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c.
.
.—*
A. INGREDIENT NAME:
-3
IODOFOM
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’cijkations)
99.0-100.5%
Not less than 99’%of CEIL
Assay:
(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, C2inica2
Otolaryngologv, 1995; 20(4): 305-307.
Holaq G. and Fuks, A. B. Iodoforn-containing paste (KM). Pediatric Dentistry, 1993;
16(6): 403-407.
—
.?
—
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-
Ej-11”
//47
.$ ~g733
CERTIFICATE OF ANALYSIS
------ ------ ------ -----
—-
PRODUCT: IODOFORM POWDER
RELEASE #: N
LOT #
:B59901C13
GRADE: PURIFIED
CODE:A925D053
SPECIFICATIONS
------ ------ --
RESULT
------
1.
DESCRIPTION
YELLOW POWDER
CONFORMS
2.
Melting point
115 deg C min.
120 deg C
3.
Moisture
1.0%
max.
<
4.
Residue on ignition
0.2%
max.
< 0.2%
5.
Assay
ATTENTION:
1.0%
99.01%
Q
TONY HATCHETT
+’
,,
Prepared by :
Date :09/02/97
A. JiAZARI
Approved by
10540
237082
Our Order #
Your PO # 53617
1,
/
*
‘—WEABOVETEST
RESULTSHAVEBEEN OBTAINEDBYOUR MANUFACTUREWSUPPLIER ANDIORINOURQUALITY CONTROLLABORATORY.
AEDATAISPROVIDED ATTHEREQUEST OFANDFORTHE CONVENIENCEOF THECUSTOMER ANDDOESNOTRELIEVE THECUSTOMER
OFITS RESPONSIBILITYTOVERIFY IT.THIS ANALYSIS IS NOTTOBECONSTRUED AS AWARRANTY, EXPRESSEDOR IMPLIED.
MATERIALSAFETYDATASHEET
Page 1of 5
.-—=.>
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MATERIAL SAFETY DATA SHEET
Iodofortn,99+%
97101
MSDSName:Iodofonn,99+%
-
Triiodomethane
Company Identification:
For information
For emergencies
For emergencies
****
Acres Organics N.V.
One Reagent Lane
Fairlawn, NJ
07410
in North America, call:
800-ACROS-01
in,the US, call CHEM’TREC: 800-424-9300
in the US, call CHEMTREC: 800-424-9300
SECTION
2
_
COMPOSITION,
INFo~TIoN
ON INGREDIE~s
+***
+----------------+--------------------------------------+----------+-----------+
CAS#
Chemical Name
I
I EINECS#
!----:----1----------l----------------\-------------------------------------75-47-8
lIodoform, 99+%
I 200-874-5
+---------------- +--------------------------------------+----------+----------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 ~SU~S
****
Eyes :
Immediately flush eyes with plenty of water for at least 15 minutes,
occasionally lifting the upper and lower lids.
Skin:
Flush skin with plenty of soap and water for at least 15 minutes
while removing contaminated clothing and shoes.
Ingestion:
MATERIAL SAFETY DATA SHEET
#ab.-
Page2 of 5
Do NOT induce vomiting. IQlow 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
MEASURES
and then
****
General Information:
As in any fire, wear a self-contained breathing apparatus in
pressure-demand,
MSHA/NIOSH
(approved or equivalent), and full
protective gear. 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 _ ~LING
and 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 in’s cool, dry place. Keep container closed when not in use.
● ☛☛☛
SECTION
B _
EXPOSURE
CONTROLS,
PERSONAL
PROTECTION
****
Engineering Controls:
Use adequate general or local exhaust ventilation to keep airborne
concentrations below the permissible exposure limits. Use process
enclosure, local exhaust ventilation, or other engineering controls
to control airborne levels.
Exposure Limits
+--------------------+-------------------+-------------------+-----------------+
IOSHA - Final PELsI
Chemical Name
~------_________~____ ____!!!!:!___________ ~-______!!l’::_______ l_________________ I
[0.6 ppm;
10
Inone listed
Inone listed
I Iodoform, 99+%
I
I mg/m3
I
I
I
+--------------------+-------------------+-------------------+-----------------+
OSHA Vacated PELs:
Iodoform, 99+%:
0.6 ppm TWA; 10 mg/m3
Personal
Protective
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
Page30f5
MATERIAL SAFETY DATA SHEET
Respirators :
Wear a NIOSH/MSHA- approved (or equivalent)
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:
PROPERTIES
Not available.
Not available.
None reported.
Not available.
Not available.
Not available.
Not available.
Not available.
(? 760.00mm Hg
120.00 - 123.00 deg C
204 deg C
freely soluble in benzene
4.oo90g/cm3
CH13
393.72
**** sEcTIoN
---.=
AND CHEMICAL
10 - ST~ILITy
MD
*+**
and acetone
R~CTIVITy
*+**
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;
470 mg/kg; Oral, rabbit: LD50 = 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 _ EcOLOG1~
lNFO~T1ON
****
Oral, mouse: LD50 =
rat: LD50 = 355
****
Ecotoxicity:
Not available.
**** sECTION
13 _ DISpOSAL
CONSIDE~TIONS
**+*
Dispose of in a manner consistent with federal, state, and local regulations.
RCRA D-Series Maximum Concentration of Contaminants: Not listed.
RCRA D–Series Chronic Toxicity Reference Levels: Not listed.
RCRA E’-Series: Not listed.
RCRA P-Series: Not listed.
RCRA U-Series: Not listed.
Not listed as a material banned from land disposal according to RCRA.
**** SECTION
.-.
14 _ T~spORT
US DOT
No nformation available
IMO
Not regulated as a hazardous
IATA
Not regulated as a hazardous
lNFO~T1ON
material.
material.
****
MATERIALSAFETY DATA SIIEET
Page4 of 5
RID/ADR
Not regulated as a hazardous
Canadian TDG
No information available.
**** sECTION
----
material.
15 _ REGu~TORy
lNF~~TION
****
US FEDERAL
T.SCA
CAS# 75-47-8 is listed on the TSCA inventory.
Health & Safety Reporting List
None of the chemicals are on the Health 6 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 reportable 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 in this product are considered highly hazardous
by OSHA.
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 product 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:.
0.6 ppm (10 mg/m3). OEL-DENMARK:TWA
0.2 ppm (3 mg/m3). OEL-FINIAND:TWA
0.2 ppm (3 mg/m3);STEL 0.6 ppm (1 mg/m3);Skin. OEL-FRANCE:TWA
0.6 ppm
OEL-THE NETHERLANDS:TWA
0.2 ppm (3 mg/m3). OEL-SWITZERLAN
(10 mg/m3).
D:TWA 0.6 ppm (10 mg/m3). OEL-UNITED KINGDOM:TWA 0.6 ppm (10 mg/m3);ST
EL 1 ppm (20 mg/m3). OEL IN BULGARIA, COLOMBIA, JORDAN, KOREA check AC
GIH TLV. OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGI TLV
****
SECTION
16
-
ADDIT+lo~
lNF-j~T1oN
****
MATERIALSAFETYDATASIIEET
MSDS
.-.
Creation
Date:
2/01/1996
Page50f5
Revision
The information above is believed to be accurate and represents the best
infornmtion 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.
--------------------------------------------------------------------------------
[\;I:
1,to productinformation
m..
#O Date: Original.
QUALITY
CHEMICAL
NAME. :IODOFORM
CONTROL
REPORT
PURIFIED
MANUFACTURE LOT NO. :B62949P30
PHYSICAL
SPECIFICATION
E-
TEST
STANDARD.
l)DESCRIPTION
.:
YELLOW POWDER OR CRYSTALS;
Om.
—.
:USP ——/BP
TEST
/MERCK
UNCTUOUS —c
TOUCH;
—
/NF_/MART._/CO.SPECS._.
CHARACTERISTIC,
-—_.
2)SOLUBILITY.
:
VERY SLIGHTLY SOLUBLE IN WATER; 1 GRAM DISSOLVES
IN
16ML BOILING ALCOHOL, 10ML CHLOROFORM, 7$5ML ETHER,
FREELY SOLUBLE IN BENZENE, ACETONE.
_“K
3)MELTING
POINT.:
MELTS AT ABOUT 120 DEGREES;
EVOLUTION OF IODINE.
~.._
4)SPECIFIC
60ML COLD ALCOHOL,
80ML IN GLYCEROL;
AT HIGH TEMPERATURE
GRAVITY. :
5)IDENTIFICATION
PASSES.
DECOMPOSITION
DISAGREEABLE
._
.:
:
FAILS .:
COMMENTS. :
ANALYST SIGNATURE.
PREPACK TEST.:
RETEST.
.-T
—
:
:
DATE .:
DATE. :
DATE.
:
INITIAL.
INITIAL.
:
:
WITH
Ammonium Iodide/ lodophores
~~phorous
acid, H]PO:. added to prevent discoloration
~ kcepmg. Wt. per ml about 1.1 g. Incompatible with
~lkalis and ox]dlsmg agents. Store m well-closed glass.
~oppercd bott[ca. Protect from light.
b
‘=,lte hydriodic
acid ,has the general properties of
M in weak combination.
II was usually administered
H>driod!c
Acid
Syrup.
.>
~tparatiom
HYdriodic Acid Syrup
(8. P.C. 1949). S yr. Acid.
Hydriod. Dilute hydriodic acid IO ml, water $ ml, and
syruP tO [00 m[. Dose. 2 to 4 ml.
+=
dS76-k
[odi~td
G]yceroi. Iodopropylidcne Glycerol. An
~
iaamcr!c mixture of icdinatcd dimera of Iyccrol,
CeHIIIOI -258.1.
[t contains about 5$6 of organkally
tiund iodine.
CAS — S634-39-9.
A pale yellow liquid with a pungent bitter after-taste.
@rrble in chloroform. ether, and ethyl acetate. Protect
from Iighi.
A&crae Effcc~ TrestrncnL arad Racautiosss.
Iadine, p.862.
As
for
Uses.hfinat~ dyCerOlk usedas an
bronchitis and bronchial
times dady with fluids.
asthma
expectorant in
in doses of 60 mg four
Pmprkecary Prepsratiom
0rgsni6isr ( WB Pharmaceuticals, UK: Bochrixrger lngelheim. UK). Elixir containing in each 3 ml mdinawd
glycerol 60 mg and alcohol 1.25 ml (suggested dihaem,
equal parts of glycerol and water).
other Propdctary Nmnea
Mucorama Rectal lnfantil (Spain).
\
4577-4
I-
(B.P.C.
—=
JQWW12=B
,[, -393.7.
19S4). Form&e
Tri-iod&.
7.
---
L
CAS — 7$47-8.
Pharmacopoeias. tn Arg., Arm., Belg.. Fr.. /1.. Jug,
Pol.. PorI.. Rrcs., Span., and Swiss.
Shining lemon-yellow
crystals or powder. somewhat unctuous to the touch, with a characteristic,
persistent, penetrating
odour and disagreeable
taste. Slightly
volatile
at room temperature.
M.p.
I I 5“; at higher temperatures
it decomposes with
loss of iodine.
Practically insoluble
in wateq soluble 1 in 60 of
alcohol, 1 in 3 of carbon disulphide, I in 13 of
chloroform, I in 8 of ether, 1 in 100 of glycerol,
I in 35 of olive oil; soluble in other fixed and
volatile oils, and in flexible collodion. [ncompzrtible with alkalis, oxidising agents, lead, silver.
and mercury
saIts. Store
in a COOI place in
airtight containers. Protect from light.
To cover its odour it may be mixed with coumarin 1 in 50, or with menthol, phenol, or thymol, or with oils of anise, eucalyptus, geranium,
peppermint,
rosemary, or sassafras, about I or
2%.
Adverse
EfTecta. Symp!oms of systemic toxicity,
as described under Iodine (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 hypersensi~ive to iodoforrn and
even small
quantities
applied
locally
may cause
an erythematous
rash.
Severe poisoning.
which may be fatal. is characIeriscd by heodache, somnolence, delirium.
and
rspid feeble pulse.
‘vl~ximum permiswole atmosph~rlc concenm~uon
‘“ 5 ppm.
,es. IcAoform has I marked anaestheuc
when applied
to mucous membranes.
[[
releases elemental Iodine when applied [o
sues and has a mild disinfectant
action.
acnon
slowly
the tMIt was
formerly
used extensively as a wound dressing
but is not very effective.
Compound Iodoform Paint has been used M a
protective
covering
and to hold gauze dressings
and radium needles in position.
Bismuth Subnitrate and Iodoform Paste (B[PP)
has been applied [o 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.
PretvaratiorralJ
B.1.~.P. Gauz[ ;Roy. Nat. T. N. and E. Hasp). Sierile
gauze impregnated with a msile paste consisting
of iodoform 40%, bismuth subnima.te 20%, and Iiqrjd
paraffin 40%.
iansrstb Subnitsstc mrd 1&e,&
ast. Blsm. Subnit. eI Iodof.: BIPP Btsmut
an lab
form Paate. Bismuth subnimate 1. iodoform 2. sterilised
liquid paraffin 1, by wt. prepard” aseptically. Store in a
cool place in wcriliscd colla paible tubes. Prolonged or
extensive application may give rise to iodo(orm pOisoning.
Aduersc c~~rcr$. Open Ic8 ulcees in a Malay child aged
13 months were treated with the paste. llrcy healed but
ocxkma and pain incrcasd
After 9 weeks. X-ray examination showed dense wansvcrsc bands of metallic bismuth deposited in me[aphyscal growth areas of long
bOnea,— H. N. Krige. S. Afr. med. J.. 1963, .i7, ItMS.
Two rmctions to dental dressings with Bismuth Subni{ratc and lodoform PZSIC occurred in which crywal.v of
bismuth subnitrate
were cmwdcrcd
to be the cause
rather than the iodofomr.— W. A. Miller and G. S.
Taylor, Er. dent. J., 1968. [24, 420.
Symptoms compatible with iodofomr toxicity occurred m
I patient and raised iodine concentrations
in 2 further
patients following the packing of cavities with gauze
impregnated
with Bismuth Subnitrate
and [odoform
Paste. tn a further patient who received a pack soaked
in Compound
Icdofonn
Paint no signs of iodoform
toxicity were olx.ewcd. II was suggested that Bismuth
Subnitratc
and Iodoform Pas!e was satisfactory
for
packing small operative cavities but for large cavitica
Compound Iodoform paint
stez were safer.—
F. F.
OConnor et al., /. Lar. CJt
#
,Odof.
~:
U?tt
c
o.; Iodoform Varnish: Whitchcd’s
Varnish. Prepared
from iodoform 10 g, benzoin 10 g. prepared storax 7.5 g,
IOlU balsam 5 g, and solvent ether 10 I(XI ml.
iodophores
Iodophorcs are earners of iodine and are usually
complexes of iodine with certain types of surfactants with detergent properties. [t is possible for
iodine to be taken up in chemical combination by
high molecular
weight surfactants
and waterThe
surfactants
may
be
soluble
polymers.
nonionic. cationic. or anionic, but generally the
most efficient
and stable iotkophorea 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 iwiine which lose strcng~h by volatilisation a,.d there is no precipitation
~n-dilution
of an iodophore
solution.
The stability
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 ~he hypwhiorites,
solutions of iodophores
can be formulated with actd and the bactericidal
action of most of them is ennanced by lowering
[he pH. Increases in rempcrature
increme the
bac:ericldd
action of iodophores. but above 430
they bre~k down with the liberation of iodine.
Stabiliry of $OIUIIOIM.
Lscdilutloms
t Wcscodyncl
iodine and 0.05% sodium nitrite lost their typical brown
coiour after standin8 for a few days and were found to
lose 24% potency in 24 hours or 42% in 48 hours SI
354. Similar dilutions without sodium nitrite were more
stable and lost 9.2% pacncy after 3 weeks at 350. — R.
J, Abrahams and H. J. Dcrcwicz, Anr J. Hosp. Pharm.,
1968.25, 192.
Uaea. Solutions of iodophores are employed in
pre-operative skin disinfection and for disinfecting blankets
and
some
instruments.
Stains
of
iodophores on skin and natural fabrics may be
removed by washing with soap and water. The
iodophorea described in this section are Povidone-iodine
(see
p.867)
and
Undecoylium
Chloride-Iodine
(see p.868).
f)isirnfectio.c of skim There was no significant
difference
in the incidcncc of wound infections when an iodophore
and hexachlorophanc
were used as surgica I hand
scrubs.— J. J. White and A. Duncan, Surgery CyrIec.
Obstei., 1972, 135.890.
TIc cffcctivencsa of iodophores
agai fisI both Gramncgative and Gram-positive organisms was an advantage
over hexachlorophanc,
but they did not persist in Ihe
skin 10 provide cumulative,
mntinuin8
antibacterial
activity. Like alcohol, iadophorca muld cause excessive
dryness of the skin with repeated USC,— Med. f.eff.,
[976, /8, 85. [odophorea were active against
both
Gram-ne8ative
and Gram-pmvitive bacteria and did not
rquirc repeated application for maximum effeetivcncas.
They were considered to be leas bactericidal
but leas
irritant than aqueous or alcoholic solutions of iodine. —
[bid.. 1977, 19. 83.
Studies invotving 95 women in active labour ncceasitating continuous epidurai analgesia indicated that skin disinfection of the catheter site with an iodophore (Prepo.
dyne) was superior to that with a benzalkonium chloride
preparation,—
E. Abouleiah
●{ al..
.4ne$rfteJ10/ogy,
1977, 46.351.
For other rcpxc.s, am Povidonc.tcdine,
p.867.
Ums OJ [email protected]$ OR farms. For a list of disinfcctama, including iodophorea, and their rate of dilution
aPProv~ for Uz,eIn Great Britain in foot-and-mouth
dis.
case, swlnc vestcular disease, fowl pmt. and tuberculosis
in animals, ace The Diseases of Animals (Approved Disinfectants) Order t978 (S1 1978: No. 32), as amended
(S1 1978: No. 934; S1 1979: No. 37).
A Iiat of proprietary
iodophorc preparations
approved
for the cleansing and disinfecting of mdk containers and
appliancm iS contained in Circular FSH 8/78, Minls[rY
of Agriculture,
Fisbcrica and Foods, London, HM Stationery Office, 1978.
4578-t
paration
865
umramuq
of an tedophore pre150 ppm Ivadable
Virus dirinfectiom For the disinfection of materials in
contact with Iasaa fever virus, see Memorandum
on
fossa Fever, Dept of Health and Social Security, London, HM Stationery OffIcc, 1976.
Recommendations
for premstions
in medical care of,
and in handling materials
from, patients with transmissible virus dementia
(Creutzfeldt-Jakob
diseasc).—
D. C. Gajduaek et al., New Engl. J Med.. 1977, 297,
1253.
For the usc of iodophorca m the disinfcctmn of fabrvcs
exposed to smallpox virus. scc Disinfectants,
General,
P.548.
Proprietary Preparations
Faringeta (Winthrop,
UK). Lozenges each containing
4 m8 of miriatalkonium
iedine chloride (myristyl berrziodine
benzylaikonium
chloride;
dimethyltetradeey lammonium
chlor!dc-ioctine
complex;
C13H.ZCIIIN -621.9).
For minor
Infections
of the
thr~t.
Dose. I or 2 lozenges to be sucked slowly every
4 hours: not more than 6 m 24 hours.
Stcsibatb (Stuafl. UK). An antlsepuc solution con:ainmg
an iodophore (complexcd with a nonoxynol) and prov[ding 4.5~ Of available iodine: available in !4-ml sachets
for addlt]on to ~hc bath.
Varrodinc (Ewws.s Vanodine, UK). A bactericidal
and
t’unaicidal de:cracnt solution conmin!ne ~vailable iodine
1.9~’% w/v (in tkc form of an iodine-&lOxamer
complex
lg.7%) For the control of foot in fectmns $n sw!mming
baths Ind changing moms, Dilucc I vol. $n 100 vol. of
water for USC.
Other Proprietary
SeptoDyne rL’.$AI.
Names
.
\
i
302
THE
THE NA
NATIONALFORMUL.4RT
mixture vigorously.
After the chloroform hsE been decolorised allow the mixture
to stand for 5 minutes.
If the chloroform develops a purple colo~, titrate further
with the iodate solution. Each mf. of 0.05 M pots.wium iodate ss equivalent ta
30.55 mg. of iodochlorbydroxy uin (CJLC1lNO ).
Tablets availablfiIodocldorhy
% oxyquin Tablets usttaUy available contain the
- following amount of iodochlorhydroxyqub:
250 mg. (4 grains).
PacJraging and storag*Preeerve
Iodochlorhydmxy quirs Tablets in tight, IighLr+
aiatant containers.
CATEGORY-kltiprOtozoan.
USUAL DOSE OF IoDoc!HLoRHYr)RoxYQIJIK-250mg. (approximately
4 grains).
IPECAC
AX
Dover’s Powder
Ip-q
in very fine powder . .
Powdered opium
. . . . .
Lactose, coarsely powdered . .
To make .
Triturate the ingredients
reduced to a very fine, unifor
Description-Ipecac
and O ium I
requer
Miting coarse, an
ve~ slowl)
up to 400 A.in len F
polarizin hght mth ~ strong disp
of ident#cation
are the tissues I
d=cribed in the U. S. Pharmacc
Packaging and storage-preserve
era.
f
Iodoform
IODOFORM
Tniodomethane
CHI,
n~o}. wt. 393.75
CATEGoRY—l)iaphoretic.
USUALDOSE—300mg. (ap]
One wsual metricdosecontains
Iodoform, previously dried over sulfuric acid for 4 hours, contains
not less than 99 per cent of CH13.
(%?!$r,.
:
.;
1,
.
“ tion—Iodofom occurs as a fine greenish yellow powder, or lustrous crystala.
Perstsmnt odor.. . IodoforM
a pecdiaK, very penetrating,
...’...slon-ly WIt.b steam. is al ight)y Vo}atile
=ven a~ oramar
tern eratures, ana d;stus
Volubility-O.e
(!’m. o?lodofonn dissolves in about 60 ml. of alcohol, in about SO
MI. of glycerin, in about 10 ml. of chloroform,, in about 7.5 ml. of ether, and in
m about 16 ml. of boiling alcohol.
about 34 ml. of olive oil. One Gm. dissolves
Iodoforrn
is practically
insoluble in water to which, however, . it irnDarts
itsodor
.
and taste.
Meltin
point-Iodoform
melts ta a brown liquid at about 115°, and decomposes
at a~gher temperature, enittirsg vapors of iodine, p~ge 691.,
LOGSon 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— f odoforrn yields not more than 0,2 per cent of residue on ignition, page 71 I.
Coloring matter, acids, and alkalies--Shake
about 2 Gm. of Iodoiormwith5 ml.of
waterfor1 minute, and filter: the filtrate is colorless and free from bit~r ~ste
and is neutral to litmus,
Assay—Diaaolve about 200 m of Iodoform, previously dried over sulfuric acid for
4 hours and accurately welg
ofalcohol
ina .500-MI.
gbmwtoppered
“% edlin20 ‘h-d.
Add 30 ml. of 0.1 N silver nitrate and 10 ml.of nitric acid,
Erlenmeyerflsusk.
stopper the flask, and set it aside overnight.
.kdd 150 MI. of water and 5 ml. of
ferric ammonium sulfate T. S., and titrate the excess of silver nitrate with 0.1 N
ammonium thiocyanat.e. Each ml. of 0.1 IVsilver
nitrate
isequi~-alent
to 13.12
mg. ofCHI~.
Packagingand storag~PreserveIodoformin tight,
light-reaistit
conta.mers,
and
avoidexcessive
heat.
CATEGoRY—Loca]
---..
. .. . .. . . . .__.
antibacterial.
Orizaba Jalap
Ipomea is the dried root c
voluulocez).
Ipomea yields not less tha
Un~ound Ipomea occurs as nearl
duwneter, and from 1 ‘m 5.5 cm
Wrinkledj and has a tough, fil:
rings mth protruding
lighte
crushed has a distinct, somewh:
what acrid.
Histology-Ipomea
shows a cork>
cells: an outer cortex of sever:
made up of thick-walled, tangen
or crystals of calcium oxalate,
to yellow resinous latex; rings
alternating with bands of pare[
outside of the wood-wedges.
numerous and distributed thro
surrounding the bundles are 1
calcium oxalate crystals.
Powdered Ipomea is pale brown
Upio 35 p m diameter, most]y
)[
‘~ /
6&@
FOI{J1{JI.A1{Y
l’il~:NATIONA1.
.——
!20
Rxtract the mixc(l (lrl]gsl}y~r(’ol:~tion,
[u+ingdilutml
nlcoholus
the
hlaccratc
tlwc
Im[lrsl
:uI{l
Iwrwolatc
:d,
a
IINNlcratA3
rate
ncns{,rlluln.
‘1’0 tliis :L(itl slll[iri(!llt [Iistillrxl
intil 250 cc. of pcrcolatc is ol)t:til]ml.
or, to ]nxqnwc Lhc Infusion
vatirti
l[lakethe pro(]uct ]))e:hs[lrc lWOCC.
;
distilled
i\41(l slljiicicitt
CXti!IIIll(Ir:LIICOIISIY,
n smwllcr quantities’an[l
to IIlakc 4 VOitIIIICS(Jf the Infusion.
water to 1 VOIUIIWof the percolate
NOTE: Thepercolute or r(nlccntr~lfmi itlfusion IIIay Iw IJITSCIWXI in
[ight containers, l-rut the lnf~tsioll Inust not be dispcnswl IIIIIWS it INM
IJ(Y!II ~CCCl}t]y prC!p:L~C{i.
Storage—Difi]wnse. C(,nll~~)llll(llllfllsi,,ll of G~l,li:,,l il}ligl,t, r,,llltti,l{.,x.
Alcohol content—krrmrOtu
il percent, by vohonc, (,f C.Ji,OII.
AVERAGEI)OSE-filCt.riC, 15 cc.; Apot.hw_wies,4 flui[lrwiuils.
INI?USUIVI S13NNAI CURI MAG NI’;SII SUl,l’’A’l’1t
\Vil!l
n~fl.~ll(!S;lllN
Slllf:l,l,{’
lli[{lsi[)ll tJf S(’lll)il
Inf.
Senn.
c.
Msg. Srrlf.
(hlnl~,uld
Sienn a . . . . . . . . . . . .
Manna . . . . . . . . . . . . .
Magnesium Sulfate . . . . . . .
Fennel,ljr!]i~~>~l.....
Distilled Water, :lslll!i~-i!’t]l quunl.ity,
‘I’or])\\k{:. . .
Infusion
,Srl}lm
. . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
.
.
.
60
120
120
20
. . . . . .
000 CC.
. . . . . . . ..1
l)OLW
8(M) rc. of Imililw (Iislilk?t! water ulmn tlw %vl!}:t,
[euncl,
d
colll:tinwl iii :1 suit:llde wswl , :IINI :tlkw
111:11111:1,
:tmf
for half tin hour, p:w tlm Ii(luid throo~ll :t slr:litwr :IIMI cxprxw the
l~)arc. l)iwolvetlw Ill:igllfisiulllslllf:ltc ill (11(’li(lili(l,:lll[l:ltl{l s{lllivicllt
distilled water throwh the strainw to m!lkc tlw Infmiol] tlumsure
1000 cc. Filter if nercw:iryj until tl]c pro{luct is clear.
Nor~;: This prqmation must not lJc (Iispcnwx{ unless it lm IJWN
recently prepared.
Storage--l)isl~l’llsf’
lllfll~itlll
AVERAGEwsm-illetric,
(J ,Wllnn
with M:oowsimn Sul[ILtc in tight rxmtni,wm.
W cc.; Apothecaries, 2 fluidounces.
10IX)FOl{hllJNl
Iodof.
“-
Iliiorfrrmcthnne
Iodoform, prwiolwly dried over sulfuric acid for 24 hours, co]ltains
not ISM than fyi) per cm}tof CHL (3!)3.78).
@
-— 7
jw+jo
221
THE NAT: ONAfJ FORMUI.ARY
Description-Iodoform
occurs as n fine lemon-yellow pnwdcr, or lost rmlg tryst.nls.
It hn9 n pecnlinr, vcrv pcnctrntiog,
rsistrwt odor. lwiofwvn is sli ht.lv vrhtile
cwn nt ortlinnry tempcrnturrsr
nn Ristils
slowlv with fhe vnfwr ,,!writrr.
%lubility—I,)d(,forlll
is ]wnrticull inwd~]btc in wnt’cr t{, \vl,irll, ht,~rcvr.r, it, ilnpnrt,s
Ita odor nnd tn.~tr. Oiic Gm. {)f Iotk]forln di.ssolvc~ in nbout M) cc. ~Ifnhx)l]{)l, in
about 80 cc. of glyrcriu, in nbnut 10 cc. of chlOrofOrm, in rd)ollt 7..5 rc. of c1 lmr
and in nhnnt 34 cc. of olive oil, nt 25* C.
Onc Gm. di.wrdvwr in nl)~mt IO rc. o1
boiling nlcohol.
]iquid at about 1150 C., nn,l rlecoJlIMeltf.ng point-lrrdcrfrwm melts trr a krwn
posen nt n higher ternlmrnture, emittin
va
Loss on dryfng-Onc
Gm. of Imloft}rm , nrd ovsw nulfurlc rmi,l f,,r 24 I,,],,rs IC,WW
not more than 1 rrcntofit~weightf”
“OrsOfiO’’i’!e”
Ash—Iodnform y “r ds not. mom ~hnu 0.2” r rent of nsh upno i~nit ion.
Colorin matter, acids, and alkaliea—Shn re nbout 2 Gm. ~Jf I{){lt)fortn ~vit II 5 m-. of
rfistil fml wntrr f{]r (jlm minute, nod filter: the tiltmtc h c(!l(}rlcss nod free fr{,m
bitter taste 00{1 is ilrwtrnl to litmus n rcr.
Assay-lkrolvc
alxmt 0.2 (_hn. of Io$ol,nm, previousl~ [11~~
Iwl ovrr snlforic nri(l
for 24 hours nnd nccuratcly wei hc{i, in 20 cc. of n cold in n 500” CC. glnsqstop] reJwl Iqklrmmcyer flask. A(I5 30 cc. of tenth-normul silver oit.rnt,e nl]{l [I)
cc. of nitric ncid, stopper tho fkk, nntl ,set it nsirte ovcrniKht. Ad(l 150 I-C.of
distilkxl lvntcr mm] 5 cc. of ferric nmmm)ium srdfnte ‘r.S., m(i tjtrmt.etile cxccw
of silvrr nitrate with tmlth-n{mnnl wnmonium tJliocynnntc.
Fmcb cc. Of trnthmwmnl Rilvw oitrntrt is rqllivnlvut It) 0.01313 (;m. 0/ (3II i,.
StoraKe~l’rescrvo
Iodu[uml iu tight ccmtllilicrs, prvtcjted from Iigllt, ntlJ Ilv{,i,l
excesmve beat.
Gm.
Gm.
Grn.
Gm.
tlw ]I!i.xtllrc to infuse
(jMf
11’Ohl(J?A
Ipollleo
Iporm
Oriznbm
Jnlnp
Nlcxiran
Iponlcw is t.lm(lried ro(d.of Ipomwr ori.rabemis IN(lrnois
SfmmmOny
(l~:~n]. (,’o~L-
Vohwluwe) .
Ipomea yiel(ls not less than 15 per cmlt of the totnl rrsills of
and not more than 3 per cent of mid-insoluble .asl~.
IIJOIIIeYL
Ungrourrd Ipomea—Neml~
flnt trnnsvcrse dires from 2 to 12 cm. in dinmctrw,
rrnd from 1 to 5.5 CM. m thickness; externnl~y brown, very deeply wrinklrwl;
fracture tough, fibrous; cut sorfnce ahowing concentric rings with protruding
Iigbter-euhn-ed fibru-vascular bundles.
Hhrtology-A
cork y in.ver of severnl rows of thin-nailed,
narrow tahu]nr cells;
outm cortex of sevmd lnycrs of thin-wnllrd cells; n brond corticn [ IaYcr mnde 111)
of thick-wnlied, tnngcnlmlly chmgatml cells, contnin ing ei thcr etnrcb
cryetrde of calcium oxala~, and numerous lnr e cells con t mining redds+
brown
“Yi”s
“r
to yellow resinous latex; rings m zones of smal 7 colinternl tibro-vrwcnlrm bundles,
aftematirrg with bnndx of parerrchymn; sieve in semi-cylindrical strands ouh
side of the w’ood wedges; med ullary rays broad ; resin cells numerous and dir+tributed throughout tlw pnrrnchyrnn;
the pnrwrrhyrnn cciis surrollndirrg tho
bundles, moro or ICSSculhqwcrl MNI containing vit]lcr stnrch or cnlcinm oxnhd,o
crystals.
Powdered Ipomea=Color
pale brown to. wcnk yellowish ornnge; odor distinct,
somewhat rwomatlc; taxte sweet, Lwcornmg somewhat acrid; starch grains up tn
35 microns h diameter, mostly simple, also 2- to 4-cnmpound, and usrmlly with
a centrnl clef ~; calcium oxalate crystnls numerous, mostly in rosette nggregntrw,
oeerwrionnliy m rhombnbedm, from 10 to 45 microns in length; frngmcnts of
Page
Number
: 1
.--=.
Database:
Medline
Set
Search
-------------------------exp hydrocarbons,
iodinated/
iodoform.tw.
exp safety/
efficacy.tw.
2 and 3
2 and 4
from 6 keep 3-5
------
------
1
2
3
4
5
6
7
<1966
to
present>
------
------
Results
-----2722
103
8472
108250
0
6
3
<1>
Unique
Identifier
96081121
Authors
Corbridge
n
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 i.n the control
of
L \ acu:e
requiring
hospital
admission.
A
total
of
50
epistaxl+
patients
presenting
with severe
epistaxis
was treated
with
either
merocel
nasal
tampons,
or BIPP. The groups
did not
differ
significantly
in 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
Their
ease of insertion
makes them suitable
for
measures.
use in the accident
and emergency
department
or in general
practice.
<2>
Unique Identifier
94203886
Authors
Holan G.
Fuks
AB.
Page
Title
A comparison
of
primary
molars:
,
pulpectomies
a retrospective
using
ZOE and
study.
KRI
paste
Number
in
Source
Pediatric
Dentistry.
15(6):403-7,
1993 Nov-Dec.
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-containing
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 radiographically
to assess
success
of the treatment.
Follow-up
interval
varied
from 12 to more than 48 months.
Overall
success
rate
for KRI paste
was 84% versus
65% for ZOE, which was
StZitiStiCEillY
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.
L‘/.
–&=J%.
<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
_-—._
: 2
Page
Number
: 3
-7
_“
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
BIPP which,
was
nasal
packs and pack removal,
particularly
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
in 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
is concern
about
persistent
hemorrhage.
In these
cases
Telfa
would be
preferable
to BIPP.
_-
—+
*
GREDIENT NAME;
METROMDAZOLE
BENZOATE
B. Chemical Name:
5-nitro-llf-iidazol-l
-yiethyl benzoate
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
99.54’%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 PharmacopoeiaVolume I (A-P) 1985
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Stolze, K. Elimination of Elyzol 25% Dentagel matrix from periodontal pockets. J C/in
1995; 22(3): 185-187.
Perioubntol,
H. Information about dosage forms used:
Suspension
L
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-
---- -. ——__
_____
.- ___
——
—
.—_;
<___
.-. _____.-=
. .—--—
.. ., .——
...----—....—.
—._ .- ,_-,.
- .—-—-----..
. .. ~..
=X.
——..———_ :-
.
Milanr
2 x
..-
llth
25-kg
—_
—-.—- ..
.
---- .-_-—__
,-— —...
_. ...=..
-7____
._-._=:_____
.
..-.
—
_ -_ -.
-—
—.:.
.
-..
-.
. --------
_.
———
——
.__.,, ._ .._-— .—
__
.__.
—.*=,
-_.—-—. .—.-— ...
.— ___
1997
December
drums
.
J
Manuf.
date
:
ANALYSIS
Your Oral. No.
CERTIFICATE
. ..,..N.O..,
.........3.2.4..3
.......................................................... ...... ... ....................................
..........of .....he.e... l,,O.t,h.....C..~C..,,l
.9,,99.,9
.7............ Our FW. NO. ............?..9.?.5.................................. ..................... ...............
.
..
MET RON IDAZOLE
MATERIAL
--.
.,,,......rn.icr.onized
.
BENZOATE
B.P. ... ...
Batch
Quantity
.,, .,.,,,,,
KG . .........
50...,.,,,,,,.,,
,.,.,,0712
,,.,.,,,,.,,,,..,,,,,,
.,,,,,.,,,,.,
.. ... ... ....... ..............................................................................
I
I
Empirical
formula ... . ......
Molecular
.. . ..
weight
Awed
-.
......... ... .. .. .... . .
.
Specific
... . ..
,.,,,,,.rni,croniz,ed,,
Color ,.,
.,slig..
powder
rotation,..., ........................ ................. ................ ....................
.
..,.,.,.,,..,,
. ..
,....
. . .. .
Light absorption
yellowish...
.
...,..
.
.
..
Odor
Loss on drying
Taste
Residue on ignition t,...o?9Wi9Wi
Melting
point .....9........?.9...-...102.
\ .O.. ................. ....
Boiling range
.
.
Chloride
...............9.~.l4e3%
.......................................... ... ,,,..,..,,,,,.,,..,,..,,,,,,,,,,.,,,,,.,,,,
Sulfate ................................................ ... ... ..
. ..,,,..,.. .
I
........
/
Volubility
freelysoluble
in Acetone
practically
in
s.......
insoluble
.in water;
Dichloromethone;
soluble
..:. .................. .. ... ... ..... .
Heavy metals.
Identification
..
PH
0’
.
99.54%
(Assay)
Titer
calculated
as
dried
.. ...Esss...than
20 ppm
“
..... :.... A) Melting
. ... ....99 -, 102°C
B) complies
““’”””””c)””””““’’”””””’”””””””’’””’”’’’’””””’””””
pE
D) Related
substances
.
.
+. .. +5\
L-r
~)
basis.
.
Other requirements,
-...
—.
-.
—_
-.,...
./
/“
notes
,~:s,u+.ts
of ..tes.~ ,.0< ,,,:::.+,Y~,+s.
.
