ &venous
p
doses
by infusion
Wdon
of sulphadiazine
or by slow
containing
Up to
sodium
intravenous
5%. It maybe
foi-
are giv-
injection
~ Wml care must be exercised to prevent damage
b mbcutaneous tissues and the intravenous route is
~ferred.
h the use of sulphadiazine with trimethopnm, see
c~~mazine.
p,2 17. Sulphadiazine has also been
;
L
Pm
*IY
*
in Wsociation with other sulphonamides,
sfdfamerazine and sulphadimidine,
tie problems of low solcsbility in urine.
parto re-
PrePmlirms are listed helmv: detmls we given in PWI 3.
%
‘mPaf’atiorrs
“%3”
Sulphtrdiazinc fnjecclo”:
*2f’sUlfad,~zl”e
so~i”m [njcc[lon.
%mdine,
&%&2
~
.?~.~’:
:z::~”.
,:
OraI S“,PC”,,O”:
S.[fadiaz!ne
Trisulfapynmidines
Tubie[s: Tri.
TableI>.
prepar,tio”g
...
~d;ent
preparations.
AU,W; Biso[vonamid. OphciIRhino”: Trig~obe: UroSpa~mo” >ine phmrazopyridimx
‘?%mbOl
acetylator
Preparations
Niurws of prepanuiom are Iisoxt below. dctmi, are given !n Pan ;
Officiat Pmpamtiocrs
BP 199.1:Paediarric Sulptmdimidine Oral ‘%pemlon: Sulphxdimidine rnjection: Sulpfmdimidine Tablets:
USP Y
Trisulfapycimldines Oral Su,pcnwon: Triwlfapyrimi.
dines T~biets,
Proprietary
Eiw
Prepamtfocss
UK Sutphanre?o[h]ne+
Sulphamezmhinc;
Muiti.ingrectient
preparations.
Cumuf Triwlfaminic;
Terwiphm: USA: Neouiz.tnet; Triple Suli2 So. ?.
—
Sulphafurazole
rue Iis[ed bctow; dccmls arc given in Pan
Proprietary
Preparations
/M/.. Chemiovdrfi+: Oelri n+: Riwtpirt:
SulfaStop+: s.Afz, Sulfadmxt.
Rimrsulrat:
3.
Sulfadrmt:
Sulphafumzole
(8AN).
Sulfafurazole
(p/NN);
CAS —
(rfNN);
(+n-r)
mldme: Sulphameckme.
+d
eno[cs a preparation
no longer acuvety
Sulfisoxazole:
Sulfamedrazme;
Sulfadim!dme
Sulphadimerhylpyn-
N1 -(4,6 -Dlmethylpynmldin
-2-yl)sul.
= 278.3.
KXS — 57-68-1.
= 267.3.
127-69-5.
.+., &r.,
k.. )pn. Neth., fbn., SWISS.
A white
c~sr.ds.
or yellowish-white,
odourless crystalline
Acetyl Sulphafrmuole
Pharmacopo.ms
In Ausc., Belg., Br.. Chin., Cz,. Eur., Fr., Ger.,
Hung., Int., ft., Nerh., WC.. Swss, and US.
Dimechylisoxszol-S-yl)-N-sulphandylaceramlde.
of Pft Eur. apply to chose countnes rhat are par-
ties to the Convenwm on the Elaborauon of a European Pharmacopoeia, see p,xtii.
White or yeilowlsh-white,
almost odourless, crystals or pow.
Vety slighdy soluble in wmec sotubte in acetone: slightly soluble in alcohol: very slightly soluble to pmcticatly insoluble
in ether ic dissolves in tillute mineral acids and in queous
solutions of Wcdi hydroxides. Pmteet from light.
Sulphadimldlne
Sodium
(.wwd)
Sodwm (BANM),
Soluble Sulphadlm{dmq
Sulfad!mldine Sodium
Sulfamerha.zme
Sodium.
C,2H13N4Na02S
= 300.3.
CAS –. 1981-58-4.
Pharmacopoems. In Ausr., Br., G..
White
or creamy -wbi[e.
and km
odoudess or almost odoudess.
hy -
goscoplc crystals or powder. 1.08 g of monograph substance
M approximately .equwolem to I g of sulphadimidine,
Freei y sohsbte in wtter spmingly soluble in atcohol.
solution hm a pH ot’ 10 m i 1. Protect from Iigbt.
A t O%
Sulphadimidine is a short-acting stdphonamide with
similar properties to those of sulphamethoxazole
[see p.280).
It is well absorbed from the gastro-intestinal trnct
and about 80 to 905Z0 ha.. been stated to be bound to
plasma protein. Reported
half-lives
have
ranged
from 1.5 to -! hours in fasr and 5.5 to 8.8 hours in
slow acetylators. Because of [he relatively high vol-
marketed
m
Sulfisoxazole
Aceryi.
C11H,5N304S
CAS –
(4937 ml
N1-Aceryl
Sulphafurazole:
N-(3,4-
= 309.3.
80-74-0,
.VOIE Aceryl sulphafumzole is 10 be distinguished from [he
@-acetyi derivative formed from sulph&&zole
by conjuga-
tion in the twdy.
der. It darkens on exposure to light.
Sulphadimidine
powder
Soluble t in 7700 of water, I in 10 of boiling afcohol: sparorgly soluble in alcohol: slightly soluble in dichloromethmre
and in ether it dk.solves in solutions O( dk.ali hycfroxldes and
in dilute mineral acids. Store in airtight contoinem. Protec[
from light.
WOTS Suifadlmechylpy rimidirw has been used as a synonym
for sutphasomldine \ p.?t33). Care should bc taken to avoid
confusion between the two compounds. which are isomeric.
The standads
Sul-
S-yl)sulphandamlde,
and US.
phandam!de.
C, ZH,4N,02S
Sulfafumolum:
Phcrrmompoeios In &.. G..
Sulfadtmemzme: %lfadinwzmurn
Sulfadimldinum:
(4936-h)
phafuraz. N’ -(3.4- DimerhyllsoxazolC, IH,lN1OIS
Sulphadimidine
Scdphadim,dlne
@4N).
S.A/K.
WreMI (st)
Preparations
Names of prepwmom
Solfametazmz
status.
Compounded pseparacions of etyduomycm eth y] succina[e
(etythromycin erhylsuccina[e) and acet> I wlphafurazole
(suh%oxazole xetyi) in USP ’23 may be represented by the
name [email protected]
Pharmacopoeias In US.
A white to stightly yellow crystalline Puder,
1,16 g of monograph subsrance is approximately eqm~ dent to I g of d.
phafurazote.
Practically insoluble in wa[en soluble 1 m ~bou[ 180 of alcuhol, I in 35 of chloroform, t in bout 2CQ of methyl atcohol,
wrd t in ~bouc 1100 of ether, Store in acrughr conjoiners, Protect fmm light.
Suiphafurazole Diethanolamine
NU-44S:
Sulfafutazole
Diolamme
olamme (USAN); Sulphafumzole
~wja.b)
(plNNML
Dtoiamme.
Sulfisoxazole
D!.
The 2. K!mmobi
-
sethanol salt of sulpi-r+fumzole.
C, ,H11N103S.C4H,
%~tions
‘Of
~ulf~Xmeth0x8ne m nr~n. Phurm
[990,12:51-9.
of a
diluted with
~urft chloride 0.9% injection, Stdphadiazine sodi~ has been given by deep intramuscular injection
.
acwl~l)on Of
venereum, and
of rheumatic fe-
In the treatment of susceptible infections sulphadimidine has been given by intravenous or deep intmmuscuktr injection as the sodium salt, in usual doses
of 3 g initially, followed by 1.5 g every 6 hours.
Children may be given O..: to 2.5 g initially, depending on age. followed by half the initial dose every 6
hours. Sulphadimidine
has been given in simihsr
doses by mouth.
Because its phartmrcokinetics differ in fast und slow
acetylators, stdphadimidine has been used to deter-
The
<<
.J
sulphamethoxazole.
Phormacopoems. In Fr. and IL
zole (see p,280). h is readily absorbed from the gastro-intestinal tract. and about 98 to 99% is bound to
plasma proteins. Half-lives of about 30 to 40 hours
have been reported.
ti urine is ~lk~hne. The haIf-life Of sulphadia~ine
ranges
tjom 7 to 12 hours and [hat Of irs metobolite from 8 to 12
ubility of the drug and its acetyl metabolize crystalIuria
may
be
less
likely
than
with
Stdphttdimidine has also been used with trime[hoprim similarly to co-trimoxazole {p.2 19) and in association with other sulphormmides, particultirly
suifi~merazine and sulphadiazine.
$ulfadimethoxine
l)sulphandamlde.
denva-
ovc is dependen[ On PH. AbOu[ 3~70 E excreted unch~ged
in
LUMJIfm and S1OW~cetYlato[s when Che umre M ~cidic ~h~re~ about 75% is excreted unchanged by slow zcetylictors when
~cokincr
Sdfadimecosslprimldma.
N1 -(2,6 -Dlmethoxypynm!din-4-y
C,2H,4N40,S
M% is excreted as the acetyl derivative.
(4932-r)
(8AM.
279
,N02
= 372.4.
CA5 — 4299-60-9.
Pharmacopoeias. In US.
An odourless, white [o olT-whue, tine. crystalline powcfer.
1.39 g of monograph substance M appro~lma[ety equivalent
to I g of sulphafurazole.
Sotuhle
mfoms.
1 in 2 of water, I in t6 of atcohoi. t in !000 of chlcr1 in 4 of methyl alcohol, md I in 250 of isopropyl
alcohol: practicably imolccble its ether. Store
tainers. Protect from light.
in ainight
cm-
the sublimate with a glass rod and mix it in a test-tube with
1 ml of a 5 per cent w/v solution of resorcfnol in alcobof.
AM
1 ml of stdphun”c acid and mix by shaking; a deep
red colour appears at once. Cautiously dilute the mixture
with 25 ml of ice-cold water md add an excess of dilute
ammonia solution; a blue or reddish-blue colour is
produced.
(E) It melts
Appendix 5.11.
at about
255°
with
decomposition,
of 1.0 gin a
Clarity and CO1OWof solution : ~solution
and 15 ml of
mixture of 10 ml of N sodium [email protected]
wafer is clear and the colour is not more intense than that
of 25 ml of mixture of 1.45 ml of~enic cblori& C.S., 0.03
ml of cobalt cblon”de C.S., 0.03 ml of copper sulPbate
C.S. and sufficient water to produce 100.0 ml.
Acidity : Heat
1.0 g with 50 ml of carbon dioxi~-fme
water at about 70” for five minutes, cool quickly to 20° and
filter; titrate 25 ml of the filtrate to pH 7.0 with 0.2 N
sodium hydroxide; not more than 0.1 ml of 0.1 N sodium
hydroxide is required.
Heavy metals : Not more than 20 parB per million,
determined on 1.0 g by Method B, Appendix 3.2.4.
Chloride
: I g dissolved
by
warming
in5
Identification
: (A) Triturare a quantity ofthc powdered
tablets, equivalent to about 0.5 g of Sulphadiazine, with
IWrOsuccessive qumtities of> ml of cblomfomz and reject
the chloroform. Triturate the residue with 10 ml of dilute
ammonia solution for five minutes, add 10 ml of warer
and filter. Warm the filtrxe until most of the ammonia is
expelled, cool, and acidify w“ith acetic acid. Collect the
precipitate, wash with water, and dry at about 100°; the
residue has z melting range between 252” and 256’;
.kppcndix 5.11 and complies with Identification tests
(A) to (D) described under Sulphadiazine.
Other requirements : Comply with the requirements
stated under Tablets.
Assay : Weigh and powder 20 tablets. Weigh accurately a
quantity
of the powder
equivalent
to 0.5 g of
Sulphadiazine and dissolve as completely as possible in a
mixture of 50 ml of water and 10 ml of Lydmcblon’c
acid. Carry out the nitn”te titration, Appendix 3.3.4, Each
ml of 0.1 M sodium nitn”te is equivalent to 0.02503 g of
CIOHI~N402S.
Storage : Store
in well-closed,
tainers.
light-resistant
con-
ml of nit~i~
acid and 5 ml of water, complies with the limit test for
cbion”ak, Appendix 3.2.2.
Sulphate :1
g
dissolved
by warmingin 5 ml of
Lydmchbic
acid and 5 ml of water, complies with the
limit test for stdpbates, Appendix 3.2.8.
Sulphated ash : Not
Wlphadi.methox.ine
morethan
0.1per cent, Appendix
3.2.7.
/
0CH3
Loss on drying : Not more than 0.5 percent, determined
on 1.0 g drying in an oven at 10Y, Appendix 5.8.
out
Assay : Carry
Succinylsulphathiazole.
equivalent to 0.02503
the
Assay described
under
Each ml of 0.1 M sodium nitn”te is
g Of CIOHION402S.
storage : Store in
weI1-closed,
light-resistant
containers.
Mol. Wt. 310.33
ClzH1qNiOJ
Category:
Antibacterial.
Dose : ktitial dose, 1 to 2 g; subsequent doses, 500
mg daily.
%lphadia.zinc
Tablets
Category: fitibacterial.
Dose : Sulphadiazine, initial dose, 3 g; subsequent
doses upto 4 g daily, in divided doses.
Usual
strength
:0.5
g.
Standards : Sulphadiazine
Tablets
contain
not
andnotmorethan105.0
per
less than 95.o per cent
llescription : Whiteor crearnywhite,
crystalline
powder;
almost
odourless;
tasteless.
Volubility: Very slightly
soluble
inwater;
slightly
indilute
mineral
acids
soluble
inakobof; soluble
and in solutions
of alkali
hydroxides
and carbonates.
Standards
:Sulphadimethoxine
isN’-(2,6-dimethoxypyrimidin-4
-yl)
sulphanilamide.
Itcontains
notless
than99.0 per cent of C1J314N404$cai~lated with reference to the dried substance.
centof the stated
amount of Sulphadiazine,
Identitkdon
CIOH,ON,O,S.
: (A) The infra-md absorption spectrum
exhibits maxima which are only at the same wavelengths
491
SULPHADIMETHOXINE
as, and have similar relative intensities to, those in the
spectrum
of sulpbadimetboxine
R S., Appendix 5.15 B.
Sulphadirnethoxine
about 0.1 gin 3 ml of sodium bydmxide
solution
and 50 ml of water and dilute to 100 ml with
water. To 5 ml add 100 mg [email protected]@zoL ~d heat to boilifrg.
solution
and a
Cool, add 0.5 ml of sodium bypocblorite
few drops of sodium bydmxide solution; a yellow CO1OUI
is produced.
Category:
Antibacterial.
DOSe:Sulphadimethoxine;
initial
dose,1 to2 g;
subsequent
doses
500mg daiiy.
Usual strength: 500mg<
Standards
:Sulphadimethoxine
Tablets
contain
notless
than95.0percent
andnotmorethan105.0
per cent of the statedamount of Sulphadimethoxine,
C12HIJN404S.
(B) Dissolve
(C) It gives the reactions ofpn”mary anmn.atic amines,
giving
anorange-red
precipitate
Appendix 3.1,
(D)Suspend
about
20mg in5 mlof
water and add
until completely dissolved.
Add a lkw drops of coppersulpbate solution; the solution
turns yellow, and a yellow precipitate is formed.
sodium
bydmxia%
Melting
range
solution
: Between 1!97”and 204°, Appendix 5.11.
Tablets
Identification : Triturxe a quantity of the powdered
tablets equivalent to 0.5 g of Sulphadimethoxine
with 5
ml of 0.5 N bydmcldm”c acid; filter, and neutralise the
filtrate to iitmuspaperwith 0.5N sodium bydmm”de. The
precipitate afier washing with water and drying at 105°,
Related
substances : Carry out the method for thinmelts at about 20 1“, Appendix 5.1.1, and complies with
layer cbtumutograpby, Appendix 5.4.3, using silicagelH
rhe ldentifk.atioa
tesrs described under Sulphadimeas the coating suhstanee and a mixture of 20 T’olumes of
thoxine.
cbiomfom, 2 volumes of methylalcohol and I volume
of dimetbylformamia% as the mobile phase. Apply
Other requirements : Comply with the requirements
separately
to the plate 10 @ of each two solutions in a
stated under Tablets.
of alcohol and 1 volume of sttvng
mixture of 9volumes
Assay: Weighand powder 20 tablets. Weigh accurately a
(1) 0.25 per cent w/v of
ammonia solution containing
quantity of the powder equivalent to 0.5 g of Sulphathe substance being examined and (2) 0.00125 per cent
dimethoxine and carry out the nittite titration, Appendix
w/v of sui’pbanikunide R.S. After removal of the plate,
3.3.4. Each ml of 0.1 M sodium niftite is equivalent to
allow it to dry in air and spray with a 10 per cent v/v
0.03103 g of cizH141’J404s.
solution of sulpbun”c acid in aicobol, heat at 105° for 30
Storage: Store in light-resistant containers.
minute-s, and immediately expose to nitrous fimes in a
[nitrous
fumes
maybe
closed glass tank for 15 minutes
generated
byadding sulpburic acid 60 per cent w/w)
dropwise to a solution containing
10 per cent w/v of
sodium
nitrite and 3per
cent
w/vofpotassium iodide].
Place the plate in a current of warm air for 15 minutes and
spray witha 0.5 per cent w/v solution of N- (1-napbtbyf)
etbyi.enediamirw bydmcbloride in alcohol. If necessary,
allow to dry and repeat the spraying. my spot in the
ehromatogram
obtained with solution (l), other than the
Sulphadimidine
principal
spot,
&romatogram
is not more intense than the spot @ the
obtained with solution
(2).
Heavy metak
determined
by
dissolving 1 gin
20 ml of water,
: Not
morethan20
parts per million,
Method A on a solution prepared by
5 ml of sodium bydmxide solution and
Appendix
3.2.4.
c,~H14N40J
Loss on drying : Not more than 0.5 percent, determined
on 1.0 g by drying in an oven at 105°, Appendix 5.8.
Sulphated
3.2.7.
aah : Not more than 0.1 ~r
cent, Appendix
Assay : Weigh accurately about 0.5 g anct carry out the
nitn’te titration, Appendix 3.3.4. Each ml of 0.1kf
sodium rzitn’teis equivalent to 0.03103 g of C1zH14N~04S.
Mol. Wt.
278.32
(2tegory: Antibacterial.
Dose:In thetreatment
of systemic
infections;
initial
dose,
3 g;subsequently
upto6 g daily, in
divided doses,
Inthetreatment
ofurinaqtract
infection;
initial
dose,
2 g;subsequently
upto4 gindivided
doses.
crystals
or
inwell-closed,
light-resistant
con- Descripdon:Whiteor creamy-white
Storage
: Store
crystalline
powder;
almost
odourless;
taste,
bitter.
tainers.
Volubility :,Veryslightly
soluble
inwater;
soluble
inacetone, inmineral
acids,
inalkalis
andinalkaline
492
Sulphadiazine
sodium rrim”teV.S is equivalent to 0.02503 ~
g of
C,,H,,N,O,S.
Storage Sulphadiazine should be kept in a well-closed
A
corminer
C,0H,”N,02S
250.3
68-35-9
Sulphadiazine is N’-(pyrimidin-2 -yl)sulphanilamide. It contains not less than 99.0 per
cent and not more than 101.0 per cent of
and protected
from light.
Preparation
Sulphadiazine Injection
Actionand use Antibacterial.
-4,
Sulphadimethoxine
calculated
withreference
tothe
dried
substance.
Characteristics
White,
yellowish-white
orpinkish-white
H,N~SO,[email protected]
crystals
orcrystalline
powder.
Itmelts
atabout
255°,
with
decomposition.
in water and in chloroform;
SoIubility
Practically
insoluble
cIoHIoN402S,
very slightly soluble in ethanol (96°JJ); slighdy soluble in
solutions
of alkali
acetone. It dissolves in aqueous
rninerat acids.
hydroxides
and
in dilute
Identification
Test A may be omitted if tesrs B, C and D crre
cam”ed our. Tests C and D may be omitted if lests A and B
are cam’ed out.
A. The infra-red absorption spectrum, Appendix II A, is
concordant with the spectrum of sulfudiazine EPCRS.
B. In the test for Related substances, the principal spot in
the chromatogram obtained with solution (2) corresponds
in position and size to the principal spot in the
chromatogram obtained with solution (4).
C. Heat 3 gin a test-tube inclined at an angle of 45° with
the lower part immersed in a silicone oil-bath at about
270’. It decomposes and a white or yellowish-white
sublimate is produced. The melting point of the sublimate,
after recrystallisation from tohene and drying at 10W, is
123°to 127°, Appendix V A, Method I.
D. Dissolve 5 mg in 10 ml of lM hydrochloric acid and
dilute 1 ml of this solution to 10 ml with water. The
solution, without further acidification, yields the reaction
characteristic of primary aromatic asnines, Appendix VI.
Acidity Heat 1.25 g of the finely powdered substance at
70° with 25 ml of carbon dioxide-free water for 5 minutes.
Cool for about 15 minutes in ice and falter. To 20 ml of
the filtrate add 0.1 ml of bronrothymol blue solution. Not
more than O.2 ml of 0.1 M sodium hydroxide VS is required
to change the colour of the solution.
Colour of solution Dissolve 0.8 g in 10 ml of lM sodium
hydroxide. The solution is not more intensely coloured
than reference solution Yj> B Yj or G Y~, Appendix IV B,
Method II.
Heavy metals 1.0 g complies with limir resr D fbr heavy
metals, Appendix VII (20 ppm). Use 2 MI of lead srarsdard
solurion (ZO ppm Pb) to prepare the standard.
Related substances
Complies with test C for related
Appendix III A.
substances in sulphonamides,
Loss on drying When dried to constant weight at 100° to
105°, loses not more than O.5°h of its weight. Use 1 g.
Sulphated ash Not more than O.1%, Appendix IX A,
Method II. Use 1 g.