...................... . ,. .,,.,.
:S,,, P:,:,,, ~,:p.
,,,.,.,.,,,,,,.,..
.
/“
/
d“
T
Analyst
L/
/3[
47
QUALITY
CHEMICAL
NAME.
CONTROL
RXPORT
:METRONIDAZOLE BENZOATE POWDER
MANUFACTURE LOT NO. :0712
PHYSICAL
SPECIFICATION
TEST STANDARD.:USP ——/BP
l)DESCRIPTION
.:
WHITE OR SLIGHTLY
CREAM TO YELLOWISH,
TEST
/MERCK
——/NF
CRYSTALLINE
/t4ART. _/CO.SPECS.
POWDER
OR FLAKES.
2)SOLUBILITY .:
VERY SOLUBLE IN CHLOROFORM,ALCOHOL;SOLUBLE IN ETHER,INSOLUBLE
IN WATER,
.-.
3)MELTING POINT.:
MELTS AT ABOUT 99-102
4)SPECIFIC
GRAVITY.
5)IDENTIFICATION
degree.
K.
:
.:
A)COMPLIES BY IR SPECTRUM AS PER COMPANYSPECS.
B)A SOLUTION PH IS 5.8.
FAILS .:
PASSES. :
COMMENTS.:
DATE. :
ANALYST SIGNATURE. :
PREPACK TEST.:
RETEST.
.-.
:
DATE. :
DATE. :
INITIAL.
:
INITIAL.
:
—“
30/04
FAX 0039 2 6693128
’98 15:58
TC
U02
1/4
l!KATEI&AL
1,
Roduct name
Cheauicnlmine
Emp. Formula
SAFETY
SHEET
cl?ElMIcALlumDucTn4ENTmfam
: MB’TlM3NIDAZC)LE13ENZOATE
: M&[email protected]=ln#@r&iitJu fnwazok
‘ W$,O,
- 27s93
$
.
1
2.
COMwaFIQN
f IwMEMA!lxw
ox
z!VaUwRNzS
-
[email protected]@
CM
name
HNEcs
W
6919$-10+
l*~*YlF2-*lwe
a.
%
99%
Symbol
Xrl
N“
1
IU2WU2 RWW21FZmZ2Z2N
Mayaroseirliiatfonto rwplramty 8pparatUs.
Efikct(s) of (mduqmnmf
Symptoms of (ovm$expomue
Jnhalatton : not wailable
SIdu
: Ltotavdlable
\ not aveilable
E~e6
Ingestion
:
not
awdlable
4.
Iiihaiatfoxu
Swu
Effects
Fht aid
Effects
F-
aid
llltlW’Alll
[email protected]@lUE&[email protected]
May be idatlng.
Removevictim to fresh dr. Keep victim at rest. Consult a doctor.
May be initadng.
IZemovecontamhd clothhg, Washoff witi plenty
soap, Comdt a doctor.
Ey-+
Effect4
First aid
May be Mtaling.
Wash out with plenty of water, Cmeult a doctor.
Ing-orx
Effects
LD= 1,050xng/Kg
Wash out mouthwithwater.
Ibt
aid
30/04
RPR 3EI ’98
E19:23
’98
15:47
Consult a
pf water
and
doctor.
NR. TX/Rx
0039 2 6693120
i
4143
Pol
P9GE. 0E12
Product name
MFXIUXXDAZOLE
r
H.
JnRE
BENZOAfi
FYGRTnV&
Page 2 of 4
UE4#UREs
*
Exttmguishing
meam.mci
Suitable
..
Not be uned
:
Wate spray, COWfoam, d.rv chemical
Hazardous thermal
decomposition and
combustion products
:
co, co,, N(JX
Ptotectfve equipmealt
:
Self-containedbreathing apparatus. [email protected]
4
L
I
6,
RELEASE MEASURES
Accidental
Personal precautions
:
Wear $titabh protective clothfng. When u.cdngdo not eat,
drink
II
Or
smokm.
Knvimnrnental pmciwdions :
Not available.
acq
Collect spdkd matdu.
p~CWdWW
:
II
II
cleanup affected area *
wtiu.
See section 8 and 13
I
7,
ILUDLLNG
AND
&!#IMGIE
Ikdl.ing
: Ventilation recommended. When wing cb nOt eat, *or
Storage
:
Kmq mntainer tightly clomi.
8.
EmxM3RE
commM18
/ PKRSOIVALPROT’EC’TICXV
Rmpiratory protection
:
Airlind
II
Hand protection
;
Rubber g.lcwe.
Eye protection
.,
Safety gogglaa or face shield-
I
skin protection
:
Working clothing.
II
smoke.
respirator or dust maak, type PZ
I
II
I
.—30/04
f2PR 30
‘ 98
09:24
‘ 90 15:47
NR.
Tx/Rf
d035 2 6693128
Po 2
4143
PQGE.003
30/04
’98
FAX 0039 2 6693128
15:58
Product name: METRONIDAZOLI?
9.
PEmwcAL
UI04
TC
BENZOATE
Page 3 of 4
AND CHEMZCAL PRa?ERTms
Appaamnce
; cxystahepowder
Colmlx
: white to yidlowiah-whke
Vapour pretmxe
VapOW density
Odour
: Odourless
Plash point
: 99°.
Autaignition
Melting
Wlfltg
point
103”C
Relative d.anaity
: Not available
Bulk d~i~
;
Not
aab]e
Sah.bility in water J 0.5%at WC
pH
z Not availabh
PartWion coefficient x Not available
II
: Not avaiIabIe
: Not available
: Not available
Fkxnmability
: Not hammabia
[email protected]:
Not availabIe
Upper lhn.it
: Lower Wnlt
: -
: Not available
point
: Not available
Vismaity
: Not avaUab4
Conductivity
: Not available
4
10. s!naBlzrfYAm3
Conditions
Matcriala
to avoid
: :
to avoid
Haza.rdoti.6
productm
decomposition
. . .
Chuduzmg agenta
: NOx
lJ , lwucoLo4w?AL
Acute
J=Acmvrn?
lmwtM417tw
tOXiCi~
oral
:
IkrlIid
Inhalation
:
:
Na available
Not availabie
May be tnitating
Eye il!ritatim’k
Skin hitUtiOIl
:
Maybe irritating
I
OWX h.fomation
:
be initatig
Not available
May
12.
ECOLOGICALRVFOmTION
: Not available
Mobility
Persistence
and
: Not available
degradability
Bioaccurnulative
pcwttlal
: Not available
Ecotoxiaty
: Not available
.-.
30/04
RPR 30
‘9S
09:24
’98
15:47
NR! TX/Rx
m339 2 6693128
4143
P03
Pf2GE.004
Ju/u4
85
15:5B
kAx
lJu3u
2
6U9J1ZU
Roduct name: METRONIDAZOLE
~
.
J3,
I?EN20ATE
Danger(6)
l’age 4 of 4
7
DISFOSiAL CimTSZDERATIOfVs
Methods of disposhl : bmbusbon
I
—
IQJU5
1(,
in an incinerator far chmnical wa5te.
:
Not available
14.
Tl?.AAWPi31tT
lNFO~T~
I
9
Speck.i precautions :
Classification
UN Code
:
Packaging group
lCAO/lATA
ADRIIUD :
IMO
:
:
:
JI
1 ii.
RJ3GULATQRYIJVIN)mmOl!f
EC ~=6ifiCa$On
__++.
~oatains:
l-(2-benzoyloxyethyl)-2-methyl-5-dtio
Symbolr
M
phases:
Riuk
safety
phra6es:
imidazole
20/22
2
18.
01’EER
RUFORWIZTON
The information contained in thti data sheet is to the best of our knowledge, true and
accurate, but any recommendations or suggestions which may be made are without
guarantee, since the conditions
Furthermore, nothing contained
1
any product
of use are beyond our control.
herein
in can.fl.ict with existing
Issued on januq
shall be constmed
patents
covering
as a recommendation
any material
to use
its use.
or
199S
. .
..
.
—.
30/04
QPR 312 ‘9S
09:24
’98
15:47
NR.
TX/Rx
4143
0039 2 6693128
P04
PRGE.005
storage
light.
Store in a welklosed
container, protected &om
Preparation
Methylprednisolone Acetate Injection
Action and uae Corticosteroid.
1/95
D. Examinethe chromatogramsobtained
Metoprolol Tartrate
Idesdfkation
Line 6. tier
Test A. Iine 4. For’1 8“’ read ‘-180’.
‘residue’insert’, Appendix D A’.
12/93
Heavy metals
Line 2.
lootId With lMhyddthC “ acid Examined between
220 nm and 350 nm, Appendix II B, the solution shows
two absorption maxima, at 232 nm and 275 nm. TIIe
[email protected] absdana
at the maximum at 232 nm is 525 to
575.
C. Examine by infrared absqosim specsmphowmesy,
Appendix II A. The absorption maxima in the specmtrn
obtained with the substance being examin ed correspond
in position and relative intensity to rhose in the spectrum
obtained with mernm&z ok btnzoare EJ%IM.
For’1 MI’ mad
’10 MI’.
7/94
Add the following staresnenr.
MetoprololInjeetion
solutionis not moreopalescentthan w$ennc4suspambn11,
AppendixIVA, and not more intensely coloured than
Metoprolol Taruate Tablets
rqfernw soiusim G~, Appendix IV
Metronidazole
Add a five-pointed star (ti) to the title.
7/94
Add the following
Metronidazole Intravenous Infusion
.+
/@zjz.&.!’
o
/
(’+-J
02N=fv”e
‘b
ERRS
N
13182-89-3
Definition Metronidazole Benzoate contains not less
g8.5~o ~d not more than 101 .0% of 2-(2-me~Y]*
benz~at~C13Hl~NJO~,
[email protected]
~e~subscamce.
Characteriatica
,~J:_o:
digbdvyellowi.sh},,~talline
.—
powder or flakes; pnxtxally insoluble in toa&@&i4j”
6 -e
in dichlowmda nq soluble in acerone, slightly
solubIe in edwwl (96%); very slightly soluble in ether.
Identification
.——==
in atone
and dike
to 10 MI with the same
solvent.
So/t&n (4) Dike
\
275.3
B, Method II.
Acidity Dissolve Z g in a mixture of 20 ml of dimethyiand 20 ml of waer, previously neutralised witi
f~
0.02M hydmdbu “ acid ~ or 0.02M so&m hydnxide VS
using 0.2 MI of methyl nxfsdusbn. Not more than 0.25 ml
of 0.02M @dsiun hjkwife W is required to change the
colour of the indicator.
Related subatancea Examine by shin-layer chmmasoWPti, Appnti
Hl & using silicu gel HFz~asthe
coating substance. Heat the plate at 110° for 1 hour and
allow to cod before use.
So&rim {1) Dissolve 0.20 g of the substance being
examined in ucewne and dilute to 10 ml with the same
solvent.
Sofu&m @) Dilute I MI of solution (1) to 10 ml wirh
acesone.
Sohusbn (3) Dissolve 20 mg of meovmduzole benzoase
Preparations
C13H[3N304
for
Appearance
of solution Dissolve 1 g in dimethyVownamsde and dilute to 10 ml with the same solvent. The
Rep!amdona
L’
in the test
Related substances under ukrarnbkt kght (254 nnr). The
principal spot in the chromatograsn obtained with solution
(2) is similar in position and size to the pMcipal spot in
the chromatogtamobtained with solution (3).
E. To about 10w add about 10 mg of ainc powder, 1 ml
of wasar and 0.3 MI of &vchk’c
ad. Heatona water
bath for5 minutes and cool. ‘llse solution yields the
reaction characteristic of prbnay ammani amk.s,
Appendix w.
5 ml of solution (2) to 100 ml wicb
acetone.
Solusion (5) Dilute 2 MI of solution (2) to 100 ml with
acewne.
Sokbn (6) Dissolve 10 mg of memmtiok
EXRS in
acerone and dilute to 100 MI with the same solvent.
Soluion ~) Dissolve 10 mg of 2-methyi-5-ninvimdazoie
in
aarone and dike to 100 ml with rhe same solvent.
Sohuion (8) Dissolve 10 mg of memmi.izzole EFW?.S and
10 mg of 2-methyl-5-nirmim&zole in acetone and dilute 10
50 ml with the same solvent.
Apply separately to rhe plate 10 WIof each solution.
Develop over a path of 15 cm using erhyl aemzse. Allow tie
plare to &yin air and examine under ukratifer light
~54 nm). In the chromatogram obtained with solution
I&nnjLzz&t
tat C may be omisud If
Idenrij%adenszj%xsnbn sesrs A, B, D and Earc carried w
(1) any spot corresponding
to metronidazole
or 2-methyl5-niuoimidazole
is nor more intense than the correspond-
rionseszs
B, Dand
and Care
_ous.
ing spot in the chrotnmograms obtained wids solurions (6)
and (7) respetiveiy (0.50/0). Any other secmufary SPOC
is
nor more intense I&n tie spot in the chromatogram
obtainedwithsolution
(4)(O.5°/0) and at most one SUC3
spor is more intense rha.n he spot in the chomatogram
.& Mefsingpox~
Emaybeonriued
99° to 102°,
tfidenstj%xsion
tes.zs~
Appendix V & Method I.
acidand dilureto
B. Dissolve0.1 g in 1,Mhydmch.knit
100 ml withtbesame acid.Dilute1 ml oftheSOIUUOUIO
ME’IRONIIMZOLE
Loss on drying : Not more than 0.5 percent, determined
on 1.0 g by drying in an oven at 105”, Appendix j.8.
zole, transfer to a sintered.glass crucible and extract with
six quantities, each of 10 mI, of hot acetone. Cool, add to
the combined extracts 50 ml of acetic anbydn’de, 0.1 ml
of a 1 per cent w/v solution of briWant gwen in glacial
acetic acid and titrate with O.I N petcblon”c acid to a yellowish-green end-point. Pefiorm a blank determination
and make any necessary correction.
Each ml of O.z N
pemhforic acid is equivalent to 0.01712 g of GJ-$N303.
: Weigh accurately about 0.45 g and dissolve in 10
ml of glacial acetic acid, add a fcw drops of i-naphtbo/-
Assay
benzein
solution
0.1 N petcblonc
and titrate with
@id
until a pale-green colour is produced. Perform a blank determination and make any necessary correction. Each ml
of 0.1 N percbfotic acid is equivalent to 0.01712 g of
W9N303.
Storage : Store in well-closed light-resistant containers.
Storage:
tainers.
Score in weI1-closed, light-resistant con-
[-
Metronidazole Benzoate
Metron.idazole
Category
giardiai.
Tablets
: Anti-amoebic;
antiuichomonal;
Benzoyl Metronidazole
[email protected]
I
Dose : Metronidazole. For trichomoniasis, 200 mg
three times daily, for 7 days.
For arnoebiasis, 400 mg three times daily, for 810
10 days.
C,jHL3N30+
Category
For giardiasis, 2 g daily for three successive days
for adults, 1g da.i.iyfor children and 400 mgdaily for
inhnts.
and not more than 105.O per cent
of the stated amount of Metronidazole, C&&j03.
The tablets may be coated.
95.o percent
Identi,flcati
on:
(A) Shake a quantity of the powdered
tablets equivalent to about 0.2 g of MetroniclazoIe with 4
ml of Nstdpbtin’c acid and filter. To the fikrate add 10 ml
ofpicn”c acid solution and slow to stand for one hour, the
precipitate tier washing with cold water under suction
and drying at 10Y’ mehs at about 1.50”,Appendix 5.11.
(B) Comply with Identifkw.ion
test
(B) describes m-
Metronidazole, using a quantity of the powdered tablets equivalent to 10 mg of Merronidazole.
der
: &mply with the test described under Metronidazole, using as solution (1), a solution prepared in the following manner: Shake a quantity
of the powdered tablets equivalent to 0.2 g of Metronidazole with 5 ml of mixture of equal volumes of chloroyonn
and metbjd aicohof for five minutes and filter. The chr~
marogram obtained with solution (1) may also show
spots due to excipients.
2-Methyl-5-nitroimidazole
Other requirements
stated under Tablets,
: Comply
with the requirements
Assay : weigh and powder 20 tablets. Weigh accurately z
quantity of the powder equivalent to 0.2 g of Nfemonida-
320
: Anti-amoebic.
Dose: Foramoebic dysenq, the equivalent of 400
mg of rnetronidazole three times, daily, fbr 5 to 10 G
says.
Usual stmqths:
200 mg; 400 mg.
Standards: Metronidazole Tablets contain mm less
than
LMOI,W[. 275.27
“-
mp O~tP
mute[y equivalent to
NOTE -200
,
i, [email protected],QtQQ”-
125mtr o fmetmniabmie.
White or cream-coloured crystalline
powder, odourles; almost tasteless.
Description:
Solubillty: SparingIy soluble in water; soluble in
in acpt~q
C~[OrOf~j
and in ~CObO[
@O&v
c~t),
: Merrohidazole Benzoate is 2-(2-methyl-5-nitro-irnidazol- 1:yl) ethyl benzoate. It contains not less than 98.0 per cent of C,3H13N304,calculated with reference to the dried substance.
Standards
Xdem.ifkuion : (~) The light absorption, in the range
230 to 530 nm ofa l-cm layerofaO.001 percent w/vsolution in etbyf aicobolexhibits a maximum only at 309 nm;
extinction at 309 nm, about 0.3, Appendix 5.15A.
(B) It gives the reacrions of benzuates,
Melting
range
Appendi.. 3.1.
: Berween 100” and 102”, Appendix 5.11.
pH : Between 5.0 and 7,0, determined in a 2.o per cent
w/v suspension, Appendix 5.10.
Free benzoic add : ?-Jotmore than 0.2 per cent, deter.
mined by the following method: Dissolve 0.50 g in 25 ml
of alcohol and titrate with O.IN sodium &dmxicfe, using
phenol rvdsolution as indicator. Perform a blank determination and make any necessary correction, Each ml of
‘~!
~
!‘;
~..,
,{
‘t
MORPHINE HYDROCHLORIDE
0.1 N sodium
lydmxide
is
equivalent to 0.01221 g of
C7H60Z.
Related
substances : Carry out the method for fbirtchtvmatogmpby,
Appendix 5.4.3, using siliGa gel
HF 254 as the coating substance and a mixture of 8
volumes of chloroJomt and 2 volumes of acekww as the
lqer
mobile phase. Applyseparatelyto the plate [email protected] of each of
three solutions in a mixture of equal volumes of merbyf
and cbfom~onn containing (I) 6.o ~r.cellt W1v
of the substance being examined; (2) 0.02 percent w/v of
afcohol
2-metlyl-5-nthvirnic&zzOle
RS.and; (3) 0.02 per cent
R.S. Mter removal of the plate,
allow the solvent to evaporate and examine under an
ultra-violetlamp 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 qxxs in the chromatogmmobtained with
solution (1).
Sulphated
ash : Not more than 0.1 per cent, Appendix
3.2.7.
Loss on dqi.ng : Not more than 0.5 percent, 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 aceric anbydn’de and titrate
with 0,I N Pettblon’c acid using b?i[iiant green solution
as indicator. Performa blank determination and make any
w/v of metmnialzzde
necessary correction. Each ml of 0. I N perchlon”c acid is
equivalent to 0.02753 g of CIJH13NJ04.
Storage : Store in well-closed, light-resistant containers.
Stanckkcls : Morphine Hydrochloride is the trihydrate of the hydrochloride of 7,8-didehydro-4,5aepoxy- 17-methylmorphinan-3 ,6a-dioL which may
be obtained from opium. It contains not less than
98.0 per cent and not more than the equivalent of
100.5 per cent of C,,H,JJ05, 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.
Identifkation:
(B) To a 2 per cent w/v solution add potarsium fenlcomaining I drop per ml of~en+c cbfom immcdixc bluish-green colour L$
produced (distinction horn codeine).
cyanide solution
n“& test-so[ution:
(C) Add 5 ml of sufpbun”c acid to 5 mg [n a rest tube,
A
add I drop of fiim’c ch[twide tes[ solu(itm.
and h<.x[
in boiling water for two minutes; a deep blue ctiour is produced. Add a drop of nirn”c acid; the colour changes co
dark red-brown (codeine and eth ylmorphine give the
same colour reactions, but dihydromorphine
and
papaverine do not produce this colour change).
(D) Addto about 1 mg of the powdered substance in a
porcelain dish 0.5 ml ofstdphutic acidcontaining 1 drop
solution. A purple colour is formed
of f~ldeby&
which turns to violet.
(E) Dissolve about 5 mg in 5 ml of water, and add 1 ml
pe?vxide solution, 1 ml of dilute ammonia
soiution and I drop of a 4 per cent w/v solution of copper
su[pbate. A tmnsient red colour develops.
of bydqpn
(F) Asolution (1 in 20) gives the reactions of chfotides,
Appendix 3.1.
Addity or Mkalinity: Dissolve 0.2 g in 10 ml of freshly
boiied and coded water add I drop of merlyl red sohtion. Not more than either 0.2 ml of 0.02PJ sodium hydroxide or of 0.02 N bydrochfon’c acid is required to change
the colour of the solution.
Morphine Hyckxhloride
HO
Sped5c optical rotation : Bemveen – 112” and -11 5*,
calculated with reference to the dried substance and deter.
mined in a 2 per cent w/v solution, Appendix 5.12.
1;
o\
H+
.\
NHCH3
Ammonium salts : Heat 0.2 g with sodium hydroxide
solution on a water-bath fcr one minute; no odour of
ammonia is perceptible.
Cl-, 3H20
%
Ho
.-’’’=3’
C1yHl&Oj, HC1, 3H,0
CategoV:
Dose:
Mol.
Wt. 375.85
Narcor;c, analgesic.
10 to 20 mg.
Description: Colorless, glistening needles or
white crystalline powder; odourks; taste, bitter.
Volubility: Soluble in wafer; sparingly soluble in
afcolwf; practically insoluble in sobent etberand in
cb[orvfm,
soluble in g[ycen”n.
Other alkaloids , Not more than 1.5 percent, calculated
with reference co the dried substance, determined by the
following method: Transfer 0.5 g m a separator. add 15 ml
of water, 5 ml of IVsodium ~dmx~et and 10 ml Of
chlomfonn. shake. allow w separme. and tmnsfer the
chloroform solutiwl to another scpmxor. Rqx2[ the
exrracdon with two further quantities, each of 10 ml,
of chloroform. Wash the mixed chloroform solutions
with 10 ml of 0,1 N sodium bydmcide and then tith two
successive quantities. mch of 5 ml, of water, evaporate to
dryness ori a water-bath, and dry the residue to constant
weight at 105°.
321
—
http//igm-06.nlm. nih.g., ,M+lient? 10900+detail+1
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National Library of Medicine: IGM Full Record Screen
~ ...
H
. . ..
..........&eti
V:’:!M**;:
=====
:[email protected];’ ‘“.n7,”:[email protected]:”’;;..’:
“:”’”
1,1‘“““*W,
i$~~tigti$[ s?’v!![y~w+;:,.
===
.,:,...af$:i:::: . ....$wlw%:”:.:
w::
i=Xm!Y#*
.::~mfi
,:=i**:R#@~* *[email protected];*,’;
.,,:.,,:
mh:*,’””
,i.,.,,.:.:...,,:,MtM::wM::w
,
—
TITLE:
Elimination of Elyzol 25% Dentalgel matrix from periodontal pockets.
AUTHOR:
Stoltze K
AUTHOR
AFFILIATION:
Department of Periodontology, School of Dentistry, Faculty of Health
Sciences, University of Copenhagen, Denmark
SOURCE:
J Clin Periodontal 1995 Mar;22(3): 185-7
NLM CIT. ID:
ABSTRACT:
Elyzo 25?40Dental el (E
) which is developed for [email protected]_of
“
ont]t~ a sus e lon of metronidazole benzoate (40°/0)
—....-..in a mixture
of glycetyl mono-o eate (GMO) and triglyceride (sesame oil). Metroni~fiole
licali.m . The “
h afte~
can be deX
in the periodonta~~ockets
-.. —. 24-36
—--—
aim of the present study was to estimate the period of~me tkat the g=
matrix persists on 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.
:-:erio
MAIN MESH
SUBJECTS:
.-,
-..-
1 of2
Glycerides/ADMINISTRATION &
DOSAGE/ANALYSIS/* PHARMACOKINETICS
Metronidazole/*ANALOGS & DERIVATIVES/ADMINISTRATION &
DOSAGE/ ANALYSIS/* PHARMACOKINETICS
Periodontal Pocket/* METABOLISM
Sesame Oil/ADMINISTRATION &
DOSAGE/ANALYSIS/* PHARMACOKINETICS
5i519812:48PM
,- —=
-—
A. lNtiKNl)lIIN’~
NAME:
PHENINDAMINE TARTRATE
B. Chemical Name:
1,2,3,4-Tetrahydro-2-methyl-9-phenyl-2-duorene
hydrogen tartrate; 2,3,4,9Tetrahydro-2-methyl-9-phenyl- 111-indeno-[2,lc]pyridine hydrogen tartrate.
c.Common
Name:
ThephoriL Dalc~ Nohrnine, Melod~
Cerose, Carrhist
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Dry Basis:
(Limits)
(Results)
98.0’%- 101.5%
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:
kg., Br., Ind., Int., and Turk.
British Pharmacopoeia 1993
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Wite~ T. J., Canastrari, D. A., and Miller, R. D. The effects of phenindamine tartrate on
sleepiness and psychomotor petiormance. J Allergy Clin Immunol, 1992;90(6 Pt 1): 953961.
Sigidinenko,L. V. Various principles of therapeutic tactics in epilepsy patients during
Zh Nevrowtol
Psikhiatr. 1984:, 84(6):
897-899.
memancv.
.,
‘w.
*
.-–
H. Information about dosage forms used:
Tablets
Liquid
Elixir
Capsules
I.
Information about strength:
25-50mg
J. Information about route of administration:
Orally
IL 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-
-----L.—
___ .—-—-- ----—-
..
.. -..—-
‘.,
_3,.:
—-——
.—
;J54
—-—.
+ 30=!W
.
iiflum
IEsIs”
Acetic
Adlydaide
A#[email protected]=-=-
c
D.
.—_
.
[email protected]*
at241k2n=
d“”
Al=
nmst not
difkrby w
Zmn
than 3.0%
.
3.0 m 4.0
T-
-
-:
1.7%
35
0.115
NMr
0.25%
NMr
O.oa%
0.007%
<0.002%
.J
NM’T
0.005%*
NMT20%
/0
--.
k Jbis BAYE
BCT %.S%
B. DXY=
98.0% to 101.5%
/
<0.005%
1.3%
99.6%
99.7%
QUALITY
.-.,
CONTROL
REPORT
CHEMICAL NAt4B. : PHENINDAMINE TARTRATE
MANUFACTURE
LoT NO.
:
PHYSICAL
SPECIFICATION
TEST
l)DESCRIPTION
STANDARD.
:USP
/BP
——
TEST
/MERCK
/MART, _/CO
/NF
——
. SPECS. —’
.:
A WHITE TO CREAM WHITE CRYSTALLINE POWDER.IS ODORLESS OR ALMOST
E
O’L5mms.
2)SOLUBILITY.
:
SOLUBLE IN 70 PARTS OF WATER;SLIGHTLY SOLUBLE IN ETHANOL (96%);
PRACTICALLY INSOLUBLE IN CHLOROFORMAND IN ETHER.
3)MELTING
POINT.:
MELTS AT ABOUT 162-167
.–-
4)SmCIFIC
PASSES
WITH DECOMPOSITION.
:
(A) AS PER CO.SPECS.
(B) AS PER CO.SPECS.
(C) AS PER IR SPECTRUM CO.SPECS.
.:
FAILS
[email protected]:ABOVE TEST IS CARRIED OUT BY SUPPLIER
ANALYST
SIGNATURE.
PREPACK TEST.:
RETEST .:
_&’-’%
.“
1<
cmwmY.:
5)ID~IFICATION.
A)COMPLIES
B)COMPLIES
C)COMPLIES
deqree
:
.:
CERT.OF ANALYSIS.
DATE. :
DATE.
DATE.:
:
INITIAL.
:
INITIAL.
:
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PflGE ,008
1316 Promethazine and other Antihktamifles
For a report of the w of methdilazine
of migraine, see Methysergide Malcate,
6148-y
MethdiIazirte (u.s.P.). IO-(l-Methylpyrrolidin-3 -y Imethyi)phenothiazine.
C,$H20P-J2S=296.4.
Preparationa
____ CAS — [ 982-37-2.
Pharmacopueios. In US.
A
light tan crystalline powder with a characteristic odour. M.p. 83” to 88° with a range of not
more than 20. Methdilazine
7.2 mg is the quivalent of approximately
8 mg of methdilazine
hydrochloride.
Practically
insoluble
in wate~
soluble I in 2 of alcohol, 1 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.
Preparations
MetbdilazinaTablets
hdllazine.
light.
Store
(.YS,P.), Tablets containing
in airtight
containers.
Protect
in the treatment
p.669.
metfrom
Methrfkzine
Hy4razhloride Syrup (U~.P.). A syrup
containing methdilazine hydrochloride, with alcohol 6.5
to 7.5%, pH 3.3 to 4.1. Store in airtight containers.
Protect from light.
Methrlhzisse HydroztdorideTsbkts (LJ.S.P.). Tablets
containing methdilazine hydrochloride. Store in airtight
Protect from light.
mntainera.
Proprietary
Naaaaea
Dilosyn (Allen & Hanburys. Ausrral.; Allen & Harrburys. Carrad,); Tacsryl (Mead Johnson, Au.rtra[.; Pharmacia, Swed.; Wesrwood, USA~ Tacryl (Pharmacia,
Denm.).
Methdilazine
hydrochloride
was formerly marketed in
Great Britain under the proprietary name Dilosyn (lJurrcon, Fkxkhart ).
6152-s
~:!,*i
CAS — 4784-4(3-1.
., ;p&
Crystals. M.p.
250”.
1] .I mg is approximately
mazine.
Adversa Effeets. Metiamide
6149-j
Hydrochloride
(u.s.P,). IO-
(I -Methylpyrrolidin-3
-yimethyl)phenothiazine
hydrochloride.
Ci8H20N#,HCl=332
.9.
CAS — 1229-3S-2.
Pharmacopoeias. in U.S.
.--—
,
;
)
i
:,
,.:
..
,,1
~
A light tan crwtalline oowder with a sli~ht characte~stic odo~r. It darkens on exposure-to light.
M.p. 184° to 190”. Soluble 1 in 2 of water and
of alcohol, and I in 6 of chloroform: ttracticallv
insoluble in ethe~ soluble in 0.1 M h~drochlor~c
acid and 0.1 M sodium hydroxide solution. A 1%
solution
in water has a pH of 4.8 to 6. Store in
airtight containers. Protect from light.
Adverse
Effects, TreatmesaL and Preearrtiona. k
for the antihistamines in general, p.1 294.
As with all phenothiazine derivatives it should be
used cautiously in patients with hepatic diseases.
Uaea. Methdilazine
hydrochloride
is a phenothiazine derivative with the properties and uses
of the antihistamines
(see p.] 295). It is more
potent than promethazine
and generally
causes
less sedation. It has a duration of action of 8 to
12 hours, [t has serotonin-antagonising
and anticholinergic properties.
Methdilazine
hydrochloride
is given
for the
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 Xg per kg body-weight
daily in
2 divided doses.
A/fergy. Ninety-six patients suffering from allergy, of
whom 58% had prrsritus and 27% hsy fever, were studied over 2 weeks in a double-blind study designed to
compare methdilazinc
hydrochloride with promethazirse
hydrrxhloride. The dose was ususlly 8 mg of the former
and 20 mg of the latter, twice daily in syrup, Both
drugs gave relief to about one-half the pa[ierrts and
there was little difference in eftkacy for pruritus, but
promethazine
was superior to methdilazine in the relief
of bay fever. Drowsiness occurred in 32% of the patients
when they were taking promethazine,
being twice the
incidence seen with the other drug, but in spite of this
!he patients genersily preferred it.—Report
No, 25 of
the General Practitioner
Research Group, Pracfitiorrer.
1962, 188, 803.
— . Migraine. .Methdilazine 4 to 8 mg thrice dail was use“ul 10 prevent or reduce the frequency o {“ mtgralne
attacks.— J,M, Sutherland, Drugs, 1973, -f, 212.
Oxomcmazirre hjw:
equivalent to 10 mg of ~
“-”w%
Oxomemazine
is a phenothiazirre
dervti~v~ @“~
propertica and ~
of the antihistammu
(X, P.y~i,
has been given both as the base and ~ ~ ~
chloride in doses equivalent to 10 to 40 mg”’~’~
mazine daily.
,;;;,;*
proprietary Names
‘[email protected]&;
Doxergan (Spccia, Belg.; Spccia, F,.; Specia:,&~
Specia, Switz.); [makol (Rhdne-Poulerrr, Ger.).
..lfi.*
. .
6153-w
A
“ - e ~artrate
CAS — 3483%7fW
Methdilazine
.s,q+~~;
Oxomemazine Hydrcrehloride.
C, SH:ZN101S,HCI=366
.9.
6 150-q
Metiamide.
SKF 9205% 1-Methyl-3-[ 2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea.
CgH,6N4S1
=-244.4.
Proprietary
Names
Tacaryl ( Westwaod, USA).
CAS — [email protected]
A white crystalline
powder
155”, Practical y insoluble in
alcohol; soluble in chloroform
may cause agransslocytosis.
Acute reversible rsmtropenia
occurred in 2 patients
given metiamide.— J. A. H. Forrest cr al. (letter), Lmrce(, 1975, f, 392. Bone-marrow depression due ta metiamide was thought ta be due m the thiourea present in
the metiamide
molecule, rather than to Hz-receptor
bk-rckade.— ibid.. 1975, 2, 802.
~.
artms; Phenindaminium
idine [email protected]
Tartrate:
,.-.
Phehin&&
Phenin”&A;-J
tartrat
C19H19N,C4H606=411.5.
CAS
... .—
4 cases of metiamide-induced
agranulocymsis
~atej,
had ocmrrcd and trials bad stapped.— W. L. Budand Z
et a[., Smith KIirse & French (letter), Lmrcct, 1975, I,
1085.
A white or almost white. aim~t Odour]-”
minous powder with a bitter taste. M.plfi&*
Furrher rcfererrcex E. J. Feldman and J. 1. [aenberg,
New Errgl. J, Med., 1976, 29S, 1178.
162°; on further heating it soiidifiea ai~wA
U- Metiamide ia a histamine H1-recep[orantagonist again at about 168° wit~ decompoa~tion~~
(see p.1294) with aetionasimilar to those of cimetidine 1 in 70 of water and 1 in 300 of alcdto~t~.
tally insoluble in chloroform and ether..
~r
(P. 13f13) but a ~h~er
duration af action. It has been
used in doses of I g daily in conditions associated with
solution in water has a pH of 3.4 to ~.?:~ “’
gastric
hyperacidity
but has been found to eauae
airtight containers. Protect from light.
.
~.
bone-marrow deprezvion.
A ,..
Iucomparibility.
Incompatible with akaiis. d~:~.
Refcrencea to the action and uses of metiamidc
R. W.
cylate, phosphates. and oxidising ssrbstanosi ;SolaBrimblecombe
et al., S. AJr. med. J., t974, 48. 1253;
, were unstable above pH 7 and were ‘--- ‘--’
D. M. Shepherd et al., Digestion, 1974, 11, 307; B.
mmc tr
3.~
mg could cause=
Thjodlei(ssort and K. G. WormaIcy, /Jr. med. J., 1974 K
.—
t~,,
J ~m
Pm rnr.7*A
2, 304; idem, Guf, 1975, 16, 501; G. L Barbezat et al.,
!l,~
Ph~.
Ldn, 19>6. h
Gut, 1975, f 6, 186 J. I. kenberg, Ann. inwrn. Med..
Adverse [email protected]>menL
aaad pr~u
1976, 84, 212; A. S. MacDonald er a/, (preliminary
communication),
Lancer. 1976, 1, 6E; J. M. Hind and T.
for the antihistamines in general, p. 129
J. Sutton, J. Pharm. Phorrrroc., 1977, 29, 244; O. R.
Unlike most other antihistamines
phcrii
Griffith ●t al., Br. J. Pharmae., 1978, 64, 416P.
tartrate may have a stimulant effec~ to av
Duodenal ulcers. References to the w of metiamide in possibility of insomnia it should not’ ~
ducdenal ulcers: M. Mainardi er al., New Engl. J.
after 4 p.m.
.“:?*
Med., 1974, 291, 373; G. J. Milton-Thampmr
et aI.,
Allergy. In a mortified ‘repeated-inssdt’ ptc~:~
.breet,
1974, 1, 693; R. E. Pounder et al., Br. med. J.,
phmindamine
tartrate was found to produ={.~
~.
1975, 2, 307; Lamt,
1975, 2. 77% ibid., 80A R.
sensitisation of the skin.—— A. M. Klignaarr,.
Earlam (letter), ibid., 973; J. H. B. Saunders and K. G.
f3erm.. 1966, 47, 393.
Wormsley, Lmcet. 1977, 1, 765.
Exrrapymmidal sympmnsz. For a [email protected]’~~
Zollinger-EIIison
syradrorrsx. References
to the use of
dyskinesia aawxiated with the Me of phenhw#
metiamide
in tbc Zollinger-Ellison
$yndrame
M, H.
Brompheniramine
Maleate, p.t 298.
, .:2%4.-.,:
Thompson et al. (letter), Lxmcer, t975, J. 35; L. G.
Uses.
Phenindamine
tartrate
has the prn~
Halloran ef af. (letter), ibid., 281; E. R. Smith et al.,
Med. J. Ausr., 1976, 1, 100& D. M. McCarthy et al.,
and uses of the antihistamines
(see p.12
Ann. inr.wr. Med.. 1978, 87, 66E; J. K. Siepler el al,.
less potent
than
promethazine
but it’@@
Am. J. Hosp. Pharm., 1978, M, 141.
generally
produce
drowsiness
and mayn~
Mmrufacturem
mildly
stimulating.
It has
a modefi~
Smith Kline & French, UK.
cholinergic
action.
‘$].
/
Phenindamine
tartrate
is given in dos~sO
a
~
50 m up to thrice daily.