Assay Dissolve 0.2 g in a mixture of 20 ml of 2.44
hydrochloric acid and 50 ml of warer. Add 3 g of potassium
bromide, cool in ice and carry out the method for
amperometric titration, Appendix VIII B. Each ml of 0.1 M
C,* H,4N40,S
OMe
310.3
122-11-2
A
Sulphadimethoxine
isN1-2 6-dimethoxypyrirnidin-4-yl)
sulphandamlde.
tcontains
not
J=-’--YD
u per cent and not more
16ss
than_99.
than
101.0
percent
‘ofCIZHNN+OJ,calculated
with
reference
tothedried
substance.
Characteristics
A white
orcreamy-white,
crystalline
powder; odourless or almost odourless.
Solubitity Very slightly soluble in ware~ slightly soluble
in ethanol (960/0). It dissolves in dilute mineral acids and in
aqueous solutions of alkati hydroxides and carbonates.
Identification A. The infra-red absorption spectrum,
Appendix II A, is concordant with the refmence specrrum of
sulphadimethoxine.
B. Yields the reaction characteristic of primary aromaric
arnines, Appendix VI, producing an orange-red
precipitate.
Acidity Heat 1 g with 50 nd of carbon dioxide-free warer at
about 70° for 5 minutes, cool quickly to 20° and filter.
25 ml of the filtrate requires not more than 0.1 ml of O. 1.M
sodium hydroxide VS for titration to pH 7.0, Appendix
V L.
Clarity and CO1OUSof solution A 5.00/. w/v solution in .2M
hydrochloric acid is clear, Appendix IV A, and not more
intensely coloured than refmence solu[ion B Ys, Appendix
IV B, Method 1.
Melting point 19Y to 204°, Appendix V A.
Heavy metals 1.0 g complies with limit test C for heavy
metals, Appendix VII (20 ppm). Use 2 ml of lead srandard
solution (10 ppm Pb) to prepare the standard.
Related substances Complies with test B for related
substances in sulphonamides, Appendix HI A.
Loss on drying When dried to constant weight at 100° to
105”, loses not more than ().50/. of its weight. Use 1 g.
Sulphated ash Not more than O.10/., Appendix IX A.
Assay Dissolve 0.5 g in a mixture of 75 ml of water and
10 ml of hydrochloric acid and carry out the method for
amperometn”c tirrarion, Appendix VIII B. Each ml of O.lM
sodium nitrite VS is equivalent to 0.03103 g of
C,* H,,N404S.
Storage Sulphadimethoxine should be protected from
light.
Preparation
Sulphadimethoxine Tablets
Action and use Antibacterial.
[dPhase:
Stdphacetamide
100
.-
Potassium
—.
80
/$
\
40
b
\
20—
---
-----
---
disc
r
I
60
bromide
----------
1(
I
1601-
o
2000
1;00
1Z)o
1&o
Stdphadiazine
1200
lm
tio
800
Phase.
Potassum
400
bromide
disc
brom(de
disc
.-
100
80~-----------
~
.-.
—.
I
1601
02000
‘“—-” 1800
1028
I
.—
1600
1200-
1400
—-----..—.—.
1Oao
Sulphadimethoxine
100 ~—-—
800
‘Phase:
800
Potassium
400
1. .
.
.
.
i
v
1028
1495
0jo~o---Wavenumber
1800
(cm-’)
‘
16430
I
‘1400
‘-
1200
1OQo
600
400
Page Number
—e%=
-—
Database:
Medline
<1966
to
: 1
present>
Results
Set
Search
-------- ------ ------------------------- ---------------------448
exp sulfadimethoxine\
1
14057
(safety and efficacy] .tw.
2
0
1 and 2
3
54760
stabili.ty.tw.
4
3
1 and 4
5
14168
(safety and efficacy) .ti.,ab,sh.
6
0
1 and 6
7
3
from 5 keep 1-3
8
44957
safety.tw.
9
108250
efficacy.tw.
10
4
1 and 9
11
8
12
1 and 10
2
13
from 11 keep 1-2
7
14
from 12 keep 1-6,8
<1>
.-
Unique Identifier
97466138
Authors
Thomas GK. Millar RG. Ansti.s PW.
Title
Stability of sulfonamide antibiotics in spiked pig liver
tissue during frozen storage.
Source
80(5):988-95, 1997 Sep-Ott.
Journal of AOAC International.
Abstract
A bulk portion of homogenized pig liver tissue was spiked
at room temperature with 0.2 mg/kg (twice the Australian
maximum residue limit) of each of sulfathiazole,
,
sulfachlorpyridazine, sulfa_d_i~ixi.ine__~:ulfamethazine)
sulfaquinoxaline, and~ulfadimethoxin~
After subsampling
and packaging, selected individual packaged units were
tested to confirm homogeneity of the prepared material. The
material was stored frozen at -20 degrees C and analyzed in
replicate by liquid chromatography on 11 sampling dates
over a period of about 6 months. Analytical data were
plotted on a log-linear scale and subjected to linear
regression on the basis of first-order kinetics for the
decay. Storaqe stabilities (decay half-lives at -20 degrees
—.
s~om._.li_n_e.s_._we.r
e
-C) calculated from the
mean-~~o~e >...mgres
—
_,
day~sulfadimidine,
457 days;
K— .—sulfadlmethox~~e~=67
—.- .sulf&51iTorpyrWz-in=, 312 days; sulfathiazole, 291 days;
Page Number : 2
.—-
and sulfaquinoxaline, 271 days. Significant depletion (65%
loss) of residue was observed for sulfaquinoxaline duri,ng
preparation of spiked bulk liver tissue. An extension of
the study to measure the storage stability of
sulfaquinoxali.ne under accelerated decay conditions
(refrigerator temperature, 4 degrees C) showed it to be
relatively unstable, with a decay half-life of 11 days.
Results demonstrate the need for both regulatory agencies
and testing laboratories to be aware of potential errors
associated with improper transport, storage, and handling
of tissue samples submitted for antibiotic testing.
<2>
Unique Identifier
70107926
Authors
Reimerdes EH. Seydel JK.
Title
[Significance of acid stability of sulfonamides for the
determination of their N4-metabolites]. [German]
Source
19(11):1863-8, 1969 NOV.
Arzneimittel-Forschung.
_—_
<3>
Unique Identifier
94257994
Authors
Parks OW.
Title
Stability of sulfaquinoxaline, sulfadimethoxine, and their
N4-acetyl derivatives in chicken tissues during frozen
storage.
Source
77(2):486-8, 1994 Mar-Apr.
Journal of AOAC International.
Abstract
The N4-acetyl derivatives of sulfaquinoxaline and
~chicken
liver anddimethoxine were stable_l_n_
duringfm~e~storage
‘=year
a$
——
In contrast, the pareITE72Um~ds
~epleted approximately 35% in liver tissues at -20 degrees
C. The transformation of the depleted sulfa drugs to their
N4-glucopyranosyl derivatives was negligible, suggesting
that products other than glucosides resulted during the
storage period.
___
—=__
..=.
Page Number : 1
Database: Medline <1966 to present>
Results
Search
Set
----- ----- ----- ----- ----- ----- ----- ----- ------ ----- ----- ----448
exp sulfadimethoxine/
1
14057
(safety
and
efficacy)
.tw.
2
0
1 and 2
3
54760
stability.tw.
4
3
5
1 and 4
14168
6
(safety and efficacy) .ti,ab,sh.
0
7
1 and 6
3
8
from 5 keep 1-3
44957
safety.tw.
9
108250
efficacy.tw.
10
4
1 and 9
11
8
12
1 and 10
2
from 11 keep 1-2
13
7
from 12 keep 1-6,8
14
<1>
Unique Identifier
71191828
Authors
Marusich WL. Ogrinz EF. Hecht B. Mitrovic M.
Title
Safety o~ sulfadimethoxin~ potentiated mixture (Rofenaid),
a new broad s~ectrum coccidiostat-antibacterial, in
&HT
“
Poultry Science.
50(2):512-7, 1971 Mar.
<2>
Unique Identifier
70050587
Authors
Marusich WL. Ogrinz E.
Brand M.
Mitrovic M.
Title
“ y of sulfadimethoxine potentiated
~fety
and compat~
mixture (Ro 5-0013), a new br=ad spectrum
.
coccidiostat-antibacterial,
Source
Poultry Science. 48(1):210-6, 1969 Jan.
Page Number : 1
Database: Medline <1966 to present>
Set
Search
Results
------ ------ ------ ------ ------ ------ ------ ------------ ------ 1
exp sulfadimethoxine/
448
2
(safety and efficacy).tw.
14057
3
1 and 2
0
4
stability.tw.
54760
5
1 and 4
3
6
(safety and efficacy) .ti,ab,sh.
14168
7
1 and 6
0
8
from 5 keep 1-3
3
9
safety.tw.
44957
10
efficacy.tw.
108250
11
1 and 9
4
12
1 and 10
8
13
from 11 keep 1-2
2
14
from 12 keep 1-6,8
7
<1>
Unique Identifier
79250686
Authors
Gates NL. Rich JE.
Title
Efficacy of selected
diarrheal disease in
Source
Veterinary Medicine,
1979 May.
.-——-..
Myers LL.
Harp JA.
antimicrobial agents in treating
neonatal lambs.
Small Animal Clinician.
74(5):707-9,
<2>
Unique Identifier
80i08976
Authors
Maestrone G. Thompson E. Yei.sley H. Mitrovi.c M.
Title
Prophylactic and therapeutic activity of Rofenai.d-40A in an
experimental Escherichi-a coli airsac infection in chickens.
Source
Avian Diseases. 23(3):682-7, 1979 Jul-Sep.
Abstract
Rofenaid at a 0.02% dose level in feed was effective
_.—.._an
.prophylactlcally ~inst
an
experlmentally Induced Escherichia coli-=-~r==c””
fnfection in
.-__= _
..
L1
I
.———
Page Number : 2
avorab-l_y
chickens. ~~~
,~lwa.pp
roved dose level of NF-18&
that
Rofenaid did not
Furthermore, the prophylactic~
interfere with the therapeutic efficacy of NF-180.
<3>
Unique
Identi.fi.er
74110196
Authors
Potapnev
FV.
Skuratovich
Title
[Comparative
evaluation
sulfamonomethoxi.n
and
gonorrhea].
[Russian]
Source
Antibiotiki.
18(5):453-6,
AA.
of therapeutic
sulfadimethoxi~-i~
effx
~
1973
f
ati
3
‘ith
May.
<4>
Unique Identifier
_—_
74084351
Authors
Mi.lxovic
Schildknecht EG.
M.
Title
Comparative chemotherapeutic efficacy of Agribon
(sulfadimethoxine) and other agents against coccidiosis in
chickens and turkeys.
Source
Poultry Science. 52(4):1253-60, 1973 Jul.
<5>
Unique Identifier
72113377
Authors
Mitrovic M. Bauernfeind JC.
Title
Efficacy of sulfadimethoxine in turkey diseases.
Source
15(4):884-93, 1971 Ott-Dec.
Avian Diseases.
<6>
Unique Identifier
72003749
Authors
Orton CT. Hambly LR.
Title
Page Number : 3
Efficacy studies on potenti.ated sulfadimethoxine as a
chicken coccidiostat.
Source
Poultry Science. 50(5):1341-6, 1971 Sep.
-—__
‘“6
<7>
Unique Identifier
87154648
Authors
Ames TR. Casagranda CL. Werdin RE. Hanson LJ.
Title
Effect of sulfadimethoxine-ormetoprim in the treatment of
calves with induced Pasteurella pneumonia.
Source
American Journal of Veterinary Research.
48(1):17-20, 1987
Jan.
Abstract
The efficacy of sulfadimethoxi.ne (SDM)-ormetoprim (OMP) was
evaluated in calves with induced Pasteurella pneumonia. A
dose-titration study comparing 3 doses of SDM-OMP was
performed to determine the optimal dose. Treatments
included: group I--nontreated controls; group 2--33 mg of
body we~~t. orall~agl_md17~~kg
on
-~group
Z~66
~~O_DM-~/kq,
ora~~~on
da~_l
qnd 33 mg/kg on @w.s 2 t~~;
group
4--29
mq of SDM-OMP\kg,
~ally
on day
land
5Q_.~kg.__~..d~ys
mg of oxytetracycline~kg,
5 --11
IV
Grou~–calves
responded
to treatment
2 to
5;
dail~for
as well
and
group
4 days.
amid
group-5 calves. Group-4 calves responded the same as did
group-3 calves. However, group-2 calves did noarespond
as
well as did groups 3, 4, and 5 calves.
~..
_-—- s.
-—
_.——
UJ-UO-YO
U1.
l’l(UNi
.llfh’l
UUCIJb/DIAU
LID/UilLJ
Iv
o/1ouuol+31uu/L+lY4
ruuL/uul
,.!
ISTRCN)[ICT1ON
ing to syncrgizc Ihc coccirfiostatic proper.
W k a new hroarl
spec!
rum tics of sulfonamides ( Lux, 1954; Jwmr and
coccidios[at
andantihaclerial
contain-Kendall, 1955, 195fi: l-forton-Smith ct d,,
ing sulfadimcthoxinc (N’-] 2, fi-dimethoxy- 1960; ]Iall, 1964, am-fClarke, 1962, 1964).
The safety O( sul{aclimethoxinc rmd ur4-pyrimidinyll sul[anilamide) potentialrfl
with ormetoprim (2,4-rliamino.5- [4, 5-di- metoprim alone and in the !i:.3 combination
mcthoxy-2-nw!hylbcnzyll pyrirnirlinc) in a has been reported for the chicken (Maruratio of S:S. Sulfariimethoxine alone has sich (’t al,, 1969). The present report is
concernerf with the safety of the S:3 combeen shown to be highly effective, [therapeutically, ii~ainst
all pa~ho~enic
species of bination in turkey broilers and breeders,
R
[)FN.I\l
hj
coccidia
inchickens
(0.05~
) andturkeys
S1’F.C’II;I~
~0.0257J when administererl intherlrink.
IWI’F,RIMI?YTAT. l’ROCill>[lRl!S
AND RESI’LTS
ing watw (Mitrovie and Bauernfeind,
1967) aid efficacious ill ihtt jjrevenliun ~~f
Ilroarl I+reasted White (13.R.W.) poulLs
turkey coccidiosis at 0.01257~ in the feed
(sex identified) it-urn a commercial
hatch(Mitrovic,
1968).
Mitrovic
(1967)
rcery were used for all experiments, ,411birds
porterl that sulfarlimethoxine was also effec- were houscrf in electrically-heated, thermotive in the therapy of fowl cholera in statically-controlled batteries with raised
chickens (0.05fi)
and turkeys (0.025fi, )
wire floors for the first 4 weeks, transferred
and infectious coryza in chickens (0.05;{)
to grower units with wire floors and no heat
when administered in the drinking water.
for thenext 4 weeksand thenmovec?
to
The combination of sulfadimethoxine am-l floor
pens where necessary. All housing
the potcntiator ormetoprim, n folic acid conditions--includin~ fkwr space, ligl~ting
antagonist, in a 5:3 ratio results in en- and temperature-in
each respective study
hanced broad spectrum coccicfiostatic and were comparable for each treatment group
antibacterial activity when fed continuously
A commercial-type mash free of antibiotics,
to broilers
at0.02%andreplacement
birds ar~enicals or 0[ her mediation was fed k
at 0.01
‘2,(Mitrovic
et d.,1969a,b). all trials. Depending on the length of the
k highly study, the following dietary
Similarly,
thesame combination
regimen
was
effective as a Lrwd spcwlrum coccicliostat
followed: 28?, protein starter from O to 8
when ferl continuously to weeks; 25 fi~ protein grower from 9 to 13
and antibacterial
turkpys
at 0.01$44- (Mitrovic
Pf
o}.,
weeks; 2 l?{)
protein ~rower from 14 to 17
197 I a, b). Previous investigators had reweeks; 16{% protein finisher from 18 Lo 24
ported on several folic acid antagonists act- weeks: and an 18% protein layer m~~
.—— —.. . .. ...--.-. —.-.. ...--- ——.
* RofenairP~ is Roche’s trademark for s coccid- from 25 to 44 weeks.
~.~~,oO) Q [email protected]#C fkl
~0.W.
~O]][email protected]
iojtat and an(ibacteria] crmtaining sulfodim~ihox{t~e
po[entiahxi wi(h nrmetoprirn.
a preliminary range-iincling experiment, 2512
aY 88
‘Sa
13:41
405 271 3297
PRGE .02
“[U b/lbUUU(43(bU/Z41Y4
JKVM UUHbL/BIKU LID/UhL
U3-UO-YU ul:JfrM
ruu.uuul
r.
C(LIre
+=;
—.-.
..—
—.-.
Treilt men t
..... . ... .
rng. /kg,
N)
Ion
240
.\20
W]
.}s(}
W
c
ey 07110
iostatic proper.
54: Joyner and
m-Smith ci d.,
SUlfrtdimethoxineormqoprim
cnn\binat!f)ll [5 13)
---
.. .... ..
—-.
.-
..-.
..
0/10
fv 10
J/lo
4/10
S/lo
fi/lo
U/lo
Pmo
l~tu
1610
203(1
244’)
2857
..—
.
(),/\(j
(y;:
lf)2
204
30s
NM
s10
600
711
.. . . . . ..
.
,Wi
,1.56
,3*
.Lu)
3(M)
,3,10
,{rlo
.1(l.1
w)
!1,{2
,111
3P)
310
--
6}10
6(10
1:/!1
. .. .
. .
17so L 2(MI
nlg. /kg.
w j. 40
n\g, /kg,
306
510
718
6f)
10(1
140
1no
220
300
..
.-.
402
)()
W]
ho
W
I(UI
120
140
e, 1962,1964),
nd breeders.
.. . .
body N 1.
.—.
---
oxine and or.
:3 combination
hicken (MarU.
*n t report is
( the 5:3 mm-
—. .
.. .
I&;
1538
..
. . ...
. -.
.. -—----
.-
.,
!..,.
PROCl?DURttS
_=—
-..
l.d.w.)
poulls
merchlhatchents. All birds
?ater!, thermo; with raised
Wcc’1{-l)kl
poults werc assembled into uniform groups of 10 each (5 females
.{”S
males),
basedon body weight. Craded
levels of sulfacfimethoxine, ormetoprim and
the combination of the 2 drugs in the 5:3
48 hours, The 5:3 combination is
variable with deaths occurring in Iess than
24 hours and up to 96 hours. All surviving
birds recover rather rapidly and subsequently show essentially normal growth
ratio
(Tabk
w, transferred
were
administered
as
a [email protected]
oraI
UP to
1),
dose in gelatin sleeve-type capsules to
All birds that died were necropsied and
rs and no heat
groups of 10 pm}lts each.
the following gross pathological lesions obThe results are summarized in Table 1. served with sulfadimethoxine: hepatonelen moved to
All housing
on the method of Miller
anfi
Tainterphromegaly, catarrhal enteritis; with orllased
pace, lighting
(1944),
the following
LD,” values
were
metoprim: hepatonephromegaly; with the
calculated: sulfadimethoxine (1750 reg./
pective study
combination:
hepatonephromegaly,
edekg. ~
zoo reg./kg.),
ormetoprim (400 matous small intestine and catarrhal enteriItment group.
ofantibiotics,reg./kg. * 40 reg./kg.) and the S: 3 com- tis.
bination (Q30 reg./kg. & 45 reg./kg.).
xlwas fedin
The onset of toxicity is rather slow and
length of the
J.\-WEEKSAFETYTRIAL WITH
varies with the specific drug. Clinical signs
SIJLFADIMETHOXINFX)
RMI?TOPRI,M
regimen was
6:3
COMBINATION
are
not
well
defined.
lli
rcls
appear
lethargic
“ fromO tos
with wings drooped; they rest on their
from9 to13
Two-day-old poults were assembled into
hocks and do not attempt to eat or drink.
rom 14to 17
24 groups of 10 each (5 females + 5
Time of death varies with suIfadimcthoxinc
mm 18 tO 24
males), based on body weight. Levels of O,
from 24 to 96 hours with the majority cly- 0.01, 0.03 and O.OS$%of the 5:3 co[nbillalayer mash
_—-.
jng durinq the latter3 days. With ormetotion of sulfadimethoxine + ormetoprim
Prh,
d~ath occursrapidly,
~enerally
Following
were fed continuous] y to 6 replicates Of10
within the first 24 hours with a few deaths birds over a 1l-week period. All turkeys
:periment, 2-
,47.,44
9
1’
TATIU.:2.– PcrJormattce Oj turkeys jed gra.dul imtis oj wljadinrcllloa’itte.
orndoprim
~=??.
. . —-
“.
<ombs’nalion
,-- ..--—. . .
(5:3)
!ov 1.1 qi)e~k~
.- -. . .. -2.
-—-,.
.
-—
Rofcnnid intake
:
‘.
.,
___
‘-’”
% Gkin Fed/)takc Feedconversion
Total
Average doily
Mortality
.-. -.—.. .—
.
(reg.)
(mg,)
(nlg,/lig.)
-_
.. ..
- —..,.
, . .. ..-—. .- .. ——:—’
——. - . .- ——— .--——-.
. ...
(1to 4-Week D:Lh
.-. ..,,
._
...-—....---—. -—-----—.. -—. —,. ---- — -,,. ,. ----- .-—
787
100
2!(4)
0.51s
1.s2
‘o
27)
—
9.2
G()
3/(il
800
1.s4
0.01 0.520
100.4
0/60
26.7
8.4
785
235 a5
lol&
1.s1
0,03
m;
,3/60
45.8
0.05
,
..
142
795
1.56
397,5
% Drug
&j
——...
0
0.01
0.03
0,05
——
o
0,01
0,03
0.05
. .
2.06$
100
3469
2.173
10s.
1
3604
2.164
2.231
104.6
107.9
3582
.Z67R
--4.224
4.545
4.474
4. S6.5
0 to 8-Week Data
—-——.
.. , —.—
1,6s
;:4
360.4
1.66
1.66
1.65
—-—-
-—. ,.-—
2/a7
3’60
[)/60
3/@
;6
16.9
28,0
—.-—
10502
10304
108. 1**
106s0
— .- —-
2/60
2,31
2,30
2.34
..—.. - .. ..
10;. 2
3091.2
S.MO,0
—.
11
‘:. 5
34,0
3/60
0/64
.5.’0
14,8
58,7
25,1
—.. ,— ,.. -. —--
.
.
6
a
f!
c
o
. . .-—.
2,35
100
107.6’*
105.V*
19,2
32.8
1074.6
1s.39.0
0 to 13-WeekDrQ
. ... .-. “.. . .
4/60
P
. _
s Average weight of 2-day-old poults waa 55 g,
● * Statistic.tlly
<ignitjcant at P <,05 (2-sicted
test).
B
y
were weighed as groups at 4 weeks and In- ter (P < 0.05) for each drug ICVCIfed,
dividually at 8 and 13 weeks. Feed con- compared with the nonmedicated controls.
Hematological data,
including
hemoglosumption data were recorded over the enhematocrit, R.B.C. and differential are
tire 13-weeli period. Hematological data bin,
were obtained on 10 representative birds (3 shown as averages for the 10 turkeys per
females + S males) from each treatment treatment group in Table 3 with no differgroup at 13 weeks. Gross pathological ob- ences seen which can be associated solely
servations
weremade on these
samebirds with drug level fed.
Postmortem examination of allvital
orselected
forhematology.
Selected
organs
including
liver,
kidneys,
spleen, hem acid gansfrom10 turkeys per treatment group
thyroid were weighed and related to body after 13 weeks on test revealed no abnorweight, Tissue portions were taken from 15
organs of 6 controls and 6 birds fed 0.05%
drug and preserved in neutral buffered
formalin for histological examination.
Growth, feed conversion and mortality
data in relation to drug level and drug in1090
take are summarized in Table z after 4, 8
and 13 weeks’ continuous feeding. No adverse effects were seen in the performance
of turkeys with any drug level, Body
weights at 13 weeks were significantly bet-
13:42
E
G
11
ej
#
01
n
;
fr
mal gross lesions which could be attributed
to drug treatment. The weight of selected
organs and their weight as a percent of
body weight are shown in Table 4 as averages for the 10 birds per treatment, The
data show the normal viiriabiliLy to be expected in turkeys of this age.
Seetions of brain, liver, kidney, lung,
heart, thyroid, pituitary, sciatic nerve, adrenal, gonads, bone marrow, pancre~,
spleen, small and large intestine tissue from
1
MRY EI13 ’98
h
405
.271 329?
P9GE .04
I
(
(
(
(
..
i
1
SAFETY
oi’
515
R(JFI?NAII)
..-=
TADIJ 3.. - llenlalology’ os twkc.wajter 1.?uveks’ jading
[cot~sIIj.!ulj~if}tcil~xinc+
... . _
I?(1
I)rtlg
Mortality
Hemo.
~~r~~~~
Min
~, lW ml. RV;!C.
7
2/60
.l/6rJ
0/60
~
_
.-
9.62
9.13
().4j
9.10
;,[)1
(),03
0,05
-.. ..-—
-.. -. —.
..-——..-.
-—. —
.-
. .... _
- .
-.
. . ...
.-. —
-.. . .-- .,-
--
phils
-—— —--—-
2.33
2,38
2.S3
::!
0.7
graded
--- --
(), 1
2.41
..--——
phifs
phds
Cyles
Cytes
.—. -—-—. — .— --—
1,4
1.8
4,4
M
45.1
%:
49.9
52,4
. ------ --- —
IS I“,lnlrol turkeys (3 females + 3 males)
2j60
3;60
0/60
3/60
43.0
----- .-.
~::
;::
.
.
---
—
~:~
on 0.057~ drug and the other fed nonmedicate~i feed. The hens were artificially in-
aml from 6 fed 0.05% drug showed no differences between the two groups in the oc- seminated weekly with pooled semen colcurrence or incidence of abnormal lesions, lected weekly from the respective 4 toms
other thanthoseabnormalities
tobe ex- maintained on the same ration as the hens.
pectecl
in a normal turkey population.
w
3/60
0/60
—
,.
oj
:3)
- . . ..——— >--- --- (5
13iflerenl id cell count-’j$
—.
. . . ---—
———. —-. —-.
. .>.- . .
ttuc
Mono- Iksiyr” l\asoI.ymplmx UY N. StN.** llcwo-
- .. . - .- —-
34.4
35.6
35.4
.~j. J
——
. ... —----w-.”..
contbtia~ion
* Average [or )0 turkeys (5 ftmnles+S males).
● “ Non-segmented neucrophlk.
3/60
---
—---
--
rtnel(~ptihb
TURKEY E REEDER TRIAL WITH
S1JLFADIMETH(XINE-OR
METY)PRIM
4/60
...-
lt,W. hens and toms maintained for 35
weekson nonmedica~edfeed from another
study were assembled into z groups of 19
hens each and 2 groups of 4 toms each.
Egg production was recorded for 10 days.
OUCgroup (hens #1-19) laid 40 eggs and
the second group (hens#20-38)laid
43
eggs.
At this point, hens #1-19 (Group
!:,
_—=_
evcl fed,
ontrols.
hemogluntial are
keys per
]0 diffcr:d solely
vital OP
rlt group
o abnor:tribtttcd
se]e.cted
rcent of
ss aver:nt, The
o be w
y, lung,
we, ads ~ncres,
-e from
M
#1) were fed 0.05% sulfaciimethoxineormetoprim 5:3 combination in the layer
mash and hens #20-38 (Group 2) were
continuedon the nonmedicated layer mash.
The 2 groups of toms were then separated
one group
was also placed
from the hens;
A 15-hour lightday wm mainlaiucd
throughout
thestudy.
A triple crossover
design was used with the medicated and
nonmedicated rations fed for periods of 21,
26, 27 and 30 days.
Eggs were collected 4 times daily and
placed in the incubator at weekly intervals.
were candled
at9,16 and 23 days
‘1’hey
andmovedtothehatching
section
on the
26]27thday.Within24hoursofhatching,
all
poults
wereplaced
onnonmeriicated
turkey~f
artcr
ration,
andtheir
growth
performancewasrecorded
overa 3-week
period.
fertilTable 5 details
theeggproduction,
ity, matchability and poult performance for
the 2 groups of hens fed the medicated and
crossover
nonmedicated rations in a triple
design, The data show that
theintermittent
TABLE 4.- SChTkd orgatt weighhoj turkeys’ facrijfcedfor gross pdhojo,eya{ler 13 weeks’
‘~
(!;:)
0
0.01
4.68
Jeedinl oj irodtd lwds Ojsuljtii~felllo.vineortnulopril))cowbittafiw (S:3)
J-,, ,,. --, ,-- ...-. .-—
——
Heatt
Thyroid
Liver
Kidneys
Spleen
—
g.
%
%
&
%
Y
70””
s
70
~.
,.-.
-—
..
— -.———
0,20
0.0042
1.6S
27,1
0.58
5.9
20.2
0.432
0.126
77.2
S.04
5.23
5.i7
784
! 56
17,2
87.6
S6.7
!.67
1.68
3[.1
27,0
=.. -—- ... . .
Body
70
0.03
00s
-.
“ ,\ verage
0.s4
0,.59
0.52
.--. —-
5.1
5.9
4.8
-----
0. !01
21..3
(). !13
;:. !
0.093
,
. .. .. . . -
0.423
m):
0,23
0.23
0.23
0,0045
0.0043
0.0044
.,.
10 turkeys (5 fenmles+5 males),
●“ 1)rgan weight
M percent of body weight.
E18 ’98
for
13:42
405
271
3297
P9GE .05
1
W, L,
$16
‘fABLZ
MARUSICH,
S.–Jig
Production,
O. 05~o $u?jaiit~lho~”ne
..——
-.
11. F. LkRlh27,
~.
FiECHT
AND
MITIZOVIC
M,
jtrtdily, halchabildy
and growiii aj potdl.$ jrom hwkc~ htn$ id
ormtdoprfm cod$natfon
(5:J) in u Irijh cruswvcr design
-- ..
_-- _,___
,.- ---. . ..—
- . .—
Hatched prmlt
Hen ~~g
N&;f ~ti:f
eggs
Do.
.
—.
———
21
26
1-19
0.05
o
0.05
0
20-38
20-38
0
0.05
21
20-38
20-38
0
0.05
;!
30
1-19
1-!9
1-19
Total
;:
—..
Eggs
Eggs
htn/day
. . . ..—-—..
lntermittenr
.. —-
Fdirw
116
}73
19
19
169
0,35
0,33
1?!
149
166
0,29
0.42
17b
)7
;!
no.
set
~
&
Fertility
0.05
0
1;
%
-..—.———
Performance
.“ .—
-
0,29
81
gain
(;;
(g.)
.-.—
— .- ...-.
——
n
.,. .—
h
177
g ‘—;?
f
$
14s
90
98
104
107
S4
54
54
191 !
204 ;
139
66
47
53
80
4S
190 ,
0<3$
&8
o,[email protected]
S70
441
. . ..
427
.-.—
52d
!!
92
ti
——
79.0 . 3-F71.7
74.9
321
.
Cln
3-week
86
0.44
174
J 1S
66
0.330
134
103
174
0,34
114
)!;
139
Combmed Feeding Performance
r;
pcrforn-mcc
l.d~y
I:!
134
127
-—1-38
1-38
‘h
Hatchabi;y
no,
~
53
51
187
He
d
7
190
i 72 i
192 y
JO
—-. —. 4
50.0
187,Y
i
75.2
49.3
188.3
1
. . . ——
—
JOY
0
S
P
a One hcn dkd whiIe on 0, 0S% drug ration.
b One hen died while on control ration,
QAdjusted to loss of 1 hen during the specificperiod.
~ I.ncuhator shut off for 2 days.
● Adjusted to deaths as noted under a, b.
feeding of 0,05~o sulfadimethoxine-ormetoprim 5:3 combination for from 21 to 30
days has no adverse effect on turkey
breeder hens or toms, based on the several
7
Lux
t
1
M:
ormetoprim fed at O.O1~O) 0.03% and\
0.05~0 total drug. These levels represent ~!
3 and 5 times the suggested coccidiostatic~
antibacterial prophylactic use level (0.01%)
l
d
m
for turkeys. No signs of toxicity wer’
seen with any drug level, based on growth,
feed conversion, mortnlity, hematolog$
gross pathologyand histopatholo
‘
Growth was significantly increased (J?
.05) with ;11drug levels.
,Performance of turkey breeder hens an”
-.,
;.
toms fed 0.05~0 drug was compared wi
.,
SUMMARY AND CONCLUSIONS
thoseon nonmedicated
feedin a tripl,
The toxicity
and safety
ofRuknaid,
a crossover
design forperiods
d 21,26,2
new broadspectrum
coccidiostat
andanti- and 30 days.Rofenaid
had no advers
bacterial
containing
sulfadimethoxine
and effect
on breeders, based on egg productiori
ormetoprim in a 5:3 ratio, was studied in fertility, matchability and performance o
>,
, ,,
turkeys. The LD6~of a single oral closein hatched pou]ts.
‘,
2-week-oldpoults was 17S0 & 200rng.fig.
,,,
REFEllENCIJS
,.
for suifadimethoxine, 400 & 40 reg./kg.
1:
Rrnll,
S.J,t 1064. Synergistic action of $u]ph~u!rlo,
for ormetoprim and 930 * 45 reg./kg. for
aline and 2-amino-4-dimethylamino-S- (4-cbloI,
the S: 3 combination.
..
phenyl)-6-clhylpyrimidinc in caecal coccidio,
parameters cited. The data for the 38 hens
were combined for the periods they r~
ceived O.OS~odrug (52 days) and compared to their performance while
on nonmedicated feed (52 days). No differencein
performance was seen between the 2 dietary regimens.
. .*
‘,,
A 13-wee3csafety study waa run with the
S: 3 combination
of sulfaclimethoxine
and
~
in chickens. J. Comp. Path. 74:487-400.
Clarke, M. L., 1962. A mixture of diaveridine WI
,,
,.
,.
R
(N
nils
4-d
Zyl
ant
bro
—.
*
mar
ing
~
Ii
:,
,,.,.,
:.i,’
.!
M(3Y
08 ‘9s
13:43
405 271 3297
PRGE. 06
pemisti
eprintd WM
1
through the Copyri$’11
Center
clearance
of antibiotic polyresistance to the E1-Tor vibrions under the conditions 0[ rapid development
of the infection did not exceed 10-’. Such a IOWT
rate of the transmission factor transfer may
be due to rapid multiplication
of the cholera vibrions in the animal intestine and unfavorable
for conjugation rat ios of the microbes.
YJIS(
615.281
:547.551
.525.211
.1].036.6:616.9~3
@ <$48
A. A. Cicgpatmxw
B. Ilomantim,
@.
)*;:.~+/
CPABHllTEJlbHAfl OUEHKA TEPAJIEBTkl~ECKOfi [email protected]@EKTHBHOCTH
[email protected] l-i CYJ_lbOAJUiMETOKCHHA
Y EOJIbHblX rOHOPEEii
@le.~ BeHepo.lorIm (3aB. — [email protected] T. B. BaCHJIbeB)
~eHTpWIbHOrO
Ha~qHO-KCCJIelOBaTeJIbCKOrO
KOMHO-BeHf2P0,10
XOXiHbIX
Ii
rHqeCKOr0
BeHePHqeCKHX
HHCTHTYTa
60.Te3Hefi
(3aB.
MHH15CTtpCTBa
—
llf)[email protected]
A.
3APaBOOXPaHeHlifl
A.
[email protected]
*’V
%,
%J%[email protected]
f+>
H [email protected]
‘~qfc+
nOi3B.TeHl!e!d
IIeHHUWIJIHHa
H 3aTeM
aHT~6nOTEiIiOB
Apj’rtix
[email protected]
.~aMHAHbIM COf?lFiHeHIifi\i
6bIJ’Ia OTBeAeHa BTOfX3CTf?IieHHaH
flOJlb.
BBeJleHW
neHHIIHJIJIHHa B apCeHa.T
IIpOTfiBOrOHOpefiHblX
CpeACTB pe31i0
COKpaTM.’iO CpOKH
JleqeHH!7
60JIbHbsX,
JS12YeHllH
onHaKO
IlpHBeJIO
ITPHBIYIO
LINipOKCE
60JlbHbSX
~
H He BCerAa
K nO$lB.leHWO
CHIiXeHlitO
K 3HfNlHTeJIbHOM~
M OC.~OXHeHHfi
KOBC J10HH)Kf2HHOfi
rOHOPeefi.
Ii l10CTefl$2HHOMy
KJIIiHWieCKHX
TeJlbHbIM
@3pMaX
HCXOfiOM
npHMeHeHtie
yB(?JIKqeHWO
qFiCJIa
K IWHHUWIJIHH}
~OJIyqeHHble
JIeKapCTBeHHOfi
npli
B nOCJIe~H&
THUFiJItiVHH, OKCaIIH.lJIi
aJIJleprWi
Ha3HaqeHHH
IIJTaMMOB
10
rOHOKOK-
aHTli6HOTH-
CJI~YaeB
[] 0—12
nOJIyCHHN?TMqeCliIie
H flp. ) He
HH
CO CMeJl-
].
ISeHHUHJIJIKHbI
(Me-
nOJiHOCTbiO
npO”
pa3pelIlli.TM
6.TeMbI TepanHH
60JlbHblX
C aHTH6HOTHKOyCTOfiWiBbIMki
@OpMaMH rOHOpeli
HenepeHOCS.iMOCTbiO
K ISCHHUWUSHHY,
TaK KaK OHH MOr~T Bb13blBaTb
Te Xe
fleprwiecme
CBH3H
B,TeKaKrT
peawuin, wro
C 3T!ih!
np~ponme
H
B [email protected]?
MHOrHX
HCCJleXOBaTW%
C}[email protected] AHbIe
[email protected](HHeHFifI.
BbICKa3blBaJII-iCb
qTO, nOCKO.TbKy CJ’[email protected]~
B TeqeHI+e MHOrHX
HHH [ ] 3],
lHHpOKO He
nOBbIHIeHki H
II JlHhi6!HHiOTCfl
qTO [email protected]
K [email protected]~HMe3HH
11pH-
npeJUlOJIOXenOCJIe,llHHx JIeT
HCKJSIOqeHa B03MoXH~Tb
Ha6moJIeHHfI
nOKa3aJSH,
60JIbHblX
rOHOpWfi
, He
K
HHM rOHOKOKKOB.
Y
q~BCTBFiTt2.’IbHOCTH
El C
aJl-
nemmuumfbr.
BPC!MR BHHMaHHE!
MaJI03(#)eKTHBHbl
Ilpli
JleqeH13H 60JibHbIX
roHopeefi.
~HTepeC
Ii
3KH,
npenapaToB
nponoHrHpoBaHHoro
[email protected]
[email protected],
THBHOCTki
CCK3AHHeHHfiM
[email protected]
nonyqeHnfi
IIpeBOCXO~fiT
npeXHHe
B HaCTOFMSJeM coo6~eHHH
HOCTH C},[email protected]?wfoHO]ieTOKCnHa
3HaYHTeJIbH0
AeilcTBHfi
H Ap. ),
lTOBbICHJIC$4
([email protected]
KOTOpbIe
nO CBOefi [email protected]@K-
[email protected]
ttpHBefleHbI
pe3~JTbTaTbJ
H3}~eHkifi
[email protected]@KTMBM [email protected]
B TepanHH
60JIbHbIX
ro-
Hopeeii.
C~JibC#)aMOHOMeTOKCHH
CHH
(CHHOHHMbI:
h{a~p}iGoH,
(CHHOHHMbl:
AHllMeTOH,
C~JIbKCHH,
[email protected])
DS-36)
pi [email protected]~feTOK-
OTHOCHTCfr
K npersapaTaM
npO.JIOHrHpOBa HHOrOzeikTBFfH.
BC(%PCHHTY331ipOBaHbl
BoBcecOm3HOhi
HCCJie~OBaTe.lbCKOM
[email protected]~qecKoM
HHcTBTyTe
(~H}[email protected]).
cnep HhieHTe
Ha XHBOTHE,IX
-"[email protected]
eAeHHfl, AepxaJlaCb
.ria.TaCb
M CocTaB.TR.Ta
l~!a KC HMWIbHaH
-
,.
,,~
,<
.
[email protected]
IIOCJIe
(MMLIIH H KpOJII.iKH)
BCMBOpOTKe
Ha
KOHUeHTpa
O~HOKjlaTHOrO
ypOBHe
MZiKCHMyMa
UH5i
MaKckiMa.TbHa53
KpOBHOnpeAe.lfiJaCb
BbSCOKOM
50%
BT12qeHHe
[141.
[email protected])KC
BBefleHH$l
1—2
%%olq.k4*
aHTH6HOTHKOB
M JlpyrHM
BnJIOTb
aHTH6WTFiKOB
BpeM$l
H, aMrSHUH,7Jl
$W74
%//
4+
+--
06C)CHOBaHHOe
~~BCTBHTeJIbHOCTbiO
;
CJl~~JaeB &3~CneLUHO-
Kahf [ 1—5 1. IlapafineflbHo c 3THM Ha6.rnoAaemsiII yBenw4eme cflyqaeB Heynaq
- w Jle~elJ~M6oJ’IbHlix rOHOpeefi ZtHTH6HOTHK21MH
[6—9].
B JIHTepaType TaKXe Bce qaIQe n05iBJIfl10TCfi CO06~eHHfl o MHOrO06pa3HbSX
rmwe
\
‘Q?
C
B
+?>
ueHTp WIbHOrO HHCTHT~T$i
AHTOHbeB)
yCOBeplLIeHCTBOBtIH
H$I Bf3aqefi , MocKBa
rO
..\
6*
+
~epe3
]()
qaCOB,
HHZl
B
Ha~qHoB 3K-
KoHLleHTpaUHH
I—XqacaHmne
TIOCJJC
Yf?ro
CbSBOpOTKe
CH~-
KPOBH
znpenapaTa onpe3enneTcfl qepe3
453
;
5w/
4vJ(&t4.
K.,5
, . ,Fv~:
f’”
~ ;;
- : ,.p<.
; .!:(”.
,
‘;
- ,.., .,.”,,
..... ./
- ‘;,,
.;%G.
~a:..,
,.1
,.f
. .
-,.
--.;.
,..
“.,
.
‘., .?<6 { ...- .*
,-
,“
;/..
..
.
!
.. ....”(.
.,,
-.. , >-.!1
.<.,
‘<:~.:. :~j.t . ..:,;”...”
“:.,,>
.+. ,;,.
., .:.:
..
qaco9; n~owHa npHHfiTofi ACC3M(50%) BIJBOAHTCfi H3 @aHH3t4a c
48—72 ~aca [1!5]. B o’rJIHWIecm EpyrHx CJ’[email protected] I
3-8
qofi ~epe3
napaTOB
AO 80 ‘6 [email protected]
riMOKypOHHAa,
BOpHMOrO
HOBeliHX
I!TO
KpMCTaJIJ!ypHH
B MOqeB BHAeXOpOIIIOpa
HaXOAHTC$i
npaKTHWCKH
HCKJIIOqaeT
B03MOlKHWTb
B03HI
[ ~4 ] .
B ormrrax Ha [email protected] H
JIHCb
Ma.~OTOKCHqHblMII,
HOCTb
lTf)li [email protected],
AH3eHTep Hfi HOfi
HOfi,
BBe3eHHe
H [email protected]
aKT
KiiUI
[ 14—17 ]. fl.THTe.Tbl
tIWIOqKaMSl
MblIIIaM He
C [email protected]
oK
[email protected]
BEJCOKYK3 XHMHOTepaCIeBTHWCK y10
lYHeBMOKOKKOM, CTpenTOKOKKOM,
n POHBJWIJIH
Bb13Ba HHbIX
0Ka3bfBa.’lO
BpexHOrO
lefiCTBHH
nOTOMCTBO 1 181.
ti~e~eHHe CyJl [email protected]
HOM H [email protected]’TOKC}i
HOhl II POBW2 HO
153 60.lbHblX
MyXWHH H 5 MeHLUHH), CTpaAaBUIHX
pa3.’IEiqHblMli
@OpMa
(148
rOHOpefiHOfi
r~e
Ha6.xOfleHHfl
HeO~HOKPaTHblX
Ha
lHefi
HaXO~Si.l HCb i 2—17
OHH
ALiCnaHCepHOrO
H
92 60,1bHMx neW_IH
[email protected]
H 60.~ee
rOHOKOKKH.
nOCJIe
TOJlbKO
OCTa.lbHbIe
60JIbHbIe
cTauHoHaj
X.lfl
Xa.TbHefiIIl(
KOM61iHHpOBaHHOfi
n pOBOKaU
JIa60paTOpHOr0
HCC.’IefiOBa H
pe3yJIbTaTOB
[email protected]?JIbHblX
ypo.norHqecKoM
B
H BbIIIHCIJBa.THCb
nOJIy~aJIH
aM6y.TaTOpHO.