. ..3Y
e reparations
:+.=
6151-p
f%arrindamine Tablets (BP.). Tablew cmztaOUO
indamine
lartra!e.
Thev
are
sugar-mated.
., #
oxomemazine.
RP 6847; Trimcprazinc S.S-Dioxide.
.
..”
10-(3 -Dimethylsmina-2 -methylpropyl)phcnothiazine
Pherrindamine
5,5-dioxide.
ma&’tTY25Yt~
(Also available
in Austral,, S. Ajr.).
C,8H22N102S-330.4.
A funher
v
tics
tntO&
ihnor[
ksklc$
Okm
ktcr)
beau
L1294
Ihsorp
pera
h We
Sminc
q+ak(
skate
kmon
rnmin
tsbssa
h
sith
L}
kp
hta
noses
R!enir
q 10
Kcpar
1~try
~Uir,
hca
*o:
kir
WC!
:;,
hpri,
~1
b j
fki,g
%
hg ,$
1
tCLIDIHE
HYDROCHLORIDE
pherrylkfriocarbafrrate.
]asaolylic agent.
‘CLSDINE HYDROCHLORIDE.
(Parke,
L(l-phenylcyclohexyl) piperidine hydro!.
!rnyl
nalgesic, anesthetic.
ETRAZINE
BITARTRATE.
Calorie
0.3/lab.
See: Plegine (Ayerst Lab. )
?INE. (MacAlliste[) Amphetamine sulfate.
oz., I pt., 1 gal.
entral nervous systemstimulant.
4 cmikcuw
54kf.kfTiON & TINC.
(Ulmer) Benzalkonium Chloride,
1%. BoL I qt. .S I gal.
.ZINE SULFATE, N. N. D. 1963. Mono(midase irrhibitot, befa-phenylethylne sulfate. See: Nardil (Wamer.Chilcott)
CAN HCI, N. N. D. 1963. (Wyeth)
[hazine) N+! ’-Dinrethylamino-2’.
!Ihyl)phenothiazine HCI.
?%, Tube 1.12 oz. Lot., Phenergan 2%,
Imirre 15%. Bet. 4 oz.
25 ●g. ) Box 12s.
dihistamimic.
GAN EXPECTORANT
TROCHES.
Phe~
1.5 ❑g.,ipecac pow. ext. 2.3
01.
i sutfonate 162 reg./Troche.
~
~
expectorant.
CAN EXPECTORANT
TROCHES W/
NE. (Wyeth) Phenergan 1.5 mg., codeine
., ipecac pow. ext. 2.3 ❑g., Pot.
d sulfonate 162 reg./Troche. Jar 36s.
~xpectorant.
CAN HYDROCHLORIDE,
N. N. D. 1960.
I. EapGcrocEnti Phenergan H Cl 5 mg.,
ephrine HCI 5 mg., ipecac Hdxt. 0.17
rol. guaiacol sulfonate 44 reg., chloro.
25 ❑g., citric acid 60 ❑g., Sod. citrate
./5 cc. Bet. 1 PL Also avail. w/codeine
ate 1/6 gr. /dr. SUpp. 25 mg. Box 12s.
Phenergan HCI 6.25 mg. /5 cc. Also
25 reg./5 CC. Bet. 1 pt. Tab.: Phenergan
!. 5 mg. & 50 mg. /lab.
Bet. 100s.
CAN INJECTION.
(Wyeth) Promethazirre
fial (25 ❑g. /cc. ) IO cc.; (50 mg. /cc. ) 10
.kf., I. V., antihistaminic.
GAN PEDIATRIC.
(Wyeth) Dextro]han HBr 7.5 mg., promethazine HCI 5.0
uidextract ipecac O. 17 min., pot.
JIsulfonate 44 mg., ❑in. chloroform 0.25
tric acid 60 nsg., sod. citrate 197 mg. /5
L pt.
hrtitussive.
name recognized as USAN or by N. F.,
wN. N. ft.
~
“pHENERIOfNE.
[email protected])-4 -carbeffeoay+ahemylpiperidine.
“PHENETHIC3LLIN
POTASSIUM N. N. D. 1963.
Alpha-phenoxyethyl penicillin pot. Penicillin-152
pot. See: Afpen, Tabs. (Schering)
BIoxil (Beecham Res. )
Chawipem, Tab. (Squibb)
ftarcil (Wyeth)
Dramcillin-s (White)
Masipefr, Tab. (Roering)
Ro-Cillin, Tabs. (Rowell)
kOfIM,
Tab., Pow. (kfassengill)
Syncillia, Tab. (Bristol)
PHENETRONINJECTABLE. (Lannett)
Chlorphmiramine ❑aleate 100 mg, /cc. Vial 5 cc.
PHENETSAL,
N. N. R. 1948.
See: Saiophser, Tab. (Wintfrrop Labs. )
●PHENFORMkN HCS, N. N. D. 1963. N’-phenefhylbigrfmide HCI.
See: O. B. 1. (U.S. Vitamin)
PNENka4TNOL.
(Parke, Davis) Phenol 2%,
ammonium ichthosulfonate, alum & lead plasler.
Use: Antiseptic.
“PNENINDAMSNE
TARTRATE,
U.S. P. ;~
#
or 1U.S. P. 2~etfryl-9-pheny l-2, 3,4,9tatrahydro-l-py ridindene tarlrate.
Seti 1%
Prep. (Roche)
:
W/Alrrmimrm asp rm, chlorpheniramine maleate,
p~tee~~e&
~A$cher) ~
: _,
lY/Chfozprophenpyridamin$ ❑aleate, phenylpro~bN~e~”
Tab. & Elis. (G. W. Camrick)
V/LSestromethorphan, chlorpheniramine, realeate,
<
phmylephrine}Cl,
menthol.
See: Nefodan, Syp. (Uayrand)
W/Destro=~harr
HBr, phenylephrine.
“ ;
(
Sew Cerose, Pedialric(tves-Cameron)
W/Phmymne
hydrochloride, cdramlphen
efhanedlsulfonate.
See: Dondril (Whitehall Labs. )
tY/Phenylephrine HCf, chloroform, ipecac fldxt.,
glycerin, pot. guaiacol aulfonate, sod. citrate,
citric acid. SeK Cerose, LA (Ives-cameron) ~
W/pYriiaISine ❑aleata, chlor6 eniramme maleata,
~.”
~phenylephrine. See: Carrh st ~Cafrfone)
~
W/Sulfadimethoxine, N-acetyl-p-aminophenol,
csffeine. See: Uadricidin, C~(Roche)
~
“PHENINDtDNE,N.N. D. 1963. (2-Phenylin~
rfana-1, 3-Oione; 2-Phenyl-1, 3-fndarrdiorre;
_
Phenylindanedion, Dindevan)
See: Damilone, Tab. (Schieffeiin)
Hedrrlin, Tab. (lyalker)
fndon, Tab. (Parke, Davis)
PNENIODOL.See: lodoalphionic Acid
“PHENIPRAZINE
HCf.
See Catmn, Tab. (Lakeside)
●PNENIRAMNE.
l-Phenyl-1<2-py ridyl)-34i■efhylaminopropane. (No pharmaceutical form
available. )
F
:~
~
‘~’
:,
‘+
,.z
.9,
>
{
~
&
$
<
W/Crxleine phosphate.
Sew Aatoaarr, Syr. (Squibb)
F/Scopolamine HBr.
Sew Nie-Piracene, Tab. (Nion)
“FHENIRAMkNE MALEATE,
N. F. , N. N. 0.
1%3 Tab., N. F.; Optrtb. Sol., N. F. l-Phenyll{2?yridyl)-34i
methylamino-pmparre ❑aleate.
Prqrhenpyridamine.
Se& Iahiston (ktpjohn)
Trimetem (Schering)
W/Acertophenetidin, aspirin, phenobarbital,
hyoscyamine sulfate, pbenylephrine HCI.
See: Pbenapbae Plus, Tab. (Robins)
W/Ammonium chloride, Sod. citrate 6 cblo[oform.
Sac Trimetoaa, Syr. (Schecing)
W/d-Amphefamirre sulfale, cbioroform, ●enthol
t aicobol.
See: Tussate, Syr. (Pitman-Moore)
WMifrydrocodeirrmae trifaftrate, Pot. gualacol
sralfonate, Sod. citrate, citric acid & chloroform.
See: Tusaar, Liq. (Armour)
Wf3ihydrocodeimone tritrattrate, Vik. C, pyrilamine
maleate POL citrate.
See: Cltca Forte. (Boyle)
W/Dibydrocodeinone bi tratfate, phemylpropanolamiae HCI, pyrilamine maleate, glyceryl guaiacolate, cillorofo[m.
~
Tussamirric Expectorant, Syp. (SmitfrDorsey)
Mtibydrocodeimme
bitarfxata, pyriiamine ●aleate,
ptrenylephrine HCI, pot. guaiacol-aulfonate,
cherry flavor.
Seti Nova-Tussa, Liq. (Dreg Specialties-prams)
Mfoaylamine
srrccinate, py[ilamine maleate.
Se~ Tridecamine, Tab. (National)
W/EpbarJrine sulfate & ammonium chloride.
SW Esfosen, SyI. (Squibb)
V/Glyceryl gnaiacolate, [email protected] HCI &
codeine phosptaate.
See: Robitessin A-C, Syr. (Robins)
V/Hesperidio,
ascorbic acid, tbmylpyramime
fumarate, pyrilamine maleate, aalicylamide,
caffeine. Seec Tripac, Cap. (Person & Covey)
W/Heaperidio, phenylepbrine H Cl, methapyrilene
HCI, pyrilamine ❑aleate, vit. C, salicylamide,
acetopbentidin, ca ffeirre.
SW Boyle Citfa, Caps. (Boyle)
U/Narcotine, phenylephriea HCI, chloroform,
❑eottxol. See: Conar, Liq. (Nassengill)
W/Pbanylephrine HCL
See Isobist, OphUr. SOL (Broemmel)
W/Phenylephrine HCI.
Sss: Pbenistan, Tab. (Chicago Pharm. )
W/Phaeylepbrine HCl, acetyl-p-aminophenol,
atmpiffe sulfate.
See: TPC, Tab. (Tennessee Pharm. )
V/Pheeylepbrine HCI, methapyrilene t4Cl, pyrilamirra maleate, aspirin, acetophenelidin,
catteine, Vit. C, hesparidin.
See: Darbacinr Cap. (Crestmed)
W/Pbaraylephrine HCf, pyrifamine mz
ascorbic acid. See: Corizahist,
W/Phamylepbrime HCI, pyrilamine m~
■etJrapyriiene H CL
SW. Cit!a H. F., Cap. (Boyle)
W/P!renylepbrime HCI & A. P. C.
W/A. P. C., Cap. (Pitmarr-Noore)
Sea Novabistirre
W/Phmylaphrine HCI, chloroform &
See: Novahistine, Elixir. (Pitmar
W/Pbmylpropanolamine
HCI, glycer
See: Oarathon, SOL (Grail)
W/Pbenylpropanolamine lkCf, pyrilal
SW Triaminic, Preps. (Smith-Do
W/Phmylpropanolam ine H Cl, phony
pyrilamine maieate.
See: Synefgen, Elix. (Lemmon)
l/Phenylpropano lamine HCI, pheny
pyfilamina ❑aieate, acetyl-p-amin
See: Pbmagesic (Dalin)
W/Pyrilamine maleate.
See: Triaminic, Tab. (Smith-Dors
W/Pyrilamlffe ❑aleate, dioxylamine
Sea: Tridecamine, Tab. (Merrell)
W/Pyrilamine maleate & ❑ethapyri Ie
SW Incowobist, Tab. (Blue Lin
PediabisL Syf. (Coiumbus)
Pyma Timed, Cap. (Testagar)
W/Pyfilamine ●aleate, phenyipropa[
See: Trialter, Tab. (Lemor)
W/Pyriiaminekkaleate, phenylpfopal
tfisulfapyfimid ines.
Sea: Tfisrrlfaminic, Prep. (Smith
W/Pyrilamine Ualeate 6 pbenyltolo>
dibydrogen citfale.
See: Wltibist,
Cap. .S Syr. (.$ml
W/Saiicyiamide, acetophenetidin, c
ascorbic acid, hesperidin purifier
SH Cocybam, Cap. (Roerig)
W/Scopolamine hydrobromide, alrrml
gel, ethyf amimobenzoate.
SeK Daptren, Tab. (Davis 6 Sly
W/Thenylpyramine HCI, pyrilamine
pkrenylpropanolamine.
Se& Histene, Tab. (Paul kkaney
F/Tyfothricio,
neomycin, benzocai
See: Nao-T-Cain, Lozenges (Chi
W/Vit. C, aspirin & aikalizing has,
Sea Cehistra, Tab. (Organon)
FHENIRATAN.
(Irwin, Neislel) Ct
tannale 15 reg./Tab. Bet. 100s.
Use: Antihistamine.
“PHENSSONONE HBr. 3, 44ihydr
isopropylaminopfopiophenone H B,
See: Dapanone H B: (Nerck, Shari
PHENISTM.
(Chicago Pharm. ) P
10 ■g., propbenpyrdamine male:
tab. Bet. 50s, 100s, \OOOs. “
—.
---
end of the titration, as indicator. Repeat the operation
without the substance being examined. The difference
between the titrations represents the amount of iodine
required. Each ml of 0.05M wdine VS is equivalent to
5.857 mg Of C*[email protected]~,[email protected]~.
—=
Storage Phenelzine Sulphate should be kept in a wellclosed container and protected from light.
Preparation
Phenelzine Tablers
Action
and use Monoamine
oxidase inhibitor.
Water Not more than 1.57. w/w, Appendix IX C. Use
1.5 g.
Phenethicillin Potassium
0/$/
H;
1’
/.
Me
’.-:
HHH
N=
Me
N
o
o~?
“.
H
Me
“’~K
adsxwticmwat~
CITH19KN205S
402.5
132-93-4
Definition
Phenethicillin Potassium is potassium (6RS)[(2S)-2-phenoxypropionamido]peniciUanate.
It contains
not less than 97.00/0 and not more than loo.50/”” of
C1THIJCN205S, calculated with reference to the
anhydrous substance.
..e=%
Assay Dissolve 0.25 gin sufficient water to produce
500 ml and dilute 10 ml to 100 ml with water. Place two
2-rdaliquots of the resulting solution in separate
stoppered tubes. To one tube add 10 ml of imsdazo&-mercury rsagenr, mix, stopper the tube and immerse in a
water bath at 60° for exactly 25 minutes, swirling
occasionally. Remove horn 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 nm, Appendix II B, using in the
reference cell a mixture of 2 ml of water and 10 ml of
imsduzobmertwy
reagent for solution A and watzr for
@JtiOn B. Cab.date the content of CITH][email protected]#
horn the difference between the absorbance of solutions
A and B, from the difference obtained by repeating the
operation using pheneshidin potassium BFCRS in place
of the substance being examined and horn the declared
content of C 17H1JCN205S in pherserhidlin potursium
Characteristics A white or almost white powder.
BIZRS.
Freely soluble in wa~ sparingly soluble in ethanol
(96%); slightly soluble in absolute ethanol and in chsbrojonn; practically insoluble in erher.
Storage Phenethicillin Potassium should be kept in a
well-closed container.
Identification
A. The infrared absmpcion specrnon,
Appendix II A, is concordant with the refmence specsrum
of phenethicillin potassium.
B. Dissolve 10 mg in 10 ml of water and add 0.5 ml of
neutral red sohkm. Add sufficient 0.01 M sodium hydroxide
to produce a permanent otange colour and then add
1.0 ml of PemWlinuse sofurion. The colour changes rapidly
to red.
C. Heat 0.5 g with 10 ml of 5Mhydrochbti acid under a
reflux condenser for 4 houm, cool, add a mixture of 7 ml
of 5M sodium hydroxzhk and 7mlof water and extract with
successive 1O-ml quantities of ether untd complete
extraction is effected. Wash the combined ether extracts
with wara, lllter through anhydrous sodium suiphare and
evaporare the fdtrate to dryness.
The
meln”ngpm”nrof the
residue, after recrystallisation from petroleum spirit (boding
range, 40° w 60~, is about 116°, Appendix V A.
D. Ignite. The residue yields the reactions characteristic
of potassium salts, Appendix VI.
Acidity or alkalkity
7.5, Appendix V L.
Labelling The label states (1) the date after which the
material is not intended to be used; (2) the conditions
under which it should be stored.
Preparations
Phenethicillin Capsules
Phenethicillin Tablets
/
??3
@#
H
OH
..’
.
Action and use Antibacterial.
Phenindamine Tartrate
o
‘1
;H
HOOC
COOH
‘.
+
NMe
H
411.5
569-59-5
‘OH
pH of a 10°/0 WIVsolution, 5.5 to
Specific optical rotation In a 170 WIVsolution in a
solution containing 0.20/0 WIVof dipotassium hydrvgen
orthophosphate and 0.8°10WIVof potasn”um dihydrogen
orrhophosphat.e, +2 17° to +244°, calculated with reference
to the anhydrous substance, Appendix V F.
—..
_-——
0.125 gin sufficient mixed phosphate buffer pH 7.0 to
produce 25 rd. To 10 ml add 10 ml of mixed phosphaw
buffm pH 4.0 and 10 ml of 0.0 lM wdine VS and titrate
immediately with 0.01 M sodium thwsulphate VS using
srarch muciluge, added towards the end of the titration,
as indicator. Repeat the operation without the substance
being examined. The difference between the titrations
represents rhe amoum of iodine-absorbing substances
present. Each ml of 0.0 lM sodium thtissdphare VS is
equivalent to 0.425 mg of iodine-absorbing substances.
Iodine-absorbing
substances Not more than s~o,
calculated with reference to the anhydrous substance,
when determined by the following method. Dissolve
&’
andenarttiornsr
c*9H~9N,c4H~o~
Definition Phenindamine Tartrate is (RS)-2,3,4,9terrahydro-2-methyl-9-phenyl-lH-indeno[2,
I-c]pyridine
hydrogen (2R,3R)-tattra~e. It contains not less than
98.5V0 and nOt mOre fian 10 1.O~OOf C ,gH~gN,CdHfjOb,
http://igm-06.nhn.nih.
g... M<limt?lO9OO+detil+
1
htip:/figm46.nlm. tih.gov/cgi-btiGM-client?lO9OO+dehil+
i!?!
TITLE:
The effects of phenindamine tartrate on sleepiness and psychomotor
performance.
AUTHOR:
Witek TJ Jr; Cane~trari DA; Miller RD; Yang JY; Riker DK
AUTHOR
AFFILIATION:
Regulatory and Clinical Development, Richardson-Vicks USA (A Procter
& Gamble Company), Shelton, Corm.
SOURCE:
J Allergy Clin Immunol 1992 Dec;90(6 Pt 1):953-61
NLM CIT. ID:
93094481
ABSTRACT:
Phenindamin~H1-receptor
antagonist ~hat was developed almost 50
.-~
y=g~s
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), diphenhydramine (50
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 dosesd
phenindam.in.e(25eudoephedrine (60 mg), phenindamine and
pseudoephedrine, diphenhydramine (50 mg), or placebo in a five-way
[email protected] . Psychomotor tests included CRT, HS, and a task that–
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<
. 5) in CRT, tracking, and HS tasks and higher SSS and VAS scores, w~h
peak effect noted at 3 hours. Phenindamine did not significantly differ from
placebo or terfenadin~ In ~he second trial, diphenhydramine produced~
slgmticant impairment relative to placebo @ < 0.05) in CR~, divided
attention, ~, and VAS, and SSS, also peaking at 3 hours. Stanford
Sleepiness Scale scores after phenindarnine were greater than placebo at 3
< ().05) but significantl~ less than diphen hydramine (p <
+R&f&mmc
T TRUNCATED AT 250 WORDS)
A
.-.7
1 0f2
515/98 12:19PM
1
http//igm-O6.nlm.oih.g...M-client?10900+detail+ 1
http://igm-06.nlm. oih.gov/cgi-btiGM-client?
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 TRIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Histamine HI Antagonists)
O(Pyridines)
299-42-3 (Ephedrine)
58-73-1 (Diphenhydramine)
82-88-2 (phenindamine)
-—.=
10900+detail+l
_—_
.--%
2of2
5/5/98 12:19PM
http: //igm-06.nlm.nih.
g., .M-client? 10900 +detail+ 1
http//igm-06.nlm.nih,
gov/cgi-bidIGM-cliat?
lWOO+detiil+
[Various principles of therapeutic tactics in epilepsy patients during
pregnancy]
AUTHOR:
Sigidinenko LV
SOURCE:
Zh Nevropatol Psikhiatr 1984;84(6):897-9
NLM CIT. ID:
84276611
ABSTRACT:
Forty-two epileptics were examined during pregnancy. According to the
severity of the paroxysmal symptomatoiogy, 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 modality treatment, which included vitamins
the substitution of of group “Btt, potassmm orotate, ~s,
antihist.amin
chloracon for phenobarbital and benzonal for diphenylhydantoin sodium;
at the later
e of pregnancy the patients were given phenindarn~
@pie
modality treatmenitfacilitated the cessation
. of attacks and served as the prevention of epileptic exacerbation in patients
——
during the pestational and [email protected]
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
Histaminel13LOOD
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)
.—-.
_—_
5/5/98
2 0f2
. .. .
12:24 PM
1
pj
TITLE:
The structure of phenindamine base and salts in the solute state.
AUTHOR
Branch SK; Casy AF; Hussain R; Upton C
AUTHOR
AFFILIATION:
School of Pharmacy and Pharmacology, University of Bath, Bath, UK.
SOURCE:
J Pharm Pharmacol 1988 Jan;40(l):83-4
NLM CIT. ID:
88214661
ABSTRACT:
High-field NMR (13C and lH) studies of phenindamine are reported
which establish structures of 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 (Thephonn) 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 ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Pyridines)
82-88-2 (phenindamine)
_n-.
Iofl
.. . . . .
5i5i98 12:22 PM
‘..,,_ .
.—= -+-
A. INGREDIENT NAME;
HENYLTOLO XAMINE DIHYDROG EN CITRATE
B. Chemical Name:
N, N-Dirnethyl-2-(Alpha-Phenyl-O-Toloxy)Ethylamine, Dihydrogen Citrate
2-(2-Benzylphenoxy)-NN-dimethyl-ethykunine dihydrogen citrate
c.Common
Name:
Rinurel, PholteA Aust.-Codipront; Fr.- Biocidan: There are various names from different
countries. See file.
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
.-.
E. Information
99.9%
about
how the ingredient
is supplied:
White crystalline powder, odorless, tasteless, crystals from water or methanol
F. Information about recognition of the substance in foreign
pharmacopoeias:
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Sunshine, A., Zlghelboim, I., and De Castro, A. Augmentation of acetaminophen
analgesia by the antihistamine phenyltoloxamine. J Clin I%armacol; 1989: 29(7): 660664.
Falliers, C. J., Redding, M. A., and Katsampes, C.P. Inhibition of cutaneous and mucosa
allergy with phenyltoloxamine. Ann Allergy, 1978; 41(3): 140-144.
_—__
.-.
H. Information about dosage forms used:
Expectorant
Suspension
Tablet
I.
Information about strength:
25-50mg -3-4 times daily
J. Information about route of administration:
Orally
IL Stability data:
Melts at about 138-140° centigrade
Stable
.-
L. Formulations:
M. Miscellaneous Information:
.-.
Page -2-
‘i..
‘=%. ,_..-::,,
..,.,
“\,,
i
i . ....—..-....-
_-
.. }– J
. . ..
. ... ..—
...
. ----
. . .. . .
. ..-.
,-
CUR’1’lFICATE
~.
-“’lQ6q
+
@J6
r .“ ---....
OF ANALYSIS
., -
Prcduct
:
PHENYLTOLOXAMINE
Quantity
:
5 kgs
:
7003
. ..—
Batch
No.
DIHYDliOGltN CI’TRA?’E I.JSi?
net
—-...
..
wh.i.tu
:
confoum
*
1,41,,4
deg.
*
0,018
%
U,V*
*
.
clear
salukion
G.Co
:
99,s
%
Assay
●
✎
99,9
%
Appearance
~dnntification
Mel.t,i.ng
(A,fS)
point
-———
—.., .
-..___- ..—.—.-- ....--— . .... ....
c~y~talline
pnwd(~r
c
●
Ra~idue
on
ignition
T~SO-lJIWW
,
GmbH
“’-
QUALITY
CONTROL
REPORT
CHEMICAL
NAME:PHENYLTOLOXAMINEDIHYDROGEN CITRATE
MANUFACTURE
LOT
NO.
:
PHYSICAL
SPECIFICATION
TEST STANDARD:USP——/NF
/
TEST
MERCK*/BP
— /COKPANY
l)DESCRIPTION :
WHITE CRYSTALLINE POWDER; ODORLESS; TASTELESS.
SPECS.
T,S F~
E
2)SOLUBILITY
:
SOLUBLE IN WATER.
3)MELTING
----
POINT:
MELTS AT ABOUT 138-140
4)SPECIFIC
GRAVITY.
5)IDENTIFICATION
PASSES
centigrade
c
:
.:
FAILS
.:
COMMENTS
.:
ANALYST
SIGNATURE.
PREPACK
TEST.:
RETEST.
degree
:
.:
DATE.
:
DATE .:
DATE.
:
:
INITIAL.
INITIAL.
:
:
—
b
------------------ 1DENTIFICATION ------------------PRODUCT #: P8404
NAME: PHENYLTOLOXAMINE CITRATE
CAS #: 1176-08-5
MF: C17H2IN101
SYNONYMS
N,N-DIMETHYL-2-(ALPHA-PHENYL-O-TOLOXy)ETHyL~~
DIHYDROGEN
gJ.&g,
*
PHENYLTOLOXAMNE DIHYDROGEN CITRATE * PRN *
------------------ TOXICITY HAZARDS ------------------RTECS NO: KR6650000
ETHYLAMINE, N,N-DIMETHYL-2-((ALPHA-PHENYL-O-TOLYL)OXY)-,
(1:1)
TOXICITY DATA
ORL-RAT LD50: 1472 MG/KG
TXAPA9 1,42,59
IPR-MUS LD50:246 MG/KG
JAPMA8 42,587,53
REVIEWS, STANDARDS, AND REGULATIONS
_&-=
CITRATE
NOHS 1974: HZD 80480; NIS 3; TNF 517; NOS 9; TNE 4176
NOES 1983: HZD 80480; NTS 2; TNF 41; NOS 8; TNE 1225; TFE 406
EPA TSCA CHEMICAL INVENTORY, JUNE 1990
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,
EXPOSURE CAN CAUSE:
NAUSEA, DIZZINESS AND HEADACHE
LIGHT-HEADEDNESS,
VOMITING, SEDATION,
THE TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY
INVESTIGATED,
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: 138 TO 140’C
VOLUBILITY: METHANOL-SOLUBLE
APPEARANCE AND ODOR
WHITE CRYSTALLINE POWDER.
------------ 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.
UNUSUAL FIRE AND EXPLOSIONS HAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS,
------------------- REACTIVITY DATA ------------------STABILITY
STABLE.
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
TOXIC FUMES OF:
CARBON MONOXIDE, CARBON DIOXIDE
NITROGEN OXIDES
HAZARDOUS POLYMERIZATION
WILL NOT OCCUR.
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
WEAR RESPIRATOR, CHEMICAL SAFETY GOGGLES, 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 --NIOSI-UNLSHA-APPROVED RESPIRATOR,
MECHANICAL EXHAUST REQUIRED,
COMPATIBLE CHEMICAL-RESISTANT
GLOVES.
CHEMICAL SAFETY GOGGLES.
_.-.
HARMFUL 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
I
Mequitazine/Phenykoloxamine
U5es
and
Administration
osatotmde, a pipcrazine derivative, is an antihista$ tie that has also been reported to have mast-cell
&bllising
properties.
Adverse
tions
Effects,
Treatment,
and
~cau.
As for antihistamines in general (see p.LD’,
Unlike most other antihistamines phenimam~tt~
};,,.
relief
ofhy- frate may have a stimulant effect; to avwti %. I},ltiml.
Csensi[ivity
reactions
includirrg
urticaria
(See biliry of insomnia patients may be adli=..i (,) l:l~c
dose of the day before 4 p.m.
,31),
andrhirrids
andconjunctivitis
(seep.430).the last
Oxa[omide
k given by mouth as the anhydrous subUses and Administration
~ce
or as the monohydrate. The dose of anhyPhenindamine, a piperidine derivativ~ is an WII119.
MUS oxatomide is 30 to 60 mg twice a day; a dose
._~atomide
is used for the symptomatic
of 30 mg tWiCe d&Iy is recommended for the elderly. Oxatomrde should ~ administered with caution
~ patients with hepauc impairment but the marrufacturer
suggestst~t
if treatment
is required pa-
famine, however it may be mild] y SttnrULWaIIR, II ,q
used as fhe tartrate for the symptomatic =.1-f O(IIY
(~,.,:
persensitivity reactions including urcc.aII:I
p.43[), andrhinitis (see p.430), and as w tr~QrI.,1 l(.,,,
tjenfsshould st~ with haIf the usual dose. Children
~ed 6 to 14 years may be given 15 to 30 mg twice
of compound
a&y.
Phenindamine tartrate is given in do,>( 2S 1,,
50 mg up to three times daily. Children CIW n y,.ll, ~
~fcrences.
I. Anonymous.Oxatomidc—a new H,-antihistamine. D-E TJW
,@ I983; 21:35-6.
L RichardsDM..$ al. Or.a!omide:,a review of its phannacndy.
,mmicpmpemes and therapeutic efficacy. D..ugJ 19w; 2?
1]0-31.
preparations
Nmwsof prxparadons are listed below; detaitz are given in Pan 3.
pmprietsay Prepsrstions
hr.: Turseu Belg.: Tmsec Fz: Thscc
Gcr:
Tmsec
hi.:
Ttnsec
Ndt.: Tk.X S.AfK:IktX Spain: Atoxm: Cc4ionS; OxIeri; Tatr~ Swim..:TmseL UK; TInactl.
preparations
for coughs ---
:hc ,:{H 1,
mon cold (see p.432).
of age have been given up to 75 mg daily ‘WI,iIv I, I,., j
doses.
Preparations
Names of preparations are Jisrcdbelow, details arc $IWWIm p,,,, ,
Ot?fciat Prepsrstfons
Bf 199-?:Pbenindanaine Tablets.
Pmprfetary Preparations
UK Thephorin: USA; Nolahist.
Multi-ingredient
preparations.
Ger.: FluP,.m:
II,Y,I
Nohrtune; P-V-Tussin.
-—
())(ornem~ine
Pheniramine
(6151.p)
tjxnmemazine (rINN).
w684Z Tnmeprazine SS-Dioxide. 10-([email protected]@nino-2mtrhylpmpyl)phenotilazme 5S-d!oxide.
C,,H21NZ02S= 330.5.
; GM— 3689-50-7.
Orromemazine
Hydrochloride
(6I52-s)
[email protected]
Hydrochloride (rINNM).
H21N10J, I+CI = 366.9.
: — 4784-40-f.
. mwwcopoeias. In Fr.
Aminosaficylate
2 pWt,IyI~
(1001>.I
Maleate
(6154-e)
Oxomemazine,a phenothiazine derivative, is an an- PhmhamineMaleace (8ANM,USAN,rfNNM).
relief
ofhy- Ftveritaminium Maleace I+ophenpyridamine
: tihistamirreused forthesymptomatic
~,pctsenshivity
reactions
(seep.430)
andinpruridc nimmme hydrogen maleate.
~ S&O disorders (see p.432). It is also an ingredient of C,.H,,N,,C.H.O.
= 356.4.
-----
prepmations
P’%ImM Iy,@.
arrtiemedc
properties
h theprevention
andcontrol
of motionsickness
(seep.432).Pheniramhte
maleate
isused as an ingredient of compound preparations for the symptomatic treatment of coughs
and the common cold (see p.432).
Phenirarnine maleate is given by mouth in a dose of
22.5 to 30 mg two or three times daily, or more commonly, in sustained-release preparations in doses of
75 mg once or twice daily or 150 mg at night. Pheniramine mzdeate is also used in combination with a
decongestant in eye and nasal preparations. In some
countries pheniramine maleate has been administered parenterally.
Usual doses of the arrtinosalicylate
two or three times daily by mouth.
The hydrochloride
used.
are 25 to 50 mg
and the tanrtate have also been
Preparations
Multi-ingmatkmt prepantfons.
Aurr.: Neo CIrratr: AusrraL:
Avil; Avil Oecnitgestanc Ttiominict; Belg.; Napbcon-A: Triaminict: Cana& &-Vcrnacont; Caktomine-DHt; Conrac [email protected]]me
Hoi Ddnkt; Dintouge; Dristan; Naphcon-A; @cott-A; Rthnorphan; Ptdmoi’phsn Pdlatrique: RohiNssin AC; Robimssin witi
Cndeine; Tantacol; Trianrimc; Tiiatninic Expsctomnc Trianainic
Expscmram DH; Ttiaminic-DM Expectorant Triatnitucin; Trismitricin with Codcimet: Trianzinicol DM Trisuifamini~ Tuzsamirdc C; Tussaminic DH; Eim: TtiominiG Fc F4bris ic Fervex;
Triatniniq Ttiamssict Gez: CnsavilT; Konjtmktivak T!ilo, Pcdanatt; Triantinict: /ral.: Mcdrsnzil; $amdin-AN; Tetramil; Triatninic: Trianrinict3u.Triatnitticolt; SAJI: Aflerta.z Calasrtwic, CoffUp Degntntx Trianri: Triamitric; $.azin: Regrssin Hemormidalt:
Rytrstant; Triominic: Swirz: Neo Cbratu Triamirdc~; UK Triominic: USA:AK.Con-A; Driwatt NasaJ Spray: Flog$sct; Nafazair
A; NaphazoIe-A; Naphazoline Plus; Napbcon-& Napboptic-A:
Opcon-& Pnly-Htstine; Poiy-HNine-D Rolantss with Hydrcatdone; Ru-llJss with Hydmcodone; Scot-lltssin Original 5-Actiom
S-T F~, Stmuss Gremv Triaminic Expectorant DH, Triarninic
Oral Infant Tussirex.
) mmpnund
for the symptomatic treat: trertt of coughs and the common cold (see p.432).
C.4S— 132-20:7.
~. his given by mouth irr rfcws equivalent to 10 to
~ ~ Mg of oxomem~ine
daily. oxomemazine
maY
A white or atmost white ~rystalti~ pnwder oduuf~.
,X ,, ,Ih
F%@ltoloxamine Ciuate (8ANM, rfNNM).
a shglx ixfour. M.p. 106 to 109 F.melY aoittble u? Msl,il, ,,t
C-558 I H (9henWtoloxamtne):
Pheny(tolyloxamme Cirratw
alcohol, and in chlomfom,
very shgbtly soluble ~ .xtwr, i
PRN (phen~ol&amine).
2-(2-Benzy4~he~oxy) [email protected]’I% solution in wa[er has a pH of 4.5to5.5.
b.f N,,,,,
6
ethylamme dhydmgen citms.
light.
c,H,,
NO,
C.H.0,
=
447.5.
..-.
CAS — 92- I ~.6-(pheny\roloxom\ ne): I I 76-08-5 (phenylAdverse Effects, Treatment,
and ~atl.
\ “sko be administered
by the rectal route.
Ox; “OMcmazine hydrochloride
has been used similarly
i’~;;:tion,
.
$ ~~
nf pqwatton~
~ ]ismd ~].w; (fetajtsarc given in Part 3.
Prepsntions
~%’%zm,,,.
$% IDoxcrgant; N.th.: Doxcrgan.
~ :~-ingredient
preparation..
Auf..’ Aplexil; Wg.: Rectn~ ~~~~~,~~p,~fi~p’’x’’’T
:.
efil:Ger:AP:ex;LNe,he:h.:
:. ..
*.+
~ Phenindamine Tartrate
(6153-w)
i“ “&amine
Tam-ate (8ANM, USAN, riNNM).
~ndamme
Ac!d Tarrrste; Phenmdamini Tatvas; Phenln‘. ‘nlum
Tartrace. 1,2,3,4-Tetmhydrn-2 -merhyl-9-phenyl-2~mne
hydrogen rarrrate; 2,3,4,9-Teuahydm-2-merhyl~ ~~’~”~d~~~~~p~dine
m 19
;
hyd~w
W - ~2-~8~2 ~phen;ndamine);
* rorr,q,
‘~Woems.
569-59-5
KS-W.
(phenindom-
In &
*lW Or almost white, odourless or afmost ndOWIc-S+,VOIII‘-’. ~
@waler Sparingly soluble in waten slightfy soluble
praCtic~lY in~o]ub[e in chloroform md ether. A
~. ● &+oI.
fim
ji’,k
ZOluti;” in W,mer hm ~ @f of 3,4 to 3.9. ~t~t
w’ k
:&s
.. ~~1
L
t
denotes a preparation
Phormacopaeias. In Mfg.
tions
As for antihistamines
and SC
A
Abuse. References to the abuse of phenirarnine b! WWIII,
1. Jones [H, et al. Pheniramine as an hdlucinogm. M’=% .) (*,,
1973; 1:382-6,
,,{ ,
2. Cslllag ER, Landaucr AA. Allea:d hallucinogenic XI
tome overdose of an anuimstarmnc preparalmn. .Mm ? I-,,
1973; 1:6534.
3. Buckley NA, d al. Phemramme-a much abused ~
Ww ~
,-tIw 1994; 16& 1SS-92.
Pharmacokinetics
The phanrtacokinetics of’phenimtnine and ifi rneQAQI\,t.$ V.
desmetiyiphenirmnine and N-di&;methylphe~-,
A\, N~lc
investigated in 6 healthy ~ubjects. After OMJ drncti .11,l(,,.,l
of pheniramine ammosabcy late, peak-plasma ti$,l
,tt\tt,w
concentrations were reached m 1 to 2.5 hOu~ 1% r..,NUN.,:
ttatf-life ranged b~een
8 and 17 hours after mtr~w,x~i. ,,.[
mhisuauo,n (phemramme maleate) and 16 and [~ %*NI ,,tt~.r
nral dnzimstrstion. The totaJ recovery of phe~.