JleqeHHe
6w0 11 6oJTbIIbIx,OT 21 rosa 2030 .leT — 1
OT31 rola JO 40 ,wr — 32 ~ cTapu.Ie40 JIeT— 8 60~lbWx.
~HKy6aUHOHHMi!
l_lepHOAnpOAOJIXCHTe.TbHOCTbiO 3-4 AHH 61J.I KOHCTa
B 130EipacTe
70
pOBaH y
’20
60wTbHMX,
AfL’lb II 60.m?
TaHOBHTb
AO
,T2T
OT 5 AO 7 AHel% —y
— y 5.
Y 6 qeJIOBeK
He v~a.loch.
46,
10—14
AJIHTWIbHOCTb
C AaBHOCTbIO
AHefi — y 26,
HHKy6aUHOHHOr0
3a60JIeBaHlifl
107
OT 2
nepHOXa
6oJIbHbI
AHefi 61J.TO ~
36, OT2 HeAeab AO 1 Mecflua — 52, OT1 AO2 MecflueB—
H 60.~ee 2 ~ecmLeB— 12.
Tawmi 06pa30M, 60.~ee qeM y nOJOBHHbI60,1bHLJX(83) xaBHocTbsa60
BaHHH 6wa
CBblUIe 2 He~eJlb.
%0
06%$ICHfleTCH TeM, qTO 113 153 6oflbmJX,
TOpblM 6M70 Ha3HaqeH0
.leWeHHe [email protected] HHOM H [email protected]~HMEYTOK
m 820
14 M&i
—
57 paHW
HOM,
JIe~e6HMI
6fZ3yCneLUH0
JTeWfJTliCb
Y
~~PeX~eHHfiX.
pa3JIHqHMhfH
17 M3 3THX 6onbHbtX
aHTH6WITiKaMH
peLIHAHB rOHOpeH
B ~P~rl
HaCT~II
nocfe .YeqeH~ifinpenapaTaMH rieHHUH.mHHa(6eH3HmeHHuH.fmHH,3KM0H0B0uH
JI!-iH,
—_
6!H.w.wIHH-3),
JIHHa
11 — lleHH1.iHJIJIHHa
H JI(?BOMHU~HHa,
Y 5 — neHHUH
y 4 — 6HUHWIHHa-3, MOHOMHUHHaH 3PHTPOMHUH
y
H TeTpauHKJIHHa,
Y 3 — 6HIiHJI,THHa
6WIH.T.lHHa
H MOHOMHUHHa,
, MOHOMHuHHa
3 —
y
6HUHJLlHHa
H T~pauHKJIHHa,
5 —
y
H 3pHTpOMHuHHa,
neHHuH,%THHa
@a3QTa,
y 2 — TeTpaUHKJIHHa,
y 2 — MeTHuHJIJIHHa,
H y 1 60.TbHOrO
IIOGW lIOCJli2f10t3aTeJIbHOI’O
llpHMt2Ht2HMfl
O.TeaHfiOMkiuHHa,
BOWiU~HHi3,
y- BCeX
60,1 bHblX
CHHOM ~PiarH03
~pl+
TOTa.TbHMfi
2 — CBeHHfi
Y
3
XeH~HH
6bUl
H TeTpau!iK.’lUH
M [email protected]~W2T0’
lIepeAHHfi
y
TOTa,lbHiSi’i
7 — TOTaJlbHbJfi
y~e’TpHT
rOHOpeH
H y
H y
~aHHbiMli.
6MIIAHL3rHOCTHPOBaH
59 — OCTpJJfi
TOpnHAHbIfi
XpOHH~eCKafI
JIa60paTopHbmfH
y 60 MyXWiH
y
H l’IpCCTaTHT,
6bI.Ta
[email protected]
nOATBep~eH
ypeTpHT,
y 1 — .’leBOMHWTHH
3KMOHOBOUW1.lHHa,
[email protected]
06C.TelOBaHHH
nepe~HHfi
ypeTpHT
CTpel_lTOuHfla,
/TeqeHH$l
rOHOpeH
K.IHHWIWKOM
H nOLOCTpbIfi
y
~0
y 3
H HOpC~,
ype’TpHT
8—
2 —
OCTp
~peTpHT,
11
H 3nIi~LizHMH
XPOHHW2CKHG
OCTpaH
~
~Pt2TPki
rOHOpefl
HHXHe
wze+~ a.
HbIX
CMeIIIaHHafl rOHOpefiHO-TpkiXOMOHazHafl
(,] O M~XV4HH
H
2 XeHLutiHbI) .
12
Y
B
CB$i31i
60.lbHbIx
.leqeH}ie
C}”[email protected]
l_IO .500 M?.
npenapaT
B KypCOBOfi
coB
Xefi,
Ii ncc.TelymmHe
20—21
?. 60.lbHbIM
Cy.lbf$aHIi.TaMH~OB,
—
Xo3e
C HeOGTOX(HeHHbIMH
14—17
flHH no
i? (nepBMe
1z3
pa3a
!’ ] 2
npenapaTaifH
Ha3Haqa.TH
@3pMaMH
2 ZHfI no
B CyTKH);
@OpMaMH
C TOpnHAHOfi
Ha3Haqa,TH
Ha6.TI02a.TaCb
60
rrpoBezeI
aHTH6HOTIiKOB.
H [email protected]
60JIbHbIe
TOpn Si~HOfi H XpOHHqeCKOfi
JIH ZO
454
cynb$aHlixaminHkniH
C IIenepeHOCHMOCTb10
Ta6.leTOK
[email protected]
rOHOpeli
qepe3
B
B
nOJI~~aJ
KaXlbIe
8
c oc.loxHeHHofi,
KypCOBy10
H XpOHH~eCKOfi
HMMyHOTepaIIHD
1,5 ?
nHuaM
BH~Tpb
rOHOpeH
~03~
c
~Be.l HWB
@OpMaMH rOHOpeM, KpO
(rOHOBaKUHHa).
~~eCTHCE!
~eHHf3ypeTpbJ
BOBpeMJ4
@3MOHOMeTOKCHHa
(cozoBafl
Bo3a,
y
NI$J
KOTOpbJX
60.Tee
B nopaxeHHohi
ypeTpHT
6bICTpOr0
opraHe
H HhfM~HOTePaJTWO,
H
JlpeJlapaTOB
B
HenpOBOIHJJU.
AHli npHeMa
[email protected]
C} Jib-
JUe.10qHOf?TIHTbe
60pX0MH).
~0.lbHbJM,
CTaTliTOM,
npUeMa
H [email protected]
COJTpOBOXQla.TCff
pa3peLJleHHfi
oxHoBpeMeHHo
HH-beK~HH
3JTH,IM2HM11TOM Ji.’lIi
LIOCna.7JlTe.7bHOr0
c [email protected]
Ha3Ha~a.~H
@i3HoTepaneBTHqecltHe
nHporeHafla,
npO-
[email protected]
ayTo-
npouelyp~
Xp.
.~eqeHHe
C~JJbI$aMOHOMeTOKCHHOM
u 5 weH~~Ha\[),
JJpH3TOM
.leqeHHH
HOrO
35
pa3.TWIHbJMli
nepeHOCH\!OCTb
~
BCeX
6HOTHKaMH)
JIe.7eHHFl
CJJe20BaHHIi
paHee
~’shi}XUJliH
~epe3
4
H306-
OKOHqaHHR
pa3JIW-IHbJMH
TePaIJHH
rOHOKOKKki
~
M(?CWRB.B9
KJJHHIJqeCKHM
JleqeHlifl
60JIbHbIX
HaXOAHJJHCb
H Jla60paTOpHbIM
OCTpbJM
ypeTpHTOM
y
~epe3
9 ~eJIOBeK(B
60JJb-
5—11 fiHefi JTOCu7f2 OKOHneqemoro neHHUFi.’l.TFJHOM,
paHHFie
TOM qHCJJe
CpeRH
6WJ ymaHoBfleH
roHopeH
paHee 6e3ycrJeuJHo
[email protected]
KOHCTaTHpOBaHbJ
HeOJIHOKpaT-
06GJeJ10BaHH5JM.
peU~AHB
Ha6JIJO-
nOAHaHIHM
IJepF?OA [email protected]
TOT
TepanHu Hy 1 60JJbHOr0,
11/2 hiecflua).
~OC.ne TepaJTHH
6bI.TH
84 MyHPUfH,CTpalaBIlHlX
llOCJle
[email protected],
y5M~WIHH(y
qaHH5i
BbJ-
rOHOKOKKFi.
~PeTPbJ
1-8
JJeqeHHbJX
aHTH-
(06WJbHbIe
?260JJbHMX
(B TOM ~HC.Te y 15 u322
paHee
Y126wbHMx
.leqeHHe
[email protected]).
H3 [email protected]
nOBTOpHblM
.X,
(B TOM
pa3,1HqHbIMH
MOqa) np020.TMa.TH
OCTaBaTbC$i 6e3
JIeqeHJiH,
a npH MHKpOCKOnHqeCKOM
6bLHnpIiMeHeHy
6e3ycne~H0
JJeqeHHbIX
MeTOKCHHOM 6JW70 6e3pe3~JJbTaTHbJM.
BCe60JJbHbIe
nOCJle OKOHqaHH$l
‘W
HCqe3.TH !“ 6660.TbHbIx
JJeqeHHbJX
CHMnTOMbJ 3a60.TeBaHHH
HWIOCPeJICTBeHHO
~#$HHeMBTtqeHHt2
OpraHOB
&3yCneUIH0
KJJHHHqeCKHe
06HapyXHBaJfHCb
rOHOj)eJi.
HCqe3JJH
nOJJOBbIX
s560JIbHbIX,
[email protected]
@J)MaMH
(61M~XiliHaM
aHTH6HOTHKaMll
H 7—B
CBH311 C yKa3aHHCM Ha He~OIB.TliRHHeM
lYpatlWi
C!.Tb+a\iOHOMeTOKCFi-
J13 ~peTpbJ,
[email protected]@y3H0
M}THa$i
Hi3
npOTHXieHIiti
BCerO Kj’pCa
ME!HeHHfi
~6960.TbHbJX
npenapaT6bmHamaqeH nocne6e3ycnew-
aHTH61iOTHJiOB.
HO\l rOHOKOKKH H30Tle.lHeMOr0
qHCJJe
npOBeXeHO
HHX
H3
peUHXliBbJ
y
2
paHee
3a60._JeBaHIi5J
.TeqeHHbIX
aHTH-
6HOTHKaMH).
TaKHM
HOKOKKOB)
06pa30M,
CTOfiKOe
HaCTynHJJOy6]
3THOJJOrHqeCKOe
(88,4%)
H3.’JeqeHHe
60JJbHOr0
nOCJIe
(WJe3HOBeHIie
V5panHH
MeTOKCFfHOM (IlpH 3TOM y 33 H3 s5&3yCneUJH0
JleqeHHbJX
63(75°0)
60JIbHbIX
nOCJle Ha3HaqeHHfl
[email protected]
H322c
aHTFi6HOTHKOyCTO%IliBbJMH
dJIfl
H3y~eHIi5t
6bJCTpOTbJ
[email protected]
BefleHbJ
HblX,
lTperJapaTaMH
6aKTepHOCKOnHqeCKHe
JJe~eHHbIX
rpaM~,
TeqeHHe
OT81O48
HHX(36
qefloBeK)
~acoB
— qepe3
HOBeHHH rOHOKOKKOB
HaqaJJa
16—40
y 6ofibHbJX,
Y
16nocne
H~
He
H3MeHeHHfl
BO
JJeqeHHbJX
TepaJIHH
6mM npOy2460Jlb-
BPC!M51Tf?P2iJlHH
OKpaIlleHHbtX
Ma3KOB,
ypeTpbt
HCqe3a.THB
y 6oJJbJ.uHHcTBa
pa3HJiubJ
B cpoKax
lJ3
licqe3-
[email protected]
Ha6JJJOnaJJOCb.
npOIleCCbJ
HMe.7FiCb S ]1
neqeHHe
[email protected],
[email protected]~HMeTOKCHHOM.
TpHXOMOHanM.
HaMH
ypeTpbJ
npHqeM
saMeTHOfi
yCneLIIHO
rJocTroHope17HbJe
BocnaJJnTelJbHbJe
nonyqaBwHx
MyXWHH H 2 XWHIuJ4HbI),
---’aHaJJa
JIOqaCOBkJX
JleqeHHsI,
qacoB.
(9
[email protected]
0TfleJJ51eMOr0
H3 OTAeJJffeMOrO
rOHOKOKKH
rJocJIe
AefiCTBHfi
H y 1560JTbHbJX
HCCJJf?JIOBaHHH
qTO
[email protected],
NaratilH~HMe
‘“
npO&TeHHOrO
Ii
TepanHH
rOHOpeH).
HCCJJe~OBaHHfJ
~PH
yCTaHOBJJeHO,
aHTJi6HOTHKaMH) Hy
(B TOM~HC.Te ~ 13
rOHOKOKKOB nOIBJJHflHHeM
[email protected]
[email protected]
nO
$JOpMaMH
HCqe3HOBeHHfl
rO-
[email protected]
y
11 MyxWiH
B
Y6H3HHX6EJJJH
lTf)H ypeTpOCJ(OnH~
CJJH3HCTOfi
060JJW.JKe
60.~bHbIX
H
06HapyXeHbJ
@JJIH
BbIflB.’J(?HbJ
MOqeliCnyCKaTe.7bHOr0
]0—npWTaTHT.
fleqeHHe
C~JIbf$aMOHOMeTOKCHHOM
Xopoulo, JJ06WHEJX
liocHnH
fiBJJeHHfi
[email protected]
H Cyi’[email protected]
H(2
ia6~loqa.nocb.
lKaJJOBafiC$i
60JJbHbJe
nepe-
~qHUJb OAHH 60JJbHOfi
Ha He60.TbUJ~IO
rO.10BH~JO
455
“+
;,[email protected]; ,
q?
;fjf
1, .
;;,
flJIfi
‘--
. ..’.
$! .,,..
,:, .,.
/’.”y
i303MoxHoro~HHHHH
BbincHeHHfl
OpraHH3Ma
MEJ H3y~aJlli
MeHTHyfo
B ~HHaMHKe
@y HKUHKI “rIeqeHH
IV+ I [email protected]
COCTaBa
Ha HeKcrropMe
TaKHM
JIaTb
06pa30M,
BMBOA,
Tepamm
HOpMbI
3HaqeHH51 erO B KypCOBOfi
HMx no.ToBbrx
@06aH
MOIK~
HaHIHX
14—17
2 60.TbHblM
xe.le3,
a TaKxe
npH T0pITK2HbIX
UeHHOCTb [email protected]
6bITb
npHMeHeH
y 60,TbHbIX,
II03BOJIHIOT
[email protected]
3a60.TeBaHH$i
Ii3J~eqeHKfi
LT$4
f103e
~p H 3TOM OTK.TOHe-
HCCJlexOBaHHfi
flBiTffeTCfi
HaM C~e-
CpeXCTBOM
xOCTaTOqHO
C HeOC.TOXHeHHbl!vfli
20—21 Z IIpH Ha.’IliqHHOGIOXHeHHfl
rOHOpeH H B 103e
KpO-
ero oKoHqaHHH.
Moqy,
He Ha6JI10AaJlCCb.
pe3ynbTaTbI
roHopeeii.
lTHr-
6HJHfPY6HHa B CbIBOpOTKe
KpOBH H COfieplKaHHff
qTO [email protected]
60.TbHblX
@YHKIIH~
KpOBH,
cocTaB Mow. J-4ccd~ezoBawfe
[email protected]~qecKoro
JO JeqeHFi$l
H Cl_i)KT$i
7— 10 nHeil rmue
BH ~pOBOflH.7H
KpOMe Toro,
liccJIefloBaJIH
BO BpeMfl
npHeMa
nperfapaToB.
HHfi OT @i3HOJIOrHqeCKOfi
!
H
Hpe~apaToB
COCTOS7HSfe [email protected]~eCKOfi
CO CTOpOHbI
H xpoHw4ecKHx
B
Ha-
i#)OpMaWi
ITpHZaTOW-
@pMax.
COCTOEiT B TOM, qTO OH C yCIIeXOM
KOTOpMM
Ha3HaqeHHe
aHTH6HOTFiKOB
llpo-
TFiBOnOKa3aH0.
YWiTbIBaH,
HbIX
rOHOpeeti,
qeM
HCK.TIOqLiT&TbHblX
3HaWTe.lbHO
CyJtb(#IaMOHOMeTOKCHH ,
l1060qHEU
B03HHKHOBeHH$l
B
qTO Cy,Tb(#)aflHMeTOKCSIH
a
MeHee 3(#teKTHBeH
TaKXe
K erO Ha3HaqeHHI0
pWiKulifi,
66JIbUI y~
C.Te~~eT
y 60.’Ib-
BF3PO$lTHOCTb
I’Spli6fWaTb
.7WIlb
C.Ty51a$IX ,
ti’I~l TEP.\TYPA.
l. OBIrir HHHKOB
H. M.,
.Typbec.
C.,
~Bac
H a SI H. i’i. Ypo.I. H Her$po.~., 1966, .V! 5, c. 40. — 2. ~ e c H H a 3. .k. B KH.: Haywue
3aIIHCKH
rOpbKOBCK.
Ha~qHO-HCC.lf3X. HH-Ta JepMaTO.10rHH
H BeHepO.10rHHH Ka(@XpbI
KOKHO1964, B. 2+, C. 272. — 3. G i ? L,,
BeHepHWCKliX
60.le3Hefi,
rOpbKOBCK.
!+iex.
HH-Ta.
rOpbKiifi,
Lo din
A., 3{ 01 i n L. et al. .%cta derm. -venereo[. (Stockh.), 1968, v. 48, p. 272. —
H., Luger
.4., Z. Haut. -u. Geschl. -I(r., 1968, Bd 43, S. 865. —
4.~resbach
H C. .7.,
5. R 6 c k I H., Munch. med. Wschr,, 1962, Bd 204, S. 1169. —6. K03H
~ep~aTo,~., [970, ~?],
c. 7’g.-i.KyHUe~!iq
J~,l.,
fl H T H K o I-I A, H. BeCTH.
cTapoc
Twua~.
d._f’aMxce,
1969,
.V’2,
C. W-8.
Typa
H
oea
E. Fi., Hio HIi
KOBil
O.lZi..
~OT~IIHt?B
@. B. Hflp. Ta~xe,1970,
N! 10, c.65. —9.
Le.
igh
D. .+., Turnbul
A.R.,
Le Franc
V., Brit. J. vener. Dis., 1969, v. 45,
.T., 1958. — i [. ~ O p
p. Is!. – [0. .T H 60 B .4. J. f%60qHNe ~erk’rBHsi aHTH6HOTHKOB,
us e B H 10 K r. A. BeCTH,xep~aTo.~., 1960, ~Q3, C.79. -12.
fiH~UIKe
B Hq~C
3.~i.,
LO!d
HHCKHfi
Mf3., l~,i~!l],C.72.—l3.nOpy
K a Y.T H II K WC Izi. Ii. IGHH.
.-.
U.
M.,
Typa
HoBa
E.
H.,
@f) MaKCb7, H
TOKCHKO.?.
H
, 1966,
M
4,
v. 239, p. 92. — 16. C 1 ar kson
17.
zer
10 H B K o B a
H
~5,C.40.—l~.naXe*CK.S
E.H.,
c.
nO.l
472.
R.,
—
15.
O.
M.
BeCTH.
YXHHa.~.
S a c u
m a
M.,
T.,
zep~aTo.~.,
~ef)UIHH
1967,
r.H.
Am. J. med. Sci., 1960,
Ma
r t i n A.,
Nature,
1961, v, 192 p. 523. —
1962, v.4,
p.386.
—I8.
Sch
nitR e d i n G.,
M CC o y M.,
Chemotherapia,
R.,
D e Loren
zo
W. et al. Proc.
Sot. exp. Biol. (N. Y.), 1958, v. 99, p. 421.
~OCTyIIH.1i3 6 I ~
COMPAR.4T1VE
EVALUATION
OF THE R.\ PEUTIC
OF SULPHAMO\OMETOXIN
AND SULPHADI.METOXIN
WITH GONORRHEA
F.
Central
V. Potapneu,
A.
A.
19;: r.
EFFICACY
IN P.4TIENTS
Skuratouich
Research Skin and Venerological institute of the USSR
and Central Post-Graduate
Medical Institute,
Ministry
Moscow
of Public
Health
Data on the treatment of 84 and 69 patients suffering from gonorrhea with sulphadimetoxin
and sulphamonom.etoxin respectively are presented, Sulphanronometoxin
was more effective
than sulphadimetoxin.
Sulpharnonometoxin was especial] y act ive in gonorrhea cases previosly
treated without any success by various antibiotics.
with pWmf$$Wl
the [email protected]!
‘aoce Center
CPABH14TEJlbHAJl OIJEHI(A TEPAIIEBTkiYECKOh [email protected]
CYJlbOAMOHOMETOKCHHA U CYJIb4A)N4METOKCJ4HA
Y 60JlbHb1X rOHOPEEh
@@l
Bf?HePO.10rHH
(3 ZIB. —
[email protected]
T.
B.
BaCHJIbeB)
KoH(ffbIXH
BeHePHqt?CXHX
6one3Hefi
(3aB.
—
~COBePILleHCTBOB2
C
Jle~eH14Fl
ro
B apCeHa.1
60.TbHbIX,
.qeqeHufi
H
OflHaKO
npHBeJIO
6~na
CCX?xHHeHS{5fSf
HHUWL~MHa
A.
A.
3ApaBooxpaHeHHsi
AHTOHbeB)
CCCP
H [email protected]
~eHTPaJlbHOP3
HHCTtfT>Ta
BpNlt!tt,MOCKBa
HEJl
neHHuWIaIuHaH 3aTeMApyrkfx aHTH6uoTuKoJ3
[email protected]
noflB.leHHeM
.~aMHAHbIM
[email protected]
HaJ~HO-HCCJeJOBaTeflb-
~E!HTPaflbHOrO
cKoro KowHo-BeHepo.lorH~ecKoro HHcTHTyTaMHHiKTtpCTBa
IIpHBeJfO
HHe
BCerfla
CpeflCTB
060CHOBaHHOe
K llO$fB.TeHHfO H nOCTeffeHHOMy
KOB C nOHWKeHHOfi
BTOpOCTeneHHafl
pOJlb.
pe3K0
CHHXeHMm
K 3HWIHTeJfbHOMY
Y 6oxbHbix
roHopeefi.
oc.qoxHeHKfi
UIFfpOKOe
OTBeAeHa
npOTFiBOrOHOpetfHblX
ne-
CpOKlf
Cfl~q2eB&3]”CfleWH0-
aHTEf6HOTMKOB
IIPHMeHf?HHe
yBeJfJi~eHWI
~yBCTBHTeJIbHOCTbfO
BBeLIeHLfe
COlipaTWTO
WfCJfa
K neHHuHJIJIHH~
llITaMMOB
M Ap~rHM
rOHOKOK-
i3HTli6HOTFf-
KaM [1—51. l_IapannenbHoc 9wM Hatimonaemfi n yrienH~eHuecay~aeB Heyuaq
‘—”i JIeYeHHH6oJIbHbixroHopeefi aHTH6HOTHKaMH
[6—91.
B nHTepaTypeTaKxe Bce~amenonBnHmTcH coo61ueHHHohfHOrw6paqHNx
KJIHHINIeC~HX
@phi2X
JIeKaPCTBf?HHOti
WIJlePrHH
BflJfOTb
AO CJI~Wf?B
CO CMf?PTf2.’IbHbIM
HCXOXOM
llPH
~OJIyfIeHHbIe
Ha3Haqf2HHH
B nOC.’leZHee
THUWIJIHH,
OKCaUH.T,lHH,
6.neMbr TepanHI?
60JlbHMX
HellepeHOCHhiOCTb10
JIeprWfeCKHe
~TO
HFfH [13],
qTO, nOCKO.~bK~
He
IIOBbIUfeHli51
npMMeHmoTcff
IIeHHUHJlflHHbl
(Me-
KaK
OHM MOr~T
Bb13blBaTb
Te
Xe
ZiJI-
neHHuWIflMHbI.
BpeMH BHHMaHlie MHOrlfX HCCfleilOBaTe.~efi
npHCOe.UHHeHH$l.
BbiCKa3blBaJIkfCb
npeflnOJfOXe-
[email protected]&l
y60JIbHbJx
q~BCTBHTe.lbHOCTH
qTO [email protected]~
TaK
H npHpOAHbIe
BCBR3HC3TIiNf
B nOCfleJIHee
BJIeKaIoT
[email protected]$f.’IaMHAHble
lIIIlpOKO
nOJIyCHHRTWleCKIie
aMrfFfUEi,TJfHH H Ap.) He pa3peIlfkf3Ff
nOJIHOCTbK3 npOc aHTkf6HOTHKOyCTOfiWiBbIMK
@pMaMIi
rOHOpeIi
H C
K neHHuWfJIHHy,
peaKuHIi,
[10—121.
aHTH6HOTHKOB
BpeMSl
K
B TeqeHHe
rOHOpeefi,
He
HOCJieAHkfx
[email protected]&KTHBHbI
npkf
neT
B03MoXH~Tb
Ha6nweHJIH
HHM rOHOKOKKOB.
H [email protected]
MHOrliX
IiCKJf~~eHa
I_fOIia3aJfH,
Jlf2YeHHH 60.’lbHbIX
roHopeefi.
~~HTepeC
nocne
K
[email protected]
nonyqeHufi
npenapaToB
31iH, [email protected],
TKBHOCTH npeBOCXO~RT
3Ha~HT&TbH0
COE!~HHf2HHffM
npoaoHrnpoBaHHoro
AeficTBHfi
CyJlbCj13AHMeTOKCiiH H ~p.),
ITpeMHHe
[email protected]
nOBbfCHflCH
([email protected]
KOTOpbk
[email protected]
[email protected]@K-
BHacTomueM
CO06UleHHH
npHBeAeHbl
pe3~JibTaTbI
I13y~eHHH
[email protected]@KTHBHOCTH [email protected]
H CyJ’[email protected]
B TepanHU
60JlbHbIX
rOHopeefi.
CIfH
[email protected]
(CMHOHHMM: hia~f)H60H,
IIJ)O.~OHNfpOBaHHOrO~
(CHHOHHMbI:
AHaMeTOH,
Cj’JlbKCHH,
Cynepcyfib($a)
&CTBSiH.
:AeH~fi,
/Ka.~aCb
r.
,..~
“,
,,
KOHueHTpauHfi
nOCJIe O~HOKfXITHOrO
IOW3COE,
i?nJ)enaPaTa
Ha?qHo-
KOHUeHTPaUHH
Yepe3
[email protected]
l—a
K IIpt?lTi3paTaM
(BHMX?M). B ~K-
M2iKCHM&~bH2ff
KpOBHOHpeleflHfiaCb
BBeleHHfl
C)[email protected]~feTOK-
BoBcecolo3HOM
FfHCTHTj’Tf?
~epXa~TaCb
Ha BEJCOKOM ypOBHf2BTEWHHC
50%
M2KCHMYMa [141.
H COCTaB.lfi.Ta
MaKCHMa.TbHaH
yJIIOAf2fi
BCbfBOPOTKe
If
0THOCffTC$7
BCwpCHHTe3FfJC)OBaHb1
FfCCJ’feAOBaT(2.TbCKONf [email protected]~eCKOM
CiIepHMC!HTe
Ha )KHBOTHbIX
(MMDIH
H K~OJfkfKH)
–[email protected]
DS-36)
B
1—4
qaca
llOCJle
CblBOpOTKe
onPe~eflfieTc~
‘Wfle
YWOCHHKPOBH
‘eP=
3+? qacof3; rmoeHHa ~pHHffToti
x~~
(50%]
BbIBo~HTcH
H3 opraHH3Ma
c M
~epe3 48-72
~aca [15]. B OT.mvweur [email protected]?iJraM$mt
n~
IIoii
llapaTOB
AO 80 ‘~ [email protected]
BOpHMOrO
HOIHIHH
-L
HaXOflHTCfl
B MOW B BHxe
XOPOU.10 Pa(
qTO HpaKTHWCKH HCKXIOqaeTB03MOXHOCTb
rJIIOKypOHHJ(a,
KpHCTaJIJIypHH
B03HF4
[14].
B
oIUITaX
Ha MbuIIaX [email protected]’roKcHH H CYJTbt+3AHMe’rOKCWI
0Ka3
MaJIOTOKCHWWhiH,
HpOHBJIWIH
BMCOK~ XHMHOIVPNIE!BTHqeCKYIO aKTH
JIHCb
Bb13BaHHEJX nHeBMOKOKKOM,
HOCTb ITPH [email protected],
HOI%,
[email protected]
BBf21eHHe
C
Ii
MbIIUaM
[email protected]
CTpenTOKOKKOM,
KHILK
naiTOqKaMH [ lA—l 7 ]. fl.~HTeJbH
6f)[email protected]
He
0Ka3bIBa.’IO
BpeAHOrO
2eI?CTBHH
nOTOMCTBO r 18].
<[email protected]
HHOMH [email protected]
HHOhInpOBefleHO
(148 MyXWHH H 5 XeHUHH),
CTpaflaBUIHX
pa3.THqHEJMH @OpMa!
1.53 60.TbHbIX
rOHOpefiHO#i
rxe
flHCnaHCepHOrO
60,TbHbIx
12—17
JHefi
Ha6.TIOAeHH$I
H HeO~HOKpaTHbIX
Ha
92
[email protected]
OHH Ha XO~H.THCb
rOHOKOKKIi.
&Ta.lbHbIe
BBo3pacTe
TOJlbKO
OTpHuaTeJIbHtJX
XO
20
B ypMorHqecKoM
JTeqHJIH
H 6m~ee
H BbInHCEJBa.lHCb
nOCJIe
60JlbHbIe
70 6(klbHbJX,
nOJIy~a.TH
JTeqeHFIe
11 6oJIbHMx,
l~lb
5 DO 7
a
60.~ee— y 5. Y 6
H
TaHOBLiTb
OT 810
He V~a.TOCb.
2
MecHueB
WJTOBeK
OT
3a60JIeBa
OT 2 Heflemb
—
46,
y
21
10—14
MHTe.’lbHOCTb
C flaBHOCTbK3
14 XH&7 — 36,
H 60.~ee
AHefi —
no
6w~a
TOPbIl[
6EJI0 Ha3Ha~eH0
57
HOM,
paHfR
fieW6HbIX
nocle
aM6y.TaTOpHO.
xoso.’IeT—
~H$l 6EJ.1
AHefi
HHfI JO 7 ~Hefi
— 52,
2 HefleJlb.
JIHHa
,leqeHHe
H Tf3TpaUHKJIHHa,
@130.7a,
BOMIfUeTHHa,
}- BCeX
nOGTe
60,TbHbIX
~pH
H(
6LWI0 34
y~
60.lbHbf!
1
—
60.nbHEIX
,
K(
H Cy.WK$a~KWTOKCL
aHTlf6WTHKaw-1
peuHmKB
B lp~rH:
rOHOpeH
HaCT~IISl:
3KM0H0B0uH.~
H lIeBOMliueTHHa,
5 — neHHuH.7
4 — 6HuHJIJIHHa-s,
y 3 —
TeTPauHKflHHa,
Y
Jie~eHHfI
MOHOMHuHHa
Y
Y
npHMeHeHHfl
HOPC~.TE
3KMOHOBOUJi.%TliHa,
tile
H TeTpaUIiK.TKHa
H [email protected]
JIa60paTopHiwH
y 60 MyXWHH
H
l–.W2BOMFiUeTHH
[email protected]
[email protected]’TOKCHHOM
noATBepxfleH
K.TJiHWIeCKOM 06C.TezOBaHHH
H 3pHTpOMHUHHa
s—IIf?HHUH,WIHHa
Z–MeTHuHJUIHHZi,
CTpenTOUH~a,
6bUf
y
6uunJmHHa H 3pHTpOMkiUHHa,y 3-
nOCJleflOBaTeJ’IbHOrO
~0
3a60.-r~
153 &),lbHblX
(& H3HJlneHHuH.%THH,
H
roHopew
laBw3cTb
qTO H3
neHHu$i,WIHHa
CLleaHIOMFiUHHa,
lHarHo3
2
neHHuHJIJIHHa
z–TeTPauHKJIHHtl,
H y 1 60.TbHOrO
cuHoM
y
TeM,
pa3JfH~HMMH
H3 3THX
H MOHOMHUHHa,
MOHOMHUHHa
Y
m
lleplio~a
OT 1 AO 2 hIecflueB
[email protected]
17
11 —
y
06WlCHfIeTCfl
,Te~HJIHCb
Y
npenapaTa,htH
y 3 — 6HUH.T,WiHa
6HUH.1.THHa,
~0
&3yCneUIH0
6HUH.WIHH-3),
KOHCTaTI
26,
— y
HHKy6auHOHHOr0
1 Mecfiua
lo
12.
}qpeXQeHHHX.
.-IeqeHHfl
JIHH,
—.
CBbllUe
HCC.7exOBaHH
rola
TaKHM06pasoM, 60.~ee qeM y noJIo6HHM60,TbHbcx(83)
BaHHH
IIpOBOKaUH
,Ta60paTOpHOr0
40 .’wr — 8 60.TbHbrx.
OT 31 roza 1040
.wT — 32 H cTapwe
~’iHKy6auIiOHHbIfi
llepHOfl
npOAOiTWTeJIbHOCTbD
3--4
pOBaH y
za.lbHefiIUer
KOh16HHHpOBaHHOfi
pe3yJ’IbTaTOB
.wr6wIo
cTauHoHapf
x.lfl
3aHHbwi.
6bi.I~HarHOCTlipOBaH
OCTpbI
Tcma.lbHNfi
ypeTpHT,
y 11 –
H nomcTpbcfi
nepexHHfi
ypffpHT,
y 59 — ocTpIJfi
TOTa.JbHI&
ypeTpIiT
H npOCTaTIIT,
y 7 — TOTa.TbHblfi
~peTp HT H 31TFizH~liMH’1
y
Y
2 — CBeXH:f
3
IIepeAHUfi
TOpnH~Hblfi
ype’TpliT
H y 8 — XpOHH~eCKHfi
6bIfla
XpOHWIeCKa$l
rOHOpe$l
H y 2 — ocTpaH
rOHOpefl
XeHq!iH
~peTpHT.
HHIKHerC
arxe.la.
CMeLUaHHi3H rOHOpefiHO-TpHXOMOHalHafi
(,10 My XWLiH
HbIX
}B
12
CBR31{
H 2
60.~bHb]x .~eqeH~e
C
C}’[email protected]?TOKCHH
lTO ~
rIpenapaT
B KypCOBOfi
COB
lKefi,
H
TOpnHaHhfi
JIH ~0 20—21
454
,W.
[email protected]’1.Te~vK)u}Ie
Cy.lbi$a
[email protected][HIHbrMH
HeIIepeHWHMOCTbIO
Ta6.leTOK
Xo3e
C HeOCJIOXHeHHbIMH
14—17
rIO
i!. 50.lbHbIM
.? (rIepBbIe
1e3
H XpOHHWCKOfi
HHvTaMHJOB,
Ha6.llOla.TaCb
~
12 60.Tb
npenapaTaw
pa3a
2 JHH
B cyTKH);
@OpM21MH rOHOpf2H
Ha3Haqa.lH
HMMyHOTePanHK3
BH~Tpb
(#)OpMaMH rOHOpeH
no
B
BH~(
nOJI~qa.1
1,5 z Wepe3KaXlbIe 8 qa
JTHua!vf C OLIOiKHeHHOfi,
KypCOB~W
C TOpn H~HOfi H .XpOHH~eCKOfi
Ha3Haqa.Tli
npoBezeH(
aHTH6WrliKOB.
H [email protected]~HMeTOKCliH
50JlbHbIe
~HH
[email protected]
MeH~MHbl).
J03y
@pMaMH
(rOHOBaKuHHa).
CBe
yBe.TWIHBa
rOHOpe H, KpOMf
~feCTHOe
.le
qeHHe~peTpbl
BOBpeMfl
@MOHOMeTOKCHHa
(coxoBan
Bona,
~0.lbHbIM,
IlpUeMa
60pwoMH).
y KOTOpbIX
CTaTHTOhf, JU15J 60.lee
B nopaXeHHoM
opraHe
H HMM~HOTf+NUHO,
u
IIpenapaTOB
H [email protected]
~peTpFiT
HenpOBOxHflH.
Ha3Ha~aJIH
BAHHnpHeMa
CyJIb-
06HJTbHCW lUe.~O~HOe IIHTbe
COnpOBOXAa.’lCfl
3nHXHN0.iIiTOM
H.’IH npO-
6bICTpOr0
pa3peUieHHH
BOCna.TlfTeXbHOrO
[email protected]
Ha3Ha~a.lH
ay-roolHoBpeMeHHo
c c>[email protected]\iHfla\fli
HH’WKIIHH nHpOreHaJia,
@H3HOTepaneBTH~eCKHe
npOUeZypbl
Xp.
.~e~eHHe
C~.Tb$a%iOHOMeTOKCHHOM
H 5 xieHiuHHa~f),
35
rIpH 3TOM
HOrO .TeYeHHH pa3.TH~HbIMH
nepeHOCHMOCTb
y
a560.~bHblX,
Y3MyWUiH
H3 ypeTpbI,
MeHeHHfi
Ha npOTWKeHHM
[email protected]@’3H0
C ~Ka3aHHeM
Ha [email protected]
ne~eHHH,
aI_IpH
~BToM
pa3.lH~HbIMH
MO~a) np030.TXa._iH
KypCa
aHTH-
(06WlbHbIeBbI-
OCTaBaTbC$i
6e3
H3-
06-
MHKPOCKOITHW?CKOM
rOHOKOKKH.
84 MyHfqHH, CTpalaBIilliX
6EW1IJPHM6!HC?H%
HenOCpeflCTBeHHO
rOHOpeH.
y 6660.nbHblx
JleqeHHbIX
CHMnTOMbi 3a60tileBaHHff
M}THa$i
BCerO
06HapyKHBa.~HCb
C~JIb+IalUiMeTOKCHH
@OPMaMH
Ha3Ha~eH
Hcqe3.lH
6e3j’CneLUHO
KnHHHqeCKHe
Ae.7eHli51
CJIelOBaHHH
noJIoBbixopraHoB
paHee
(6i MyKiHHaM
nocne6e3ycriem-
~6960flbHbIX
aHTH6HOTHKaMH H 7 —BCBH311
~Ofl B.TlifIHIieM
TepaI’IHl{
M30Tfle.3Hehforo
BCeX
6HOTHKaMH).
npOBeXeHO
npenapaT6bI.n
HHX
aHT~i6HOTJiKOB.
HoMroHoKoKKM
~HGTe
H3
nOC,Te
OKOH~aHHSl
pa3JlH~HbIMH
TepanHH
rOHOKOKKH
oTxenfieMoroypeTpbi y 7260flbHMx (B TOM wic.~ey 15 H322paHee
y]260JIbHbIX
.le~eHHe
[email protected] aHTH6HOTHKaMH).
ncqe33rH
H3
6bIJIO6e3pe3yJlbTaTHbIM.
MeTOKCHHOM
Bee.
6031bHble
~eHHeMB
‘%
IIOC.Ye OKOHqaHHfi
IIOBTOl)HbIM
X,
ne~eHHH
HaXOLUinHCb
TWeHEie ]-8 MeCflUeB.B3~nepHOA
KnHHHqeCKHM
JIeqeHHbrX
H [email protected]
C}[email protected],
Y5M)W-IHH(Y
4 60JIbHbIX
nOXHaUJHM
OHHnOWepraflHCb
06C.leJ10Bi3HH$iM.
P2UHWB
OCTPMM ypeTpHTOM
IVHopeH
@Wi
6WI
5—11
~epe3
Ha6J’no-
Hf.?OAHOKpaT60Jlb-
yc’raHoBJeH
2HE% llOCtiTe OKOH-
>’
qaHHH TepanHHHy 1 6onbHoro, paHee 6e3ycnemHo neqeHHora neHRuw~.viHoM,
~epe3 ll/z Mecfiua).
paHHHe
pf?UHNiE!bl
3a60.leBaHHfi
~OC.~e Tepal_iHH [email protected]
6bl.7H KOHCTZiTHpOBaHbl }’ 9 ~eJIOBeK (B TOM qHCne y 2 paHee JleqeHHbIX aHTH6HOTHKaMH).
l_aKHM
HOKOKKOB)
06pa30M,
MeTOIiCHHOM(npH
63(75°0)
H322c
CTOI%KOe 3THOJ10rHqeCKOe
HacTynHnoy61
3TOM y
flJlHH3~qeHHH
HblX,
33
li3
6blCTPOTbl
nO
HCW23HOBeHHflr
6aKTepHOCKOnHqeCKHe
JIe~eHHbIX
rpaM~,
HHX
yCTaHOBneHO,
0T8A048
rOHOKOKKOB
(9
MjWIFiH
y
16noc.~e
rlocTroHopefiHble
H
Haqana
[email protected]
OTJlenReMOrO
~
13
HaMH 6bIJIH
ypeTpbI
y24
npO6onb-
BO BpeMfITepaIIIiH
H3 OTAenfieMOrO
neqeHHfi,
npw3eM
~peTpbl
HC~e3a.~MB
y 6onbIuHHcTBa
H3
16—40 ~acog. Sahiemlofl pa?,HMuMB cpo~ax licqesHe
yCneU.lHO
JleqeHHbJX
[email protected]
Ha6JIK)~aJ10Cb.
BocnanHTenbHMe
nOJIyqaBUJHX
npOUeCCbi HMe.lHCb ~ 11 60.~bHblX
neqeHHe
[email protected],
H
2 XeHuHHbI),
TepanHH
TOM~HCti~e
1701B.lHfiHHeMTePaHHH
flefiCTBHfi
H y 1560JIbHblX
rOHOKOKKH
nocJIe
C>[email protected]~HMeTOKCHHOM.
~ara,lH~HMeTPHXOMOHanM.
.
IiCCJle,40BaHHH
nO~aCOBIJX Ma3KOB, OKpaUIeHHbIX
6onbHMX,
Y
C~nbI$aDHMeTOKCHHOM,
rO-
[email protected]
aHTH6HOTHKaMH)Hy
(B
OHOKOKKOB
IiCCnelOBaHHJI
qTO
~acoB
H
.~HaJia
(JiCWX3HOBeHHe
TepanHH
JleqeHHblX
i7pO~eHHOr0
[email protected]
(36 Ye.noBeK)—~epes
HOBE!HHH
nocxe
s56e3~CneLUH0
IIP.31FiPaTaMH
[email protected] ~~H
Te~eHIie
H3.’le~eHHe
6onbHoro
60nbHMx nOCJIeHa3Ha~eHHfi
[email protected]
aHTH6HOTHKOyCTOI%[email protected] rOHOpeH).
[email protected]
BeAeHbl
(88,4?w)
~
H3MeHeHH5i
11
MyxqHH
B
CJIH3HCT0fi
y6H3HHX6bInki
npH ypeTpOCKOnHIi
060.JIO~JK!
06HapyXeHbl
6wH
BbIflB.’IeHbI
MOqeHCrI)’CKaTe.’IbHOrO
;:
H y ]()-npOCTaTHT.
ti~eqeHHe
[email protected]
rl-060qHbIx fiBJIeHHfi
[email protected]
‘.