,t. ,,tk.
changed drug and merabdites from the mine W’3.SS h\ &JL~,
of tie intravenous dose and 70 to 83% of the oral Jaw,
1, Wiuc pKJ,cr d Phwtna.mkinetlcs of pheniram.ine\.\\+*) A,,,I
[email protected] in healthy wbjects after oral and mu’wcwk,. .,,
mmwraoon. ho J Clin PiIarm4cof T&v Toxicol 19S% L\, w
..
Oz
no longer actively marketed
Phenvltdxamine
,
Citrate
(6155-O
Coloxomine citrate).
in general, p.427.
I
symptomatic relief of hypersensitivity reactions includ]ng tmicaria and angioedema (see p.431 ), rhini!is and conjunctivitis (see p.430), and in pruritic skin
disorders (see p.432). It has aIso been used forits
Avil; Eim; Danemt SA. Gen: Avil; Avilettent: ftaL: Ittbkton;
S.Afx: Avil; UK: Daneraf SA.
C,6HZON*,C7H7N0,= 393.5.
CAS– 3269-83-8.
Pheniramine
Uses and Administration
Pheniramine, an afkylamine derivative, is an antihktamine with antimuscarinic and central sedative
properties.
It is used as the maleate or aminosalicylate for the
PrOpri~ PtepSt40nS
Aur.:Avik AturraL: AUer-Gt; Avil; Avi]eues; Femmrine; Be/g.:
Phet-wamme p-Aminosalicylare; Phemrsmine +%wN+ ,,aI1.
cy!atK Pheruramme Pam-ammocaliiare.
Phennn-w~
+ ~llil
no-2 -hydroxybenzoate.
~ ‘Oxomemazine hydrochloride
11,1 mg is approximately
: @valent to IO mg of oxomemazine.
!?\
449
Names of preparations arc listed below, derails arc given in Pm-I3.
(147WI)
Fttennrnme (&IN, dNN).
NN-Dimethyl-3-pheny!->.
Propnenpyndamine.
pmpylamme.
C,6H10N1 = 240,3.
CAS — 8.5-21-5.
Phenisamine
Citrate
r,
Phenyltoloxarnine citrate is an ethanolamine derivative with the actions and uses of antihistamines (see
p.427). It is usually gi~trfh
in combination
preparations with a decongestant or analgesic. Phenykoloxamine citrate has been used in nasal preparations. Phenyltoloxarnine pciistirex has also been
administered by mouth.
Preparations
Names nf pmpatarinns am listed WOW; details we given in Part
3.
Proprietary Pseparstfons
Multi-hrgmdent
pr’epxrztfons. Au,tr.: Codipront; Ccdipront
h with Ccdeine: Be/g.; Sinutab
‘“” ‘xvAus*~”’”’
Canad.:
Onrni- uss Smuts ‘e SA, Tusslonex: Fz: Bincidan; Wtux; Rinurel: Rinum.rcGer: Codiprorm Codiprom cum Expec[oranst: ergo sad speziai; Naldecnlt: [tal.; CndipronC. S.Afr.:
[email protected] Co: &con: Pholtex: Sinus:op Sinuslop with Ccdeine;
Sinumb; Sintmh with Cndeitte; Suncodin; Spare: Codipronc
Switz.: Cndipronu Codiprom cum Expectomns: Etgmannl sp+cial;
UK: Pholtex?; Rinurelt; Sintttab Nightime; U.% Aceta-Gesic:
Bimabt; Comhist LA: 13econgesrabx Decnngesraw Decongest.mI SR; Kutmsc; Lnbac; Magsat; Major-gesiC Medatttssin P!ust;
Menopiex: Mnhigesic: Momenrtutx Myogesic Natdec Pedkmict;
NaJdecmt; Natgesq New Dxnngesmm Pediatric: Nnrel Plus; Par
Decnnt; Pe~ogesic: Pbena-CMort: Phenylgesic; PoIy-Hkrine:
,!
,1
;I
I
1,
Methdilazine/Pizotifen
;ie Mal,eate(B.P.).
Pheniraminium
~henpyrldamlne
Maleate. NN-Dime.
-li-3-(2-pyrldyI)
propylamine hydrogen
~
●
H 0~=356,4.
4
~ 86.21-5
(pheniramine);
132-20-7
,C4
~;,
@@, In Br.
~ almost White crystallinepowder with
.qine.like odour. M.p. 106” to 109”.
0.3 of Water, 1 in 2.5 of alcohol, and
‘ chloroform; very slightly soluble in
,J Soiution in water has a pH of 4.5 to
~ in amtlght containers.
Protect from
recta. AS
134,
for
the
antihistamines
in
eliminated intact, should not be prescribed in patients
with Cmhn’s disease or other intestinal disease in which
strictures may form.— J.L.Shaffer er af. (letter), Larcec, 1980, 2. 487.
Other proprietary Names
Aeovil, Acoviletaa flrmh Spain); Avil (aminoaalicylale
and/or maleate) (Austra[.. Belg., Ger., Neth., S. Afr.);
Avilettcn
(aminosalicylatc)
(Cer.);
Avilcttes
(aminoaalicyiate) (Auswul.h Fenamine (aminoaalicylate and/or
maleate) {Auslraf.): Inhiston (Ital.).
A preparation
containing
pheniramine
tamsate
was
formerly marketed in Great Britain under the proprietary name Rynabotrd (Fisons).
6155-1
Pheatyltoloxamioe Chate.
C 5581; Phenyltolylosamine Citrate PRN. 2-(2-Benzylphenoxy)-Nf4dimethylethylamine
dihydrogen citrate.
C,7H2,N0,C6H807
-447.5.
1317
cxactrbation of epilepsy (I), and dreaming (2). Adverse
effects necessitating withdrawal from the study cccurred
in [ I patients. Advantageous effects were mood elevation in 3 and increased alcrtrseaa in 6.— K.M. S.Peel,
med. Res. Opinion, 1977, S, 192.
Curr.
Uses. Plzotifen
malate has the properties of the
antihistamines
(ace p. 1295).
It also has pronounced antiscrotonin, antitryptamine.
and weak
anticholinergic properties.
Pizotifen malate is used for the prophylaxis of
migranoua headache. The usual dose is the equivalent of 500 pg of pizotifen thrice daily; some
patients may be controlled on S00 pg daily; up to
6 mg daily has been given. It has been recommended that treatment
should commence with
500 pg daily increased gradually over the foilowing 5 days.
Reviews and comments on the action and uses of pize
tifmr.— T. M, Spcight and G. S. Avery, Drugs. 1972, 3.
159 M. Anthony and J. W. Lance. ibid., 153; Drug &
Ther. Bull.. i 976, 14, 29.
The use of pizotifen in 3 patients to prevent or reduce
the side-effects following ealcitonin injections.—
A. J.
Crisp (letter), Lmcet. 1981, f, 775.
~ine
aminosalicylate in cloaca exceeding
CAS — 92-12-6 (phenyltoloxamine): [176-08-5 (citrate}.
4 hallucmato~
effects followed by exhausde-effect?
were c~mp,
dilated pupils, Phenyltoioxamine
citrate ia an ethanolamine
&rivative
(see
uia, and Incoordinat]on. In I patient the with the cmoocrtiea and uaca of the antihistamines
Apperite stimxdariom. In a double-blind
study in 40
~ clouded for several [email protected]—
L H. JMICSp. 1294). it ;a a stmctural
isomer of diphcnhydrarnine ~ticnts
with tubcrculasis the mean weekIy weight gain
]. At#St., 1973, 1, 382.
Z(aee
P.1311). f~ has hem gkven in doses of 25 m 513mg
m these given pizotifen 5CS3pg thrice daily for 4 wccka
me or four umea daily.
was 890 g compared
with 2308
for those given
i transient toxic psychosis in 2 young men
P
ten ~tween
o.? and I g Of phenlmmlne
A~Of
the abuse of a mugb mixture con- placebo.— A. Taougranis, Curr. ther, Res.. 1972, 14,
372.
m.- E. R. Csdlag and A. A. Landaucr, tainins hydrocuxtonc with phenyltoloxamine.— Y. J.
_; 1973, 1.653.
Berry (letter), Nxw Engl. J. Med., 1976, 295, 286.
Ciwcirxoid syndrome. Pizotifen was found to stop diarrhoea and facial flushing in a patient with malignant
~tfallucinatory cffecta lasting for 2 days and
proprietary Preparatfom
carcinoid
syndrome,
the excision of whose primary
n reported in a child wbo took 750 to
Phcnyltoloxamioe
citrate is an ingredient of Rsnurc see
tumour w~- followed by rcgrcxaion of metaatatic ‘lesions.
erxiramine maleate.— 1. H. Jones et al.,
under Pherrylpropanolaminc
Hydmcbloride, p.# 6.
chlorpromazine,
methyaergidc, and cyprolsqrtadi”c
were
1, 382.
ineffective.— S, C. Loong et al., Med. J. Au.rf.. 1968, 2,
Ptmsyltoloxamine
is an ingrdlcnt
of P>
see under
the neonate. For studkx on the adverse
845.
Phoicodine, p. 1260.
tiirsminc
and other antihistamines
during
Cermodyxeia. A favourablc rcpofi of the use of pizotifen
~ p,1294.
in the treatment of 4 patients with carotodynia, a form
~~ti Adverse Effects. AS for the antiof vascular neck and face pain.— T. J. Msmay, Can.
Ltrtgeneral, p. 1294.
med. Ass. J., 1979, 120, 441.
%udica in vitro indicated the phcniramine is 6156-y
Chrarer headache. Patients with cluatcr headache who
rbed by activated charcoal.— J. J. Pfprfssfaydrfnatte. The diphcnylpyraline salt of 8-chlodid not respond to ergotaminc might be mtiived by metL Clin.Toxicol.,1978,f2, 523.
hyaergide 3 to 6 mg daily or by pizotifcn 1.5 to 3 mg
rotbcopbylline 4- Bcnzhydryloxy- I-methylpipcridinc
salt
daily for the duration of the bout.— lfr. med. J,, 1975,
of 8-cb30rotheopby ltine.
~ mmmcnt that pheniramirte is associated
4, 425.
C=HmClN503=496.0.
c arrhythmias in ovcrdossge and that elcctrFurther refcrenma.—
K. Ekbom, Acfa ncurol. stand.,
xing
may be n-iccaaary.—
D. W.
CAS — 4od-90-6.
1969, 45, 601.
J. Au.rt.. 1976.2.212.
See also J.
Piprinhydrinate
is
di
henylpyralim
thcoclate
and
haa
the
u), ibid.. 1, 895. The usc of tacrine in a
Cmkrix ‘s diseuce. Administration
of pizotifcn 500 xxg
pbenirsminc overdmage.— G. Mendctaon general properties o ? dlphenyipyraline hydrochloride (see
thrice Lily for 2 to 7 months bad a beneficial effect in
p.1312). It has ken given in doaea of 3 to 9mg up to 4 of 5 women with Custring’s disease, without serious
2, 110,
,.
thrica daily.
side-effects. On stopping pizotifcn onc women remained
~c,.$ for the antihistamines in general,
in remission for 10 months before relapsing, another
Pmprfetaxy Namsa
2 months after stoppingt and 2 were still in
Colton (Byk [email protected], Arg.h Kolton (SSC also under [email protected]
remission 3 and 6 months reapectwely after withdrawal
mad Fate. ..4s for the antihistamines in
Diphenylpyratinc Hydrochloride) (Promonra, Be/g.; Pmof
pizotifen.
One patient’s weight increased by abut
mortta,
Ger.).
:295.
4 kg after 7 mmrtha of therapy. In paticnta being pre22.6% of an administered
dose of phmspared for surgery or in those in whom other forms of
axereted unchanguJ
in the urine. Under
therapy have failed, pizotifcn may have a plsce.— A.
k dosage with 37 mg of pheniramine
[email protected],et
d. (letter), fimcet, 1980, f, 490.
.,.
was excret~
unchanged, 26.1 % as N6157-j
lheniraminc, 0,5% ss f4deadimethylpheDepressiam” A double-btind study involving 20 patients
with minor to mcderate depression indicated that pizoout 49% was unaccounted
for.— P.
Pizotifen Malate. Pizotyline Malattx BC- 105 tifen paeaaed certain antidepressant pmpertica.— J. E.
H al,, J, pharm. Sci., 1968, S7, 621.
(base). 9, 10-Dibydro-4-( l-methyl-4-piperStandai, Acra psychiat. scarxd.. 1977, 56.276.
kamine
is an alkylamitte
derivative
idylidene)-4H-bertzo(4,5
]cyclohepta [1,2-b] thiophFurther rcferencca.— W. V. Krumholz ef al., Curr.
!rties and uscs of the antihistamines
ene ,hydrogen maiate.
ther. Res., 196g, 10.342.
..
]. lt is less potent than promethazine,
CIJ-IZINS,C4H605
=429.5.
,...
Migraine. Of 26 patients suffering from sever-c attacks
k duration
of actio~
and generally
of migraine (classical migraine in 25) treated for 8
CAS — 15574-96-6 (pizori-fen).
.Mlation.
weeks in a doubIc. blind croaaavcr trial with placebo or
c maleate
has kn
given ha doses of
Pizotifen malate 145 mg is approximately equipizotifen in dines increased ap to 1 mg thrice daily (in
Og thrice
daily
but sustained-release
valent to 100 mg of pizotifen.
addition to any existing medication). 9 obtained mmI are more commonly used in doses of
picte relief or a reduction of at least one-half in the
rsx twice daily or 150 mg at night if Adverse ‘Effect% Treatnaen~ and Precatsfiom. As number of their attacks. Ten patients noted increased
for the antihistamines in general, p.] 294.
.1 ,,,
appetite. 6 a change of nmcd, and 5 experienced depres{ncrcascd appetite and weight gain may occur. .
alon when active treatment
ceased. Other side-effcda
@! children given up to three times
A review of the actions and uses of pizotifcn. Tolcrancc were tiredness (5), facial flushing (l), and increased
~r 1 year of age 7.5 mg, 1 to 5 years
vomiting ( I ).— R. C. Hu8hea and J. B. Foster, Curr.
to. alcohol could be lowered by pizotifen. The effects of
K $ years and over 15 to 22.5 mg.
tranquilliaera,
acdativca.
and
aomc
tricyclic antither. Res.. 1971, 13, 63. Scc also J. B. Foster, ibid.,
~ la also administer~ as the amin. depressants
could be enhanced. It should not be given
1976, 19, 66.
(c16f4xJJ1,C7H7N01
=- 393.5) in with monoamine oxidaae inhtbkora. Because of its struc- Further references.— F. Sicuteri et al,. Inl. Archs
; of 25 to 50 mg thrice daily. It has
tural similarity
to tricyclic antidcpreaasrxts
it might
Allergy appl. Immun., 1967, 31, 7S. J. W. Lance and
sntagonise the admncrgic neurone bhxckadc induced by
M. Anthony. Med. J. Au.tt., 1968. 1, 54; O. Sjaastad
hen as the tannate.
some antibypcrtenaive
agcms.— T. M. Speight and G.
and P. Stcnsmd, Acts rreurd. stand.. 1969, 4S, 594; J.
!preparations
S. AverY, Drurs. 1972.3. 159.
W. Lance et al.. Br, med. J.. 1970, 2. 327: J. Schaer,
Iabkts fH&chsr, c/K). Sustained-rC]easc
Headache, 1970, fO, 6T B. Anaclmi, Schweiz. nred.
Of 47 >tient~ with severe migraine given pizo~ifen I to
~ Mntaining
phcniraminc
ma}eate 75 org. 2 mg daily adverac effects were recorded in 22 patients.
U’.<hr., 1972, 102, 487; A. J. Krakowski
and R.
hbh~ daily.
Engi~h, Psychosamarics.
1973, /4, 302; J. D. Carroll
These reactions included wcigbt increase ( 15), muscle
: risk of i“t=tl”a[
obstruction,
SUStaind
and W. P. Macia y, Curr. med. Res, Opinion, 1975, 3,
pain or cramps (3), heavy legs or restless legs (3), fluid
~lions such ss Daneral-SA,
where the retention
68; E, R. Lawrence er al., Headache. 1977, 17. 109: K.
(3), drowsiness (2), more frequent
milder
*
in transit, Ijut the matrix ghost is often
W. G. Heathtlid
et al., Practitioner, 1977, 2/8. 428; K.
headaches (2), facial flushing (l), reduced libido (l).
“d
k
.
Augmentation of acetaminophen analgesia by the antihistamine
phenyltoloxamine.
AUTHOR
Sunshine A; Zighelboim I; De Castro A; Sorrentino JV; Smith DS;
Bartizek RD; Olson NZ
AUTHOR
AFFILIATION:
New York University Medical Center, New York.
SOURCE:
J Clin Pharmacol 1989 JuI;29(7):660-4
NLM CIT. ID:
89341003
ABSTRACT:
A double-blind, placebo-controlled, parallel-group study was ~
compare the analgesic activity_of the combination of 650 m~
acetammophen plus 60 mg phenyltoloxamine
citrate with______
that of 650 mg
_——...-...-.——
alone. Two hundred female inpatients who ha~se~e-re–pain
-.acetammophen
—
associated with a recent episiotomy procedure were randomly assigned to
receive a single dose of one of the two active treatments or a placebo.
Analgesia was assessed over a 6-hour period. Treatments were compared
on the basis of standard subjective scales for pain intensity and relief, a
number of derived variables based on these data and two global measures.
For essentially all measures, the two active treatments were significantly
superior to the placebo control..~
combination was significantly superior
.to acetaminophen alone for all analgesic measures including
-..— SPID,
------TOTAL, and global ratings. The results of thfiXtii~monstrate
that 60
produces significant augmentation ——..-.
of the an~sic
genyltoloxamine
activity
of -650
mg acetaminophen
in p~pisiotomy
pain.
—..—..-___,_..._—.
--—
—-—-——.
——.
—..-—..
—-----
MAIN MESH
SUBJECTS:
Acetaminophen/ADMINISTRATION
& DOSAGE/* THERAPEUTIC
Benzhydryl Compounds/ADMINISTRATION
&
DOSAGE/* THERAPEUTIC USE
Histamine H1 Antagonists/* THERAPEUTIC USE
Pain, Postoperative/* DRUG THERAPY
USE
.-._
1 of2
5/5/’98 12:08 PM
http://l3O. 14.32.46/cgi. ..M-client? 10900+detail+l
n
2 of2
ADDITIONAL
MESH
SUBJECTS:
Adolescence
Adult
Comparative Study
Double-Blind Method
Drug Synergism
Drug Therapy, Combination
Female
Human
Pregnancy
Random Allocation
Support, Non-U.S. Gov’t
Time Factors
PUBLICATION
TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Benzhydryl Compounds)
O(Histamine HI Antagonists)
103-90-2 (Acetaminophen)
92-12-6 (phenyltoloxamine)
http://l3O. 14.32 .46/cgi-bin/TGM-c!ient?10900+detail+ 1
5/5/98 12:08 PM
❑
Citations 1 to 1 of 1 from MEDLINE 1975-79
1
~
TITLE:
AUTHOR:
SOURCE:
/.
I~hibition of cutaneous and mucosal allerpv with ~henvltoloxamine. @~~&[email protected],
Falliem CJ; Redding MA; Katsampes CP
odb~
Ann Allergy 1978 Sep;41(3): 140-4
NLM CIT. ID: 78255039 (abstract present)
)
ff,
e
+$J!J
_—_
lofl
5/’5(98 12:10
PM
http://l3O. 14.32.46/cgi-bin/lGM-client? 10900+detail+ 1
http:/1130.14 32.46/cgi...client?10900+detail+l+l
M
.#%
TITLE:
[Clinical comparison of butamirate citrate with a codeine-based
antitussive agent]
AUTHOR:
Germouty J; Weibel MA
AUTHOR AFFILIATION:
Centre hospitalier et universitaire, Hopital du Cluzeau,
Limoges, France.
SOURCE:
Rev Med Suisse Romande 1990 Nov;l 10(11):983-6
NLM CIT. ID:
910958
--–
*THERAPEUTIC USE J
MAIN MESH SUBJECTS: - A~v~itussi
Benzhydryl Compounds/*ADMINISTRATION & DOSAGE
Codeine/*ADMINISTRATION & DOSAGE
Cough/*DRUG THERAPY
Phenylbutyrates/* THERAPEUTIC USE
ADDITIONAL MESH
SUBJECTS:
Adult
Aged
Comparative Study
Drug Combinations
Female
Histamine H1 Antagonists/THERAPEUTIC USE
Human
Male
Middle Age
PUBLICATION TYPES:
CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Fre
REGISTRY NUMBERS:
O(Antitussive Agents)
O(Benzhydryl Compounds)
O(Drug Combinations)
O(Histamine HI Antagonists)
O(Phenylbutyrates)
18109-81-4 (butamirate)
—
92-
_—_
2of2
5/5198 12:07 PM
I
I
Augmentation of Acetaminophen
Analgesia by the Antihistamine
phenyltoloxamine
-_:
I
Abraham Sunshine,* MD, Itic Zighelboim, MD, Ana De Castro, RN,
James V. Sorrentino, PhD, Douglas S. Smith, PhD, Robert D. 13artizek, MS,
and Nancy Z. Olson, MPS
A double-blind,
placebo-controlled,
parallel-group
study was perfarmed to compare the
analgesic activity of the combination of 650 m acetum[nophen PIUS60 mg phen yftofoxamine citrate with that o) 650 mg acetaminop [ en alone. Two hundred )emale inpatients
who had severe pain associated with a recen [ episiotom y procedure were randomly
assigned to receive a single dose of one of the ovw active treatments or a placebo.
Analgesia was assessed over a 6-hour period. Treatments were compared on the basis o)
standard subjective scales fir pain intensity and relief, a number of derived variables
I
based on these data and two global measures.
For essentially aiJ measures, the two active treatments were significantly superior to
the plaoebo control, The combination was significantly superior to ocetaminophen olone
for all anolgesic measures inchtding SP1f),TOTAL,and globalratings. The results o~this
study demonstrate
that 60 mg phenyltoloxamine produces significant augmentation of
the analgesic activity of 6S0 mg acetaminophen in poslepisiotomy pain.
in addition to their traditional
A uses, are becoming
recognized for their analgentihistaminica,
sic or analgesic adjuvant effects. Animal data indicate that certain antihistamines show analgesic activity and others do not.’ Many mechanisms have
been proposed. It may well be that more than one
I
mechanism of action exists for the antihistamines.
Evidence in the literature suggests that histamines
play a role in both inflammatory and vascular pain,
which may explain why someantihistaminic drugs
exert analgesic effects alone or in combination.z In
clinical studies antihistamines such as diphenhy dramine,’ hydroxyzine,’ orphenadrine,s and pyrilFrom
New
Hosplta(
York
University
Materrridad
Medlcid
Conception
Center, New York(Dr, Sunshine);
Palacio$,
Caracas,
Venezuela
(Dr.
Ms, Oe Castro);RichardsonWicks
Inc., Shelton,Cam
ntilcut (Drs. Sorrentino, Smith and Mr Batilzek);andAbrahamSun.
shine, M.D., PC., New York,NY (Ms, Olson),Supportedin part by a
grsnt from Richardson-Vicks,
Inc., SheltonCannetilcut.Presentedat
tha 1987 AnnualMeetingof the AmericanWage of CllnicalPharme
calogy.October15-16, 1987, Phdadelphia,Pennsylvania,
Addressfor
repdnts:AbrahamSunshine,MD, PC,907 Flkh Avenue,NewYork,NY
10021.
Zifghelboim
and
“ Fellow, American College of Clinical Pharmacology,
-—=.
660 Q J
CM
Pharmacol
1989:29:660-664
amine~ have been reported to produce analgesia
when tested alone, Analgesicadjuvant effectsof several antihistamines demonstrating the analgesic superiority of the combination over each drug alone
have also been reported: orphenadrine + acetaminophen,’ hydroxyzine + morphine? meperidine + hydroxyzine’ and phenyltoloxamine
+ acetaminophen.io’]’
Antihistaminics may act as analgesics via substance P, prostaglandin, bradykinin or cyclic nucleotides. Substance P is a potent histamine liberator
and the vasodilation induced by substance P in the
rat hind paw has been shown to be inhibited to
about 500Aby antihistaminics.l The release of bradykinin and prostaglandin, two agents important in
the induction of inflammatory pain, is partially mediated by histamine.3 Another possible pathway for
antihistamine analgesia may be related to the activation of cyclic nucleotides
which have recently
been shown to act as CNS regulators of analgesia.l
Phenyltoloxamine is an ethanoiamine-type HI
histamine antagonist. The results with phenyltoloxamine as an analgesic have been equivocaL [n clinical studies involving tension headache and musculoskeletal pain associated with anxiety pheriyltolox.
amine was shown to have analgesic-ad juvant effects
-%
ACETAMINOPHENANALGESIAAUGMENTATION
-.
TABLE
distribution
Characteristic
Patients
Mean Weight (lb)
Mean Height (in)
Mean Age (yr)
Ambulatory Status
Semi
Fully
Days Postpartum
Total
<1
:
>2
of Selected
I
Patient
Characterlstlcs
Placebo
Acctaminophen
650 mg
Acetaminophen6S0 m&/
Phenyltoloxamine 60 mg
50
134.4
61.9
25,7
75
13144
61.8
25.8
75
131.9
61,7
25.0
35
13
2
55
53
22
0
1
when combined with acetaminophen.lO.ll However,
in postsurgical dental pain, phenyltoloxamine did
not appear [o augment the analgesic effect of acetaminophen,t2’i$ This clinical trial was undertaken to
determine the relative analgesic efficacy of orally
administered acetaminophen alone compared with
acetaminophen in combination with phenyltoloxamine citrate and placebo in the treatment of pa=+nts with severe postepisiotorny pain.
METHODS
Subjects
This study was conducted in Caracas, Venezuela at
the Hospital Maternidad Conception Palacios and
used a double-blind, parallel groups, single-dose design. The protocol was approved by the hospital’s
Institutional Review Board. The study subjects were
selected from a population of multiparous postpartum inpatients with severe postepisiotorny pain who
could tolerate oral medication. Patients who were 18
years or older, able to communicate meaningfully
with the nurse-observer and who gave written informed consent to participate in the study were considered. Patients with known allergic sensitivities to
any of the test medications were excluded from the
study, as were patients with active peptic ulcer disease, gastrointestinal disease, or other complicating
illness, Patients with diabetes not controlled by established therapy, and those with a history of drug
abuse or alcoholism were also excluded. In addition,
patients were not eligible if they had taken any
anti-inflammatory, tranquilizing, psychotropic or
analgesic ~etication within four hours of the test
_mediMtion that could confound quantitating post%tum analgesia.
17
2
0
0
!.
Medications
All medications were identical in appearance. Pa.
tients were randomly assigned to receive either placebo, acetaminophen 650 rng, or the combination of
acetaminophen 650 mg plus phenyltoloxamine citrate 60 mg as a single two-tablet dose which was
administered double-blind. The randomly-assigned
study medication was consumed with an adequate
amount of water (approximately 4 fluid ounces].
Whenever possible, the patient was asked to either
sit up or lie on her right side for at least one hour
after medication was administered in order to promote gastric emptying. Treatmerds were randomized in blocks of eight so that, in each group of eight,
the two active treatments were represented three
times and the placebo twice. The three treatment
groups, two of which consisted of 75 subjects plus
the placebo group consisti~ of so subjects provided
a total of 200 subjects. No medication that might
confound the efficacy and/or adverse effect liability
of (he study analgesics were permitted concomi tantly or during the four hours prior to the administration of the test medication.
Evaluation
When the patient’s postepisiotomy pain was severe,
study medication was administered by the nurseobserver. The same nurse-observer interviewed the
patient at the time medication was administered,
and at each of seven follow-up evaluations (0,5, 1, 2,
3,4, s and 6 hr) after taking the study medication,
All interviews were conducted in Spanish, (he native language of the patients. If the patient was
asleep at a scheduled interview time, she was awakened. At each evaluation, the patient was asked to
661
*MACOKINETICS
C“.-l
lIAI I
u-l TGl : m
9A,
7T
,(HU
..IIF
I
,...
,
.’! ‘,
,.,.$
<;! ,$
‘.
,,:,.;
::
Q“,};
SWSH1NEE7’AL
_——-.
TABLE
II
MeanValuesforMeasuresof AnalgeslcEfficacy
Placebo
(n=
Etiicacy
Baseline Pain
Acotambephur
mg
Acatamhraphen 650 mg/
650
(n= 75)
50)
Phcny[toltwmlno
60 mg
(n = 75)
3.0
3.0
3.0
0.76
0.74
0.52
0.26
0.14
0.18
0.36
1.27P
1.60P
1.72P
1.37P
1.09P
0.8V
0.77P
2.16PA
2.47P~
2.61p’~
2,~A
2.37p~
1.52pa
0.42
0.67P
0.91P
1lx?
0,83P
0,10
0.68P
Pain Relief
1/2 hr.
1
hr,
2
3
4
5
hr
hr.
hr.
ht.
6 hr.
Pain Intensity Difference (P!D)
1/2 hr.
1 hr.
2 hr,
3 hr.
4 hr.
5 hr.
6 hr.
_—-_
I
1.50
2.21
4,46
0,50
‘ = Signdkantfy better than pfacabo, 1S0, P c 0.0S.
‘ = SigIM4iry better than scddmkvopty SS0 q. SD, P c O.tlS.
mea
~SPIO= We#ned sum at psin inteneity ~
1 7UTA1 - Weightd nun of gsh retk#safes
8.31p~
13,45p~
5,73PA
2.17PA
s -M4MgMdJ-~-~b7=~wh&flef:w
the V*
Uve hefferme psuenf‘aevwumionof WUdf impmwmenf,
hIsner
‘&dma*g*ket
0-wh&W3-
uce&nt;
thw~lbv~
Ma better h pwthnt%Owrauimprsa$ionof ffvestudy [email protected]
assess
the intensity of her pain which was scored as:
none (0), slight (1), moderate (2], or severe (3]. The
patient was also asked to estimate her degree of pain
excellent (3), Adverse reactions were noted if they
were obgerved or volunteered.
relief with the analgesic as: no reiief (0),25% relief
(1],50% relief (2),75%relief (3),or 100%relief (4].lf
at 2 hours ot later a patient requested an additional
analgesic because of inadequate relief from the test
medication, she was given a conventional analgesic
and was included in [he efficacyevaluation. In the
event a patient rededicated, a severe pain intensity
score and a zero pain relief score were assumed for
Statistical Evaluation
observations. If a patient was rededicated before the second hour, she was excluded
from the efficacy analysis.
In addition, at the last interview, or prior to rededication, the patient was asked to assess her
overall improvement and her overall rating of the
test medication. These were respectively quantified
on a seven-point scale: very much worse (I]; much
worse (2]; a little worse (3); no change (4); a little
better (5];much better (6];very much better (7], and
on a four-point scale: poor (0): fair (1); good (2]; and
all subsequent
–-.
0.85PA
1,24PA
l.slp~
1.68p~
1,67PS
1.51p~
0,91*J’
0.56P
o.57r’
4.43$’
7.29P
5,07P
1.49P
0.16
0.28
S$101
TOTAL2
Overall Improvement
Global Rating of Study [email protected]
I
0,42
0.34
0.20
1.60P’A
I
662
.
J Clkr Pharmacol
1989; 29660-664
Several measures of analgesia were derived from the
interview data. The pain intensity difference (PID)
score was calculated for each observation by subtracting the present pain intensity from the initial
pain intensity. The sum of the pain intensity differences (SPID)is the sum of the PID scores weighted by
the length of the time interval between observations
and is an estimate of the area under the time-effect
curve of the treatment. The weighted sum of pain
intensity differences was determined by multiplying
each PIDby the fraction of an hour elapsed since the
previous
seven
observation
observations.
of the relief
values
and
The
adding
variable
also weighted
the
produot
TOTAL
for all
is the sum
by the length
of the
between observations,
The TOTAL
value was similarly determined by multiplying each
relief score by the fraction of an hour elapsed since
time
interval
u
The mean scores for the hourly and summary
measures of analgesia, and significant treatment differences are displayed in Table IL The time-effect
curves for pain intensity difference (PID) and pain
relief are shown in Figures I and Z, respectively,
I
\-
Ptmsbe(m=se)
1-
Amumiaaghea asthssg(0 = 7s)
2
~
[email protected] 6SOmg+
PhenYIidwarnias 60mE (n = 7S)
Time Effect Curves
Placebo was clearly the least effective treatment and
the combination of acetaminophen plus phenyltoloxarnine was the most effective treatment. Acetaminophen alone was midway in effectiveness between the combination and placebo. Acetaminophen alone reached mean peak effect at hour 2 and
then decreased in activity. The combination
reached mean peak effect at hour 3 and had a sustained effect through hour 5 after which its effect
decreased (Figures1 and 2).
Differences Between Active Treatments and
Placebo
Figure L Timtwfbct
subtracting thG pain
curve: mean P?C).Scam are calculated by
intensity score Jiom the pofn intensity at o
hour. Patient raspofl~
Placebo was clearly the least effective treatment.
Significant pairwise differences between placebo
and each of the two active treatments were seen for
were stmred on a jbu~paint scaleas0- na
pain, I = slight pain, 2 _ madsrola pain, ands = severe pain.
—-_
the previous
observation
al) seven observations.
To study the differences
and
adding
among
the product
test treatments,
for
~
~
a
bioassay computer program performed an analysis of
variance (ANOVA)for medication, calculated as a
one-way layout on each of the study variables and
dmived measures.” When the ANOVA was significant at the O,OSlevel, pairwise contrasts between the
treatments were carried out wiing Fisher’s protected
least significant difference test (LSD).lSSince the
ANOVA assumption of homogeneity of variances
was violated for some efficacy variables, the analysis
wac confirmed by performing the Kruskal-Wallis
test and nonparametric pairwise comparisons. The
results from both analysis procedures were in
agreement and for simplicity only the ANOVA results are reported here,
1.0
Ii
2<s
., 2.0
i
: 1s
&
10
0.s
RESULTS
Two hundred patients were enrolled in the study
and all are included in the efficacy anaIysis. The
distribution of some of the background variables of
the study population are given in Table I. There
were no significant differences among the three
_A_eatment groups in either age, he~t, weight, amlatory status or number of days postpartum.
pHARWCOKINETICS
..!
,(,
,,/.; >
..
@##’
.’ >’..,;
: ,.,”.!’,,,’, ,,
,
[email protected] @hng (o = 7S)
[email protected] Whng +
Ptsenyhalosamlnt 60mg (n = 7S1
0.0
0
~
I
3
4
5
6
lhe In Hours
Figure
2. Time-eflM[
curve;
Mean pain reliej, Mean pain relief is
as a percentage of the initial pain [hat was reiieved. Patien[
res rises were scored on a fsve-pdnt scale 0.s:0 = no relief, f - a
IJI
F c [25%) relief, 2 = some rdte~ (S0%), 3 = a h ofrdief (75%),
ond 4 = comp~ete relief (mo9$J.
plot~d
,.
663
.“,
C“-1
11,11
tLlA7ra *CC+
Q&
7T
lH1.t
=I~;>k
auwa
.
SUNSHINE ET
.s-+
all of the hourly measures, the summary measures
(SPID, TOTAL), and the two global measures.
Differences Between Active Treatments
The combination of acetaminophen plus phenyltoloxarnine was found to be significantly more effective than acetaminophen alone for practically all
measures including the hourly measures, the summary measures (SPID, TOTAL), and the two global
measures.
00,
Cb
AWN
AL
ever, in this study, the global evaluations revealed
the combination to be significantly more e~cacious
than acetaminophen alone. We speculate that the
contribution of the antihistamine may have contributed to the patient’s sense of overall improvement,
The results of this study demonstrate that the addition of 60 mg phenyltoloxamine produces a significant enhancement of the analgesic activity of 650 mg
acetaminophen in postpartum pain resulting from
an episiotomyo
REFERENCES
Adverse Reactions
During the course of this single-dose study two patients re rted adverse effects. Both patients had received tP e combination as the treatment. The reported complaints consisted of dizziness, slertpiness,
and sweating and none were considered of serious
nature, It is not unusual for patients in this pain
model to report or volunteer few or no adverse reections. The extremely low incidence of adverse effacts has been documented in this patient population in previous publications.ls
If at any time following the second hour evaluation,
a patient obtained inadequate pain relief and requested remedicaticm, a conventional analgesic was
given, Only ten patients requiwd rededication be.
cause of inadequate pain relief. These differences
were significant at the 0.001 level based on the chi
square test. None rededicated before the second
hour evaluation. Of the ten patients who rededicated, eight had received placebo and two had received acetaminophen. None of the patients who
had received the combination required rescue medication,
DISCUSSION
This study indicates that the combination of acetaminophen 650 mg plus phenyltoloxamine 60 mg
results in more analgesia than is produced by acetaminophen alone. Compared to acetaminophen
alone. the combination produced significantly more
analgesia for all time points from 1/2 hr through 6
hours as well as for the summary measures SPIDand
TOTAL, For the global evaluations, the combination
was rated as a significantly more etiective medics.
tion and as providing a greater degree of overall improvement, In our experience, global measures often
do not distinguish between active treatments. I-1ow.
..—<
664
● J Clin
2. Rumore MM, .%hlichting DA; Ciinical
minics as analgesics,Pain 19SSi26:7-22.
effect of antihista-
efficacy of antihieta-
3. Campoa VM, Sdis EL The analgmicand hypothermiceffecb
of nefopam, morphine, aspirin, diphenhydramine, and placebo, j
Clin Pharmacol 198fk20:42-49.
6. Huper[ C, Yacoub M, Turgeon Lit Efhct of hydroxyzine on
mo hine analgesia for the treatmentof posloperrtthre pain. Anest
AnoT g 1980;59:690-696.
of analgesicovahra(lon:experi.
s. Batterman RC: Me[hactology
citrate compound. Curr Ther ftes
ence with orphenadrine
196%7:639-647 .
S. MCCOI1 JD, Durkin W: The effaci of pyrilamine on relief of
symptoms of the premenstrual syndrome (PMSI and primary dys.
Rededication
-.—
1. Rumore MM, Schlicting DA: Analgesic
minica. Lijk Sci 19SS;S6:403-416.
Pharrrtacol 198~29:660-664
menorrhea. Fed Proo 1982:41 :S572.
7. W/inter L Anaigasic combtnationa
@sx.rrgkal
vith orphenadrina in oral
pain. ~ Inl Med 2%6 19797 ;240-246.
& Beaver WT, Mae
of (he enelgesic effect of
W+lfr
Bonica (Ed,], Advance% in PainResearch
G: ‘Comparison
morphine, hydroxyzine and (heir combination in Wienk
postoperative pain. In])
and Therapy, Vol 1. RavenPreae,New York. 1976; S53-557.
and pharmacokinetic
9. Stmmbauah JE: Pharmacologic
consider-
regimens.tfoep Pracl 197%35-39.
10. Gilbert MM The ei5cacy of Percogeaic in relief of mtssculoskeletal pain associated with anxtety. Psychosomotics
1976;17:190-3.
11. Cdbert MM, Pool ND, Schec[erC Amigaaic/calmaiive ISL
fecta of metaminophen and phenyltokmarnine in treetment of
ation in analgesic
simple nervous tensionaccompaniedby headache.Curr Ther Res
197020 :53-s8.
12. Forbes ]A, Barkaszi BA. [email protected] RN, Hankle l): Am&sic
efbcl of ace[aminophen, phenyltoloxamine and !heir combination in postoperative
oral surgery pain. Pharmacoftrerapy
1984 ;4:221-226.
13. Winter
L, Appleby
F,
CicGone PG. [email protected] JG: A comparative
study of an acetaminophen analgesic combination and aspirin in
tha Oeatment of postoperative oral surgery pain, Curr Ther i%s
1983; 33:200-206.
Laska E, GorrnleyM, Sunshine A, IX al: A bioassaycomputer
program for analgesic clinical Irlals, Clin Pharmacol Ther
1967;6;658-6S9.
15. Miller R Jr,: Simultaneous statistical inference. ed. 2,, New
14,
York: Springer-Veria~
Isal; g~%
10. Sunshine A, Olson NZ, Laske EM, et al: Ana[geslceffect of
graded dosesof flurbiprofirn in poatepisiotomy pairs. PhorrrIrJuotherapy 1983:3:177-181,
. -.
.. . . .,
..’,
,, .
>
,
,:..,
.
i
,+
.,,
, ,.
“f
. . ...’-
*
,,
.,’
;,..
.$..
:,:
‘
‘:.
\’. ~,
Within one hour following
(he oral administration
of phenylfoloxamine
[email protected]
with pem issh)i{~
citrate, a Class 1 {ethanolamine-type)
H, antihistaminic,
a significant
through the @Wght
~,j
suppression of reagin-mediated
skin reactivity was observed and this was
:
Clearance
Center
;4,
correlated with a concomitant reduction in allergic nasal manifestations.
:
;{$:,’[email protected]
AND MUCOSAL
INHH31TION OF CUTANEOUS
WITH
PHENYLTOLOXAMINE
ALLERGY
NOTICE
TM%MATERIALMAYBE PROTECTED BY
CCWYRfifl LAW (TITLE 17, M. CODE)
CONSTANTINE
MARIE
ORAL
ANTIHISTAMINIC
PREPARATIONS
A. REDDING,
,,~
commonly administered for the symptomatic treatment
of upper respiratory allergy and, more specifically, for
the relief of clear rhinorrhea,
nasal pruritus, edema
(“congestion”)
and impaired
nasal ventiiatory
flow
characteristic of allergic rhinitis. One of the in vivo
manifestations
of the anti-allergic
effect
of oral
antihistamines
is their
capacity
to inhibit
the
wheal-and-flare
skin
reactions
induced
by the
epicutaneous or intracutaneous application of allergenic
extracts on the skin of subjects with reagin-mediated
hypersensitivity.U Several studies have documented the
therapeutic efficacy of selected antihistamines” and
some investigators have also measured the reduction in
the size of the immediate skin reactions following the
ingestion of standard doses of antihistamines and certain
other drugs.’-s The present study was undertaken in order
to evaluate, in a controlled manner, the dose-related and
time-dependent
effects of phenyltoloxamine
citrate
(Figure 1), a Class I, ethanolamine-type
H, antihistaminic compound’ on (a) the existing upper respiratory
allergic symptoms and (b) the magnitude and duration
inhalant
of immediate
skin
reactions
to known
allergens.
Materials
and
Methods
The subjects of this investigation were 10 properly
informed and consenting adults (six females and four
tkc~or
Fallicrs is 4[!ending
Allergist, National
Jewish HospIIal. ~nd
Assai~~e
Professor. LmversIty
of Colorado
School of Medic!ne,
Oenver.
Colorado.
VJrie .?. Rcdding is Clinical Research AssE.Iant, Allergy rind Asthma Clinic.
PC . Denver, Colorado.
Ooctor Katsampes is Consultant,
Clin!cJl Inves[lgation.
W’arneri Chilco[t
Lihrs[orws.
Morris Plains, New Jersey. and Clinical Professor of Pedialries
(retired). College of Physiciam dnd Surgeons, Columb,a Un[verslty. New York.
Xcw York.
la
M.A., and
J. FALLIERS,
CHRIS
M. D., F. A.C.A.,
P. wTSAMpES,
M.D.
males) with a confirmed
diagnosis of intermittent,
seasonal allergic rhinitis (Table 1). The age range was
18-38 years for the six females (average 26) and 30-39
for the four males (average 34 years). They all had
histories of allergic rhinitis for at least three years, either
strictly
seasonal (three
patients)
or perennial —
intermittent
or continuous — with seasonal exacerbations (seven patients).
All participants
had shown
strongly positive skin reactions with the automatic triple
puncture (Sterneedle),
as well as with the intradermal
techniques, to pden
allergens concordant with their
clinical symptomatology (Table 1). This reagin-mediatccl
skin reactivity was again confirmed, for the purposes of
this study, by the intradermal
injection of two selected
antigenic extracts per subject in a I: 1,000 aqueous
solution. Standard methodology was employed and the
PHENYLTOLOXAMINE
W
CITRATE
/c’”
~–<0-.”2-,”
\CH3
Figure 1. Phenyholoxaminc citrate, a Type
1,
I
CH1 -COOH
H,
ANNALS
antihistaminic.
OF
ALLERGY
INHIBITION WITH PHENYLTOLOXAMINE—FALLIERS
--;~.
ET AL
the day for each subject. Due to scheduling ecmstraints,
gtions were applied alternatively
on the external
ct of the right or left upper arm.
Clinical
symptomatology was determined by means of standard
physical examination procedures, with the patient at rest
in the examining room, and scored on a O-3 scale of
increasing severity (Table 11) for the cardinal symptoms
of (a) nasal obstruction, (b) nasal discharge, (c) nasal
and/or ophthalmic pruritus and (d) sneezing, before the
ingestion of the study tablets and at one and two hours
post-treatment.
the timing was not the same for all subjects but in this
experiment the known circadian variability in skin test
reactions was considered to be relatively unimportant
for comparative purposes. All three treatments consisted
of the administration
of two tablets orally, in a
controlled, double-blind
fashion and in a randomized
sequence. On one of the three treatment days the patient
received two 22 mg. tablets of phenyltoloxamine citrate:
on a different day the treatment consisted of one tablet
Three treatments were administered on three different
days, at least 24 hours apart and at the same time of
of phenyltoloxamine citrate 22 mg. and another identical
placebo tablet and on the remaining treatment day —
Table
L Clinical
No.
and
Demographic
Initials
Age
Sex
1
SM
2
Ss
22
20
39
F
F
M
3
6McK
4
NB
5
JK
20
18
F
F
6
DM
35
M
7
AV
38
F
8
MS
33F
9
JM
30M
10
EJ
32M
_—_
.-——
-—.
Table
Il. Data
Treatment.
Clinical
Form
and
Data
on
10 Petienta
Diagnostic
with
Elm, June
Grass
Cottonwood,
Common
Prairie
Sage,
Russian
Thistle
June
and Rye Grass
,,
,!
,!
!!
,,
.,
!,
,,
,,
,,
,,
!!
Method
Baseline
O-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
(No
for
Rhinitis.
Allergens
tested
int racutaneously
Pattern
Seasonal/Perennial
,,
,,
,,
Scoring
Allergic
Sage
Red Top and
Timothy
Grass
Timothy
Grass,
Giant
Ragweed
Lamb’s
Quarters,
Western
Waterhemp
Rye Grass,
Russian
Thistle
June Gr~,
Russian
Thistle
Oak,
Common
sage
Clinical
and
Skin
Test
Changes
Following
Evaluation
Nasal obstruction
Rhinorrhea
(clear)
Nasal/ophth.
pruritus
Sneezing (ptarnysmus)
Headache-front
al
Other
Nasal Microse.
Eosinophilia
Allergy
Skin
Allergen
Smear
(pre-Rx)
None
+
Rx)
+ +
1 hr. ~ Rx
O-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
+++
2 hrs. ~ Rx
O-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
++++
Tests
Baseline
wheat
(a)
(No
size
Rx)
1 hr.
~ Rx
wheal
size
2 hrs. ~ Rx
wheal
—
erythema
O-l-2-3+
erythema
O-l-2-3+
erythema
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
wheal
size
x
x —mm
size
—x—mm
wheal
size
x
mm
x
wheal
mm
—
mm
size
x _mm
erythema
O-l-2-3+
erythema
O- 1-2-3+
erythema
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
Comments
Legend:
O= None,
“VMl? 41, SEFTEMBER, 1978
1 =Mild,
2= Moderate,
3= Marked
or Severe
141
$q
INHIBITION WITH PHENYLTOLOXAMINE-FALLIERS
which could happen to be the first, second or last session
— the patient received two placebo tablets and no
phenyltoloxamine. Nasal smears were taken from each
individual for eosinophil counts before the study and the
results were graded on a O-4+ scale (Table 11). The skin
test results were assessed visually and then the two
perpendicular diameters of the wheal were measured
before, one hour and two hours after the administration
of the test tablets. The two diameters were multiplied
to give an approximation
(in arbitrarily
“squared”
numbers) of the area of the wheal and erythema, in
square millimeters. Erythema and pruritus were scored
on a O-3+ scale. Adverse reactions, subjective and
-#J=-
objective, were explored, with particular attention to the
possible development of somnolence, mucosal dryness,
vertigo, irritability, gastric distress and other localized
or systemic side effects.
Results
ETAL
‘$“>.
!/
nor a change frofii
to 2 as 100% aggravation,
as “infinite” (!) improvement. Also, under the dd
the possible effect of othei’’?l.
of the ex~riment
the relal
such as physiologic circadian periodicity,
clean environment in the laboratory or other influi
.,
could not be excluded.
The size of the urticarial wheals induced b~~~
intradermal injection of the allergenic extracts was
found to be remarkably
consistent prior to t~
administration of treatment. Mean baseline wheai si~
were 484 mm: on the day phenyltoloxamine 44 mg. was
it was 492
mmz when
the dose was
given;
phenyltoloxamine
22 mg. and 484 mmz when t~
randomized schedule provided for the administration of
placebo. One and two hours after the administration of
the two active phenyltoloxamine
doses a signifi~nt
decrease in the wheal size was noted, greater than that
following placebo at the p=O.01 level. The 44 mg. dose
The mean baseline clinical scores were quite close for
the three treatment days, being 5.2 for the day when
44 mg. phenyltoloxamine was given, 4.8 when 22 mg.
phenyltoloxamine was given with one additional placebo
tablet and 5.0 for the day when two placebo tablets were
administered (Table 111). At one and two hours after
of phenyltoloxamine
reduced the size of the wh~]
significantly more than the 22 mg. dose at the p=O.05
level, which was somewhat less than the difference of
either drug from placebo (Table lV). Thus it was
observed that 44 mg. phenyltoloxamirte provkkcl 88.6%
and 97.170 protection, respectively, one and two hours
after treatment;
22 mg. phenyltoloxamine
provided
70.7% and 75.2% protection. and placebo reduced the
wheal size by 7.6% and 4.4% at one and two hours after
administration,
respectively.
treatment two tablets of phenyltoloxamine and one
showed a significant
tablet of phenyltoloxamine
difference (p=O.01 ) from placebo, in the direction of
The larger dose of phenyholoxamine
improvement.
differed significantly from the lower dose but less than
when compared to placebo (p= 0.05) one hour after
administration
of treatment.
At two hours after
medication 44 mg. of phenyltoloxamine
citrate was
significantly different from 22 mg. at the p=O.01 level.
lt was thus noted that the antihistaminic inhibition
of the wheal, caused by the intradermal injection of two
selected
allergens
among
demonstrably
sensitive
in terms of percentage over baseline the improvement
after 44 mg. phenyltoloxamine citrate was 67.3%, after
22 mg. phenyltoloxamine 47.9% and after only placebo
was ingested there was a 16.0% improvement in nasal
allergic symptomatology after two hours. Of course it
provement
individuals,
Ill. Effect
of Medication
on Clinical
No,
Treat
Tabs,
ment
Phenyltoloxamine
Phenyltoloxamine
Placebo
Placebo
L
Il.
Ill.
Table
IV.
..—-.
Ill.
Phenylt oloxamine
Phenyltoloxamine
Placebo
Placebo
two
with
doses
the
of
clinical
in comparison to changes observed after the
administration
of identical-appearing
placebo tablets
(Figure 2). The higher dose of phenyltoloxamine,
44
reg., or two tablets, was found to be more effective than
the lower dose of 22 mg. (one tablet) both in terms of
symptomatic relief and in the prevention of whealing
after intradermal application of allergens. Noteworthy
is the fact that, under the conditions of this experiment,
Scores,
1 Hour
After Rx
10 Ss with
Allergic
.
Rhinitis.
Percentage
Difference
2
Improvement
Percentage
Hours
After
Rx
Difference
Improvement
5.2
4.8
2.2
2.7
3.0
57.7
1.7
3.5
67.3
2.1
43,8
2,5
2.3
47.9
;
5.0
4.5
0.05
10,0
4.2
0.8
16.0
No.
Tabs.
2
1
;
Following
Baseline
Score
ID Tests
1 Hour
After Rx
im-
phenyltoloxamine
2
1
Mean Wheal Area (aq. mm.)
Treatment
1.
Il.
Baseline
Score
Symptom
well
by
citrate,
must be recognized that these percentage changes are
relative to the grading system employed. In fact, one
could not easily define a change from a score of 2 to
a score of 1 as a 50% improvement or a shift from I
Table
correlated
induced
(two/
Ss) performed
Difference
Percent
Protection
on
10
Ss Before
Two Hours
After Rx
and
After
Madieation.
Difference
Percent
Protection
484
55
429
88.6
14
470
97.1
492
484
144
447
348
37
70.7
7.6
122
463
370
21
75.2
4.4
I
[42
I
ANNALS
OF ALLERG}
INHIBITION WITH PHENYLTOLOXAMINE—FALLIERS ET AL
~m
patient showed any adverse effect which might
‘-inish the clinical usefulness of phenyltoloxamine,
>cially
in higher doses.
After it was ascertained that the skin reactions began
(o subside and that the patients were not experiencing
any systemic adverse effects from the medication given,
they were allowed to return home, They were all
specifically requested to report any delayed reactions
noted but none did, either spontaneously or after
questioning at a subsequent visit.
,
reactions by phenyltoloxamine
is of more than casual
pharmacologic interest. Indeed, it can be considered as
being comparable in its therapeutic implications to the
experimental demonstration of a protective antihistaminic effect against the histamine-induced
increase in
pulmonary vascular permeability and pulmonary edema,
demonstrated in certain selected animal species.]8 The
clinical improvement
in the nasal symptoms of the
patients in the study can be viewed as evidence of this
therapeutic antihistaminic
effect.
Summary
Discussion
The capacity of histamine
mucosal changes and urticarial
allergy has been recognized
to produce respiratory
skin reactions typical of
for several decades.9 ‘0”
Inhibition of histamine-induced wheals has been used as
a means to test the potency of antihistaminic drugs: the
intradermal injection of 10-30 mcg. histamine phosphate
resulted hr 200-260 mmz wheals, which were found to
be reduced by 50% or more by certain antihistaminic
placebo-controlled
compounds.~ In a double-blind,
comparative study four common antihistaminics were
found to suppressor reduce the size of skin test reactions
to high concentrations of selected “major” and “minor’”
allergens,’> with peak effects noted between one and two
hours after ingestion of the drugs. Likewise, another
study of five representative
drugs — including
hydroxyzine — found 30-63’% wheal diminution, with
— average duration of this effect from 1.89 to 4.31
.=~‘3 Spontaneous variability
of the immediate skin
rea~~ions to standard allergens of verified potency is not
common,
provided that uniform
and meticulously
controlled techniques are applied. ” Circadian variability
in skin reactivity around the 24-hour biological cycle,
although measurable: is several times smaller than that
associated with the biological potency of the allergens
employed and with the medication administered prior
it can be considered
negligible
to the testing: therefore,
for a study placing primary emphasis on medication
and/or allergenic exposure. Non-immediate
or delayed
skin responses, occurring six to 12, or 24 to 48 hours
after the intradermal applkatkm of the allergens, have
been described and have been attributed
either to
immunoglobulin E antibodies’s or to Type 111 and Type
IV immune reactions.” Such reactions have generally
been assumed to be extremely
infrequent and in some
IXSeS they have been only noted following
the
suppression of the immediate
wheal-and-erythema
” When this was noted it has
reactions by anti~istamines.
that the immediate “flush” reaction
been hypothesized
does indeed serve a useful teleologic purpose and that
only its suppression allows a delayed-type reaction to
hme
manifest. It is considered noteworthy that in the
Present study no “late” or delayed skin reactions were
observed among the 10 patients tested, either when they
rWeived
oral antihistaminic
medication or when only
was given.
----ebo
Jtc’inhibition
of classical Type I wheal-and-flare skin
,;#E
41, SEPTEMBER,
1978
A dose-a rid-time-related-effect
of oral phenyltoloxa-
a Class 1, H, antihistamine
compound.
has been demonstrated
against
allergen-induced
skin reactions among 10 adults
wheal-and-erythema
with a diagnosis of allergic rhinitis and seasonal
pollinosis.
Clinical
improvement
in the existing
symptoms of rhinorrhea, nasal obstruction, pruritus and
sneezing, showed a significant correlation
with the
inhibition of reagin-mediated skin reactivity caused by
phenytoloxamine. No adverse side effects were observed.
It can be concluded that oral phenyltoloxamine citrate
possessesantihistaminic properties and a range of safety
which make it a useful agent for the symptomatic
management of upper respiratory allergy.
mine
citra[e,
References
1. AMA
Edi[ion.
-J
-.
Follicrs
Dcparlmcn!
of Drugs:
,4MA
f)rug
Chicago:
AMA.
1977, pp. 672-682.
cJ:
Re.!piru[orj Al)ergj, American
Evaluation,
Lecfure
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in
Living
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Springfield:
C. C Thomas.
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W B tijpersen.ci!ivi[ l-Me choni.rm.r
and Managemem.
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W’. B. S~undcr
Co,. 1968, pp 405-407.
4. Fdliers CJ: Respirator)
Allergy
in Childhood
In ~urrenl
T/Ierupj,
H. Corm (Ed. ) Phil~dclphio: V’. B. Saunders Co.. 1968.
PP. ~~6-533
~. Fcingold BF. lufroducrion
fo C1/nica/ Allergt.
Springfield:
C. C
Thonm.
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6. W“ilhclm RE: The newer an[i-allergic drugs. Mcd Clin N Am 45:
8X7, 1961.
7. Hoek>lra
JB. Tisch
DE.
Rakieten
N
and
Dickison
HL:
of s new an[ihistaminic
agent.
Ph~rmucologictil
propcr[ics
❑ placebo
❑ Phenyltoloxamine
■ Phenyltoloxamine
L
22mg
ddmg
A_..._
,““
Ihr
~ RX
2hrs
ii Rx
Figure
2. Comparative
changes(perantage of baseline) in nasal
symptoms and in skin whealing responses after oral phenyltoloxamine
and after placebo.
143
INHIBITION
WITH
PHENYLTOLOXAMINE—FALLIERS
phenyltoloxaminc
(Bristamin).
J Am Pharmaceut Assoe 42:587,
1953.
8. Rcinberg A and Sidi E: Circadian changes in the inhibitory effects
of an anlihistaminic
drug in man. J Invest
Dermatol
1966.
9. Curry
JJ: The action of histamine on the respiratory
normal wrd asthmatic subjects. J Clin
10. Bain WA: The quantitative comparison
46:
415,
tract
of
Invest 25: 785, 1946.
of histamine antagonists
in man. Proc Royal Soc Med 42: 615,
1949.
I 1. Beavcn
MA: Histamine:
the classic antihistamines
(H,inhibitors).
NCW Eng J Mcd 294: 320. 1976,
12. Galant
S. Zippin
C, Bullock J and Crisp J: Allergy skin tests.
1. Antihistamine
inhibition. Ann Allerg
30: 53, 1972.
13. Cook TJ. MacQueen
DM, Witting HJ. Thornby J1. Lantos RL
~nd Virtue CM: Degree and dur~tion of skin test suppression and
side effects with antihistamines, J Allerg & Clin Immunol 5 I: 71,
1973.
14. Reddy PM.
Nagoya
H, Pascual
HC et al: Re~ppraisal
of
in[racutancous
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& Clin Immunol 61: 36, 1978.
ET AL
15. SoIley GO,
Gleich GJ, Jordan RD and Schroeter AL: The ~~
phase of the immediate wheal and flare skin reaction. J Clin Invat
58: 408. 1976.
16. Pepys J. Turner. Warwick
M. Dawson PL and Hinson KFw:
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Exerccpm
Med Int Corrgr Ser
162: 221. 1968.
17, Brostoff J and Roitt IM: Cell-mediated
(delayed)
hypersensitivity
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Reques:s Jor reprirri.~ ~hould be addressed
LM. Constantine J. Falliers
155 Cook .$lreel
Denver, Colorado 80.?06
(o:
“For better or worse, there are few occupations of a more satisfying
character than the practice of medicine, if a man can but once get orierrtirf
and bring to it the philosophy of honest work, the philosophy that insists
that we are here, not to get all we can out of life about us, but to see
how much we can add to it. The discontent and grumbling which one hears
have their source in the man more often than in his environment.”
Sir William Osler
On [he Educational
Value OJ [he
,kfedical Society
I
t44
ANNALS
OF ALLERGY
.,,
>
..
.’
,.
,~.
. .
$-,
.. ..
,p
1
;.
..
:1
!
Within one hour following
the oral admim”stration of phenylto~oxamine
[email protected]
with pevnissior~’t
citrate, a Class [ (ethanolamine-type)
H, antihistaminic,
a significant
through the Copyright
.,,>
suppression of reagin-mediated
skin reactivity was observed and this was
:..
Clearance
Center
.,
correlated with a concomitant
reduction in allergic nasal manifestations.
.#==
~
:
ti;g~
OF CUTANEOUS AND MUCOSAL
INHIBITION
ALLERGY
PHENYLTOLOXAMINE
WITH
NoTICE
THIS MATERIALMAYBE PROTECTED BY
COPYRWW LAW (TITLE 17, W. CODE)
ORAL
ANTIHISTAMINIC
CONSTANTINE
J. FALLIERS, M. D., F.A.C.A.,
MARIE A. REDDING, M-A., and CHRIS p. [email protected] M.D.
PREPARATIONS
,,,
for the symptomatic treatment
of upper respiratory allergy and, more specifically, for
the relief of clear rhinorrhea,
nasal pruritus, edema
(“congestion”)
and impaired
nasal ventilator
flow
characteristic of allergic rhinitis. One of the in vivo
commonly
administered
manifestations of the anti-allergic effect of oral
antihistamines is their capacity to inhibit the
wheal-and-flare skin reactions induced by the
.. .
---
epicutaneous or intracutaneous application of allergenic
extracts on the skin of subjects with reagin-mediated
hypersensitivity.~ Several studies have documented the
therapeutic efficacy of selected antihistamines*’
and
some investigators have also measured the reduction in
the size of the immediate skin reactions following the
ingestion of standard doses of antihistamines and certain
other drugs.’> The present study was undertaken in order
to evaluate, in a controlled manner, the dose-related and
time-dependent
effects of phenyltoloxamine
citrate
(Figure l), a Class I, ethanolamine-type
H, antihistaminic compound’ on (a) the existing upper respiratory
allergic symptoms and (b) the magnitude and duration
reactions
to known
inhalant
of immediate
skin
allergens.
Materials
males)
with
a
confirmed
of
diagnosis
intermittent,
range was
18-38 years for the six females (average 26) and 30-39
seasonal
allergic
rhinitis
1). The age
(Table
for the four males (average 34 years). They all had
histories of allergic rhinitis for at least three years, either
strictly
seasonal (three
patients)
or perennial
—
intermittent
or continuous — with seasonal exacerbaAll participants
had shown
tions (seven patients).
strongly positive skin reactions with the automatic triple
puncture (Sterneedle),
as well as with the intradermal
technique+
to pollen allergens concordant with their
clinical symptomatology (Table I). This reagin-mediated
skin reactivity was again confirmed, for the purposes 01
this study, by the intradermal injection of two selected
antigenic extracts per subject in a I: 1,000 aqueous
solution. Standard methodology was employed and the
PHENYLTOLOXAMINE
CITRATE
and hfethods
The subjects of this investigation were 10 properly
informed and consenting adults (six females and four
b.mor
Fill Icrs is Attending
*llerg!si.
~atmoal
Je*lsh
HospIt.11. md
4SIXMIC Pro(cs.sor. L nivcrslty of Colorado S.’- ml of Uedlctne,
Ocnver,
Ctilor~ do.
WJr\c * Rcdding IS Cl!n(cil Research \ssislant. Allergy ~nd ~sthm~ Chmc.
P C Den\cr. Colorado.
Owtor K~twmpes m Consultant,
Clinlcai Invcstigo[]on. W’~rner, Chllcotz
L~hr~torws.
Worrls Plalns. New Jersey, and Cl!nlc~l Professor of Pcd!i[rlcs
(retired). College of Physlclans ~nd Surgeons. Columbla Lntvcrs!r), ~ew York.
\cW York.
.&=-
1
140
‘C113
I
CH2-COOH
Figure
1. Phenyltoloxamine
citrate,
a Type
1, H,
ANNAUS
antihistaminic
OF .ALLERG}
INHIBITION WITH PHENYLTOLOXAMINE—FALLIERS
;-:ections
were appli~
alternatively
on the
external
the day for each subject. Due to scheduling constraints,
the timing was not the same for all subjects but in this
experiment the known circadian variability in skin test
-.
ct of the right or left upper arm. Clinical
>tomatology was determined by means of standard
physics] examination procedures, with the patient at rest
in the examining room, and scored on a O-3 scale of
increasing severity (Table 11) for the cardinal symptoms
of (a) nasal obstruction, (b) nasal discharge, (c) nasal
and/or ophthalmic pruritus and (d) sneezing, before the
ingestion of the study tablets and at one and two hours
post-treatment.
reactions
i. Clinical
No.
and
Demographic
Initials
Age
Sex
SM
22
20
39
F
F
M
1
Ss
2
3
BMcK
4
NE
5
JK
20
18
F
F
6
DM
35
M
7
AV
38
F
8
MS
33F
JM
9
10
EJ
Diagnostic
Form
and
10 Patients
with
,!
.,
,.
,,
,,
,,
,,
!!
!!
Scoring
Method
Baseline
O-1-2-3
O-1-2-3
O-1-2-3
O-1-2-3
O-1-2-3
O-1-2-3
(No
for
Rhinitis.
Elm,
June
Grass
Cottonwood,
Common
Prairie Sage.
Russian Thistle
,.
,.
,,
Allergic
Allergens
tested
mtracutaneously
Pattern
Seasonal/Perennial
,!
!!
,,
32M
Sage
June and Rye Grass
Red Top and
Timothy Grass
Timothy Grass,
Giant Ragweed
Lamb’s Quarters,
Western
Waterhemp
Rye Grass,
Russian Thistle
JUne Grass,
Russian Thistle
Oak,
Clinical
and
Common
Skin
Test
Sage
Changes
Fotlowing
Evaluation
Nasal
obstruction
Rhmtorrhea
(clear)
Nasal/ophth.
pruritus
Sneezing
(ptarnysmus)
Headache-frontal
Other
Nasal
Microsc.
Eosinophilia
Allergy
Skin
Allergen
Smear
(pre-Rx)
None
+
Rx)
1 hr. ~ Rx
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
+++
+ +
2 hrs.
0-1-2-3
0-1-2-3
0-1-2-3
0-1-2-3
o-t-2-3
0-1-2-3
~ Rx
++++
Tests
Baseline
wheal
(No
size
Rx)
1 hr. ~ Rx
2 hrs. ~ Rx
wheal
wheal
—
size
x —mm
erythema
O-l-2-3+
erythema
O- 1-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
size
x
EL’
mm
erythema
O-l-2-3+
wheal
(b)
size
x
_x_mm
(a)
-&’%
on
30M
Table
Il. Data
Treatment.
Climcal
Data
was considered to be relatively unimportant
for comparative purposes. All three treatments consisted
of the administration
of two tablets orally,
in a
controlled, double-blind
fashion and in a randomized
sequence. On one of the three treatment days the patient
received two 22 mg. tablets of phenyltoloxamine citrate;
on a different day the treatment consisted of one tablet
of phenyltoloxamine citrate 22 mg. and another identical
placebo tablet and on the remaining treatment day —
Three treatments were administered on three different
days, at least 24 hours apart and at the same time of
Table
ET AL
mm
wheal
size
wheat
size
—mm
—x_mm
—x
erythema
O-l-2-3+
erythema
O-l-2-3+
erylhema
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
itching
O-l-2-3+
Comments:
Legend:
O= None,
1 = Mild,
2= Moderate,
3= Marked
or Severe
141
INHIBITION WITH PHENYLTOL
which could happen to be the first, second or last session
— the patient received two placebo tablets and no
phenyltoloxamine. Nasal smears were taken from each
individual for eosinophil counts before the study and the
results were graded on a O-4+ scale (Table 11). The skin
test results were assessed visually and then the two
perpendicular diameters of the wheal were measured
before, one hour and two hours af[er the administration
of the test tablets. The two diameters were multiplied
to give an approximation
(in arbitrarily
“squared”
numbers) of the area of the wheal and erythema, in
square millimeters. Erythema and pruritus were scored
on a O-3+ scale. Adverse reactions, subjective and
objective, were explored, with particular attention to the
possible development of somnolence, mucosal dryness,
vertigo, irritability, gastric distress and other localized
or systemic side effects.
Results
The mean baseline clinical scores were quite close for
the three treatment days, being 5.2 for the day when
44 mg. phenyltoloxamine was given, 4.8 when 22 mg.
phenyltoloxamine was given with one additional placebo
tablet and 5,0 for the day when two placebo tablets were
administered (Table 111). At one and two hours after
treatment two tablets of phenyltoloxamine and one
showed a significant
tablet of phenyltoloxamine
be
recognized
that
these
percentage
changes
Ill. Effect
of Medication
Treatment
1.
Il.
Ill.
Phenyltoloxamine
Phenyltoloxamine
Placebo
Placebo
Table
IV, Mean
Wheal
Treatment
Phenyltoloxamine
Phenyltoloxamme
Placebo
111, Placebo
1.
Il.
on Clinical
No.
Tabs.
Area
Baseline
Score
Symptom
1 Hour
After Rx
found
to
be
consistent
prior
to
given;
it was
492
mm~ when
the dose Wa$
phenyltoloxamine
22 mg. and 484 mm’ when [~
randomized schedule provided for the administration of
placebo. One and two hours after the administration 01
the two active phenyltoloxamine
doses a significant
decrease in the wheal size was noted, greater than that
following placebo at the p=O.01 level. The 44 mg. dost
of phenyltoloxamine
reduced the size of the wh~i
significantly more than the 22 mg. dose at the P=O.05
level, which was somewhat less than the difference of
It was thus noted that the antihistaminic
inhibition
of the wheal, caused by the intradermal injection of tw{
selected
allergens
among
demonstrably
sensitiw
correlated
well with the clinical
im
individuals,
provement induced by two doses of phenyltoloxamim
citrate, in comparison to changes observed after tht
administration
of identical-appearing
placebo tablet:
(Figure 2). The higher dose of phenyltoloxamine,
44
reg., or two tablets, was found to be more effective thar
the lower dose of 22 mg. (one tablet) both in terms o
symptomatic relief and in the prevention of whealin~
after intradermal application of allergens. Noteworth!
is the fact that, under the conditions of this experiment
are
Scores,
10
Ss with
Difference
Allergic
Rhinitis.
Percentage
Improvement
2 Hours
After Rx
Difference
Percentage
Improvement
5.2
4.8
22
2.7
3.0
57.7
1.7
3.5
67.3
2.1
43,8
2.5
2.3
47.9
;
5.0
4.5
0.05
10.0
4.2
08
16.0
(aq.
2
1
;
mm.)
Following
Baseline
Score
ID Teats
1 Hour
After Rx
th<
of treatment.
2
1
No.
Tabs.
wa!
Mean baseline wheal sim
484 mm? on the day phenyltoloxamine 44 mg. wa:
administration
were
remarkably
and 97.170 protection, respectively, one and two hours
after treatment;
22 mg. phenyltoloxamine
provided
70.7% and 75,2% protection and placebo reduced the
wheal size by 7.6T0 and 4.4~o at one and two hours after
administration,
respectively.
relative to the grading system employed. [n fact, one
could not easily define a change from a score of 2 to
a score of I as a SO% improvement or a shift from I
Table
The size of the urticarial
wheals \nduced
extracts
intradermal
injection
of the allergenic
either drug from placebo (Table IV). Thus it was
observed that 44 mg. phenyltoioxamirre provided 88.6’%
difference (p=O.O 1) from placebo, in the direction of
improvement.
The larger dose of phenyltoloxamine
differed significantly from the lower dose but less than
when compared to placebo (p= O.05) one hour after
administration
of treatment.
At two hours after
medication 44 mg, of phenyltoloxamine
citrate was
significantly different from 22 mg. at the p= O.01 level.
In terms of percentage over baseline the improvement
after 44 mg. phenyltoloxamine citrate was 67.3~o, after
22 mg. phenyltoloxamine 47.9% and after only placebo
was ingested there was a 16.0% improvement in nasal
allergic symptomatology after two hours. Of course it
must
-“
.,,.
??
by’~h{
could not be excluded.
(two/
Ss) performed
Difference
Percent
Protection
on
10
Ss Before
TWO Hours
After Rx
and
After
Medication.
Difference
Percent
Protect ion
484
55
429
88.6
14
470
97.1
492
484
144
447
348
37
70.7
7.6
122
463
370
21
752
4.4
ANNALS
OF ALLERG
INHIBITION WITH PHENYLTOLOXAMINE—FALLIERS ETAL
-- patient showed any adverse effect which might
~- _ inish the clinical usefulness of phenyltoloxamine,
:cially in higher doses.
After it was ascertained that the skin reactions began
to subside and that the patients were not experiencing
any systemic adverse effects from the medication given,
they were allowed to return home. They were all
specifically requested to report any delayed reactions
spontaneously
or
after
noted but none did, either
questioning
at
a
subsequent
reactions by phenyltoloxamine
is of more than casual
pharmacologic interest. Indeed, it can be considered as
being comparable in its therapeutic implications to the
experimental demonstration of a protective antihistaminic effect against the histamine-induced
increase in
pulmonary vascular permeability and pulmonary edema,
demonstrated in certain selected animal species.” The
in the nasal symptoms
of the
clinical improvement
patients
in the study
therapeutic
visit.
can be viewed
antihistaminic
as evidence
of this
effect.
Summary
Discussion
The capacity of histamine to produce respiratory
typical
of
mucosal changes and urticarial skin reactions
allergy
has been recognized for several decades.g’0”
Inhibition of histamine-induced wheals has been used as
a means to test the potency
of antihistaminic
drugs:
the
of 10-30 mcg. histamine phosphate
resulted in 200-260 mm2 wheals, which were found to
be reduced by 50% or more by certain antihistaminic
compounds.’
In a double-blind,
placebo-controlled
comparative study four common antihistaminics were
found to suppress or reduce the size of skin test reactions
to high concentrations of selected “major” and “minor”
allergens,’z with peak effects noted between one and two
hours after ingestion of the drugs. Likewise, another
study of five representative
drugs —
including
hydroxyzine — found 30-63% wheal diminution, with
__average
duration of this effect from 1.89 to 4.31
;.’3 Spontaneous variability
of the immediate skin
.ctions to standard allergens of verified potency is not
common, provided
that uniform
and meticulously
controlled techniques are applied, ” Circadian variability
in skin reactivity around the 24-hour biological cycle,
although measurable,a is several times smaller than that
associated with the biological potency of the allergens
employed and with the medication administered prior
to the testing: therefore, it can be considered negligible
for a study placing primary emphasis on medication
and/or allergenic exposure. Non-immediate
or delayed
skin responses, occurring six to 12, or 24 to 48 hours
of the allergens, have
after the intraderma] application
been described and have been attributed
either to
immunoglobulin E antibodies’~ or to Type III and Typ
lV immune reactions. ” Such reactions have generally
been assumed to be extremely infrequent and in some
intradermal
injection
cases they have been only noted following
the
suppression of the immediate
wheal-and-erythema
reactions by antihistamines. ” W’hen this was noted it has
been hypothesized that the immediate “flush” reaction
does indeed serve a useful teleologic purpcse and that
only its suppression allows a delayed-type reaction to
~me
manifest. It is considered noteworthy that in the
Present study no “late” or delayed skin reactions were
obse~ed among the 10 patients tested, either when they
r~%ived oral antihistaminic
medication or when only
~s
?bo was given.
,M inhibition of classical Type I wheal-and-flare skin
E 41, SEPTEMBER,
!978
of oral phenyltoloxaA dose-and-time-related-effect
mine citrate, a Class 1, H, antihistamine compound,
has been demonstrated
against
allergen-induced
wheal-and-erythema
skin reactions among 10 adults
with a diagnosis of allergic rhinitis and seasonal
pollinosis.
Clinical
improvement
in the existing
symptoms of rhinorrhea, nasal obstruction, pruritus and
sneezing, showed a significant correlation
with the
inhibition of reagin-mediated skin reactivity caused by
phenytoloxamine. No adverse side effects were observed.
It
can
be
concluded
possesses
that
antihistaminic
oral
phenyltoloxamine
properties
and
citrate
a range
of safety
which make it a useful agent for the symptomatic
management of upper respiratory allergy.