H CYnb&3nHMeTOKCHHOM
He
~a6~io~a.mcb.
ManOBanCfI
w~WJb
Ha
60nbHble
nePe-
OAHH 60JlbfiOfi
Hf?60JbUl~i0
rO.10BH~IO
455
I
;
Lq;
f
[!f :..
., .’.
J..,..;,
.=——.
‘G
.npenapaToB Ha HeKoTopMe
I$yHKUH
flJIH
BEJRCH6!HHH
rmwoxmoro WIH51HHfi
OPraHH3MaMMH3y~aJIHBhHHaMHKe
C~O$iHHe
MeHTHYIO $YHKUHIO-IWWHH
;
!+- .
cocTaBa
‘.i?
.’
BH
:,.”’
:.?
[email protected]~eCKOfi
KpOBH
TOrO,
IICC.TC?flOBaJfH
BO
HHfi OT @H3HOJIOrHqeCKOI?
TaKHM
JIaTb
~
MOqH.
[email protected]
~CCJleA0Bi3HHe
HCOflepXfaHH$l
06pa30M,
BP(3M$I
HOpMbl
l’IpHeMa
KPOBH, llHr-
[email protected]’W-If2CKOr0
B CblBOpOTKeKpO-
6Hmipy6HHa
20 .leqeHuff H crryffn 7—10flHei’i nome
HpOBOAH.TH
KPOMt3
H COCWIB
ero
oKoHqaHHfi.
IlpfYIap ZiTOB.
~jllf
3TOM
MoIIy,
OTK.70H&
He Ha6JH0AaJ10Cb.
pe3yJIbTaTbl
HaUIHX
HCCJieXOBaHHfi
I103BOJIfIK)T
HaM Cae-
BbIBOA,
qTO C~,[email protected]
HB,TfleTCfl [email protected]& KTHBHbIM CpexCTBOM
B
[email protected]
Ha60._fbHMx
roHopeefi. JUSH H3.~eqeHHfS 3a60.7eBaHHfl
Tepanim
3HaqeHHH erO B KypCOBOfi A03e
rOHOpeH H B ~03e 20—21 ZIIPK
14—17
HbJX 110.10BbJX
npHTOpnH~HEIX
@tiafl
We.Te3,
a TaKXe
Z60.TbHbIM
C HeOC.’lOXiHeHHbIMH @3pMaMH
Ha.THqKH OGIOXHeHHSl
CO CTOpOHbl npH~aTO~H XpOHW-IeCKHX
ueHHOCTb [email protected]~OKCHHa
MOIKeT 6bITb
npHMeHeH
y 60JIbHbIX,
@OpMaX.
COCTOHTB TOM, qTO OHC yClleXOM
KOTOpbN
Ha3HaqeHHe
aHT136W3THKOB
llpo-
THBOnOKa3aH0.
YqHTMBaH,
[email protected]
HblX [email protected],
B03HHKHOB(?HHH
B HCK.lfOWTe.ll,HbtX
H
3HaqHTetiTbH0
\[email protected]
~eM [email protected]?TOKCHH,
a TaKXe
l1060qHblX
[email protected],
KC?rO Ha3HaWHWOC.
y60.Tb-
BI+IOfITHOCTb
66flbmyro
TeJyt2T
ITpM&lllTb.THIHb
C.TyWHX.
JfIi TEP.4TYPA.
l.O BqMHH$l KOB H. M.,
c. c.,
.-fypbe
a R H. M. Ypo.T. H [email protected], ]966, .Y! ~, c. 40. — 2. fT e c H H a 3. .~. B KH.:
3a17HCKH
rOpb
KOBCK.
Hayq
Ho- Hcc.Te~.
60.Te3Efeii. rOpbKOBCK.
BeHepHWCKHX
xephiaTe.lorHri
HH-Ta
Me~.
H Be Hepo.7orHH
~Bac-
Hay ’wrue
H Ka($expbl
KOXHO-
rOPbKHJ%, 196+, B. ’24, C. 272. — 3. G i P L.,
HH-Ta,
Lo din
A., .M 01 i n L. et al. Acts derm. -venereo[. (Stcckh.),
1968, v, 48, p. 272. —
4. Kresbach
H., Ll]ger
A., Z. Haut. -u. Geschl. -f Q., 1968, Bd 43, S. 865. —
5. R 6 c k I H., Miinch. med. Wschr.,
1962, Bd 204, S. 1169. — 6. ~ 03 H H C. .T.,
11 x T H K o n
CTap
HHKOBO
igh
p.
.\.
BeCTH.
S,~.
O.
Pi.,
K
r.
Ka y.7 HfiKMc
M.,
l&5,
Typa
c.40.
-14.
.+.
Tan
HeB
B
.\.
H. Pi.
HoBa
tiq.
E.
XeAc
N9[,
c.
c.+4.
—
Le Franc
fT060WHfJe
xep~a-ro,y.,
i(.IHH.
1970,
.N_s2,
79.
—7.
&Typa
KyHlIei?Hq
MeJ.,
H.,
Kafl
c.65.
v,
~eI%2TBH$7
Brit.
J. vener.
aHTH6HOTHKOB.
.~.,
19~,,~Qq,C.79.—l2.fiH~WKe
1960, N:ll,
H 10 H H K o B
E.
H.,
c.72.
a
l_f 0.7Yx
O.
-13.
H.
HHa
—9.
1.,
Hm Le-
Dis., 1969, V. ZLj,
1958. — [ [. K O p BHq~C
3,~1.,
llopy
BeCTH.
fl.
.7.
E, H.,
HoBa
@.B.HApTa~xe,1970,N~]0,
[ A, R.,
BeCTH.
Ila
AepwaTo,~.,
Ta~xe,1969,
l_lo
D. .1,, Turnbu
151. — 10. .1 }160
ur e B H o
EL
M.
OCTHHa
,lOMHHCKHfi
Xep~aTo.q.,
~ep
JM.,
UIHH
1967,
r.fl.
OapMaK&l. H TOKCHKOJI., 1966, N 4, c. 472. — 15. S a c u m a T., Am. J. med. Sci., 1960,
V. 239, p, 92. — 16. Clark
son
R., Mart
in A., Nature, 1961, v. [92 p. 523. —
17. Re din
G., .Mc COy
M.,
Chemotherapia, 1962, v. 4, p. 386. — 18. S c h n i t zer
R., D e L o ren zo W. et al. Proc. sac, exp, Bio[. (N. Y.), 1958, v. 99, p. 421,
rZOcTymi.~a
6 I X
i9T2
r.
COMPA R.4T WE EVALUAT ION OF THE R.\ PEfJT IC EFFICACY
OF SULPHAMO\OMETOX
IN AND SULPHADIMETOX
IN IN PATIENTS
WITH GONORRHEA
F. V. Potapnev,
Central
A.
A.
Skuratovich
Research Skin and Venerological Institute of the USSR
and central Post-Graduate
Medical Institute,
Ministry
Moscow
of Public
Health
Data on the treatment of 84 and 69 patients suffering from gonorrhea with sulphadimetoxin
and suiphamonometoxin
respectively are presented. Sulphamonometoxin
was more effective
than sulphadimetoxin.
Sulpharnonometoxin was especially active in gonorrhea cases previosly
treated without any success by various antibiotics.
_—_
—
A. INGREDIENT NAME:
TINIDAZOLE
B. Chemical Name:
l-(2-ethylsuphonylethyl)-2-methyl-5 +itroimidazole
C. Common Name:
Fasigin
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
—.-
99.36’XO dry basis
E. Information about how the ingredient is supplied:
Analmost white or pale yellow, crystalline powder, odorless.
F. Information about recognition of the substance in foreign
pharmacopoeias:
British Pharmacopoeia 1993
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Rip% T. The plasma half-life was about 13 hours. Chemotherapy,
Basle, 1977; 14:
1084.
Jokipii, A.M. M Concentrations in the CSF. Jantimicrob.
Chemother.,
1977; 3:239.
Sawyer, P. R. A review of tinidazole in the treatment of trichomoniasis, amoebiasis, and
giardiasis. Drugs, 1976; 11:423.
Wust, J. Figures achieved with metronidazole and ornidazole. Antinzicrob, Ag
Chemother. 1977; 11:631.
—_
Wise, R. The median minimum inhibitory concentration of tinidazole against Bacteroides.
Chemotherapy, Bade, 1977; 23:19.
[email protected], J. The activities of clindamyc~ tinidazde, an doxycycline in vitro.
Antimicrob. Ag. Chemother., 1977; 12:563.
Bakshi, J. S. Amoebiasis. Drugs, 1978; 15(Suppl): 1,33.
Apte, V. V. and Packard, R. S. Excellent response was achieved in patients with
trichomonal vaginitis. Drugs, 1978; 15(Suppl 1): 43.
Welch J. S. A single doe of tinidaz.de was as effbctive as the longer regimen. MedJ
Aust., 1978; 1:469.
Levi, G. C. A cure-rate in patients with giardiasis treated with tinidazole. Am J trop Mea!
HM.
1977; 26:564.
Anjaneyulu, R. Trichomoniasis. J int. medRes.,
_—_
1977; 5:438.
H. Information about dosage forms used:
Capsules
I.
Information about strength:
150mg twice a day
J. Information about route of administration:
Orally
IL Stability data:
Manufacture Date: June 1997
Expiration Date: June 2002
Store in a well-closed container, protected from light.
L. Formulations:
Page -2-
—_
M. Miscellaneous Information:
___
----
Page -3-
. .........—.
. .,.
. .
.. .
..... ..
~
ANALYSIS
CERTIFICATE
NO... ?030:. . ............. . ....
.. . . October
... .. . 1997
. .. .
Your Oral. No. .. .....8th
.,.
..
..:. . . .....-.
. ~~~
Our Ref. No. ,......2..9.0.5 ......... ..... . ...
.
l-/~-
(ethylsulfonyl)
Jp
~2
.
Batch
. ,.
-e~hy~~-2–me~yl-5.
. -nitrOimidazOle’
I
.,.
5723<
. .. .
Quantity
TINIDAZOLE
MATERIAL
““ *
o--Jjf/
..Kg..
.10.-..
75179. .,.....
—
Empirical
formula
Molecular
weight
c8H13N204s
Specific
-
rotation, .... ....... .....
247.28
Light absorption
powder
Aspect
crystalline
Color
creamish
Odor
characteristic
.
odour ,.
,,, Loss on drying
Residue
Taste
Melting
126.1°C
point
on ignition
0.046%
Chloride ........................... ................
Sulfate
Boiling range
.’WX.
10
Identification:::
. .
PH.
Titer
. .
.
(AssaY)
99.36%
.
........... .... . ........ ..................
Heavy metalS.,
conforms
Solubllity
.o,.2565%
Ppm
positive.
.
dry basis
/
!2
h’
. ..
Other
. ... requirements,
.
. ...-
notes
Related substances
Bulk density
....4-.
by TLC
>.-’
:
passes.
0.6502
gin/U
--~
.gz:.: .:”:;;
’’-/+/”””
~““””::.:ExPIRY.DATE”-:”.=_JuNE.2ti2
-
.
.
.
[z
..
. . . .. .. . .: ..----- ——.
_
.
.. ... .
T
..
.. .
...........
.
/
nalyst
‘-
//q/
/
-
QUALITY
CHEMICAL
CONTROL
REPORT
NAME. :TINIDAZOLE
MANUFACTURE
LOT NO. :77405
PHYSICAL TEST
specification
~
TEST
STANDARD.
l)DESCRIPTION
.:
pALE YELLOW FINE
CRYSTALLINE
:usp
—
/BP —. /14ERcK —. /NF
POWDER;
/MART. — /CO. SPECS . —“
ODORLESS.
Y
K-
2)SOLUBILITY.
:
SPARINGLY
—.
3)MELTING
MELTS
SOLUBLE
WATER AND
IN
ALCOHOL;
SOLUBLE
IN
DILUTE
POINT.:
AT
4)SPECIFIC
ABOUT
126-127
GRAVITY.
:
5)IDENTIFICATION
A)COMPLIES
PASSES.
IN
degree.
.:
(A)
AS
PER
IR
SPECTRUM
CO.SPECS.
FAILS .:
:
COMMENTS. :
ANALYST
SIGNATURE.
PREPACK
TEST.
RETEST.
:
:
DATE. :
:
DATE. :
DATE. :
INITIAL.
INITIAL.
:
:
ACIDS.
.—
POSSIBLE MUTAGEN
FIRST AID
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVIDED PERSON IS
CONSCIOUS
CALL A PHYSICIAN.
IN CASE OF SKIN CONTACT, FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES REMOVE CONTAMINATED CLOTHING AND
SHOES. CALL A PHYSICIAN
IF INHALED, REMOVE TO FRESH AIR. TF BREATHING BECOMES DIFFICULT,
CALL A PHYSICIAN.
IN CASE OF CONTACT WITH EYES, FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES. ASSURE ADEQUATE FLUSHING BY SEPARATING
THE EYELIDS WITH FINGERS. CALL A PHYSICIAN.
—
——.
-------------------- PHYSICAL DATA -------------------MELTING PT: 127- 128’C
VOLUBILITY: CHLOROFORM-SOLUBLE
APPEARANCE AND ODOR
SOLID.
------------ FIRE AND EXPLOSION HAZARD DATA ----------EXTINGUISHING MEDIA
CARBON DIOXIDE, DRY CHEMICAL POWDER OR APPROPRIATE FOAM.
SPECIAL FIREFIGHTING PROCEDURES
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES.
------------------- REACTIVITY DATA ------------------STABILITY
STABLE.
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
THERMAL DECOMPOSITION MAY PRODUCE CARBON MONOXIDE, CARBON
DIOXIDE,
AND NITROGEN OXIDES.
HAZARDOUS POLYMERIZATION
WILL NOT OCCUR
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
WEAR SELF-CONTAINED BREATHING APPARATUS, RUBBER BOOTS AND HEAVY
RUBBER GLOVES
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOID RAISING DUST
—
VENTILATE AREA AND WASH SPILL SITE AFTER MATERIAL PICKUP IS
COMPLETE.
WASTE DISPOSAL METHOD
DISSOLVE OR MIX THE MATERIAL WITH A COMBUSTIBLE SOLVENT AND BURN
INA
CHEMICAL INCINERATOR EQUIPPED WITH AN AFTERBURNER AND SCRUBBER
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --MOSHM4SHA-APPROVED
RESPIRATOR
USE ONLY IN A CHEMICAL FUME HOOD
COMPATIBLE CHEMICAL-RESISTANT
GLOVES
CHEMICAL SAFETY GOGGLES
HARMFUL BY INHALATION, IN CONTACT WITH SKIN AND IF SWALLOWED
_.—_
POSSIBLE RISK OF IRREVERSIBLE EFFECTS
WEAR SUITABLE PROTECTIVE CLOTHING
DO NOT BREATHE DUST
POSSIBLE CARCINOGEN
POSSIBLE MUTAGEN
THE ABOVE INFORMATION IS BELIEVED TO BE CORRECT BUT DOES NOT
PURPORT TO BE
ALL TNCLUSIVE AND SHALL BE USED ONLY AS A GUIDE SIGMA ALDRICH
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
SHALL
.-.
—-.
------------------ IDENTIFICATION ------------------PRODUCT #: T3021
NAME: TINIDAZOLE
CAS #: 19387-91-8
MF: C8H13N304S1
SYNONYMS
BIOSHIK * CP 12574 * 1-(2-(ETHYLSULFONYL)-ETHYL)-2-METHYL-5NITROMIDAZOLE * FASIGIN * FASIGYN * lH-IMIDAZOLE, 1-(2(ETHYLSULFONYL)ETHYL)-2-METHYL-5-NITRO- * PLETIL * SIMPLOTAN *
SORQUETAN * TINIDAZOL * TINIDAZOLE * TRICOLAM * TRIMONASE *
------------------ TOXICITY HAZARDS ------------------RTECS NO: N16255000
IMIDAZOLE, 1-(2-(ETHYLSULFONYL)ETHYL)-2-METHYL-5-NITROTOXICITY DATA
IYKEDH 11,811,80
ORL-RAT LD5O:271OMG/KG
IYKEDH 11,811,80
IPR-RAT LD50:2720 MG/KG
IYKEDH 11,811,80
SCU-RAT LD50:3000 MG/KG
YKYUA6
32,204,81
IVN-RAT LD50:>250 MG/KG
ORL-MUS LD50:3200 MGKG
JMCMAR 21,781,78
IPR-MUS LD50:2730 MG/KG
IYKEDH 11,811,80
IYKEDH 11,811,80
SCU-MUS LD50:3940 MG/KG
YKYUA6 32,204,81
IVN-MUS LD50:>250 MG/KG
TARGET ORGAN DATA
BEHAVIORAL (SOMNOLENCE)
BEHAVIORAL (CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD)
LUNGS, THOMX OR RESPIRATION (CYANOSIS)
ONLY SELECTED REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES
(RTECS)
DATA IS PRESENTED HERE. SEE ACTUAL ENTRY IN RTECS FOR COMPLETE
INFORMATION.
------------------ HEALTH HAZARD DATA ----------------ACUTE EFFECTS
HARMFUL IF SWALLOWED, INHALED, OR ABSORBED THROUGH SKIN.
EXPOSURE CAN CAUSE:
GASTROINTESTINAL DISTURBANCES
NAUSEA HEADACHE AND VOMITING
URTICARIA, FLUSHING, PRURITUS, DYSURIA, CYSTITIS, DRYNESS OF THE
MOUTH,
DIZZINESS, VERTIGO, AND VERY RARELY, INCOORDINATION AND ATAXIA,
A METALLIC, SHARP, UNPLEASANT TASTE, FURRY TONGUE, GLOSSITIS,
AND STOMATITIS
EXPOSURE TO ANIYOR CONSUMPTION OF ALCOHOL
MAY INCREASE TOXIC EFFECTS
CHRONIC EFFECTS
POSSIBLE CARCINOGEN
-.
POSSIBLE MUTAGEN
FIRST AID
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVIDED PERSON IS
CONSCIOUS.
CALL A PHYSICIAN.
TN CASE OF SKIN CONTACT> FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES.
REMOVE CONTAMINATED
CLOTHING
AND
SHOES. CALL A PHYSICIAN.
IF INHALED, REMOVE TO FRESH AIR, IF BREATHING BECOMES DIFFICULT,
CALL A PHYSICIAN.
IN CASE OF CONTACT WITH EYES, FLUSH WITH COPIOUS AMOUNTS OF WATER
FOR AT LEAST 15 MINUTES.
—<
—
–~
ASSURE ADEQUATE
FLUSHTNG BY SEPARATING
THE EYELIDS WITH FINGERS, CALL A PHYSICIAN
-------------------- PHYSICAL DATA -------------------MELTING PT: 127-128’C
VOLUBILITY: CHLOROFORM-SOLUBLE
APPEARANCE AND ODOR
SOLID.
------------ FIRE AND EXPLOSION HAZARD DATA ----------EXTINGUISHING MEDIA
CARBON DIOXIDE, DRY CHEMICAL POWDER OR APPROPRIATE FOAM.
SPECIAL FIREFIGHTING PROCEDURES
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES.
------------------- REACTIVITY DATA ------------------STABILITY
STABLE.
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
THERMAL DECOMPOSITION MAY PRODUCE CARBON MONOXIDE, CARBON
DIOXIDE,
AND NITROGEN OXIDES.
HAZARDOUS POLYMERIZATION
WILL NOT OCCUR
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
WEAR SELF-CONTAINED BREATHING APPARATUS, RUBBER BOOTS AND HEAVY
RUBBER GLOVES
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOID RAISING DUST
_—_
VENTILATE AREA AND WASH SPILL SITE AFTER MATERIAL PICKUP IS
COMPLETE
WASTE DISPOSAL METHOD
DISSOLVE OR MIX THE MATERIAL WITH A COMBUSTIBLE SOLVENT AND BURN
INA
CHEMICAL INCINERATOR EQUIPPED WITH AN AFTERBURNER AND SCRUBBER
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --NIOSHM4SHA-APPROVED
RESPIRATOR
USE ONLY IN A CHEMICAL FUME HOOD
COMPATIBLE CHEMICAL-RESISTANT
GLOVES
CHEMICAL SAFETY GOGGLES
HARMFUL BY INHALATION, IN CONTACT WITH SKIN AND IF SWALLOWED
POSSIBLE RISK OF IRREVERSIBLE EFFECTS
WEAR SUITABLE PROTECTIVE CLOTHING
DO NOT BREATHE DUST
POSSIBLE CARCINOGEN
POSSIBLE MUTAGEN
THE ABOVE INFORMATION IS BELIEVED TO BE CORRECT BUT DOES NOT
—..
--
PURPORT TO BE
ALL INCLUSIVE AND SHALL BE USED ONLY AS A GUIDE SIGMA ALDRICH SHALL
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
Sofunort (~j Mute
4 ml of solutton
(4) tO 10 MJ ~~
me[hanol.
Solurwn (6,J Dissolve 10 mg of 2-methyL5-nirroimtizo~
(tinidazole impurity A) in methano[ and dilute to 100 MJ
N<
C~HIJN}OJ
19
f./
Me
~47.3
19387-91-8
Definition Tirudazole contains ~
98.0 ‘/o and
-ethvlsulphonyledty
l)-2not
more
than
101.0°60(
l-(2
. —___
methyl-5-nitroimidmole,
CaHl JN30JS, calculated wlti
reference to the dried substance.
Characteristics
An almost white or oale~~w,
crystalline
powder; practically insoluble in u’atec soluble
.
in acetone and in dichhrmrerlrune; sparingly soluble in
rnerhanoL
IdentificationIdennfiwwn
rest C may 62 omitted f
tdennfiarion [CSUA, B, D and E are cam~d out. Idennfi<o non rests B, D and E may be omirred If idenrifianon rest.i A
and C are catid ou~.
A. Mtlting poinr, 125‘ to 128°, .4ppendLx VA, Method I.
B. Dissolve 10 mg in rntrhanol and dilute to 100 ml ~tith
the same solvent. Dihue 1 ml of the solurion ro 10 ml
with methanol. Examined between 220 nm and 350 nm,
Appendix II B, tie solution shows an absorption mawmum at 310 nm. The spmfic absorbance at the maximum
is 340 to 360.
C. Examine by infrared ~bsotpctbn sptcrrophotomet~,
———
Heavy metals 1.0 g complies with limit rtsr D~or heaz~
merafs, Appendix VII (20 ppm). Prepare tie standard
using 2 ml of lead s[andard soiu[wn (10 ppm Pb).
Loss on drying NOI more than 0.50/., determined on 1 g
by drying in an oven at 100° to 105°, Appendix IX D.
Stdphated ash Not more than O.10/. determined
Appendix IX A, Method II.
on 1 g,
Appendix II A. The absorption maxima in the specuurn
obtained with the substance being examined correspond
Assay Dissolve 0.15 g in 25 ml of anhydrous acecic acid.
Titrate with O.1$.tperchloric acid KS, determining the end
in position and relative intensity to chose in the spectrum
obtained with rsnsifazolt EFCRS. Exunine the substances
point potentiometrically, Appendix VIII B. Each ml of
0.1 M perchloni acrd KS is equivalent co 24.73 mg of
prepared as discs.
D. Examine the chromarograsns obtained in the tes[ for
Sto=ge
Re[ared substances. The principal SPOCin tie chromarogram obtained with solution (2) is similar in position and
size to the principal spor in tie chromatogram obtained
widt
solution (3).
E. To about 10 mg add about 10 mg of =Inc powder,
0.3 ml of hydrochbnr acrd and 1 ml of uarer. Hea[ in a
water bath for 5 minutes and cool. The solution yields
tie reactson char-menstic
Appendix VI.
C~H,,NJ04S.
&.. .
Score in a well-closed con[ain~tected
from
J&w
Action and use Amiprorozoan;
antibacterial.
1/96
The irnpurit.les lhnited by the requirements
monograph kclude:
of this
of pn”ma~ aronracti amines,
Appearance
of solution Dissolve 1.0 g m acetone and
dilute to 20 ml with the same solven[. The solution is
ckar, Appench IV .+, and nor more intensely coloured
than reference solunbn Y:, .\ppendix N B. k{ethod II.
substances Examine by rhm-la~er chrornarogmph-v, Appendix III .\, using sdicu gel GF:5, as rhe
.——.
with the same solvent.
SoIurion (7) Dissoive 10 mg of riniiazole impun’~ B
EPCRS in merhanol and dilwe to 100 ml with the same
solvent.
Heat rhe place at 110° for 1 hour and allow to cool.
Apply separately to the plate 10 @ of each solution.
Develop over a path of 15 cm using a mixrure of 25
volumes of buran-f-ol and 75 volumes of tthyl acetate.
Allow
the plate to dry in air and examine in ukravider
fight f’2S4 nm).
Any spots corresponding to cinidazole impuriry A and
to tinidazole impurity B in the chromarograrn obtained
with solution (1) are not more intense than the corresponding spots in the chromatogram obtained with
solurions (6) and (7), respectively (0.5°/0).
Any other seconday spot in the chromatogram obtained
with solution ( 1) is not more intense than the SPOCin the
chromarogram obtained with solution (4) (0.50/o) and at
most one such spot is more intense than the spot in the
chromatogram obtained with solution (5) (0.20/.).
NOZ
2 -methyl- 5-nitro- I H-imidazo[e
(ttida.zok implsity N
.
N
NH
Me
00
Related
1 -(2 -ethy[sulphonylethy
coating substance.
2-mer.hyl-4-ni&oimidar.ole
(tinidazofe kqxrity B)
So[unon (1) Dissolve 0.20 g of rhe substance being
twu-nined in mdranoi wirh rhe aid of ultrasound and
dilute to 10 ml with tie same soivenr.
Soiurwn (2) Ddute 1 TI of soluuon (1) [o 10 ml With
merhanol.
Solurwn (3) Dlssoive 20 mg ofnndasok.EPCRS m
mcrhuno( and dilute [o 10 ml wth the same solven[.
.! Munon (’4) Ddu~e 1 mi ofsoluuon
.2”; to 20 ml ulti.
mzrhano[.
“
l)-
O* >,.” N . ../ S. >CH3
N.
Me
-.. —
suramin
probably
had difiermg
also
az~~cd
Tram. R Sssc, mop
toxiti:>.
SSOCXge in the ~
the
p~.—
E. Ntiiri,
Med. Hyg.
Adverse EfTecvs
Stsramin
vomiting,
abdominal
pain.
a=-
.r.
COllaP6C.
paras~hcaia,
hands
and
soles
of the
1964.58.413.
hypcracsthcsia
feet.
peripheral
urticaria,
of
tlvc
neuritis,
SVCr. skin rash. dermatitis,
photophobia,
lach,’mation, am bi>opla, and uvcItis. A serious CffSCI
IS al buminurla.
with the passage of casts and
blood CCIIS.Agranukxymais and hacmolytic anaemia arc rare.
When used in onclroccrciasis some of the effects
may represent an allergic reaction to the killed
.
4798-p
advmsccd wypanmusmmsis
suramin
md mclarsoprol.
TCCkaSS.
●pparently
J Zambia,
495.
n-l
child.—
M.
1971. S. i 75, per Trap.
she gaw bictb to
N. Loawnrksal. Med.
&31J, Bull.. 1972, 69,
[email protected] and Fate. Following intravenous injection, suramin becomes bound to plasma proteins
and a low con.mstration
in plasma is n]airstaittcd
for up to 3 months,
early
cially
Suramin
is used in thx trcastmcnt of the
stages oi African
trypanosomiasis,
espeT’ryparrcssoma rhadcsiessse in fcctiorta. but ● s
it does not reach the cercbrtrapinal fluid it is
inefft%tivc in the advanced disease when the cmtral nervous sys:cm is affected.
Suramin is administered by intravenous injection.
To tsst the pattcm’s tolcrancc, it is advisable to
begin treatment
u ith an injection of 200 mg foi== -!~wexf, if well tolerated after 24 to 48 hours by a
‘SC of 20 mg pcr kg body-weight (up to 1 @ on
ys 1, 3. 8. 15. and 22. The urine should bs
Std before each dose, and if protein is present
the doss should be reduced or administration
delayed.
Combined therapy with [ryparsamide has been
used, particular} for late T. gambicnse infection:
at inter.
I 2 injections cac be given intravenously
up to
of 5 days. each Cotttatning suramin
10 mg per kg lmdy-weight
(max. of 500 mg) and
tryparsamidc
up to 30 mg per kg (max. of 1.5 g),
as a 20% solsujon prepared immediately
before
use, Two or 3 such courses have been given at
Intervals of 1 month, Suramin is more commonly
used in conjunction with melarsoprol.
Suramin has also been used in the prophylaxis of
trypanosomiasis.
in a dose of I g to provide
protection for up to 3 months,
but it may mask
latent
infections.
As
with pcntamidine.
it is
importac( to dc]ect more advanced infections and
to treat these w~th melarsoprol.
Suramin
is aiw effective in clearing the adult
filariae
of onchc.xrciasis
but has only a limited
action on mlcrofilariac.
The usual dose is I g
(after
an
initl?i
tc$t dose) weekly for 5 or 6
w~ks.
Dieth~i=rbamazine
is
active
on
the
and the 2 drugs are sometimes
used
mlcrofilariac
in conjunc{im.
vals
Oachorc’rciasis.
Less ocular detenorat!on
was obsc z~””
In a group of paucnts ulth onch~rc~mls
who had ken
!rcawl
14 LO 15 >cars earlier with a stnglc full course of
suramin
4.2 g. than
was seen m a similar
untreated
group —
F H
Buddcn,
Tray
R SCSC ~rop Med.
Hrg.,
19’76, 70, 484 The
[ncldencc
of optic atrophy
incrcased from 1 In 2S 10 S !n 25 three years afwr
52 E (total
patlcnu had been treated wtth suramtn
dose) for mular
onchoccrc!as!s
There was no change !<
~_hc
Incidcncc
[i
in 23)
!n 23 pae”t.s
not gw.m&
ram!n —
B
To>lcf.rs
and ,4
Rolland.
Bu//
W/d
th Org, 197q, >-. 4?9.
C( d!scuss)ons
—.——.
.
.
propvietmy
Namaa
(s9aycr, Ger.);
Moranyl
(Specia,
F,./
of
__
the
[r~(mcn,
of
onchocercrasl~
.—
_
The biological
kralf-life
of tinidazolc
was 12.7 hours
after
admintstmtion
of 150 mg as a snsgle dcae anc
when admtnistcrcd
twice daily for 7 days 10 1 volun.
teem. The maximum serum
per ml.— P G Welhrag and
CmHuCl,NzO.
about
142”.
Slightly
aohrbkc
in
diarrhox!s,
tccloun
M
with
chronic
inr..?stinal
amocbusis
given
tcclozan 750 mg daily in dwldcxl doses ak
meals for 2
to bs cured; a further 5 paucnts
43 were rcponcd
~~dd
10 a scmnd course of trcxlmcnt
with tcdozan.
clap.
Thx dru~ was wctl tolerated — D. Huggins,
Arrmf
WC. Sszssde psibl. Med. trop., 1971, 3, 29, per Trop
Em.
DJS.
399.
d~rrhm
totmtcd.—
wed
Ass..
which was 01hcrwisc
cl al., J. Phil[pp.
durin8
tr=lment
A. Arcilla-latonio
1972, 48, 137, per
70.345
Trop.
Ois. Euil..
1973,
4 cure-rate of 92.8% (at 4 weeks) was achieved m 28
Itoys wi[h
chronic
amocbiasts
given
tcclozarr
[00 mg
[email protected]
daily
for 5 days — A
Z., E1-Abdin
ef al,. J
Egypi med. ..4ss.. 19?3, 36, 174. ~r Trop Dis. Bull,,
1974. 7/. 1028,
(~ure in 56 of 60 patwnts
w}th
intestinal
a moeblasts
Iftcr treatment
with wclozan
1.5 g in 3 divided doses !n
/4 houfi.—
P. Fcrnandrs
e! al., Fo{ho med., 19?4. 69,
)93.
Cure in 26 of 27 children,
aged 1 10 5 years,
wtth
Imocbiasis
(usually
chronic)
after trcatmcm
w]th tecle
F.
!an 750 mg in 3 dwidcd
doses in 24 hours — H
Rrwa bros
Med., 1977. 34, SUppl
?wzcrra
et al..
Aug.),
50.
I%wprietary
I‘almonox
Name
/Wtn!hrop.
Arg.. Wtnthrop,
USA),
4799-s
sulphonyl)cthyl
CAS
—
Colorless
given a single dose of t)n,.
dardc
2 g peak serum concmwations
were 3210 52 .g
per ml 3 to 6 hours after the dine, and 18 to 3$ Pg per
ml 8.5 to 15 hours aflcr
the doss. Concaatratlons
in
fluid. and var,ous
saliva, vsgirml
secretions,
peritoneal
dsauc hosrxogmatea wers broadly comparable
with those
in serum. ~c
plasma half-life
was about 13 hours.—
T
Ri
●t al.,
Chemasherapy,
Ba.dr, 1977, 23, 227, PC:
19387-9)
crystals
]-2-me
thyl-5-nitroimida
‘“[2-
zole
-8
M,p
Advetw
Effects and
ronldazole, p.968.
about
127°
Precautions.
As
for
Abrption
ad Fate. Tln]dazole
is absorbed
—he gastro-intestinal
tract
pharmaco
,
~
,a
or
~l”~dazolc
and
~c[ronldazolc
+man and rn mtce.—
J A Ta}lor
e{ al.. Anlim!crob
Chemo!her
!969, 261,
.—
1977, !4, 1064,
subjccr.s given tinidazolc
2 g concentration,
90 mirrsttcslater (1 7 to 39 ug per ml) were
O( those in serum.—
A. M. M. Joki ii 61 sd., J
Chemarhrr.,
197~
mctronidazolc
has antiprotozoal
activity
and Lj
effcctivc against Trichomonas
wrgitru(is, ErrrurrI.
aeba histolyrica,
and Giardia Iambiia. 1t IS al w
active against anaerobtc bacteria.
In tnchomoniasis
it is ivcn bv mouth in a dme
of 150 m
twice daily
or 7 days or as a singie
-~
both mc~and
women. It has beet
given Tii_%I ilar doses in the matment
of g]ar.
(diasis.
[n amocbiissis dsrues of 2 g once daily for 3 da},
arc commonly uad.
A review of tinidavzkc
in
the
treatmen[
of
t:
:hotnoniasis.
ansoebiasis, and giardiasis.—
!( al.. Drzsrs, 1976. II. 423.
bcecding~
I hx
with mild amoxtxiasis,
25 wccc reported
:urcd a her receiving tcclozan
1(Kt mg tbricc dail> ror 5
iayq
2 patients
required
a second coucac of lrcatmen[
md 3 cmraisrcd resistant 10 teclozan, Two patmrrs dcvc.
[email protected]
well
,4r:netm/;
Uses. Tinidazolc which is a nitroimidazole [iLe
Uses. Txclozmr u used in the trcatmcm
of intestinal
arnoebiasis.
Abosat 20%
of a doss is stated
10 bx
excreted.
T?sx usual dose is
absorbed ●nd ta be rapidly
llXJ m
thrice
daily
rOr 5 daya, or S00 mg daily,
in
divrd
dcaes, ia 3 days
J
thdi.. 1972,69,
Df 30 ptiestss
Monro.
Abstr. Hy#.. 1974, 49.593.
In 6 gynacdogical
patimts
mtimbxsb.
Hvadacbc. OSUSU, vomiting.
Ad?aras Ellaxt&
md
mrtstipadon
have been reported,
but
gmccally
well tsvtcralcd.
patimts
M.
tr.awecn 20 and 40 Pg per ml, and 48 houm after inpm
lion tbc serum mrtccrrtratiosr
was still above [he mimma
!richomorsacidal
concmtration
for mcwt of the 8 strain!
wsp”rsxriis examined.— A. Forsgrcn anc
or Tn’chomonas
J. Wallm.
Br. ~. vsrscr, fh.,
1974, X3. 146 and 148, P;
88%
-502.3.
White cryasala. M.p.
5I
A
1972. 22. 2[ 28. Scc also B. A. Wood an<
197s. 5/ 51, ~
A
M.
Monro.
#r. J, vrner.
D/f,.
Absfr. Hyg.. 1975.50, 382.
-”
The pzak scnsm Con&ntmtions of tinidazole tn 4 volufi
a single dose of 2 g wer:
tcers 6 IO I 1 hours after
[n 4 haltby
in the CSF
13,146. A’A”.pPhcnyl2,24ichlor~N-(2
.cthoxyethyl)acct.
water.
Of
concentration was 8.9 I s!
rri-Fsxrsch.,
AO#r..
Win
mcdimethylcraebis(
amide].
CAS — SJ60-7B-I.
Precautions. It should not be used in the
presence of rcnai disease or adrcna[ insuffiicsscy,
Uses.
.
/973).
A sterile aoiuuon
of
ssaraminin Waza for inJCCtlOXtS, prepared by dmsolwng.
imnradiately bcfox-x USC. the sterile contents of a scaled
casrtairacr in the requisite
amount
0( Water
for 1nJcctiorss Store the scaled container
in a ma] plsee. Protect
from light.
Ocrmsnin
spy, hoxn the 20th Wek of pcg~q,
.
Preparatiosts
(JZ.PC
~
kjadioa
Pregasaq? ●d
SAc xeoaa$e Suramm had scratogmic
cffcCtS in mice — H. Tucbsmarm-Dup&nia and L
Mcrcixr-Parot. Cz. Seassc.Sax, Bid.. ]973, J67, 1717,
per Tnxp. Dis. Bull.. 1974. 71. 1107. A worzsm whb
an
.
Tcypuaaeasiasi~ .% Repon of a Joint W’HO Expcr!
Committee and FAO Ex n-w Consultatmn. Tech Reo.
Ser. WJd Hlth Org No 6~f5. 1979.
filariac.
Rcfcrcncas: Sccosad Rcpz-rt of a WHO Expect CuxtrnitIec an Oncboccrmxsn, Trch. Rep. Set, Wfd Kllk ~.
?40. 335. }966.
was sumfully
trcatcaf with
in addirson to srrppacrivx tbcr.
.
Br. J, Dphthsd,. 1978.6.2.427:
B. ‘tlylefors.
BUi~. Wid
Hl[h Org.. 1978, 56, 63.
Further rcfermccx: E O. L. Duke CT al.. Tropenmed
Psrrast[.. 1976, 27, 133; J. Ander’san et a[., Troperuned,
Porczst:,. 1916, 27. 263, J Anderson et IzI.. Tropenmed
Para.xit.. 1976, 27.279
may cauac nausea,
diarrhoca,
-------
Ve[-
irom
,“
,4g
of a synspium
trulmcm
of
(:hssmoniatis.—
.
I?se following
1.1 rig per ml
Bacte~”dts
~
~ragili$
R
Saw> c,-
usx of tinida ZOIC
amosbiasis,
giardiasis.
and
1978, 15, Sxsppi. [. 1-60
anaerobic
of tinidazalc
rrrJn”ngerza and
on the
P
md
bacteria
were
inhibited
and killed by 6,3 pg per
mtkrninogenicrss,
Clostrfd!
OVhcr species of clostrid i a, Esrbactwi
;
[-Is.
rr:
u -ur-
Pept ONrep/ocorcus,
a ?:
‘Issabactrrt ssmx. PeplorcXcus,
IveiIloncIla spp. Propiordbacltrium
ocrrcs was rc la m c,.
r‘es.istam. The
sanac figures
were achieved
w i[h mc
ronidazole
,-frsfinucrob 4:
and ornidazolc. — J. Wilst.
(~henrother,,
1977, 11, 631.
—
1rhe median
minimum
inhibitory
concenlratton
of l,.
cIazolc
fhscreroides spp was 0.12 “g pcr m
againsl
cmmparcd
w!ch 0.25 pg per ml for metrontdazolc
urIimorazolc
—
R. Wise
et al,.
Chrmorh?rupj
LlaJ/:
I 977, .?3. 19.
—
rhe actw’i[ies
of clindamycin,
tinidazole,
and dox~ c!
:Ilnc in wwo were compared
aga!nst 376 anacroblc
ba; cna. Clindamycin
and tinidazole
had MtCs
or 0.5 arc
I pg per ml respectively
a8atnsl 90% of 200 slralns ~‘
1?acferoides jragi/#~. Ttnidazole
had an M!C
or 12 .!
spp kw
ml agatrrst 72 slrains of the Clostrtd{um
Knzylpcnlcillln
and ampicillin
were more amwe
Trr.
lazolc was generally
less actjvc
than benzylpccm!li,
r
mpicillin,
cephalothm,
erylhrom~ c>-,
carbcntcillin.
hloramphcnlcol,
tetracycline,
and doxycycltnc
agatn,
!0 swatns of Eactcroides
mctantnogrmcus,
54 of tn:
or anaerok,;
‘usobactertum
spp.,
and
30
strains
~ram-pos!livc
Cocci —@tersky
er a/,, Ant/7 mc,61977, 12, 563
Ag Chemorher..
Amucbiasis,
In a series of controlled
studies 436 pallen:.
wjth intes!lnal
amoebi asis were treated
with unidazo,:
600 mg [.AWC daily
for 5 days or 2 g once da)i:
for ?
days. or mcIronidazole
400 mg thr!cc daily for 5 days c.
2 g once daily for 3 days, Cure-r.!es
for t!nidazolc
WC::
97,2% and 88.3% rea~ctively
In p~{!cnls passing Irophc.
tones and 8 l.?% and 93.4% in those pass, ng cvsts. COT.
pared wtth 87.5% and 73.3%, and 84 2% and 47 3% ic.
mctromdazolc
A cure. ra[c o(’ 96% was achmvcd tin 5.
mttcn:s
with
hcpattc
amceblasls
gtvcn omdazole
2 :
mm daily for 2 days, compared
wtlh 75.5% ,n 49 gl\e A cure-rate or 88.3’% was achlcved [n J;
mctronidazolc
pstlenrs w![h g!ardiasis
given zinidazolc
!n a mtan dw:
>r 61 S mg per kg as a single dose, compared
u!::
46 1% !n 9? g[vcn mctromdazole
56 mg per kg — J S
Bakshi er al
f)rug~,
1978, /5. .Supp/
1, 33
Teclozan/Tryparsamide
In a multi=atre
study in 8 cottntrica acure-rateof
Jchieved in 502 patlenra with amocbiasis
given
‘1
-was
95%
!inl -
dazole
2g
on=
daily
f.50mg
per kg body-weight
for
chddren)
,for 2 or 3 da>s. An excellent
rcaponax was
.achlev~
m 61J. and a gmd
response in 17. of 82 with
‘-epatic
amoebiasiz.
A cure-rate
of 88% was achieved
in
of about
i“childrcn
with giardiasls
given a single dw
.Omz ocr kg. Amre-rawof
952% wssachievcd in 859
pa[,e~~wit~wichomonal
.a8initis
given a slngiedoscof
-
(
2$. —
V.
V.
Suppl.
1,43.
Apte
and
R.
S.
Packard,
~1978.
15,
Of 88 aboriginal children mfcctcd with Giardia
Iamblia
or Eruamoch
[email protected]
23 received a single doss of
I to 1.5g daily for 3
[in}dazole
1 to 1.5g. 23 tintdazok
twice daily for 5 days.
da>s, 23 metrorsidazole
XX3mg
metronidaraieand tinidazole successfullyckarcd tk majority of C. /ambiiu
and
19
were left unmxd.
mfcccions but E.
uvely trmtcd
with
hisrolj mu
tinidazole,
Both
imfcctiona were more effcc(A single dcsc of tinidazoie
was as effective
as the longer regimen. No adverse rcacuons axurrcd
with either
drug.—
J. S. Welch
er af.,
(
references:
N.
[slam
and
M.
Res.. 1975, 17, 161; J. X. scragg
Childh.. 1976.51, 385.
ihet.
et al., Archa Dis.