References
I
7
-.
AMA
Edition
Fallicrs
Dcpartmcn!
of
Chicitgo:
AMA,
cJ:
Re.{pirororj
Lmng
Chcmistr}.
.3 Sherman
Drugs:
AM,4
fhg
1977. pp. 672-682.
A//erg,r,
American
Springfield
C. C Thomas.
h B Hjpvr.cen.$;/iti r~-Mechani.~m.v
Evuluariorr,
Lec!ure
Series
(in press),
and
Third
in
1978,
Managemem
Philudclphla.W.B Saundcr Co.. )968, pp. 405-407.
4 Falliers CJ. Respirator} Allerg} in Childhood In C’urrenr
Therapl, H. Corm (Ed ) Phil~dclphifi. W.B Saunders Co.. 1968.
pp
526-533
.5 Fclngold BF /IIIrOdIKIIOn10 C/,n,ca/ Allergl. Springfield:C. C
Thomas. 1973.
drugs
Mcd Clin N Am 45:
6 M“!lhclm RE The newer an[i-~llcrgic
887.
1961
7. Hockstra
JB.
Ph~rm~cologlcal
Tisch
DE.
propcrllcs
Rakictcn
N and Dickison
HL
of a new untihlsmmlnic
agent.
—
- loot
lhr
15 Rx
2hrs
b Rx
Figure 2. Comparative
changes
(percentage
of baseline) in nasal
symptoms and in skin whealing re.qmnscs after oral phenyholoxamine
and after placdm
1.43
INHIBITION WITH PHENYLTOLOXAMINE-FALLIERS
plscnyltoloxamine
1953,
8.
.—
9
10
(Bristamin),
J Am Pharmxeut
Assoe 42:587,
Rcinberg A and Sidi E: Circadian
changes in ihc inhibitory
effects
of ~n isntihist~minic
drug in man. J Invest
Dermatol
46: 415,
1966.
Curry
JJ: The action of his[aminc on the respiratory tract of
norm~l tnd as[hm~tic subjects. J Clin Invest 25: 785. 1946.
Bain WA: The quantitative comparison of his[amine
in man. Proc Royal Soc Med 42: 615. 1949,
antagonists
II
Beavcn WA: Histamine: [he classic antihw[amines
NW
Eng J Mcd 294: 320. 1976,
I 2.
Galont S. Zippin C. Bullock J ond Crisp J: Allergy skin [ests,
1. ,lnlihist~minc
inhibition. Ann .411erg 30: 53, 1972.
Il.
(H, inhibitors).
Cook TJ. MacQueen
DM, Witting HJ. Thornby Jl, L~ntos RL
Jnd Virtue CM: Degree and duration of skin [est suppression and
side effects with an(ihismmines,
J Allerg & Clin Immuno[ 51:71,
1973.
H, Pascual HC ct al: Reappraisal
of
I4. Reddy PM. Nagtyo
intracutancous !csts in the diagnosis of reaginic allergy. J Allerg
& Clin
lmmunol
61: 36.
ET AL
15. Solley GO, Gleich GJ, Jordan RD and SchroeterAL. The b~
phase of the immediate wheal and flare skin reaction. J Clin Invest
58: 4(38, 1976.
16. Pcpys J. Turner-Warwick
Arlhus
ologicai
M,
Dawson
PL
and
Hinson
KFw:
(Type Ill) reactions in man: Clinical ~nd immunopath.
fca[urcs. In Allrrgology,
Exerccpt~ Wed Inl Congr Ser
162: 221. 1968.
17, Brosloff J ~nd Roitt IM: Cell-mcdi~ted
(delayed)
hypcrscnsilivity
in puticn[s wilh wmmcr
h~y fever. L~ncct 2: I ?69. 1969.
18. Brigham KL. Bowers RE ~nd Owen PJ: Effects of ~ntlhis[aminm
Skp.
on [he lung vascular response
tOhisi~minein unancs~helized
J Clin Invest 58: 391. 1976.
Reques!s for reprin:.s rhould be oddrersed
Dr Cotrstan!inr J Fallier~
I 55 Cwk
to:
Slree[
Dwrvrr. Colorado
80206
1978.
i!
,,
●l
1
I
“For better or worse, there are few occupations of a more satisfying
character than the practice of medicine. if a man can but once get orien(ir[
and bring to it the philosophy of honest work, the philosophy that insists
that we are here, not to get all we can out of life about us, but to see
how much we can add to it. The discontent and grumbling which one hears
have their source in the man more often than in his environment.”
Sir William Osler
On rhe Educational
Value OJ the
,Wedical Socie[y
,
la
ANNALS
OF
ALLERGY
●
GREDIENT NAME;
I’ENT=ENE
TETRA ZOLE
B. Chemical Name:
1,5-Pentamethylenetetrazole, 6,7,8,9-Tetrahydro-5H-tetrazoloazepine
c.Common
Name:
Leptazol Injection Giazol, Angioto~ Angiotoniq Cardiazol, Cardiazole, Cardifortaq
Cardiol, Cardlotonicu~ Cardosal, Cordosan, Cenalene-M, Cenazol, Centrazole, CerebroNicin, Coranormal, Coranorrnol, Corasol, Coratoline, Corazol, Corazole, Corazole
(Amdeptic) Corisan, Corsedrol, Cortis, Corvasol, Corvis, Coryvet.
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
---
Assay
@k?inimum)
98%
(Resuslt)
99.80%
E. Information about how the ingredient is supplied:
White crystals, slightly pungent and bitter, very stable, not easily attacked by other
substances.
F. Information about recognition of the substance in foreign
pharmacopoeias:
Aust., Cz., Hung., It., Arg., Belg., Br., Eur., Fr., Ger., Hung., Ind,, Int., It., Jug., Mex.,
Neth,, Nerd., Pol., Port., Rus., Span., Swiss., and Turk.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
JUN H. W. Absorption and Fate. J l%zrm. Sci., 1975;64: 1843.
Khazi, I. A., [email protected], C. S., and Gadad A. K. Pentylene tetrazole induced
convulsions. Arzneimitte~orschung, 1996;46(10):949-952.
Erol, D. D., Calk, U., and Demirdamar, R. Pentylene tetrazole-induced seizures in mice.
J Phann. Sci. 1995; 84(4):462-465
H. Information about dosage forms used:
Orally
[email protected]
I.
Information about strength:
100-200mg
J. Information about route of administration:
Given by mouth
K
Stability data:
Melts at about 57-60°
—*
L. Formulations:
Leptazd is a sterile solution of pentetrazol 10% and sodium phosphate 0.25’%in water for
injections, adjusted to pH 7.8 with dilute hydrochloric acid or potassium hydroxide
solution.
M. Miscellaneous Information:
.-:
Page -2-
—..
“PRODUCT: PEN~LENHmWOLE
-
CATALOG NO:
LOT NO:
.-
—---”
--------
–
A-
Page 1
.
.—
**
PE104
MJ0251
... . .
—.
.
DESCRIPTION
-.
-.
.
LIMIT
MIN.
ASSAY”
;
. ~ .,,.
-.++----.
..-.L. . ..---- . ..—
. .... -—.
-. -. MELTING RANGE
.-
..
RESULT
99.80’10
..
59-61C
--
.D .
59-61C
i
.
.. .
.
.. -.,
...= —-—-.
;,.
.—.
. ....
—
-.
L-
.
. .
.
.-
.--.’
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[email protected]&%zth-
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.,,
APPROVED BY:
L/L/AN- D. CA5ABAR
.’
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-..
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:
QUALITY CONTROL
CHEMICAL
NAME .:
REPORT
PENTYLENETETRAZOLE
MANUFACTURELOT No. :MJ0251
PHYSICAL
SPECIFICATION
l)DESCRIPTION
TEST STANDm.:USP_/=
TEST
— /~RCK_/NF_/~TO_/Co”
.:
WHITE CRYSTALS, SLIGHTLY PUNGENT AND BITTER;
ATTACKED BY OTHER SUBSTANCES.
~
‘pEcs”_c
VERY STABLE? NOT ~SILy
2)SOLUBILITY. :
FREELY SOLUBLE IN WATER AND IN MOST ORGANIC SOLVENTS. SLIGHTLY SoLUBLE
IN ALCOHOL.
3)MELTING
POINT.:
MELTS AT ABOUT 57-60
-.-=
DEGREES.
k4)SPECIFIC
qvITY.:
5)IDENTIFICATION.
:
FAILS
PASSES .:
.:
cOhMENTS. :
SIGNATURE.
ANALYST
DATE.
:
PREPACK TEST. :
RETEST
.&-%
—
.:
DATE.
DATE.
:
:
:
INITIAL.
INITIAL.
:
:
------------------ IDENTIFICATION
------------------NAME:
1,5-PENTAMETHYLENETETRAZOLE,
PRODUCT #: P720-7
CAS if: 54-95-5
Ml?: C6H1ON4
98’XO
SYNONYMS
ANGIAZOL
.-...—... . * ANGIOTON * ANGIOTOIWN * CARDIAZOL * CARDIAZOLE *
* cm
CARDIFORTAN * CARD IOL * CARDIOTONICUM * c~os~
OSAN *
/’-
~ORANORMOL
* COFLU30L * CORATOLINE
* CORAZOL * CORAZOLE *
(ANALEPTIC) * CORISAN * CORSEDROL * CORTIS * CORVASOL * CC!RVIS *
CORYVET * ALP~BETA-CYCLOPENTAMETHYLENETETRAZOLE
*
DEAMOCARD *
DELZOL-W * DIOVASCOLE * DEUMACARD * GEWAZOL * KARDIAZOL *
KORAZOL *
KORAZOLE * LEPAZOL * LEPTAZOL * LEPTAZOLE * METRAZOL * METRAZOLE
..—.
*
NAURANZOL * NAURAZOL * NEDCARDOL * NEOCARDOL * NEUk4ZOL * NOVO
coluVTNCO * OPTICOR * PEMETESAN * PENETRASOL * PENETR4TSOL * PENETIAZOL
*
PENTACARD
* PENTACOR
* PENTAMETHAZOL
PENTAMETHYLENETETIL4ZAL
PENTAMETHYLENETETRAZOLE
* PENTAMETHAZOLUM
* PENTAMETHYLENETETRAZOL
*
* PENTAMETHYLENE- 1,5-TETRA20LE
*
* 1>5-
PENTAMETHYLENETETRAZOLE
* PENTAMETILENTETRAZOLO
(ITALIAN) *
PENTAZOL *
PENTAZOLUM * PENTEMESAN * PENTETR4ZOL * PENTETRAZOLE *
PENTRAZOL *
PENTROLONE * PENTROZOL * PENTYLENETETIUZOL
* PENTYLENETETRAZOLE
*
PETAZOL * PETEZOL * PETRAZOLE
* PHRENAZOL
* PHRENAZONE
* PMT * PTZ *
STELLACARDIOL * STILLCARDIOL * TETIL4COR * 6,7,8,9-TETRAHYDRO-5* 7,8,9,10AZEPOTETRAZOLE * 6,7,8,9-TETRAHYD RO-5H-TETRAZOLOAZEPINE
TETRAZABICYCLO(5.3
.0)-8, 1O-DECADIENE * 1,2,3,3 A-TETRAZACYCLOHEPTA-8-&
2-CYCLOPENTADIENE
* TETRASOL * TETRAZOL * TETRAZOLE,
PENTAMETHYLENE*
5H-TETRAZOLO(1,5 -A)AZEPINE, 6,7,8,9-TE TRAHYDRO- (8 CI,9CI) * TT87 *
VASAZOL * VASOREX * VENTR4ZOL * YETRAZOL *
.--”
------------------ TOXICITY HAZARDS ------------------RTECS NO: XF8225000
5H-TETRAZOLOAZEPINE,
6,7,8,9 -TETRAHYDROTOXIC.ITY DATA
85DCAI 2,73,70
ORL-MAN LDLO 147 MG/KG
85DCAI 2,73,70
IVN-MAN LDLO:29 MG/KG
JPPMAB 13,244,61
ORL-RAT LD50: 140 MG/KG
TXAPA9 18,185,71
IPR-RAT LD50:62 MG/KG
TXAPA9 18,185,71
SCU-RAT LD50:85 MG/KG
AIPTAK 135,9,62
IVN-RAT LD50:45 MG/KG
AACRAT 46,395,67
REC-RAT LD508 MG/KG
JPETAB 128,176,60
ORL-MUS LD50:88 MG/KG
AIPTAK i23,419,60
IPR-MUS LD50:55 MG/’KG
BCF&iI 111,293,72
SCU-MUS LD50:70 MG/KG
AIPTAK 103,146,55
IVN-MUS LD50:3 1400 UG/’KG
ARZNAD 6,583,56
PAR-MUS LD50:72 MG/KG
JAPMA8
29,2,40
SCU-RBT LD50:76 MG/KG
PHTXA6 21,1,58
IVN-RBT LD50:30 MG/KG
PLRCAT 1,7,69
SCU-FRG LD50: 1600 MG/KG
REVIEWS, STANDARDS, AND REGULATIONS
“—
.n.
NOHS 1974: HZD 84704; NIS 1; TNF 68; NOS 6; TNE 2770
EPA TSCA CHEMICAL INVENTORY, JUNE 1990
TARGET ORGAN DATA
BRAIN AND COVERINGS (RECORDINGS FROM SPECIFIC AREAS OF CNS)
BEHAVIORAL (TREMOR)
BEHAVIORAL (CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD)
BEHAVIORAL (EXCITEMENT)
BEHAVIORAL (MUSCLE CONTRACTION OR SPASTICITY)
LUNGS, THORAX OR RESPIRATION (OTHER CHANGES)
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 IRRITATION.
EXPOSURE CAN CAUSE:
CNS STIMULATION
CONVULSIONS
TARGET ORGAN(S):
CENTW4L NERVOUS SYSTEM
FIRST AID
IN CASE OF CONTACT, IMMEDIATELY FLUSH EYES OR SKIN WITH COPIOUS
CHELII(’AL INCINERATOR
EQUIPPED WITH AN AFTERBURNER AND SCRUBBER
OBSERVE ALL FEDERAL. STATE, AND LOCAL LAWS
--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE --WEAR APPROPRIATE NIOSW’MSHA-APPROVED RESPIRATOR,
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE CLOTHING
SAFETY SHOWER AND EYE BATH
USE ONLY ~ A CHEMICAL FUME HOOD
DO NOT BREATHE DUST
AVOID CONTACT WITH EYES, SKIN AND CLOTHTNG
AVOID PROLONGED OR REPEATED EXPOSURE
WASH THOROUGHLY AFTER HANDLING
TOXIC
KEEP TIGHTLY CLOSED
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 SUITABLE PROTECTIVE CLOTHING, GLOVES AND EY’WFACE
PROTECTION
TARGET ORGAN(S)
NERVES
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 PACK~G SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
Modafinil/PhendimetrazineTartrate
funclimr during the hrst few weeks of pmoline therapy was
considered essential and it was recommended that serum enzymes should be measured at no less thn every 2 weeks for
the first 6 weeks and then e~ery other mrmrh
1. Anrmymou5 ‘Hypcrkinc~ is’ can havr many cauws. <ymptoms.
JAMA 1975, ZX& 120$-16,
2. Paaerwm JF. Hepaams associated wilh pemollnc. SW),
1984, 77:938
Effects on muscle.
tem, p 1555.
$MedJ
See under Effects on tbe Nervous Sys-
Effects on the nervous
system. Choreoathe!osis and
rbabdomyolysis developed in a patient following a marked
increase nr intake of pemolme, I Abnormal movements responded to diazepam
For a discussion on cenrral stimulants provoking Tourerre’s
syndrome,
see Demnrphetamine
Stdphate, p. 1548.
1. Bnscoe JG. CI al. Pemolmc-mduced chnreoathelosis and rhab1988,3:71-6.
domyolysl$ Med TOXICOI
Effects on the prostate. Experience in one patient suggesled that pemoline might adversely affect the prosrafe gland or
interfere with rests for prosrmic acid phrrsphara.w used in the
diagaosis of prosratic carctnoma. 1
I L]nda. W. de Glrrdam, E Pemolmc and the prostalc &Tcel
1986. i: 738
1555
Pentetrazol is a central and respiratory stimulant
similar to doxapram hydrochloride (see p. 1550). It
has been used in respiratory depression but when
respiratory stimulants are indicated other agents are
generally preferred. It has also been included in
multi -ingredient preparations intended for the treatment of respiratory-tract disorders including cough,
cardiovascular disorders including hypotension, and
for the treatment of pruritus.
Administration
(7
has been by mouth and by injection.
Porphyria.
Pentefrazol has been associated with acute attacks of porphyria and is considered unsafe nr patients with
acute porphyria. ]
GIaSgW.
i >Orc MR. McCOII,KEL Porphvrim dwg ri~f~.
phyna Researeh Uml, Umvcrsoy of Glasgow. 1991.
47
7’
pOr.
.>
Preparations
Names of preparations are listed below; details are given in Part 3.
Proprietary Preparations
Spain: Cardiorapide.
Multi-ingrectht
preparations. FL: D&intex-Pentazolt: Ger:
Cartilnolt;
JMivi&It; Poikilo!ont; Sympattxanit; /ra/.: CardIazol-Paraccdina: Spuin.’ Cardior.?pide Efcd; Espectona Composemm: Ffuidin Iafantilt.
Pharmacokinetics
Pemoline is readily absorbed from the gastro-intestinal tract. About 50% is bound to plasma protein. It
is pamially metabolised in the liver and excreted in
the urine as unchanged pemoline and metabolizes.
It has been suggested that magnesium hydroxide
might increase the absorption of pemoline. PemoIine with magnesium hydroxide is known as magnesium pemoline.
References.
1. Vcrmeulen NPE. rr al. Pharmacokmet)c< of pemohne in plas.
ma. saliva and urlnc follm+mg oral admuvstration. Br J Chn
Pharmacol 1979.8:459-63.
2. Sallce F, rr al Oral pcmohm kmeucs m hypcracuvc children
Chn Phnrnnzcol Tlwr 1985,37: 60f-9.
3 Coiher CP. cr ./ Pcmohnc pharmacoklnetics and long lerm
therapy m children wnh attcnl!on dcfictt disorder and hypcrac.
[wlty Clin P60mwcokint1 1985, 10:269-78.
Uses and Administration
...
Ilk
&Dexamphetamine
Sulpha[e,
p.1547; howev~?ffects of over-stimulation
and sympathomi$,.%ctivity
are considered
to be less with
, ~ e: ‘1’l-terehave been reports of impaired liver
“~. ttr patients taking pemoline; its use is con-
.’[email protected] inpatients with Iiverdisorders.
’flere
@SO been’rme or isolated re~
chores,
iuti% and neutropenia.
,-).
P
~Paranoid
psychosis was o
k Pemoline 75 m 225 mg
~ of the drug, development ‘
M syndrome. and ~rrahility?l t
~-and it waa evidem that [he p
E.
WISE, Momc RM Pemolinc ahusc
~1.:s
,s,,
% on growth. Results of a studyY tn .
~ Sugges[ed that growth suppression u
kt.of pro]o”ged [reatmen! w,th climcdl
~dpenroline and tia; [his effect migh[ be dos
~Under Dexampheramine Sulphme, p. 1$!8,1
~U LC, ,, at. impa, red growth In h?fwrkmecl. <
?g Fcmolmc J Pt’d!.rr 1979.94: 538-II
*?.: the liver. Of childrcu ad.]ng Pemollne fo!
T had elevated crmcemnrcimrs of scram a.
<ferase (SGOT) and scmm alanme amm
L“
p.~l~n); the effec~ wit!. stated to be trans!enl 1a
)
-1
[email protected]& was associated with pcmo],ne In a 10-ye
tier enzyme vidue< fell 10 normal after u Ithdr
‘rig.?
wirb I<,wec dcjses did not increaw the en
.
Wing a toxic threshold. Close anenuon m he
,,
k] t de”o[es ~ ~re~~ation
iii
Pemoline has similar actions to dexamphetamine
(see p. 1548) and is used as an alternative to dexamphetamine or methylphenidate in the management
of hyperactivity disorders in children (see p.1544).
In the UK the initial dose by mouth in such children
is 20 mg each morning. increased by 20 mg at weekly intervals to 60 mg. Ifnoimprovement
occurs the
dose can be gradually increased to a maximum of
120 mg each morning. In the USA 37.5 mg is given
each morning initially. increased gradually at weekly intervals b~ 18.75 mg; the usual range is 56.?5 to
75 mg daily and the maximum recommended daily
dose is 112.5 m:.
Pemoline
is also an ingredient of an oral prepara-
Phenbutrazate
Hydrochloride
(1485-y)
Phenbutrazate
Hydrochloride
(&ANM).
R-38 1. 2-(3 -Mechyl-2phenyfmorphohno) etbyl 2-phenylbutyrace hydrochloride.
C23H29N03,HCI = 403.9.
CA5 — 4378-36-3
(phenbutrozote);
6474 -85-7 (phenbutrozote hydrochloride).
Fenbutrazate
Hydrochloride
(rffWM);
Phenburrazate hydrochloride
an anorectic agent.
Phendimetrazine
was
formerly
used
Tartrate
as
(1486-j)
Phendlmemzine Tartrate @4NM, rlNNM).
Phendlmetrazine Acid Tartrate; Phendimetraztne Bitartrate.
(+).3,4. Dlmethyl.2-phenylmorpholme hydrogen tarrrsce,
C12H{7N0,C,H606
= 34! .4.
CAS —
634-03-7
(phendimecrozine);
7635-5 I-O
(phendimetrazme
hydrochloride); 50-58-8 (phendimetrozlne torrrote).
Pharmocopc-ws. In US.
A white odourless crystalline powder. Freely solubte in wratec sparingly soluble in warm alcohol; practically insoluble
in acetone, in chloroform, and in ether. A 2.5% solution in
water has a pH of 3 ro 4. Store in airtight cornainers.
Adverse
tions
Effects,
Treatment,
and Precau-
tion. also containing yohimbine hydrochloride and
methyhestosterone, which is given with the intention of managing failure of sexual desire and func-
As for Dexamphetamine
tioning in males and females.
Phendimetrazine tartrate is readily absorbed from
the gastro-intestinal
tract and is excreted in the
urine, partly unchanged and partly as metabolizes,
including phenmetrazine.
Pemoline has been given with magnesium hydroxide (magnesium pemoline) in an attempt to increase
its absorption.
Preparations
Name~of prepumom areIi,wd below. demili are given m Pan 3.
Proprietary Preparations
Canad.. Cylen. Gt=r: Semor: Tradon: S.Afc Dytalert: .Wil:.:
Shmul. UK. Vohml: LrSA Cylen.
Multi-ingredient
preparations.
Ger.; Cephalo-Teknmidt:
Itul. Deadyn: S.Ar’K. Lemogesic, Spnm Neurnmrdm. UK. Prowess.
Pentetrazol
(1437-VI
I?
Pemetrazol (BAN dNN)
Corazol: Lepuzol, Pentamethazol. ~5-Pentame&&enererra.
&
~:
Pemazol, Pentetrazolum: Pemylenetetrazol 6,7,B,9-Te1rahydro-5H-terazolo azemne,
~2-—
54-95-5.
:otmm
In AUSL, Cz.( Hung., and k.
—
Sulphate, p. 1547.
Pharmacokinetics
Uses and Administration
Phendimetrazine tartrate is a sympathomimetic
agent with the actions of dexamphetamine (see
p. 1548). It is used as an anorectic and is administered by mouth as an adjunct to dietary measures in
the short-term treatment of moderate to severe obesity. The use of adjuncts in the management of obesity is discussed on p.1 544 where the use of stimulant
anorectics such as phendimetrazine is questioned.
The usual dose is 35 mg two or three times daily 1
hour before meals, but doses should be individualised and in some cases 17.5 mg twice daily may be
adequate: the dose should not exceed 70 mg three
times daily. An alternative dose is 105 mg once daily in the morning as a sustained-release preparation.
Phendimetrazine hydrochloride is used similarly;
is given try mouth in doses of 15 to 40 mg daily.
it
no ]on~er actively \
————.
—...
-s—..
_
..-.=~ki
368
~
IL
Central
and Respiratory
Stimulants
1438-g
Pentetrazol (fI.P., Eur. P.). Leptazok Pentazol;
Pentamethazol: Pentylenetetrazol; Pentetrazoium:
Corazol; 1,5-Pentamethylenetetrazoie. 6,7,8,9Tet rahydro-5H-tetrazoloazepine.
Phenatine.
N-(a-Methyiphenethy
diphosphate; N-(a-Methylphenethy
oxamide diphosphate.
C15H16N:0,2HJP0,
=436.3.
C6H,0N4=
CAS — 139-J8-4
138.2.
Cropropamide. NN-Dimethyl-2.{~.
crotonamido)but yra m ide.
d
c,, H24N~03=240.3.
l)nicotinamidc
l)pyridine-3-carb-
(diphosphate).
Pharmacopoeias.
In Arg., Aust., Belg.. Br., Cz., Eur.,
Fr., Ger., Hung., Ind., Ire.. It., Jug., Me.r.. Neth.,
oral.. Pol., Port., Rus., Span., Swiss, and Turk.
In Ru$.
Uses, Phenatinc
ia claimed to stimulate
the central
nervous system in a similar way to dcxamphetamine
without causing vaaoconstriction. It is also claimed that
it reduces blood pressure. [. the USSR it has been
employed similarly to dexamphetamine
as a central stimulant; it has also been suggested in tbe treatment of
hypertension.
High dosage produces epileptiform convulsions, and overdosage may result in
respiratory depression.
Treatment of Adverse Effects.
As for Nikethamide, p.367. If pcntetrazol has been ingested the
stomach should be emptied by aspiration
and
Iavage.
Precautions. Pentetrazol may provokeseizures
h
patients with epilepsy or other convulsive disorders.
Absorption and Fate. Pentetrazol is readily
absorbed after administration by mouth and by
iniection. It is rapidlv metabolised, chiefly in the
6-
li~er. About 75%” of-a parenteral dose has been
reported to be excreted in the urine.
Peak plasma concentrations of abut
2gg per ml were
obtained about 2 hours after a dose of 100 mg of petrtetrazol by mouth. The drug was excreted in the
urine,— W. R, Ehert PI al., J. pharm. Sci., 1970, 59,
1409.
Plasma-pentetrazol
concentrations
in 3 patients, who
were taking the drug regularly, ranged from 1.45 to
3.1 gg per ml when measured 1.25 to 5 hours after a
100-mg dose.— H. W. Jun ●[ al., J. pharrn. Sci., 1975,
64, 1843.
Uses. Pentetrazol
isa respiratory
stimulant
with
,/
J
$
/%
i+
,
L’
~
~..i?=--~~_y_y?3
as an aid to the dlagnows of epdepsy.
~
J
L
.’.
:
.1, “ :1;
,,.
.;:.
l;
1
i$,
4
:;’[~:
{
actions and uses similar to those of nikethamide
(see p.367). ft has been given in usual doses of
administered
subcutaneously,
intra‘0%
muscu
arly,
or intravenously.
Pentetrazol
has
been employed
in the ekferly to alleviate
the
symptoms of senility. For this purpose it has
been given by mouth in a dose of 1
usually in conjunction wit
‘~
ntcohmc act . but Its value has not- been substantiated in trials.
Preparations
L#[email protected]@
(8P.C. ,963). Inj. Leptazol. A sterile
uuon of Pcntetrazol
10% and sodium phosphate
0.25% in Water for Injections, adjusted to pH 7.8 with
dilute hydrochloric acid or potassium hydroxide solution.
The addition of a bactericide is unnecessary. Dose. 0.5
~to I ml s“~utanermsly.
“
Proprietary
Names
Cardiazol (Kno/1. Ger.: Medirrsa, Spain: Knoll, Swifz.);
Cardiorapide (Rapide, Spain~ Metrazol(Krroll, USA).
Crotethamide.
1439-q
picrotoxin (B.P. 1963). Picrotox.; Picrotoxinum;
Iin.
C30HJ,0,3=-602.6.
Coccu-
CAS — 124-87-8.
Pharmocopaia.t.
and Turk.
1. Arg., Inl., It., .Wex., Span., Swiss.
An active principle from the seeds of Anamirta COCCU{US
(-A. parricu/ata) (Menispermac.a.).
Odourless, colour[css, flexible, shining prismatic crystals
or white or nearly white microcrystalline powder, with a
very bitter taste. M.p. about 1994.
Soluble 1 in 350 of water, I in 35 of kiling water, 1 in
16 of alcohol, and 1 in 3 of Wiling alcohol; soluble in
glacial acetic acid and solutions of acids and alkali
hydroxid~, slightly soluble in chloroform and ether. A
saturated solution in water is neutral to litmus. SOlutions are steriliaad by autoclaving or by filtration.
protect from light.
The potency of picmtoxin solutions diminished as the
pH increased above 7.— P. W. Ramwell and -i. E.
Shaw, J. Phorm. Pharmac., 1962, 14, 321,
Adverss Efieets snd Trestsnent.
As for Nikethamide,
p.367, As little as 20 mg may cause severe poisoning,
Uses. Picrotoxin
and uses similar
duration of effect
It was formerly
intravenously.
is a respiratory stimulant with actions
to those of niketbamide
(p.367).
Its
is brief.
given in usual doses of 3 to 6 mg
.?ef
Pipradrol Hydrochloride (B,P,C. /963). a-(2-Piperid yl)benzhydrol hydrochloride; aa- Diphenyl-a-(2-piperidyl)mcthanol hydrochloride,
C18H11N0,HCI= 303.8,
71-78-3 (hydrochloride).
Odourless, tasteless. small white crystals or white or
almost white crystalline powder. M.p. about 290” with
decomposition.
SoJubl- 1 in 30 of water, 1 in 35 of
alcohol, 1 in 1000 .of chloroform, and 1 in 8 of methyl
alcohol; practically insoluble in ether. A 1% solution in
water has a pH of 5 to 7. Protect from light.
Adverse Effects. Pipradml
hydrochloride
may cause
nausea, anorexia, aggravation of anxiety, hyperexcitability, and insomnia.
Epigastric
discomfort,
skin rash,
dizziness, and hallucinations have been reported.
“3
&
!ij
1443-m
Prethcamide. G 5668. A ~=
parts by wt of cropropamide ~~
CAS — 8015-51-8.
is soluble
in
..(Z
~...
.-Q
Adverse Effects. Side-effects ~h~
paraesthesias,
restlessness, 01 _
tremors,
dyspnoea,
and [email protected]
Gastro-intestinal
disturbances .W
..’41
have also been reported.
Precautions. Prethcamide s~$
care to patients with epilepsy.. ~~
UaeS. Prethcamide
is a rdi _
which has been given in usui4’t
three or four times daily in .,<ti
respiratory insufficiency in chrorti
It has also been given intramtiq
intravenous
injection,
and by> d
+!
sion.
Proprietary Preparations
~~
Micorers (Geigy, UK). Prethcamide,:a{
of 400 mg. (Also available as [email protected]
Neth., Swirz.).
i
Other Proprietary Names
Micorene (Be/g.).
‘.i
‘%?
... .
“)
1444-b
Prolintane
Hydrochloride.
Propylphenethyl) pyrrolidine
C15H23N,HCI=253.8.
CAS -– 493-92-5
ch[oridej.
[440-d
.1,”
CAS — 6168-76-9.
A white
CAS — 467+50-7 (pipradral);
2-( N-Ethylcroto&_
butyramide.
C11H,1N10L=226.3.
Prethcamide
ether,
from light.
Adverse Effects.
“.!:%
1442-h
Pharmacopoeiu$.
Odourless colorless
crystals or white crystalline powder
with a bitter saline taste, Soluble in water and alcohol:
practically insoluble in ether. A 5% solution in water
has a pH of 1.8 to 2.4.
An aqueous solution of pentetrazol iso-osmotic with
serum (4,9 l%) caused 100% haemoiysis of erytbrocytea
cultured in it for 45 minutes.— E. R. Hammarlund and
K. Pedersen-Bjergaard, J. phurm. Sci., 1961, 50, 24.
Pentetrazol
in a concentration of 1 to 3% inhibited the
growth of Escherichia coli, BacilIus subtiiis, Staphyl*
coccus aureus, and Pseudomonas aerug”nosrr.Thissubstantiated the statement in the B.P. 1958 that no bactericide needed to be added to solutions for [email protected] J. Gilbert and A. D. Russell, Phtsrnr. J.. 1963, 1,
1[1.
4.
CAS — 633-47-6
(base); 2964-234
CAS — 54-95-5.
Colorless,
almost odourless crystals or white
crystalline powder with a slightly pungent bitter
taste. M.p. S7° to 60°. Soluble 1 in less than 1
of water, of alcohol, and of chloroform, and 1 in
less than 4 of ether; soluble in cartxmr tetrachloride. A 10% solution in water has a pH of
5.5 to 7. A 4.9 I % solution is iso-osmotic with
serom. Solutions are steritised by autoelaving or
by filtration, avoiding contact with metal. Protect
,.,J?!
144!-n
1437-V
B
$
h3jtfia
,~,~
(prolinrarre)~fi
,4<!s
odourless
powder Mtb
M.p. about 133°. SoluiIble in
chloroform; practically insohtbl~ I
7
Adverse Effects
and P~”~&
nausea, and tachycardia
have%
patients receiving prolintane. “~,,,,
with care in patients taking tII$~
inhibitors, and should not Lre, ”g
with hyperthyroidism
or [email protected]
2
K?’
Uses. Prolintane hydrochlorid~’ - ~
a
stimulant of the central nerve”’
been given, in fatigue and t~$
usually with vitamin supplerrte~u
10 mg twice daily, with the .,
given not later than mid-aftem<~
Usas. Pipradrol hydrochloride is a stimulant of the central nervous system which was formerly given in usual
doses of 2 to 6 mg daily in fatigue and some depressive
states.
Proprietary Preparations
.:+
Villescon (Boehrirrger [ngt+keim, UK ) 4
in each 5 ml prolintane hydmchlorid~
1
hydrochloride
i .67 mg. riboflavin;
&
salt) 1.36 mg, pyridoxine hydmchk?&
namide S mg, znd alcohol 12.2% w/Y,@!!
water) and Tablets e~ch containing ~
chloride IO mg, thiamine mono-nitrate.5
3 mg, pyridoxine
hydrwhlorid.
\[email protected]
15 mg, and ascorbic acid 50 mg. [email protected]
of atmetite and mood. Dose. 10 ml Of IK
lwic~ ’daily; children
Proprietary Names
Detaril (MOM. fral. ); Stimolag
Other Proprietary
Pmmotil (Fr,).
Prscautiorss. Pipradroi hydrochloride is contra-indicated
in endogenous
depression,
in agitated
prepsychotic
ptients,
chores, pdranoia, obsessional disorders, and
anxiety statea, and in patients for whom ECT is indicated
Fortis (Lagap, .Switz. ).
---
I!a
RI
/+
“Qlui.fJ~+i’q-=&
TITLE:
Facilitation of pentylene tetrazole-kindled seizures by mild thyroid
hormone deficiencies.
AUTHOR:
Pacheco-Rosado J; Angeles-Lopez L
AUTHOR
AFFILIATION:
Department of Physiology Mauricio Russe~ Escuela National de
Ciencias Biological, I.P.N., Mexico, D.F.
SOURCE:
Proc West Pharmacol Soc 1997;40:75-7
NLM CIT. ID:
98098613
MAIN MESH
SUBJECTS:
Convulsants/* TOXICITY
Kindling (Neurology)/* PHYSIOLOGY
Pentylenetetrazole/* TOXICITY
Triiodothyronine/BLOOD/* DEFICIENCY
ADDITIONAL MESH
SUBJECTS:
Animal
Dose-Response Relationship, Drug
Hypothyroidism/BLOOD
Male
Rats
Rats, Wistar
Support, Non-U.S. Gov’t
Time Factors
.~..
PUBLICATION TYPES: JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY NUMBERS: O(Convulsants)
54-95-5 (Pentylenetetrazole)
6893-02-3 (Triiodothyronine)
— =
-—
lofl
5/5/98, 11:53 AM
http:// 130. 14.32.461cgi...M-client? 10900+detail+3
http://l3O. 14.32.46/cgi-bin/IGMdient?
10900+detail+3
National Library of Medicine: IGM Full Record Screen
la
TITLE:
Synthesis, anticonvulsant and analgesic activities of some 6-substituted
imidazo(2,1-b)-1,3,4-thiadiazole-2-sulfonamides and their 5-bromo
derivatives.
AUTHOR:
Khazi IA; Mahajanshetti CS; Gadad AK; Tarnalli AD; Sultanpur CM
AUTHOR
AFFILIATION:
Department of Chemistry, Karnatak University, Dharwad (India).
SOURCE:
Amneimittelforschung 1996 0ct;46(10):949-52
NLM CIT. ID:
97085798
ABSTRACT:
A series of 6-substituted imidazo(2,1-b)-1,3,4-thiadiazole-2-sulfonamides
(V) were prepared by condensation of
2-amino-1,3,4-thiadiazole-5-sulfonamide (H.)with an appropriate
2-bromo-ketone (Ill). Bromination of V in glacial acetic acid gave the
corresponding 5-bromo derivatives (W). Five selected compounds (15-18
and 28) were evaluated for their anticonvulsant and analgesic activities.
Compounds 15-17 showed maximum protection (83%) against ~entyle~
tetrazole induced convulsions and maximum electroshock induced seizures
while the standard phenobarbital sodium and phenytoin sodium showed
100”Aprotection, respectively. Compounds 15, 16 and 18 showed superior
analgesic activity to acetylsalicylic acid in rat caudal immersion test.
/-
MAIN MESH
SUBJECTS:
1 of2
Analgesics/* CHEMICAL SYNTHESIS/PHARMACOLOGY/TOXICITY
Anticonvulsants/* CHEMICAL
SYNTHESIS/PHARMACOLOGY~OXICITY
Sulfonamides/* CHEMICAL SYNTHESIS/PHARMACOLOGY
5/5/98 11:54 AM
http://l3O. 14.32.46icgi.. .M-client? 10900+detail+3
~=
ADDITIONAL
MESH
SUBJECTS:
Animal
Convulsants
Dose-Response Relationship, Drug
Electroshock
Female
Indicators and Reagents
Male
Mice
Pain Measurement/DRUG EFFECTS
Pentylenetetrazole/ANTAGONISTS & INHHI
Rats
Rats, Wistar
Spectrophotometry, Infrared
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Analgesics)
O(Anticonvulsants)
O(Convulsants)
O(Indicators and Reagents)
O(Sulfonamides)
54-95-5 (Pentylenetetrazole)
http://l3O, 14,32 .46/cgi-bin/IGM-e[ient? 10900+detail+3
-_
2 of2
5/5/’98 11:54 AM
http://l3O. 14.32.46/cgi. ..M-client? 10900+detail+5
http://l3O. 14.32,46/cgi-binlIGM-client?10900tdetail+5
Synthesis and biological activities of some 3,6-disubstituted
thiazo10[3,2-b][l,2,4]triazoles.
.-i
H—
2of3
AUTHOR
Erol DD; Calis U; Demirdamar R; Yulug N; Ertan M
AUTHOR
AFFILIATION:
Hacettepe University, Faculty of Pharmacy, Pharmaceutical Chemistry
Department, Ankara, Turkey.
SOURCE:
J Pharm Sci 1995 ApIy84(4):462-5
NLM CIT. ID:
95356086
ABSTRACT:
Some new 2,3-dihydro-3-hydroxy-6-phenyl-3-(4-substituted(phenylthiazolo[3,2-b] [l,2,4]triazole derivatives were synthesized as
antifungal agents. After their structures were confirmed by microanalysis
and IR and NMR spectral analysis, their antifungal activities against
Candida albicans, Candida parapsilosis, Candida stellatoidea, and Candida
pseudotropicalis were investigated. Contrary to our expectations, all proved
to have poor antifungal activities. Because
2,4-dihydro-3H-1,2,4-triazol-3-ones are a new class of anticonvulsant
agents, a series of thiazolo[3,2-b] [l,2,4]triazoles was evaluated for
anticonvulsant activity and observed as potential anticonvulsant
candidates. All compounds examined exhibited activity against both
maximal electroshock and pentylene tetrazole-induced seizures in mice.
MAIN MESH
SUBJECTS:
Anticonvulsants/* CHEMICAL SYNTHESIWPHARMACOLOGY
Antifungal Agents/* CHEMICAL SYNTHESIWPHARMACOLOGY
Thiazoles/*CHEMICAL SYNTHESIWPHARMACOLOGY
Triazoles/*CHEMICAL SYNTHESI!VPHARMACOLOGY
ADDITIONAL
MESH
SUBJECTS:
Animal
Candida/DRUG EFFECTS
Convulsions/CHEMICALLY INDUCED/PREVENTION & CONTROL
Electroshock
Male
Mice
Microbial Sensitivity Tests
Pentylenetetrazole
Spectrophotometry, Infrared
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Anticonvulsants)
O(Antifungal Agents)
O(Thiazoles)
O(Triazoles)
54-95-5 (Pentylenetetrazole)
‘-
5/5198 11:55AM
,.—
A. INGREDIENT NAME=
●
PmCE
TAM
B. Chemical Name:
l-Acetamido-2-Pyrrolidinone, Euvicor, Gabacet, Genogris, 2-Ketopyrrolidine-lYlacetarnide, Nootro~ Nootropil, Nootropyl, Normabrai~ 2-Oxo-Pyrrolidine-Acetamide,
2-Oxo-Pyrrolidin- 1-Ylacetamide, Piraceta~ Pirazet~ Pirroxil, Pyracetam, Pyramem, 2Pyrrolidininnoneacetamide, 2-Pyrrolidoneacetamide, UCB 6215
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
AS=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.
International hwndpf
Psychophysiology,
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. Scam!,
1976; 54(2):150-160.
Simeo~ J., Waters, B., and Resniclq M. Effkcts of Piracetam in children with learning
disorders. Psychopharmacol.BulI., 1980; 16:65-66.
Stegi~ K. J., The clinical use of Piracete~ 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. Psychopharmacology. 1979; 65:107-109.
Wilsher, C., Atkins, G., and Mansfield, P. Effects of Piracetam on dyslexic’ reading ability.
J Learn. Disability. 1985; 18:19-25.
Mondadori, C., Petschke, F., and HWsler, A. The Effects of Nootropics on Memory: new
Aspects for Basic Research. Pharrnacopsychiatry. 1989; 22:102-106.
YaI, V., Derzhiruk, L. P., and Mogilevskii, A. Piracetam-induced changes in the
fl.mctional 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; 13 Suppl: 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 Deyn, P. P., Reuc~ J. D., and Deberdt, W. Treatment of acute ischernic stroke with
Piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Strokv.
1997; 28(12): 2347-2352.
Di Ianni, M., Wilsher, C. R., and Bl~ M. S. The effects of Piracetam in children with
1985; 5(5): 272-278.
dyslexia. d CIin Pychopharmacol.
Wilsher, C. R., Bennett, D., and Chase, C. H. Piracetam and dyslexia: effects on reading
tests. L Clin PsychopharmacoI. 1987; 7(4): 230-237.
Reisberg B., Ferris, S. H., and Gershon, S. An overview of pharmacologic treatment of
cognitive decline in the aged. Am J Psychiatry. 1981; 138(5): 593-600.
Bartus, R. T., Deaq R. L., and Shermaq K. A. Profound effects of combining choline and
Piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol
A~”ng. 1981; 2(2): 105-111.
Page -2-
.
Buresov~ O. and Bures, J. Piracetam-induced facilitation of interhernispheric transfer of
visual information in rats. Psychopharrnacologia. 1976; 46(l): 93-102.
Dimond, S. J., Scarnmell, R. E., and Pryce, I. G. Some effects of Piracetam (UCB 6215,
Nootropyl) on chroNc schizophrenia. Psychophahnacology. 1979; 64(3): 341-348.
Dimond, S. J, and Brouwers, E. M. Increase in the power of human memory in normal
1976; 49(3): 307-309.
man through the use of drugs. Psychopharmaco/o~.
Sarq S. J., David-Remacle, M., and Weyers, M. Piracetam facilities retrieval but does not
impair extinction of bar-pressing in rats. Psychopharmacology. 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., Cronhohq B., and Levander, S. E. Does Piracetam counteract the ECTinduced memo~ dysfimctions in depressed patients? Acts P~chiatr. Stand 1975; 52(5):
319-326.
Mondadoori, C., Classen. W., and Borkowski, J. Effects of oxiracetam on learning
memory in animals: comparison with piracetam. Clin Neurophannacol. 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 Piracetam 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-3.3 g
J. Information about route of administration:
Orally
Page -3-
_—
K. Stability data:
L. Formulations:
M. Miscellaneous Information:
See File
———_
-
Page -4-
. .. ___ .—__
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ANJALYSIS
3c -22//’
4 5ymq
Coa No: 7777
T
.
,
f
Batch No: 96120006
Manufacturing
-~
Date: Dee-3, 199[
-!
Resuit
#“-%.
Appearance
Identification
Melti.ng point
Ch.ri~ of Solution
~yhite
CVSM
*
powder
&---’
-
Poswe
152.5 -153.5°C
Clear
< 20ppm
Heavy Metals
Residue on lgnitio~
0.02%
0.12%
99.27%
Loss on Drying
Conforms to China Provincial Standard
‘
marks: The above testing result is per rnanufacaer’s informaribufi
—
.n.
, ‘/
--
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,-_..
—=————.-. —
. —_—-
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—-—-
QUALITY CONTROL
REPORT
CHEMICAL NAME. :PIRACETAM
MANUFACTURE LOT NO. :97060036
PHYSICAL
SPECIFICATION
TEST
TEST
STANDARD.:USP_/BP_/~Rm_/NF_/~T._/CO”
SpECS._.
l)DESCRIPTION .:
WHITE TO OFF WHITE CRYSTALS FROM ISOPROPANOL OR WHITE TO OFF WHITE
CRYSTALLINE POWDER.
2)SOLUBILITY.
:
VERY SOLUBLE IN WATER; SOLUBLE IN ALCOHOL, ESPECIALLY IN ISOPROPANOL.
n
3)MELTING
POINT.:
MELTS AT ABOUT 151.5-152.5
4)SPECIFIC
degree.
GRAVITY.:
5)IDENTIFICATION .:
A) COMPLIES IR SPECTRUM AS PER COMPANYSPECS.
PASSES.
FAILS
:
.:
COMMENTS .:
ANALYST
SIGNATURE.
PREPACX
TEST.:
RETEST.
-_
_-—
:
DATE.
:
DATE.
DATE.
:
:
:
INITIAL.
INITIAL.
:
:
..-=. .
------------------ IDENTIFICATION ------------------PRODUCT #: P5295
NAME: PIRACETAM
CAS #: 7491-74-9
MF: C6H1ON2O2
SYNONYMS
1-ACETAMIDO-2-PYRROLIDINONE
* EUVIFOR * GABACET * GENOGRIS * 2KETOPYRROLIDINE- 1-YLACETAMIDE * NOOTRON * NOOTROPIL * NOOTROPYL
73 *
NORMABRAIN
* 2-OXO-PYRROLIDINE
ACETAMIDE
* 2-OXO-PYRROLIDIN-
1-
YLACETAMIDE * PIRACETAM * PIRAZETAM * PIRROXIL * PYRACETAM *
PYRAMEM *
2-PYRROLIDINONEACETAMIDE
* 2-PYRROLIDONEACETAMIDE
* UCB 6215 *
------------------ TOXICITY HAZARDS ------------------RTECS NO: UX9660500
1-PYRROLIIXNEACETAMIDE,
2-OXOTOXICITY DATA
IPR-MUS LD50:>I0 GM/KG
PCJOAU 23,795,89
SCU-MUS LD50: 12 GM/KG
KHFZAN 11(8),132,77
IVN-MUS LD50: 10 GM/KG
KHFZAN 11(8),132,77
IVN-CAT LD50: 10 GM/KG
RPTOAN 47,205,84
UNR-W
LD5O:>1O GM/KG
RPTOAN 44,22,81
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
MAY BE HARMFUL BY INHALATION, TNGESTION, OR SKIN ABSORPTION.
MAY CAUSE IRRITATION,
EXPOSURE CAN CAUSE:
CNS STIMULATION
THE TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY
INVESTIGATED.
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
SHOES, CALL A PHYSICIAN,
IF INHALED, REMOVE TO FRESH AIR, IF BREATHING
CLOTHING AND
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,
.r=
-
-------------------- 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 ------------------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 PROTECTIVE EQUIPMENT.
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 NIOSI-UMSHA-APPROVED RESPIRATOR
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE CLOTHING
—
MECHANICAL EXHAUST REQUIRED
CAUTION
AVOID CONTACT AND INHALATION
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
——_
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Saarlos
I
I
Nootropics: Preclinical Results in the Light of
Clinical Effects; Comparison with Tacrine
Cesare Mondadori
Hoeehst Marion Roussel, CNS Research,
&
P. O. Box 6800, Bridgewater, NJ 08807-0800
ABSTWCT: This review is meant to serve several purpxes. FirsL. it suncys the prec[inical and clinical
profiles of piracetam-like nootropics. Second, the conditions under which the nootropics are active in preclinical
studies are identified and analyzed with a view co finding a common denornina[or that could explain the
obserwed effects. Third, the clinical profile is examined. on the one band to assess u beckr thesedrugswe in
fact active in humans, and on the other to determine hou the clinical cffecrs of the noorropics compiue with
those of tacrine. Lastly, the clinical data are then further scrutinized ro zssess whether the: fulfill the expectauons based on the preclinical findings.
KEY WORDS:Nootropics,piracetam.
oxiracecarn. pram.racetarn. ammcecam. racmm. preclinical. clinical.
responders, nonresponders.
INTRODUCTION
.-=
The discovery of piracetaml 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 discove~, the “nootropic” class of
substances newly created to accommodate piracetarn still splits pharmacologists into two camps.
For some, the absence of toxicity indicates a lack
of any pharmacological action, while others see it
as pointing to a new therqxutic approach. Depending on the observer’s standpoint, either the
nonresponders in clinical trials testify to the inefficacy of these agents, or the responders bem 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 is long since not the sole representative of this class. In the meantime a -qeat many
srrucrurally related active compounds have been
.~:ynthmized.
confiing
rhe need to assign the
Loomopicsto a category of their own. The [errn
noorropic
derives
from the Greek words nooJ.
1(!=$5-4-$03!96/S!(KJ
C 1996 by Begell House, lnc
mind, and .TopoJ. toward. and thus reflects not a
class of chemical structures, but the supposed
effectof these compounds on cognitive processes.
h is consequently inevitable that a certain tendency exists to attach this label to all memoty enhancing substances (for a comprehensive review, see references 3.4).
The present review is devoted entirely to the
piracetam-like preparations and focused on their
direct nootropic effects. i.e., the spectrum of effects on the memory of intact animals, mther than
on their mechanism of action. T’helaner aspect
was the subject of recent reviews.45 Since it is
impossible to assess tie activity of a substance
without recoume to reference compounds, both
the preclinical and the clinical results are discussed on hat basis. Tacrine, the only compound
registered for the trem-sent of Alzheirner”s disease. is taken as the sole reference drug for comparisons of the clinical results.
Il. PRECLINICAL EFFECTS OF
THE NOOTROPICS
..
tion of central nystagmus in [he rabbit.’ firther
tindings made during the past 25 years showed
that its main action consists in the improvement
of cognitive functions. The earliest studies were
concerned with pharmacological modulation of
the amnesiogenic effects of a cerebral electroshcxk. When Giurgea and Mouravieff Lesuisseb
demonstrated that piracetam reduced the disrupting influence of ~ e]ec~osh~k on [he orienm.
tion of rats in a water maze, this effect was taken
as an indication that piracetam improved memory
consolidation. Over the years, this antiarnnestic
action of the piracetam-[ike prepamtions has often been confined. Studies with animcetam.’
oxiracetam,g pramiracetam, and a series of analogues9 all showed a distinct protective 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
and piraceta.m10.II ~d ofiacet~l~ were found to
exert direct effects on the acquisition and retention performance of rats and mice in both passiveand active-avoidance paradigms. Of particular
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 learning situation without being under the influence of the
dmg ~d is likewise uninfluenced during the retention test. Any demonstrable
.-.
effect can then be
of the substance on
memory processes [hat outlast the learning siruation for some time. Several experiments showed
that nootropics can improve the memory under
such conditions.13i4
Tle learning situations in which piracetamlike nootropics were active were noc limited to
experimems involving avoidance behavior. Ramimcetarn had positive effects in a place navigation task;s and was also found to improve the
acquisition rote in a 16-a.rmradial maze.‘bwhereby
the effect related exclusively to reference memory,
no[ working memory. A slight. but sigruficant.
effect of przrniracemm was aiso demon xrable in
a delayed alternation trial!: .Miraceum likewise
displayql positive effec:s in ~ radial mazes md Q
ma[ching-to-smple [es[.“ N[oreoker. it A as found
ascribed
35a
[o a direct action
that piracetam and pramiracecarn improved performance in an object recognition test.:o
.Aniracetam:1and oxiracw.m22 were observed to
have positi~e effects in a social-recognition test
in rats.
In sum. from [he data so far ava-ilableit 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 s[orage of the information occurred under the inlluence of the
drug and retention was assessed after an intend
of at least one day. Effects on short-term retention
have been described (e.g., in a delayed-alternationor delayed matching-co-sample task, and social recognition after short intervals), but these
observations have not yet been confiied.
A. Which Memory Processes Are
Facilitated by Nootropics?
The many experimental situations in which
nootropics have been asserted to exen a memorymhancing 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
nootropics is the same. The available evidence
would suggest that their activiry spectra are not
identical, but at least very similar. inasmuch as all
r.hesepreparations improve passive avoidance:::’
and active avoidance, 12.Xand all of [hem improve
retention performance. even if ~dministered posttiaL13 The results of studies with post-trial ~dministration reveal a high degree of concordance:
i[ has been demonstrated that all four prototype
nootropics-oxirac etam. piracetam. pramiracetam, and aniracetam--can enhance memory
even if administered up to eight hours after the
learning trial. After an internal of 16 hours, an
effect was no longer evident.1’14It can be inferred
that under these conditions all these drug affect
a process that outlasts the learning sima[ion by
more than 3. but less than 16. hours (a hypothesis
rela[ive to the process affected is advanced in
reference 11). The improvement in retention performance in all these experiments was assessed
.H-ter24 or 72 hours, i.e.. at a :ume when the
-nemory content is generally Supposed to ke
4
_&—
---sent in a long-term form. 1[was further shown
.t the retention perr”orrnanceof mice exposed to
a learning situation tier receiving a single dose
of oxiracetam was distinctly bermr than that of
controls even after one. two, or four months.:d
This finding lent additional suppon not only [o
the assumption chat the substances ultimately
improve long-term memory (Llll 1 storage, but
also to the supposition that after imenals of 1 to
120 days memory is based on the same substrate.
Also in accord with the hypothesis that the
nootropics improve LT34 storage are the responses
evoked by pramiracetxn ‘cand 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-temmple tes[:’ and the improvements seen in the social-reco-gnitiontest after
a two-hour intenal.: If these efi-?cts hold good
for all nootropics, they can be taken as art indication that the facilitation of LTM is just one aspect
of a whole range of activity; if not, they could
indicate differences in the activiq spectra of the
.ztious
nootropics. Many indicanons of differ-es have been obsemed. Comparative studies
of prarniracetam and etiracetam. for example.
showed that only etiracetam had effects on memory
retrievaI.:7 Moreover. a long list of experiments
indicate quantitative and qualitative differences
in the biochemical activity spectrum of piracetamIike nootropics’zgw so that there is hardly cause
to expect such drugs [o display an identical spectrum of activity.
Thus, the most obvious common feature of
the nootropics is their capacity to facilitate LTM
storage. This concision is consistent with the
majority of the available preclinical results. Despite the high de-greeof similariq in the observed
effects, some experimental finding do appear to
indicate differences in the ac[i\i? spectra.
B. Effects of Nootropics
of Other Memory
Those
Compared
Enhancers
with
the ACE inhibitorcaptopd. the calcium antagonist
nimodipine. and the gamma-aminoburyric acid B
(GABAB)-receptor antagonist CGP 36742 in a
passive-avoidanceparadigm (Figure 1).h was sub
sequently observed that all these LTM effects were
equally steroid sensitive: i.e.. experimentally elevated aldosterone or co~icosterone levels suppressed the effects of all these memory enhance]!
to the same extent.u31 The pharmacodynam.icsof
oxiracetam. arecoline, CGP 36742. and cap[opril
were similar there was an 8-hour drug-sensitive
window afterthe learning trial ([email protected] 2). Note that
the memory+mhancingeffects inducedby captopril.
CGP 36742. and the muscarinic cholinergic agonist arecohrte foilowed almost exactly the sam
pattern as that of oxiracetarn, in that they were not
immediately detectable, i.e., not in evidence as
soon as the animals showed si=wsof retention. At
leas[a further 16-20hours elapsed beforeit emerged
(13e~ 3). This surprhing concordance in the findings 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 an
exhausti~e description of the activity spectrum,
The totality of the cholinergic effects induced by
physostigmine activates the brain quite differently from blockade of the angiotensin-converting enzyme or the effects of piracetam. It is consequently logical that, despite the common effects,
differences in the activity spectra are to be expected. Such differences have been observed in
experimental studies: only captopril facilitated
memory retrieval after a 2-month retention interval: piracetam did not.3: Piracetam and pmrniracetam improved performance in an object recognition test.~”whereas physostigmine had no such
effect. ~s In contrast to pramiracetam.’b and
aniracetam.18physostigmine had no memot-y-enhancing effec[ in radial-maze tests.” mus:. however, be conceded that these results are not derived from comparative studies.
In summary. all memory-enhancing
compounds dispiay similarities in their activities and
In the intensifies ma dynamics of their eti:ects in
LTV experiments, The ~ffe:[j are steroid s.ensi~l~eand ~~~omedete~:[email protected],iv Ifter 3 !ZIDW Of’
359
J
I
I
..
so
1
40
.-.
X-M*
I
30
20 I
1
NS
C
Nthl
CAP
LO
3.0
SIX
CC?
0.1
c
0.3
THA
ARE
3.0
0.3
P3iY
0.03
d
c
PIR
100
.
PM
AM
Oxt
U30
lca
m
mgf’kg p.o.
FIGURE
1. The effeets of various memory-enhancing
substances on the retention performance of mice in a
passive-avoidance task. Mice were given footshoek for leaving a “safe” small pfatform in the center O( a grid flow.
The spontaneous (%aseline”) Iateneies to step onto the grid were measured. Retention (i.e., the retest Iatencies)
was assessed 24 hours later. The histograms represent the step-down Iatencies in seconds. Solid columns: baseline
Iatencies; blank columns: retest Iatencies of drug-treated animals; hatched eofumns: retest Iatencies of the vehicJeCAP: captopril;STR: strychnine; CGP: CGP 36742 (GABA8 antagonist); THA:
treated controls. NIM: nimodpine;
tacrine; ARE: areedine; PHY: physostigmine; PIR: piracetam; PRA: pramiracetam; ANl: aniracetam; OXI: oxiracetam.
Ph ysostigrninewas given orally 30 minutes, all other substances, two hours, before the learning trial. C)ptimal doses
for memory improvement were determined in independent pilot experiments. Prolongatiotl O([l~f, I ot~s[ !..tencws (,:)
wmparison with the no-shock controls [NS] and baseline Iatencies) indicates learning. Prolongation of the retest
Iarencies in comparison with the retest Iateneies of the vehicle-treated controls ind.kates drug-induced memory
improvement.N = 25 mice/group. “2p< 0.05, ●*2p< 0.01, ●.”2P<0.001 (Mann-Whitney U-test)
several hours. There are, nevertheless, experimental findings indicating differences in activity spectm both within and between the various groups of
memory enhancers. above all in tests not related
[o LTM.
Ill. THE CLINICAL EFFECTS OF
THE NOOTROPICS
Any attempt [0 pinpoint common features in
the available clinical data on these compounds
quickly runs into cemin problems. One major
difficulty is due to the heterogeneity of the patient
populations. Studies have been carried out in prob
able cases of Alzheimer’s disease, w;s in a mixed
~pulation of Wzheimer and multiinfarct dementia
pa[ients’k :n multiinfarct patiems.’~ in pa[ients
witi psychoorganic syndrome, m aged volunteers. 19 in students. so in epileptic patients.:’ in
d>slexic ~choolclhildren.:~ in patients suffering
-.=
from effects of exposure to organic solvents,~~”
360
in victims of head trauma.J5ss in patients with
Korsakoffs syndromes’ and even in patients with
atlificiai pacemaicers.~8The numbers of patients
in each study ranged from 4%to 289.41Durations
of treatment also varied greatly: for example, 9
days,s84 weeks, ‘3’s3 months.;wl”*’73’
and up to
1year.” The study design was variously open,:g~
single-blind,~Jbl double-blind,~jga parallel with
placebo controls]b.3g414Zor active controls,szd~
Crossover,J7~4 or enriched::s even comparisons
with historical controis were used.ti
No less heterogeneous was the clinical and
psychometric instrumentium ernpioyed to assess the effects. Besides neuropsychoiogicai tests
and scales. psychophysiological tests were also
used. The quality of reporting differed -neatly. In
some studies. the test used is not simply mentioned but described exacdy (e.g., reference 40).
whereas in others the soie indication of the nature
of the effect obsewed and tie methodology appiied was the single word vremov.h3[n evaluating
the effects, the psychomemc tests were some-
times supplemented by staff-rated scalesi~; somemes only staff-rated scales were used,bs or even
,~st the clinician’s global impression was given.fi
The study design was entirely adapted to demonstrating the existence of an effect of the preparation in patients.
Supisingly, at fus[ glance, sctutiny of the
results of the published clinical srudies reveals
that the majority (more than 60%) of the reports
are positive; i.e., the authors conclude from their
findings that the treatment was effective. Villardita
et aL,]9for instance, showed that after dtree months
the 30 patients treated with oxiracetam in a doubiebiind, 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 patients.
on the other hand, showed no impro~ements, and
even performed si=nificandy worse in [WOof the
tests. The positive effects were particularly clearcut in the Mini Mental State Examination
(MMSE), the Auditory Continuous Performance
Test (ACPT), Rey’s 15 Words Test. the Block
_n
FIGURE 3. The emergence of the memory facilitation
effect induced by the nootropic oxiracetam (100 mcj
kg), the ACE-inhibitor captopril (3 mg/kg), the muscarinic agonist areecdine (0.3 mgkg), and the GABABreceptor blocker CGP 36742 (1O mg/kg). The animals
were trained m a passive-avoidance
situation and
treated immediately thereafter. Retention performance
was measured at various intetvals (1, 2, 8, 16, or 24
hours) after training and treatment. The columns indicate the drug-induced
prolongation
of the retest laten-
aes (in percent of the vehicle-treated controls). “2p-d.05,
●**2P.cO.001. Prolonged Iatencies indicate
-2pco.ol,
better memory. Ail treatments were given intraperitoneally immediately after the Ieaming trial (hum Mondadori
et al., %c. Nati. Acad. Sci., 91, 2041, 1994).
1
Tapping Test (BTT’), the Mattis Word Fluency
Test, Luria’s Alternating Series, and the Instrumental Activities of Daily Living Test (IADL-E).
Senin et al.38 performed a study with aniracetam, using a test battery different from that
applied by Villardita. At the end of the 6-month
Ih
<l&
FIGURE
2.
The
2h
4h
effects
8h
16n
of various
compounds
on
memory if administered at various intewals after the
learning experience, The animals were ex~sed to the
~ssive-avoidance situation, and after the indicated mintervals(<10 seconds, 1, 2, 4.8, 16 hours) treatedwth
optimal doses of the memory enhancem. Retest was
indicate
me
performed after 72 hours. The columns
-~rolongatlon of the retest Iatcmcies (h” wsrcent of
hlcle-treated
dicate
matched
better memo~
OXI: oxiracetam.
controls),
Prolongeo
AF?E. arecaline:
‘2c4..O5.
.“2P4.01
:he
Iatenc:es
CAP: caDIoDn:
“-2 D4.001
treatment period the authors found significant
improvements of performance in all 18 parameters assessed. As in Villardita’s study, positive
effects were recorded in Rey ’s 15 Word Test.
yore tha[ besides effects on cognitive parameters. these authors also observed distinct effects
on behavioral parameters. The 6-month study
with aniracetam performed by Pa.rnetti et al.6T
according to a similar design yielded practically
identical results: in 17 of 18 tests, aniracetam
improved the patients’ performance, In this comparanve study the activity spectrum of animcetam
In some tests was distinctly differen[ from that
of piracemm. Unlike aniracetam. for instance.
;mce:am displayed no effects in Rey”s 15 Words
TesI. m ~he Toulouse Pieron Test. and In [he
361
Raven Test. According to the Sandoz Clinical
Assessment Geriatric (SCAG) Scale, however.
the effects were nearly iden[ical. Bottini et al.w
observed distinct effects of oxiracetam in five of
eight comitive
tests. In particular. there were
.
signitlcant positive effects on verbid tluency-.
similar to [hose described by Villardita et al..
and the retention of a short story (after a delay of
10 minutes) was also improved. In ~he 12-mon[h
study with piracetam conducted by Croisile et
ai..~~indications of a retardant effect of :he drug
on the progress of mental decline were noted: in
the placebo group a significant deterioration 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 contrast to the
findings of Senin et al. and Parnetti et al., direct
comparisons of the performance of placebotreated and piracetam-treated patients yielded
scarcely any statistically significant results. The
study carried out by hfaina et al.’[ in the largest
population samples of all (~ = 144 + 145), positive (good to very good) effects of oxiracetam
were recorded in 90 of 145 patients (global evacuation), whereas, according to the j~e criteria.
only 27 of 144 placebo-treated patients were
rated as showing good or very good responses.
Only 51 of 144 patients taking oxiracetarn as
against !07 of 1-Wreceiving placebo were rated
as showing no effect or a poor effect. Note that
the patients in this study, in contmst to those in
the study by Villardita et al.. showed positive
effects in the IPSC-E (Inventory oi Psychic and
Somatic Complaints, Elderly). Stxisticdly significant increases in the IPSC-E scores were also
recorded in the 6-month study performed by
M~goni et ~.,315while no ch~ges were seen in
the placebo-treated controls.
Itil et al.%also reported significant effects of
oxiracetarn in the IPSC-E, not in .lIzheimer patients, but in diagnostically less precisely defined
cases of organic brain syndrome (OBSJ. These
effects were more pronounced than the corresponding effec[s of piracetam. Such changes in
the IPSC-E suggest that oxiracetmn exerts effects
that can be manifest as an mprovement in the
quality of life of
by .%letu et al.’s
population were
improve thent in
362
the patients. The results obtained
in their Stud? of a similar patient
far less distinct: JDan from WI
verbal memory. or~y the overall
score in the SCAG was significantly better (the
IPSC-E was not used). The dura[ion of treatment
in this study was only four weeks. .More modest
still were the clinical effects noted in the study
of piracetam performed by Abbuzahab et aI.48in
OBS patients (geriatric memory): apart from a
slight overall improvement. no relevant effects
were observed. Much more pronounced positive
effec[s emerged from the investigation by Moglia
et al.’z In this parallel-design study in 21 + 22
OB5 patients, these authors showed that oxiracemrn induced an overall improvement in cognitive and behavioral parameters. Particularly notable were the significant improvements seen in
the Ben[on 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 treated with oxiracetam had improved
is consistent with the many global clinical assessments, as exemplified by a 3-month placebo-controlled study in 60 patients with two
doses of piracetam carried OUIby (_?muinard et
aL~7 In this study, the results of the monthly
evaluations by the nursing 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. Another
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.
FJocmopics were also [ested for efficacy in
completely different clinical indications. McLean
et al..~ for example, examined prarniracetam in
four patients with headinjuriesorartoxia and showed
that the drug exerted clear-cut effects on immediate
and delayed recall. In patients with pacemakers. in
whom the fried heart rate often leads to diminished
cerebral circulation and consequent disturbances of
performance during exertion, piracetam was found
to induce a Jight improvement in psychomotor
tests% no cognitive tests were performed, however. In a smd~ in epilep[ic patients with memory
disordem. Aldenkamp e: al.sl observed no effects
after 12 weeks. but all parameters measured revealed a trend favoring oxiracetarn.
In some investigations, comparative evrduations were made of the effects of nootropics. In
—1
the above-mentioned study by hi] et al.,% oxira$=eta.m was found to have a slightly better effect on
cognitive parameters than piracetarn, whereas
piracetam displayed a slightly better antipsychotic
effect than oxiracetam. Although the greater efficacy of oxiracetam in regard to cognitive aspects
was confkrned in the studies by Gallai et al.b[and
Ferrero.AFthese studies were not carried out under
double-blind conditions and are consequently no[
admissible as 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 emerging as the more effective treatment. A.niracetam was also shown to be slightly
more active than piracetarn in the study by Parnetti
et aLdLrtcontrast to the many positive results reported. a 3-month study in Alzheimer patients
performed by Green et al,~ and using a broad
battery of neuropsychological tests revealed no
signs of efficacy of oxiracetam, either on the basis
_=
-- ~f group analyses or in individual patients. Simimrly, a 3-month trial by Hjorther et al.sj with a
very extensive test battexy gave no indication of
any effects of oxiracetam: neither behavioral nor
memory 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.
Som.nier 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 trials have also revealed
no positive effects. Lloyd-Evans et al.” were
unable [o detect any effects of piracetam in a 6month double-blind trial in OBS patients. The 2 x
4-wesk crossover study with oxiracetam performed by Molloy et al.37in Alzheimer patients
likewise showed no effects. In none of these crossover rids was the fwst drugplacebo phase evaluated separately as a parallel study. Negative results further emerged from an enriched-design
study by Claus et al..~s who concluded from their
~~results
tJIat pramiracetam A ineffective m a symp[omauc trea[ment for Alzheimer patients. This
rating was based on tie scores achieved b> 10
patients in the Alzheimer’s Disease Assessment
Scale (ADAS). In patients witi alcoholic organic
mental disorders also, a study conducted by
Fleischhacker et al.s~demonstmed no relevam
improvement after treatment with piracetam.
Given the existence of srudies with posi[ive
and others with negative results or overall raring, one question that arises is what ‘positive’
or “negative’ means to the individual pa[ients.
As regards the positive studies. that question has
already been answered, insofar as it was often
mentioned that oniy a limited number of patients
responded to the [reatment (e.g., reference 4 l),
Unfortunately. in the clinical studies with nootropics, only scant information is given about the
frequency of significant therapeutic effects and
the quality of such effects in individual patients.
The fact tha[. despite many nortresponders. positive overall ratings were still reported would at
least seem to j ustify 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..~fthe conclusion
that piracetam was ineffective was based on the
lack of significant effects in the ADAS in 10
patients. In fact, however, there was a[ least one
responder with a reduction of more than four
points in the ADAS and signifkan~ drug-related
improvements in both the Visual Selective Reminding Task (total and delay) and Logical
Memory Immediate Recall. These effects were
inevitably submerged in the calculations of the
means values and statistical analysis. In the study
by Baumel et al.’? also, where the drug effects
were rated as very modest, 4 of the 12 patients
showed responses. In that the case reports were
described as ~pical. this was a substantial effect
from the viewpoint of the quality of life. This
outcome is closely similar 10 the results of the
open study in six patients b} Dager et al.,s9 in
which there was one definite responder. Irrespective of the exlent to which the ci[ed data were
atu-ibutable to drug effects. L+<> demonwrate the
need for analyses of this namre.
it can be concluded that Lfie plracetarn-[ike
noo[ropics can ?voke si~~~fican[ effe:[j [n
Ixcotnms
manliest on the
.A!zheimer p~[ie~[j.
363
I
one hand in cognitive improvements and on the
other in behavioral aspects. The effect appears to
become more marked during prolonged treatment.
The variousnootropics differ in their activity 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 cholinomimetics. 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 these patients.w In this respect, the
patient population studied is homogeneous and,
unlike the very mixed populations treated with
nootropics, 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 tetrahydroaminoacridine
(THA,
tacrine, Cognex”), a cholinesterase inhibitor and
the only substance so far registered for the treatment of Alzheirner’s disease.
The fwst srudy by Summers et ai.’Owas conducted in three phases. tn the first phase, the
tolerability and efficacy of incremental doses of
THA were assessed in 23 patients. THA was
always administered in combination with lecithin. In a second double-blind, crossover phase,
15 of these patients were treated with the best or
highest dose of THA, or with placebo, for three
weeks. after which the treatments were switched.
Only the 12 patien~ showing a clear-cut response
to THA in the second phase went on to receive
long-term treatment over pxiods ranging from 3
to 26 months (enriched design). The final assessment revealed distinct positive results ~global
_-=
assessment, orientation. Alzheirner deficit scale,
names learning test), wherebyonly patients classed
as Stages 3-4, bu[ not Stages 5-6, on the Reisberg
scale responded.
.n=
364
---
Most of the subsequent studies initially failed
to confii Summers’ results. A crossover study
conducted by Davies cc al., ” for exampie, in
which 10 patients were treated for up to four
months. showed hardly any notable effects of
the combiiled treatment with THA and lecithin.
Only in 1 of 10 tests were positive results recorded. The same results were obtained by Chatellier et aL;2 In this crossover study with 67
patients. tacrine (combined with lecithin) was
administered orally for four weeks. Apart from a
slight improvement in the Physician’s Score, TH.A
was ineffective. Neither in behavioral scales
(Stockton) nor in cognitive scales (MMSE) were
any effects demonstrable. Similariy, in a crossover triaJ done by Gaudier et al.” over two 8week treatment periods. the response to THA was
limited to an improvement in the MMSE. Despite
this improvement, the autiors rated the effect of
THA as clinically irrelevant. No effect whatever
was observed by .Molloy et aL74in a multiple
crossover study with treatment periods of three
weeks. Neither’ the overall evaluation 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.is The
215 patients who had responded to tacrine in a
preliminary crossover phase were subsequently
treated for six weeks in a parallel study. By comparison with the placebo controls, the tacrine group
showed a slight. but si-d]cant. decrease in mental decline (ADA.S cognitive subscaie). Two of
the three quality-of-fife assessment scales used
indica[ecichanges in fa~or of tacrine: Progressive
Deterioration Scale LPDS) and Activities of Daily
Living (ADL). The changes in the M.MSE were
slight and statistically not significant, and the
clinicians global assessment (CGIC) likewise
failed to detect any effects. In a similar, but more
prolonged ( 12-week) parallel study by Farlow et
al.,’s vem much the same results were obtained:
the .AJ)AS cognitive subscale indicated some retardation of cognitive decline. but the MMSE
jho~d
no changes. In contrast to the study by
Davis. however. the physicians’ and caregivers’
global raring were sigtilcantly
better. In a crossover jmd~ bv Eagger :: al..y in which 468 patients were rested for considerably longer ( 15
weekj) LbarIL!cjse in Yfoiloy ’s jmd~.-~ the \fMSE
——
.—
and the A..lTS (.Abbreviated Mental Test Score),
.-–Au. not the .~L. revealed an effect of tacrine.
ie effects in the .MMSEwere consistent with the
findings of Gauthier e[ al..-s but not with those of
Farlow e[ ai.-b and Davis et al.;s; the absence of
effects in the .MIL were a[ variance with the
results obse~~d by Davis et al.75
Recent studies disclosd the entire range of
possible effe.-s. Distinctly positive effects emerged
from a 30-week parallel study by Knapp e[ al’s In
this study witi an initial population of663 patients,
w three prhag” outcome measures (ADAS coetitive subsca.k. Clinicians’ Interview-Based I.rnpression. and Find Comprehensive Consensus lrttpression) showtd significant effects of tacnne. In
addition. positive effects. among others, were demonstrated b}- the Progressive Deterioration Scale
and the hf31SE. but no[ the A.DL. The effects
indicated b> the MMSE were in agreemen[ with
those noted by Gauthier et al..73Eagger et ai.,n and
Davis et al..-: but contrary to those seen by Farlow
et al.’band Niolloy et aI.74Although consistent with
the findings of
Eagger
et al..” the absence of ef-
fects in the .M3L conflicted with those of Davis e[
.d.js
Exacd\. tie opposite, i.e.. no indications of any
.=ect whatever, emerged from the study by Maltby
et al.79with an initial population of 57 patients and
a 3&week duration of treatment. Neither the Camgivers’ rating-based scales nor the cowtitive scales
showed signs of changes. Halfway between positive and negaive results lie the findings reported
by Wilcock et al.w In a 2 x 3-month crossover
srudy in 41 patients these authors noted positive
trends in favor of tacrine, but statistically the dif-
ferences were scarcely significant. Lna study with
154 patiems. Wood et al.g] likewise merely ob
served psitive trends, but there was no significant
effect of tatie in the overall group analysis. The
results nevenheless indicate that there were individual responders. The same applies to a 3 x 6week crossover Stt.tdy of .Qzheirner patients conducted by Gustafson8z in which there was no
detectable o~m.11effect. but individual responders
were noted. It is. obove all. tie enrichment studies
that confirm the existence of a subset of responders. althou~! men after the enrichment not all
patients respmd to the meatment. In tie light of
_*+iese fintiti-~~ ~d in \riev Af the need [O optimize
2tiemp). :1:s mrpnsing .Aat scarcely an>’~ffOrts
have been =fice to estabhsh 2 pha.rmacolosya!.
biochemical, and endocrinologica.1 profile that
would serve to identifj likely responders.