Haaan,
Cam.
abscess. Tinidazole
57 mg per kg body-weight
for 5 days or 50 mg ~
kg daily for 3 days was
effective
in the treatment
o amoebic hver akccsa
in 23
of 25 children
aged 3 months to 6 cars.— J. N. Scra
and E. M. Proctor. Arc/u Dis. Chj / dh.. 1977, 52, 408. %
ti>er
tidy
Of 16 patienta
wilh hepatic amocbiaais 15 were cured
after mcatment
wi[h timdazole
2 g as a single dose daily
with
12 of 1S given metfor J to 6 daya. comparcxl
romdaxole
in the same dosage regimen
for 4 to 10
Hasan, CZrrsgs. 1978, /S,
days.—
N.
[slam
and
K.
Supp[.
1, 26.
E. A/r. med.
refercncu.—
H. A. Meyer,
i974, S/, 923, pcr Trop Dis. Bull.. 1975, 72. 72Q
X, Wathur er al.. J. inf. med. Res,, 1977. J, 429 M.
Quaderi
●t al,, J, trop
Med. Hyg.. 1978, 81, 16.
Funhcr
Giardiaais.
Cure
(Iettcr), .S. A ~ med. J,. 1977, 32, 708, pcr
fid!..
1978. { 5, 783.
‘-;urc.rate
of 96.7% in patients with giardiaais
treated
I tinidazolc
150 mg wi=
daily for 7 days.—
G. C.
m, J trop, .Ued. Hy ,, 1977, 26, 564, pcr
‘+~u,,,
‘19,8, ?5. 648. !%s also S. Y. Salih
TrOp.
J. crop. Med. Hyg.. 1977, 80, 11,
and R. E. AMalla.
per Trap. Dis. Eu/f., 197?, 74, 731.
Hatchuel
Dis.
Cure of 53 of 55 oauenss with giardiasis
given tinidazOIC 2 g as a singlc”dosc. — N. A: El Masfi
eI a/., Am.
J. rrop. Med. Hyg.,
1978, 7J. 544.
above
J.
140, 984, M.
J. &~p:.
Sac. Pararit.. 1979, 9. 467, ~r
Trap, Di$. Bull. 1980
77, 125; A. Sabcharcar er IS ,, S.E. Asian J. tmp. med~
~b~6~[th,
1980. 11, 280, pcr Trop, Dis. Bull.. 1981.
L.
Jokipti
and
1978. 27, 201, per Trop. Dis. Bull,.
A. M. M.
B. Tadroa,
Jokipii,
ProphylaziJ
in Jargery.
In a prospective,
rsndomiaed.
dorable-biind
study of 6 months’ dssmtion involving
71
given tcfom surgery pr-cverstcd
patients 2 g 0( tinidazole
wcwrd infection
after elective colonic surgery in 37 of
40 ~tienta
in comparison
with 28 of II paticrsts ts-cacd
with placebo.—
P. S. Hunt e( al., Med. J. Assaf.. 1979,
1, 107.
Poatopcmtivc
infections occurred in 6 of 5s3 @caata
wbo
before
received
2 g of tinidazole
12 to
18 hours
undergoing
dcdvc
abdominal
by$tccutonsy
and 2
48
hours postopcrativelfi
infectiorss orxxsrred in 28 35s3
similar
control
paticnta.—
P. C. Appdbaram
rf al.,
Chemotherapy.
Bade.
1980.26.
145.
references: J. Adno and
J.. 1979, J6. 565 (gynaccological
et al., .9r. J. CMsttr. t7ymzec..
tomy).
Trkhoaoaiasia,
duced
~raailologial
R. Caaacl,
m
19WW7!
S. A/?.
\
med.
~!~
M so
gAWSI
m~.
J. irrr. ‘med.
Rer.,
J. 438. —
fi~~l~i~~~n~~
;Fti!
~o
~;-l
?S;:
J. in;. med.
Res.. 1978.6, 46; J. P, Ward. Md. J,
AUSI., 1976, 2. 651; R. Jona and P. Endera. ibid., 1977,
2. 67% M. Maasa ●t al., Boln chil. Paro$it.. 1976. 31.
46, per Trap. Dss. Bull., 1977.74.291.
my.
usc in men
Kawamura.
O( single
l-g
cloaca of
tinidsz-
B? J, verrcr. Dis,. 1978, 54. 81.
Ifyg., 1978, 53.465.
See also under Ansocbiasis.
above.
Vcgirnirir.
Administration
of a single dose of tinidazoie
2 g to 35 women with GardrurelIa voginalis (Haemophi(uj vagrnafis/ infection
led to diaappesrsrrcc
of tk bsctena in 33: O( tbe other 2 women Iha count was tduccd
in onc arsd a repeat
w~tment
waa sssc~ful
in the
tCCOX16. Two women
relapsed after
15 to 20 days and
repeat treatment
wu successful. All tlsa patienta’ partners were
ivcn
the
same
dose of
tinidaadc,
and
abstincnca t rom sexual irrtcrcoursc was rccommcnrJuJ for
at lust 24 hours.—
M.
Wardi #r af. (letter),
,Gmcer,
1980. /. 1029.
Scc also under
Trichomoniasis.
above,
Nmatcs
Proprietary
Fasi in (Pfizer.
Itaf. ); Fasigyn
Roerig. Belg.; Pfizer,
(7/+ us ral.;
Pfizer.
Norw.;
Pfizer,
S. Afr.;
/Prrzer.
Fr.): Simplotan
(Pfizer.
ltaf.); Tricolam (PJ7:cr, Spain).
Swirz.);
Fasigync
Trichogin
(Chic$i.
Tryp~mi&
Tryparsamipsrcosrc. Sodium
hydrogen 4pkrrykamratc
hcmihydrate.
T
7
CcH,~NINaO,.!+HZO
CAS — SW-72-3
Pharmacopoeias.
G<r.):
(B.P. /96S). Trypsrsam,:
durn. Glypkaaraine;
(arbamoylmcthylammo
- 305.1.
(anhydrosir): 61 J9-29-I
In lrrd.. Int.. It., Mcx.,
A CO&SStlaS, odourlcs.
crystalline
(hemthydrate}.
and
Turk.
which
is
aiorcly affcctcd by light.
a neutral
solution;
1 in 1.5 of wamr. forming
aokrabk 1 in 3500
of almhok
practically
insoluble
in
and ether. A 4.62% solution is ian-osmotic
chloroform
with acrum. Aqueous solutions deteriorate on stora8e
powder
and sbosskdbc used immediately after preparation: scdutinna for injection arc prepared aseptically. Store in a
cool pkacc
light.
Tirsidaxsde
2 g as a single doss procrsre in 47 of 50 patienta with tri-
with 32
corrmarcd
R. Anjancpiu
CI al.,
chO~l=is,
ronidazok.—
.1977,
Succeaaful
oke.— N.
per Abstr.
/.,
S.
A.
in 35 of 38 children
with giardiasis
after a single dam of unidazole:
2 others were cured
after a second dose. Doses were: under I year, 500 m ;
7 }UB,
I g; 12 years. I 5 g.— S, Danzig and W
L. f
-=Tron.
Amcebiasis,
Fufiher
rcferencca:
infect. Dis.. 1979.
Further
.Wrd. J. Ass.rt., 1978, 1.469.
FurI her
Sec also under
985
in
M-
k?ff+
-qmg,
~~
~~.
small
airtight
Side-effects
bcdack.
●nd
cmrtamcrs.
Protect
from
include diuincaa,
tinnitus.
exfoliative
dermatitis,
fsy,
bndycardla
immediately
after
an
Tha
‘-‘w moat acrkoua
‘MF tssxsc Yc cct‘W la ‘r’upon the optic nerve
Traataracot should ba diacmrtinucd
immediately
if wsuai
daf~
a~~
though
blindncas may rxcur
suddenly,
~UY
If OptiC Injury
is already
present,
dcfaXa
may not k-scome apparent
until
a few
after a murac of trcmment
has km
completed.
visual
weeks
Uaa
Trypnamidc
is trypsnocidal.
Because
it pcnetk
arcbrmpinal
fluid it has been used in the
Afnun
tryparaoaomiasis
with
central
narvoua ayatcm involvement
particularly
in Trypanosoma
gansbierzse infcctiozss. It has ken 8ivcn in doses of 30 to
60 rng pcr kc body-wci
ht (up to maximum
of 2 g)
intracmstmaly ach
week ! or 12 to 14 weeks. The trypan.
oasmaea may koasre
resistant to trypamamide.
Because
is now preferred
of tbc risk of bkindneaa, mclarzoprol
For
the
usc of
tryparcamide
in conjunction
with
aaramiss. scc p.984.
trntaa
trutmcrsl of
-lnjcdoa (B.P. /968). Tryparsam.
[nj, A
atartk +utism
in Water
for Injections,
prepared
by disaolwing. tmrrscdiatcly
before USC, the sterile contents of J
rcdcd container
in the requisite amount
of Waler
for
Iojcmiona.
T~
(Pfizer,
,4rg.;
Pfizer,
Denm.; Pfizer.Nelh.;
Pfizer, Swed.. Pfizer,
I
I
i
Page Number
Database:
Medline
<1995
to
February
: 1
1998>
<1>
Unique
Identifier
96415043
Authors
Salo
JP.
Salomies
Title
H.
High performance
thin
layer chromatographic
analysis of
hydrolyzed
tinidazole
solutions.
II. Hydrolysis
kinetics of
tinidazole.
Source
Journal of Pharmaceutical
& Biomedical
Analysis.
14(8-10):1267-70,
1996 Jun.
Abstract
In a citrate-borate-phosphate
buffer, 5 MM tinidazole
solutions
exhibited
maximum stability
stability
around pH
4.0-5.0. The hydrolysis
of tinidazole
was mostly a
first-order
reaction. At pH 10.0 and 60-80 degrees C,
tinidazole
had an activation
energy of 122 kJ mol-1 for
hydrolysis.
It was postulated
that tinidazole
decomposes
by
different
mechanisms
under basic and neutral/acidic
conditions.
<2>
Unique Identifier
96415042
Authors
Salo JP.
Salomies H.
Title
High performance
thin layer chromatographic
analysis of
hydrolyzed
tinidazole
solutions.
I. Development
and
validation
method.
Source
Journal of Pharmaceutical
& Biomedical
Analysis.
14(8-10) :1261-6, 1996 Jun.
Abstract
A stability-indicating
high performance
thin layer
chromatography
method for analyzing
hydrolyzed
tinidazole
solutions
using silica gel plates was developed
and
validated.
The mobile phase used was methanol-diethyl
ether-chloroform
(1:9:3, v/v/v) allowing small changes in
its composition.
Detect_Lon was at 314 mm. Rf values being
0.1-0.4,
baseline
resolution
was achieved
for tinidazole
and the hydrolysis
products.
The analytes were stable on
the sorbent and could be precisely
and accurately
measured
Page
----
in the range
——=—-
20-170
ng per band.
Number
: 2
TaAXSACTJONS
OF THE
Treatment
tinidazole
RCSYAL
SOCIETY OF TROPICAL MEDICISE
AND HYGIESE, VOL
77, No.
6, 845-846 (1983)
of non-invasive
amoebiasis. A comparison
alone and in combination
with diloxanide
845
between
furoate
PEHROLOV PEHRSOX AXD ELIAS BEYGTSSOX
Dep[. of Infectiow Diseases,Karolinska Institute, RoslagstuilHospital, BOX S651, S-1 1489 Stockholm, Sweden
Sumttrary
Tinida.zole (40 mg~g body -sveighr in one daify dose for five days) and tinidazole (same dose) plus
difoxanide furoate (20 [email protected] body-weight divided into three daily doses for 10 days) were compared
as treatments for amoebiasis. The parasitic cure rates were 44 and 91?40respectively. We cannot,
therefore, recommend tinidazole alone in this dowge as a treatment for non-invasive arnoebiasis.
Introduction
Tinidazole (Fasigyn) has reeently been widely used
as an alternative to metronidazole for the treatmem of
infections with Entamoeba hiscolytia. In a previous
study &H-tRSON, 1982), tinidaxole was given to a
==-.ri~ of patients with chronic intestinal or asymp
natic amoebiasis. When checked by at least three
O! specimens taken on difYerentdays, one month
~ter treatment, we found a parasitic cure rate (p.c. r.)
of 0’% (0/14). This should be compared with the
results obtainrd in other studies, showing a cure rare
of 77 to %Yo (MISM& LAIQ, 1974; PRAKASH er al.,
1974; JOSHI & SHAH, 1975; BAKSHI et al., 1978),
using the same dosage schedule but mainly in cases of
acute intestinal amoebiasis.
To investigate the reasons for the unsatisfactory
response we obtained, which could be due to too low a
dose or to a low efficiency of tinidazole in the gut
lumen, we carried out a new trial with a higher daifv
dose of tidazole
and compared the effect of thi~
higher dose with that following treatment with
rinidrszole and diloxanide furoate (Furarnide) in combination. This latter was found ro be an effective
intraltsminal asnoebicide @700 DRUFF & BELL, 1960,
1%7; WOLFE, 1973), whose mode of action upon the
amoeba is unknown. We omitted Furamide as a single
“regimen, because it is considered to be ineffective
against invasive amoebiasis and there is always a risk
of developing an invasive form of the dlseasc if
zymodeme differentiation of strains of Errramoeba
histofyrica is not performed routinely :S.kRGEAUNT &
W’ILLLAMS,
1978; SARGEALIYT
ef al., 1982).
Materials and Methods
During the p-iod of the srud!’, 41 paticnrs were
diagnostxl as suffering from amoebiasis. ,411of them were
supposed to have contracted their infections abroad, as
amoebiasis is nor considered ro be endemic m Sweden. No
cases of acure, dywmteric amoebmis or di+m+
or
—- suspcwd cases of liver abscess were included. The patients
lad not reeeived any anti-amoebic drag during the previous
ear. Nine of the patients had a concomiran~ irrfecrion with
hardia farnbha, two with Shrge[la fixw’,
two with CarrrpyIobacesrjt+cru, one with Salmonella pararypht A, one
Hymereolcpe.r tuna, one with Ascati.r Iumbncmdes
and one with
Dosage schedufa
(I) tinidazole
40 mg’kg
body-weight in one daily dose for five
as above plus cfiloxanide furoate 20 mgkg
body-wcighr divided info three daily dews for 10 days.
Appro&ately
one month after &e treatment was c6mpleted, checks were made, including tbe examination of at
least dues stool specimens taken on dif7erenr days. One of
these was examrrsed by &sect microscopy of freshly passed,
loose faeces induced by a 50% magnesium sulphatc purgative
and the other normally passed speeienens were examined
by the formol-erher-concentration technique described by
/’;Y&dazolc
FLIDIH’
&
HAWGOOD
(19S6).
Failure
was
delirred
as
the
of amoebic trophozoites or cysts in any of these
persistence
speeimens.
Those in whom tbe treatrnem with tirddazole failed were
later treated with the combination of tinidazole and diloxanide furoa[e and those in whom the combination faifed were
created with merronidazole 40 mg’kg body-weightdaity for
10 days.
Resuhs
Data on the participants and the results of the
checks one month after treatment are shown in Table
1. In no case were the side effects severe enought to
cause cessation of treatment. Statistical analysis was
made, using the chi-square test, and showed a
significant difference between the two groups on the
1%-level (two-tailed test) and in favour of the
combinaticm. No differences could be found between
the response of Swedes and that of the immigrants, or
between those infected on different continents (Asia,
Africa, South America). The presence of other
parasites did not seem to affect the outcome of the
treatment.
Discussion
Our results with tinidazole alone (440/. p.c.r,), in
treating non-dysenteric amoebiasis, are unsatisfactory
obmined in previousand differ ven much from
those
ly published srudies by different authors, using the
same dosage schedules (77 to 960/. p.c. r.) (ISLAM &
H.MAX,1975; APTE & P4CKARD, }978) or lower
(MISM
& LAIQ, 1974; PRAKASHer al., 1974; JOSHI &
SHAH, 1975; B.\ KASHI ef al., 1978). The patients in
these studies were, however, mainly cases of acute
amoebic dywntery, a factor which may have in-
With
Trrcku& trichiura
In a predetermined,
i alone
dkdtO
two
group,
nbhg
Wadwith tinidazde
23 withshe
wd
in-patients
I
ad
kept
mrsdom
order,
combination.
under supervision
the patients
were
All were hospital
during treatment.
fluenced the results.
A weak amoebicidal effeet of the nitroimidazoles on
the cyst stage of E. histdytica was observed by
COMPAFUTIVE
846
Tabk
I-Some Cbcferistics
-d
lTt~TMENTS
OF
NON-tNVASIYT
SrcauneesfreSdSS of 41 patients ~UI
No.
Median age
(age range)
ycasa
Patients with
symp~oma v.
asyrnptomatic5
4orngikgxl+v
18
28 (9-68)
11:7
Tinidazolc 40 mgkg x 1
x V + difoxanide
fbrrxtc500mg
x3xX
23
26 (6-68)
15:8
Treatment
Tinidazok
SPILLMAN er aL (1976),
but
this report was contra-
[email protected] by BAKSm t-raf. (1978 ),. Our drup @d was
carmd out in a country tn wtuch amceblasls is not
endemic, making reinfection during follow-up very
unlikely, and confirming that the low p.c .r. was
caused by “true” treatment failures.
We therefore believe that our poor results with
tinidazole done are due to its ineffectiveness in
eradicating cysts in the lumen of the gut, either
beeause of too effective absorption (MONRO, 1974) or
inactivation by aerobic orynisms as shown by RALPH
& CLARKE (1978).
When tinidazole
was combined
with diloxanide
firoate, we obtained a cure rate of 91%, which maybe
compared
with studies
by WOODRUFF
& BELL
(1%7), in which they reported a cure rate of 95’%0in
.-
amoebic cyst-passers treated with diloxanide furoate
alone for 10 days and WOLFE (1973), who found a
cure rate of 83°A using the same schedule. It is also
noteworthy that all our failures with tinidazole alone
have proved to be freed from their infection after
treatment with the combimtion.
Acknowkdgemcnta
We wish to thank Mrs. Inger Ponttn, the head nurse in
the tropicalwardand Birgit Lindberg, the chief mchnician at
the labora[o~ of tropical diwaws, for their devoted work
with the patients.
References
Atstc, V. V. & Packard, R. S. (1978). Tinidazole in the
- rr”=tmcnt of trichomoniasis, ~ardiasis and amoebiasis.
Report of a multiccntre study. Drug$, 15 (Suppl. 1),
43-48,
Bakshi,
J. S., Ghiara,
J. M. & Nanivadekar,
A. S. (1978).
How does Tinidazole compare with Metronidazolc? A
summary
report of Indian trials in amoebiasis and
@rdiasis.
Drugs, 15 (Suppi. 1),, 33-42.
Islam, N. & Hasan, M. (1975). Tirudazole in the treatment
of intestinal amoebiasis. Curww Wrapeuric Research, 17,
161-165.
A comparative study of
Joshi, H. D. & Shah, B. M. (1975).
rinidazole and metronidazole in treatment of amoebiasis.
Indtun Pracnnonm, 28. 295-302.
AMOEBIASIS
non-invasive
Swedes v.
other
nationalities
amocbtasis
Parasitcfree at
Par-asiw
cure
check
me
8:10
8
44%
11:12
2[
92%
●
isrs,
N. P. & Laiq, S. M. (1974). Comparative trial of
tinidazole and mc~ronidazok in intestinal amoebiasis.
Currmt Thmapeueic Research, 16, 1255-1263.
Bkwd Icvels
of ,chemotherapmtic
Mooro, A. H. (1974).
drugs and the pharrnaco!rirretics of rinsdazole and metrooidazole. Cwent Medual Research and [email protected], 2,
130-136.
Pehrson, P. O. (1982). The treatment of non-invasive
amcebiasis--a comparison between, merzonidazole and
tinidazok. .4nnafs of Tropics! Medicrrseand Parasrmloa.
Prskash, C., Bazssal, B. C. & Bansal, M. R. [1974;.
Titudazole in symptomatic inmstinal arnoebiasis. ~ournal
of TropuaAMedicine and Hygiene, 77, 165-167.
Ralph, E. D. & Clark, D. A. (1978). Inactivation of
merronidazole by anaerobic and aerobic bacteria. .%rrimtiobitd Agenu and ChmwAera~, 14, 377-383.
Ridky, D. S. & Hawgood, B. C. (1956). The value of
formol-ctbcr concentration of faecal cysts and ova.
Jaurnal of Clinua[ Pathology, 9, 74-76.
Samcaunt, P. G. & Williams, J. E. (1978). The differenda~on o(”invasiveand non-h~asivc Entarrroeba hurolyerca by
isocnzyme clectrophoresis. Tramacriorrs af the Royal
Swiety of Tropical Medicine and Hygrerre,72, 519-521.
Sargeaunt, P. G., Jackson, ,T. F. H. G. & Sirnj~, A. (1982).
“whcmdhOmOgene’7
‘f ‘nu-ba
‘“fobMa
laws. esceaallv those rom
kver abscess.
Lancer,‘%1,
138d 13838. ‘
C. E. (1976).
[email protected], R., Ayafa, S. C. & de
Double bfind test of metronidazole and tinidazole in the
treatment of asymptomatic Entarnoeba hiseofyrria and
Enearnwba harnnanni carriers. American Journal of Tr&
pical Medicine and Hygiene, 25, 549-551.
Wolfe, M. S. (1973). Nondysenteric intestinal amocbiasis.
Treatment with difoxanide furoate. _7aumal of rhe.4rneTtian Me&al Association, 244, 1601-1604.
Wocdrtsff~ A. W. & Bell, S. (1960). Clinical tnafs with
enwnssde furoate and related compounds: [ In a nontropicalenvironment. Transacnom of the Royal .soaq of
Trapscal .Uedicine and Hygiene, 54, 389-39S.
Woodruff, A. W. & Bell, S. (1%7). The evaluation of
ansoebicidies. Transactionsof the Royal Soaety of Troptcd
.$anchez
.Uedicine and Hvgierre, 61, 435-439.
Accepted for publication
30th iUarch,
1983
Fly UP