To sum up, aJthougtt there are clear indications that cholinesterase inhibitors do exert clinical effects, it is equalIy clear that only a certain
number of patients respond to the treatment. The
use of enriched-design studies ofien makes the
proportion of responders appear larger than it
really is. As with nootropics, longer durations 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, A.DL) were used, the effects observed
were of roughly the same ma=tit-ude as those
produced by the nootropics. .Ahhough the methodology was much more nearly
uniform than in
the nootropics studies, there was no test that
yielded consistentl~ positive results in all trials.
V. PRECLINICAL EFFECTS OF THE
NOOTROPICS IN THE LIGHT OF
CLINICAL FINDINGS
Before considering the extent to which the
clinical data meet the expectations based on
preclinical findings. I must stress once again that
the cIinical investigations were exclusively aimed
at showing whether or not the preparations exerted any therapeu~ic effects. For that reason a
wide battery of tests was used, comprising bah
behavioral
somewhat
make use
explaining
aspects and cognitive performance. The
unfortunate efforts of many authors to
of data from animal experiments in
the rationale of their smdies and dis-
cussing the clinical results should not be allowed
to obscure the fact that neither were the studies
designed to validate the preclinical results, nor
were the clinical results in any way adjusted to
serve that purpose,
In the vast majority of the prechnical studies.
a design was used in which the experimental animals were exposed to the learning situation while
under the influence of the drugs and then tested
for retention 24 hours later. eitier s[ill. or no
longer. under the inlluenc~ of the drug; In the
cl]n]cal studies. hcwe~er, reten[]on pe~-ormance
was tes[ed after snort-term inte~.als. i.e.. either
365
..- . .
. .. . .
A
.-,
-
—
.&’-’==
immediately after acquisition or after a lapse of
10 minutes. The sevtmd hours’ delay preceding
the emergence of detectable memory-facilitating
effects that has beeri observed in the most recen[
animal experiment’~ ‘J strongly emphasizes the
crucial importance of allowing long enough retention intervals, provided only, of course, that
the clinical effect and the memory facilitation
observed in animals come about by way of the
mechanism, ~llat the long-term memory
same
[escs used in the clinical studies detected was not
the influence of the substances on long-term storage. but their influence on retrieval from LTM.
i.e.. on the recall of information acquired while
noc under the influence of the drugs. Often, learning capacity was [ested before and at the end of
the ueatment period: i.e., performance without
the influence of the drugs was then compared
with performance while under the acute influence
of the drugs. There is thus stilI no sound scientific
evidence of the predictive validity of the animal
procedures. This aspect should be examined in
specifically designed clinical investigations.
The various repofis nevertheless do contain
at least a few allusive remarks consistent with
the expectations b=ed on animal experiments.
[n the study with osiracetam by Dager et al.,sq
for example, there is a sentence reading: “although long tern recall improved only negligibly, his long term memory storage (learning
capacity) and reco-tition memory were moderately enhanced. ” Similarly McLean et al.%state
tha[: ““Themost drmatic demonstration of impro~ement with pruniracetarn . .. occurred in the
selec[ive reminding test-delayed recall. long term
memory retrieval and long term storage.” Last.
but not least. there are a number of reports concerning the effects of piracetam in dyslexic children that possibly pint to effects on LTM storage. In a double-bbnd. placebo-controlled study
by \Vilsher et al.$: che children showed greater
faciIity in reading and comprehension after a 36week phase of treatment with piracetarn. It is very
probable that the improved performance at the
end of the treatment period reflects. not an acute
effect on memory rerkwal. but rather art improved
avaiIabiliry of the !=owledge acquired throughout “Je duration of ~eatment. i.e.. long-[enn re-
superior to the nootropics, or vice versa. The
effects of these drugs seem to be similar. although
the complication that the double-biind nature in
connection with cholinomimetics is very probably wishful thinking (dicrirninativestimulus prop
erties,w side effects. e.g.. reference 74) has been
tention of inforrna[ion acquired under the iniluence of piracetam. T;JS view is strongly supported
completely left out of consideration. In the abjence oi comparative srudies. the ucit assump-
366
by the fac[ that the combination of psychological
training and nootropic therapy proved particularly effective, not only in dyslexic children. but
also in other forms of cogui[ive underperforrnance.~3Moreover, it appears very likely that
the effects observed after long-term treatment 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. Itis
conceivable that the effect comes about via a
modification of general processes that play an
important role in the performance of brain cells.
The improvement in long-term storage would then
be only one of the measurable consequences. The
reason for the usually modest extent of tie clinical effects could be that the action of the substances is confkd
to cells that are still functionally competent. But since the individual patient’s
speciilc pattern of functional deficits reflects the
impairment of the neuronal circuits esst?nti?l 10
this function, it may be that the aspect mos[ impaired through degeneration also affords the least
room for improvement. This applies equally to
cognitive and noncognitive performances. It is
therefore perfectly conceivable that while measurable effects in one aspect or another may be
detectable in a wide-ran-tig psychomernc investigation. these aspects may be of little therapeutic
relevance to the symptoms that are particularly
disabling for the patient.
V!. SYNTHESIS AND OUTLOOK
Given the obsemed overall positive effects of
the nootropics and their occasionally quite distinct effec[s in individual patients, this category
of compounds would appear useful. The results
available so far give no indication that tacnne is
tion that the cholinomimetics are more effective
~~ost likely reflects the supefilcial plausibility of
~eunderlying hypothesis rather than the existing
clinical results. Together, 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 steroid dependence of the memoty-facilitating effec[ of the nootropics~3J]opens up a practical possibility in view of the fact that a ve~ large
percentage of Alzheimer pa[ients have eleva[ed
plasma cortisol concentrations.as This approach
would, of course, be valid only if the memoryenhancing effects seen in preclinical srudies and
the effect obsemed in patients come about by way
of the same mechanism. This brings us back to
the question of the validity of the preclinical
models, which urgently need cht-ifying by ciinica.1trials specifically designed for that purpose.
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A7”
k dcohoiic
Lieder. F. and Miller. C., Piracea
a piacebo-controlled smdy
organic mental cikrdm
comparing two dosages. lnt Clin. Psychophamuscol.,
1.210.1986.
58. Lagergren, K. and Levander, S.. A doubie-blind
study on the effects of puacetam upon perceptual and
psychomotor performance at varied heart rates in patients mated wirh artificial
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59. Dager.
39.97.
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Prychophar-
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J. P., Claypool. K., CM.,
D. L., tlximceram in tie
ueannen[ of primary dementia of the Alzheimer’s
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905.1$92.
E. c-.
a. Bmnccmnier, R J. Coi% J. 0. ~
Spen K. F. G~ML
S., and De Vim D., The
Therapeutic efficaq of pmrnhxc tam in Alzheimer’s
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61. GaUai. V., }fazzorta. G.. Del Gatto. F.. T$lontesi,
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A., .+ clinlcdand neurophysiolcg]cal
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.Yeuro[,, 13. 1. [991.
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6:.
.~..
S. ~
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Falsqwla.
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knencu.
CIIn. Ther.. 12.3-6. 1990
Ferrero. E.. CcmrmUeti :Iirucal o-Iai Jf oxmcetwn m
~ne ~emnen[ of :--mmc :mebrovas~~jw lnsuf5c]enc}
:n W tlcieri>. C’Jr- Tne” Ref.. XI. 198. !9W
64. Parnetti. L., Mecocci. P., Petrksi, A., Longo, A..
Buccofieri, A., and Senin, U.. ?Jeuropsychoiogiczl
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22, 97. 1989.
65. Foltyn. P.. Lucker, P. W., Schnitker, J., and
Wetzelsberger, N., A test model for cerebrally acti$ e
drugs a-s demonstrated by the csample of the new
substance artiracetarn..4 r~eim -Forsch/DrugRes..?~.
865, 19S3.
C., Molaschi, F., Fabris, F., and
66. Macchione,
Feruglio, F. S- Results with pimcetam in the management of senile psycho-orgtic syndromes, ACM
Ther., 2.261, 1976.
67. Parnetti. L., Bartorelli, L., Bonaiuto, S., CucizIoM
D., Cuzzupoii, M., ErmiNo. F., ,Maggioni, \L.
Marini, G., Paciaroni, E., Pedrazzi, F., Peruzza,
M., and Senin, U., Aniracetam (Ro 13-5057) for the
treatment of seniie dementia of .41zheimer type: re2.
sults of a mukicentre ciinical study, Demenna.
262.
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68. Greem R C., Goldstein, F. C. .Auchu$ A. P..
Presley, R, CM% .% Van ToYI,L* Green. J..
Hersch. S. Mw and Karp, H. F& Treatment trial o{
oxiramam in Alzheirner”s disase, Arch. Neurol.. 49,
I 135, 1%2.
69. Davie& P. and Maloney, A. J. F., Selective loss of
central cholinergic neurons in alzheimcr’s disease.
Lancer, 2. 1433, 1976.
70. Summew
W. IL, !klajowsici. V., Marsh, G. M.,
Tachiki. K., and Kling, A., Oral tetraftydroamisloacridine in long term treatment of senile demertti~
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TuckweU, V. and DavL%.% Tacrinein Aizheimer”s
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73. Gauthier, S- Bouchard, Q Lamontagnv+ A? Btiey,
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Cbn41e1tLM- Collier, B., Dastoor, D.. Gautider. L.
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C.
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-M., Kushnir.
~fik
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S.,
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R., Rees. L., and Singer, J., Effect of tetrahydroammoacndine on cogrution. function and behallour
In Alzhe]mer’s disease. Cam .Med. .4s50c. J.. IS.
29, 1991.
-5. Davis. K. L.. Thai. L. J.. Gamzu. E. R, Davis. C. S.,
WMison.
R. F.. Gracon.
.S, L. Drachman.
D. .$..
Schneider, L. S.. Wlitehouse- P. J.. Hoower. T. 31..
>Iorris.
J.C..Kawas. c.H..Knopman. D.S- W.
369
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N. L., Kumar, V- Doody, R. S. Tacrine Collaborative Study Croup, A double-blind. placebo-controlled
multicemer study of tacrine for .Mzheirner’s disease.
,$( Engl, J. Med.. 327, 1253, 1992.
76. Farlow, X!., Graco~ S. I., Hershey, L. A., Lewis, K.
Ww Sadowsky, C. H., and Dolan-Ureno, J.. A conmolled trial of tacrine in Alzheimer’s disease, JAM.4.
268, 2523, 1992.
77. Eagger, S., Momnk Nw Levy, R.. Sahakian, B..
Tacrine in Alzheimer’s Disease. Time course of
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160.36, 1992.
7S. Knapp, M., Knopsnan, D. S., Solomon. P. R..
Pendlebtuy, W. W- Dam C. S., and Gracon. S. I.,
A 30-week randomized controlled trial of highdose
taerine in patients with Aizheimer’s disease, JAMA,
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79. .Mahby, N., Broe, G. .%, Creasey, H., Jorm, A. F.,
Christensen, H., and Brooks, W. S., Efficacy of
tacrine and lecithin
in mild to moderate
Alzhei-
mer’s disease: double blind trial. Br. Med. J., 308.
879. [994.
80. WdcoclL G. K., Surmo~ D. J., Scow Ma Boyle,
‘M. .Mtdligan, & Neubauer, K A., O’Neill, D., and
.n.
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Roystost, V. H., An evaluation of the efficacy and
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Ageing, 22, 316, 1993.
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Alzheimer(s dkease, lru. J. Griatr. P~chtirn,
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82. Gustafson,
L., Physosrigmine
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Neurol. Scard, 149 (Suppl.), 39, 1993.
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Lye Sci., 55, 2057, 1994.
84. Loekq K W. Gomey, B., Comfeldt, M.. and Fielding, S., Characterization of the discriminate ve stimulus effects of physostigmine in the rat, J. Phannacol.
Exp. Zker., 250, 241, 1989.
85. Martignoni, E., Petragli~ F., Costa, A., Bono, G.,
Genazzini, A. ~ and Nappi, G., I%menria of the
Afzheimer type and hypothalamus piulitasy-adrenocordcal axis: changes in cerebrospinal fluid- corticotropin releasing factor, and plasma cortisof ie~els.
Acts Neuro[. .hmi., 81, 452, 1990.
-’~
NCmcx
‘ALL’.4TIO.%
OF THE
10CESSl%G.
Plra~e[am.
Placeh<,
ble~no
●11 .Uhlec[s
neur..ii~gwai
f:
below
cc)
and memo~
(ruments.
>ro\ements
bO:S
Compared
aboie
Iirm~::.IpI!Ilh,wghl
@
~e~
!-
g.~ti
ph}sical
10 enhance speclflc cognlltve sLJIIs. was grven In a 3.WO mg datl> dose m half of
hed[h.
lhelr baseline
Oral
Reading
group.
Individuals
lrealed
on measures of percepuon.
utth
Plrace[arn
as compared
[o plxeho
were also wgnlfican[l>
I-miera(ed
and medlcai examination:
imrmlne
more
precid>
:mpro~ed
jh~~~d
(he mech.imsm
Effecwe
reading
In the P[racetam
wl:h
memo~.
ung accuracyH.>umer.read,ng
j~ d and numlwr~ of words wntlen
](ed
Tew
Non-verbal
and reading. spelling. language and wiing
conwol
sc.xes
Islderauon.
placttso-controlled
n.lrmal educatmnal
,tud>
TIM
,.pporiunl
ncx [dung other p.>chowop~c medlcwon.
age cc~~t Jlenf on [he Gdmore
piactL~-
lXFOR\l,ATIOX
IS D}”SLEXIC CHILDREN
11
,kills were ewmined.
10 tht
IN’ TRE.4TING
\cars, In a 12.week. douhlc.blind
(h< ‘.,ilc.wing cn[cria normtil In[elllgenc~
hmdlcaps.
the]r mental
OF PIRACET,A31
WRITING DISORDERS
.AYD
a ntu c!aj> of drug
r~up of fi([y.(l.C d}~l.eI}c
~i$ej
EFFIC,AC}”
RE.4DING
O[her half Of [he subjects
lies. no $?~’tfe ernOt}Onal
and scoring
~audimfi
abtlitms were measured using smndardized
Plracelam
did mm show staustlcall}
and
sigmfkumt
language. readusg accuracy or comprehension.
m a Ilmcd period were $Ignlflcxstly
unung
as compared
onc mrd one
at Iem
and visual) and verbal
ahihty.
taking
or
enhanced m $ubJects
both ra[e
and accurac}
10 (he placebo trea(ment group. The medlca(ton
Inlo
was
no slgruflcan[ adterse reacl!ons. These results encourage fur[her s[ud} of Plracctam
oi ac~mn b: Whsch spemfic cogmwe
TRODL’CTIOY
and
Aman.
havior
Recen[ re~ieus of chemotherapeutic
Lreatmenl
lmrning dlsab]lities have emphasized [hat the
rceptual
and behavioral
changes induced by
U:S do
no[
necessaril~ lead LOImpro$”ed academic
rfm-mance (.~m~n, “1980: ~~ mr}. 1%1 ). This
ncluslon has E-retn based prima rll> cm research
th cen[ral nemaus system stlmulan[s such as
:th\lphenldate
~FUtdin) and cfexlroamphe[amirw
Ie\ednne).
Such stimulants hate been shown to
prove
attention
span \ Barkie>. 1977: BarkJe>
d J~chson. l+--,. mem,>r} (S:rague. 19-2: U err!
Jalls
areaffecled
1975). and impulsivity
(Barkley
and U’ern,
and [email protected]
1979). However.
studies
and
social
be-
1980: Conners
of educational
abthues us]ng standardized reading. spelling and
arithmetic
[ests have failed to demonstrate
ani
significant
differences
in the performance
of
[rested children (Quinn and Rapoport. 1975. Weiss
et ~1.. 1975 I or non-hyperactive
cluldren (Gittle m~n-Kleln and Klein. 1976: .Aman and Werry.
1QS2),
Th]s discrepancy> between the drug-induced impro~ ements in behavioral control and [he absence
ma~ be due in
of ch~nge in school-performance
pdri
10 [he
u“~>
e~~h child :S ~sslgr)d
;he proper
Jnci
lnic::!g[or>
dos3se. In the pm;, clini~;dn>
;hJ\e
J>>U~Cj
!h,l[
[he .lC[lITlll d.~~.lg?
[L>
iMpr\~t~
. .
.&-%
.=-.
cdl!td r.~w[roplls. Piracetam.
a noo[ropic
subof
s[J,-.L-e. +M been ~iudi~d for its fxilita[ion
trial of” 1S00 mg daily Jose of Pirwxt~m.
The
dyslexic subjec[s met the cri[eria out!ined
by
Thomstm 11977). Since jubj~~t~ in [his jtud} ciemonstrated
significant car~wer
effects due [o [he
crossover design. Wilsher <t al. only e.wmtned
results from the first period of treatment
[o ~vmd
the confounding effects from previous e.sposure [O
Pirwetam.
[n comparison
to placebo tre~tmen[.
resui[s jh~wed that in the dyslexic group ~ho
receited Plr~cetam ~erbal le~rning impro~ed b~
almost tuice that o( the non-dyslexic concrol group
receiving Pirace[am ( 157 compmwi to S.6~ ). The
test used was a serial memory verbai Ieurnlng t~jk
with 10 [hree-let[er nonsense syllables. [n ~ddi[icm.
the number of instances tha[ z Subject le~rned the
nonsense j} liable and then forgot it on [he very
ne.x[ tri~l dropped by dmcst half among the dyslexic group treated with Pirwx[am ( – 4-.1?).
but
was no[ changed in the dyslexic placebo treatment
group.
Simiwn e: ~1. ( 19S0) were the first [o [es[ [he
etTicwy ~~iPlrmxt~m on Ietirning skills oi children.
They [r<aI<d 29 .le~rning disordered. boys be-
[wetn [he Jges of 8 and 14 with J WOO mg dJil\
crosswer
d~se of Plr~cetam in J double-biind.
plwebo-controlled
4-week jtud~. All children were
at Ieaj[ one year behind their age group In either
reading. spelling or arithmetic on the V“ide Range
J Full
Acnie\emen[
Tes[ (WR~T)
and all hd
ScJIe U ISC-R IQ of at le~>[ S5. Thetr findings on
measures of global behavior .ind learning
were
nc>n-signlfican[. a]though
[he ~uthor pc>ln[s OU[
that the ~horl duration
oi (re~tment.
carr]over
eif<c[j due [o [he cross~~er de>ign. ~nd the jm~ll
number ~1’pJLI<nts In ~an~’us [re~[ment ~ubgrc~up’
nl~de ;I.i[:>[Ic~l Jntiiyse> dlfficul[ to In[erpre[.
e[ J1. I 19S5). W
[n ~ second jtud~ b} Ikilsher
.->
Perf,wnance Scale IQ or a Verbal Scale IQ of 90
or m~~rt. ~~bt~ined ulthirl 9 mon[hs of the ini[iid
{ISI[. ( ~ I
or
The\
I-d
a
Reading Quo[ien~ of less than
equli ICI().s~. {-$)English
langu~gc. (5 j Informed
both
me~ns of [he two trwtmen[
groups 1( the &~;nning
and the end of [he ~ ueek> jhc~~d
no
significm~
Differences
cm
m~
of
the
depencltn[
Howel’er. further analysls comparing ihe
mean ueatmen~ changes from baseline. using the
different<
between the pos[- and pre[rea[men[
scores for each subjecl. re\ called imprcw emtn:s In
re+-- g speed and accurac\ and mtal words wri[Ie.
indi~iduals treated uith Plracelam, in J]] 3
studies. [he Plracetam medication was extreme!}
uell-[~]era~ed.
measures.
The prcs.ent s[ud> was dcs]gned to replicate and
extend [he findings of R“ilsher et al. ( 1984). ilore
rigorous patien[-selec[ion
inclusion and excluslona~ criteria were used, Drug dosage ancl regimen
were equ[~alen[.
but the clinlcal [rial was ex[ended
subjec[s.
[es{ sI!es. And
[o 12 weeks and additional
psvchometnc
.METHODS
[ests were
included.
was [heir
primar)
consent was ob[ained from
p~tien[ and parent
or legal guardian.
(6)
They hd normal audiological and ophthalmological functioning (7) There was no significant neu roloy~l
hancflcap. (S ) They had no severe emo[lonal dls[urbance aj a primau symptom. (9) There
u w n~~s<rere educational deprivation. ( 10) The?
had n~~climcally significant labora[o~
abnormalities. n,~r on} medical conditions v hich might put
tht p~;jen[ ~1 addl[ionat risk or interfere with the
conduc: of the s~uci~, ( 11 ) They had no his[on of
SI:nI
fl.ln[
acfvcrse rcac[ion or hypersensitivity
to
Plrace:~m. (12) The}- were not involved in any
[herapies u tuch mi~~[ interfere with the evaluation
of efficacy and safe[>. including: psychostimulan[
medic~t]on uithln 6 months of the initial \’isit.
concormm[
drug [herapy with ps}chostimulan[s
or an> drug for emcxional dis~urbance. concomitant [herapy with Tofranil for any indication.
ln\es[igatlonal
drug therapy wilhin one month of
the ln}tial ~lsit. or concomitant chronic treatment
wi[h bronchodilators
uhich have cenlral stimulan[
actiwt\.
Th; Reading Quo[lent was calculated as equal
to: Reading Age x 100% bv [email protected] Age x
Full Scale W’ISC-R IQ. The Reading Age was
derl\cd from the Accuracy Score of the Gilmore
Oral Reading Test — Form C. Grade Scores from
[he Gllmore were converted m Age Scores using
Table [1 provded
in the Gates-%lcKillop
Oral
Reading Test. Abnormal audiological functioning
was de(lnecf as a loss of greater than 20 dB in
ei[her <ar for two frequencies in the normal range
(500. 1000. ?OOO.3000.4000 Hz. using pure tones).
.Abncmal
ophth~lmological
functioning
was
de-
then 20,/40 corrected vision m both
e}es as [es[ed b) [he American Optic~l E Chart.
Slgnlfic~n[ neuroimycai handicaps uere defined 3S
disan} or [he follow lng: acquired neurological
e~w, ~laj~]csl neurol~>ycal sly-is w:[h functional
]mp~lrrnen[ or ~etzure> wi[hln the Iaj[ 5 ycm. The
p~[]er.:~ h~d rio[ rece]\ed an~iconmlwnt ther~p}
.IS; :
f[>r J: ;e~~[ [u<.> \etir> pn~>r (LI [he inl[i~l
tn(I:I.>CJl
<I
Jill.lil,’,!l>
‘Atrt
m~.1~
EJu<~::~ni
Jn~
fined
M
1<ss
I
I
‘1
-u
by the medical Staff fol]owing
USUaI cllnical pr~cfrom [he jtutl}”
[t~e. Four subjects were dropp<d
one moved. one suffered from ~n ~sthmir attack
(in viola[lon
and WaS treated with bronchodil~tors
with the pro[ocol) and two were r<moved from [he
S[Ud V
due [o
medical
complicatic~rrs
unrelated
[O
The
fact [h~t a child was currently recei\ing acmfemic
rerncdial ~ssistance or had receiwd ju~h [u[oring
in the past did rro[ preclude <n(r> irr[o [he j[ud}.
s[ucfy
medication
(both
were
[akin:
placebo).
wos [Jken during the second visit Snd .lhbre\ia[ed
phy-siuai examinations
were performed at the je~ond and sixth week visits. Observations for pc&slbie ~d~erse effects and assessment o(general he~i[h
were emph~sized. Labora[orv evalu~tions werc ob[ained at (he induction ~isit. the 6-ueek. and [he
12-week visits. The l~boratory
tests inciuded
hematology. urinalysis and biood chemistry to ws[
for possible adverse side-effects.
Tt’s[s
procedures
Placebo and Pirace[am
[re~tmen[s were rmdomiy divided among 6 groups of 10 subjtms.
basis with the res[ric[ion
each on a doubie-blind
that there be equal numbers of each treatment
within each of the 6 groups. P~[ients were then
assigned to one of the 6 groups on the basis of
their age: that is. S-year-oIds were assigned [L>
Group One, 9 years oids [o Group Two. and j~~
forth. When all the treatment medication had been
used up within a group. the patient was assigned
[o the group
with the fewest members. Patients
-.
received either 3.3 g of Piracetam dailv or~
/’+
.’
$
F
Each dose of tes[ medication
i~g placebo syrup.
was 5 mi. admlmstered~%reakf ..—-—. as[ and amin
before the evening meal. A 5 ml dose of &e
me~ica[ion
con mined 1.65 lz of Piracetam. S0
@sage adjustments
were ailowed. —
The study consisted
of j%sits.
An initiai
screening visit usually occurred one week prior [o
the start of treatment. The [reatmen[ period was
12 weeks long. with foilow-up visits a([er 2 ~eekj.
6 weeks. and 12 weeks of treatment. <t week -1and
week 9. [he pa[ient”s p_arents were contacted to
review
~ether
~.
dosage
instructions
and [o determ/n~
inv-ad~rs~effqC~>.Js~~
~~n~~sem~d.
... . .. .
At [he initial
screening.
patien[s were tested to
determine
their eligibility.
Hearing and visu~l
acuity tests were given. a de~eiopmentai
h}s[on
mken. IQ testing was done as needed. md the
Giimore Oral Reading Test was aiso odmln~stercd
to provide a calculation of the Reading Quo[ien[.
Assessment of education experience w-d emotional
health WJS also performed at this [ime.
W3S
perA compiete
physical
examlnsuon
formed bv a physlci~n at [he second or lnducti(’n
\isit and again J[ the Iaj[ visi[. .3 medic.d hlj[~m
All 6 study centers followed the same protocol
and used a common battery of tests to mcwsure
drug efficacy. In addi[lon.
each si[e conducted
additional ‘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 battery was administered
at the induction and finai (week 12) visits. w bile
the special study tests were given at the induction
md week 6 visit. At the San Diego Cenwr. JII
testing for an individual patient was administered
by the same tester and took approximately
1 ~ h,
These tests included: [he Gil more Oral Reading
Test — Form C at the inititd visit and Form D at
for Reading Accuthe final visit —. Information
racy. Comprehension
and Rate were inciuded: the
Digit Span subtest of the WISC-R. both digits
forwards and backwards administered via a tape
recording; the Gates- N[cKillop Syilabica[ion sub— Form 1 at the induction and Form 2 at the
n-week visit: the Wide Range Achievement subtejt for Spelling: a 5-rein free-writing sample wm
taken to include the total number of words. number of words misspeihal ~nd [he number of occurrences of [he most frequently written word: the
Rapid Automatized
Naming Test (Denckl~ ~nd
Rude], 1976); a behavioral assessment in the testing situation made at [he induction and l?-~eek
vijl~s on a rating scale of 1 to -1( 1 being excellent.
4 being poor), measuring distractibility
from foiIowing instructions. social appropri~[eness.
cooperativeness. ~[ten[ion and gener~l motor ac[i~i[v:
Jnd a parent’s global msessment of the child-s
behawor obtained ~t the 1~-week visit on J r~[lng
w~le of 1–5. where 1 IS much im,proved ~nd 5 I>
much worse. con>tdering ~hetr beh~vlor JI home.
interaction with peers ~nd school reports concern wst
I
—m.
.=—
I
~ behavior
and performance
in ef’aluat]ng
the
ange from the start of [he s[udy.
In addition to [hese common [es(s. we conc~ed additional
special s[udies. Subjects were
en the Repetition
Test. developed by Tallal
)80). with 3 se[sof stimuli: (1) non-verbal audi“y tones (75 ms dura[ion). differing in funda:ntal frequency: (2) non-verbal visual nonsense
lpes (75 ms duration):
and (3) auditory stop-
mcman[ vowel syllables (ha/da) ui(h 40 ms
ration formant transitions, The Repetition Test
~ been shown to be a highly sensitive measure of
-ceptual and memon functioning. In addition.
s theoretically based on a model of perception
~ is comprised of a series of substesls designed
and
memo~ in a
assess levels of perception
rarchical manner (see Tdlai. 1980. for a detailed
,cription of these procedures). Four dependen[
asures
were made
on each of the 3 versions of
RepeIi tion Test. Subjects were scored for the
al number of correc[ trials. the number of cor[ ‘using interstimulus
intervals (1S1’s) of
) n. .rie number of trials using 1S1’s less than
) ms and the number of trials needed to reach
:erion. Improvements in trials to crilenon scored
icate an increased rate of learning stimulus–remse associations.
Increases in scores on trials
h short 1S1’s suggest an improvement in rate of
wessing
and temporal
sequencing
abilities.
provemen[s in [he longer 1S1 scores suggest an
rease in short-term and serial memory.
In addition [o these experimental perceptual
i memory tests. subjects were also given the
ken Test (DeReti
eptive
language
and Vignolo,
comprehension
1962) [O assess
skills
and
a
red associate
visual memo~
testdesigned for
> study. In ~he visual memory test the tester
[rutted the child by saving. ‘1 would like [o see
differen[ pa[rs of
~ we]] vou can remember
[ures. I will show you two pictures. one after
other. Try to remember them as a pair that go
ether’, Testing took place in [WO parts.a learnthe learning
secand a recallsection, During
1. children
ln:ed
as
were
a
se~.
presented
with
ied al] pairs
rlc ,llqh~~jet
of pictures
Children were presen[ed ~ilh
! of 1 4. 6 and [hen 8 pairs.
A.
\ .–
pairs
Jnd
If a’ciuld success-
wl[h]n 2 se:.[hey moved [~~
u<~e
[eS[ed
[f ~n~ fJJlure
occurred. [he final testing took place using the
next Ioues[ set: e.g.. failure on set 6. final [es[ing
on se[ 5. During the learmng p~micm. children
were presented with pa[rs of pictures. one after [he
other. until the se[ was completed.
presented for 3 s yith an inter[rial
Each pair was
in[erval of [wo
seconds. After all of the pictures in a set had been
presented. [he child’s recall abili[ies were tes[ed in
the following way: [he $~cond plc~ure of each pair
was grouped. mixed and then laid down on [he
table in front of the child. L’sing the same order as
presen[ed in the learning
first picture
I
I
portion of the tes[. the
of each pair
~as presented
to the
child. and he was asked to find the picture
I
that
goes with it among [he p!ctures laid dcm n on the
table
in front
tinued
uniil
of turn. l%is
all
pIcIur?>
procedure
had
was cc~n-
been
matched.
Children
were scrored for the total
correctly
matched pictures. Improvements
number
of
on [his
test suggest Increases in \isual learning and recall.
RESULTS
From ~he init]al sampie of 61 children.
57 suc-
cessfully completed Che stud>. From [his group.
two children had poor compliance during the Ias[
6 weeks of the clincial
trial pencd
I
(below 70% as
measured from the remalnlng bottled medication I.
Consequently.
they were removed
from the da~a
analysis leaving 55 children. 28 from the p[racetam
treatment
group and 27 in [he placebo [reatmen[
group.
Table I presents [he demographic
and baseline
characteristics
of the Piracetam and placebo tre~[ment groups. T-test and x: comparisons be-m een
[he two groups showed nc significant demographic
differences.
\ote
thal a hI~A percentage
of the
children were actit’e!} receillng remedial ~utcrln>
for their reading problems ICa. ~CIZ).
Table
11 Shows
Pirace[am-
and
[he
basc!ine
pll~eb~~[re~ied
common test bat[e~. N“o[e th~[
Readin~
[es[
\Idual
and
more
re2dins
r3te
was
sloul\.
imprc~ed
‘uaj
[he
for
on
CiilmCnre
[he
the
oral
.n :!~,~ wa\s. Flr~[. lndi ior accurjm. Com Drenen>lon
sc.nred
JhIIItl
scored.
%
.3c:ur3cI
~>r \ I:e
scores
groups
‘.ers:.
?nd.
Jrjd
‘bec3usc
17\
;.~m. ~rehen<i(~r,
:om:,..;le
rca~,n2
reodln~
rrI.J\
.(,~r:~
‘he
I
.,
~>[her significant
----
baseline
diffc’rences
be[~~een
test batter>.
T~ble 111 gives the baseline scores for the
Pirmxtam- and pl~cebo-tre~ted
groups on the experimental
lest battery.
T-test comparisons
between groups at bajeline again Showed no significant difference on Jll but one measure. The placebo
group performed
sig,nificandy
better than the
Pirocetam group on the Paired .Asswiate L“isual
\lemor-y
Test Jt baseline (/ = 2.0. P < O.0~
}.
Th<re
were no other baseline differences on [he exper]men(al test battery.
To assess (he effect of drug treatment. the mean
change from baseline WJS calculated for each >ubjec[ on each measure md then averaged and compared for each treatment group.
Table IV show’s the mean change from baseline
(pos[test-pretest scores) for each measure in [he
common test bat[ery for the Piracetam and plwxbo
groups. AS seen in Fig. 1 for individual re~ding
scores, the Piracetam group demonstrated
a s[at[s[icidly signifkm[
improvement
over the placebo
group (at the P <0.003 level O( .lccuracy) on [heir
reading rate from the Gilmore test. The Piracccam
group increased [heir reading speed by almost 8
words per min ( - 10’%) whereas the placebo $roup
decreased by 3 words per min i – 4% ). le~~ ing a
difference of almost 11 words per min between the
groups
I = – 1).05 n.>
:1.-!
1.6
]()- 1
=~On.>
1:.1
–0.1 n.>.
f=
10:.5
11:
- f)
\ : = ().0 n.>.
:1
t:=
I) 5 n.s.
6
-?-’%
were calculated
to reflect the interxt[cm
on
[he
common
between
reoding Speed. and reading .uurxy
~nd compr+
hensiun. A composi[< score [or “effec:l~e reading
[he perJticurocy” was caluul~[ed b} mul[ipi}lng
centage of words red corrml>
b! [he r~ading
r~[e. Slmll~rIy. ‘effective reading comprehensionscores were calcuia[d
by multlpl>lng
Ihe percentage ot’ correc[l>
answered
comprehension
198~).
questions
by [he reading ro[e (-f~ckm.
Scores ~re multiplied mther [ban added together.
be~~uje
they
us< d] fferent
uni[s
of
Medsure,
non-slgnific~n[
The
plxtbo
difference
:roup
on
Jil
performed
but
one
slsylfi-
grout ~[ buseline
on [h< percentage 01 $peillng errors in [he freeWn[lng W[ ( { = 2.64. P < 11.01). There ~~re no
c~ntl> better [h~n th< P[rxe[~m
.&--=
L
0
L
c
measurement.
Composlw
reading scores ~re JIua~s a poslti~e
number and reflect ~ child’s (o[al reocfing effort.
between
:roups
Jt baseline
T-[est comparisons
jh~~ed
—
.L-j-l’a
lCCU?AC”
-
cwPWIE\s::N
?.!1[
~
4-/
\BLE
II
,.reiinr .rcorcs .rr,r ri:~ Ptru<L,ran:
\r
tmrd plact,,i.
vaup T w :irr t mvrm(m rtvr twrer,
tldme
Plru(t’tulr
Plu[eiw
/-le$l
]more oral re~dlng
+ccurac)
~grade railng)
j.-l
?.1
n.s.
49
n.>.
.,,. 6
n.s.
Reading comprehension
:grade ra[lng)
4s
‘mflng ra[c {word.
mlnl
169
Imore compostte redcilng
$ correct x rate I
+ccurac}
b 774.3
6ss;.9
n,s.
Comprehension
6646.3
66S3,3
n.s.
#l
-.,.
span (scaled s;,nrel
llts-McKIilcIp
-...-
n.s.
sillahlc~[ton
r~w xor<)
116
::1
n.>.
jri.i> wn{[en ([~[al,
41.0
a.1
n.~.
rcem of spelling errors *
21.5
12.3
P c 0.01 =
m color h
.$2.?
46 ?
ns.
,n number h
.n
.n ‘
31.4
35.0
n.i.
~~,~
37. [
n.s,
n object h
61. ?
6S.0
n.s.
nc. t.mled IeSI of s[gnlficmcc.
\BLE
h reducll<vi
in score lndlca[e~ lrnprov~men[
111
sehne scores /or
Terrmenral
(he
P!ra( e[om
und
piurebo
groups
on [he
G:. YORE ORAL READING
C31P!ISITE
[es{ bufien
SC3RES
PERCENTCORRECTX UWDS PER !IIWTE
S( name
Plraceiam
)n.ierbal
_
ual Iesf
Long 1S1”s
Short
1S1’s
pelluon
[esl —
labies
Long IS[”5
$h~vl 1S1’,
Pe[ilmn
[es[
n-$erbal
audl[om
Long
IS I”,
Short
IS I”,
—
Placebo
f.iesf
.
.&’%
-4’-:
This increase in reading speed for the
Pirx<tam
group wM wxornpartied
by improved
reding
accurx~
acd comprehension.
~lthough
;imllsr g~ins were ~ls~ found in [he placebo group
~nd. [bus. canmx be ~cnbed m Jrug effect. There
were no slgnlfic~n[ differences between groups on
reading accuracy or comprehension.
Composite reading test scores shown in Fig. 2
demons[ra[e [hat the Piracetam group significan~l>
lmproted [heir tffecti\e reading by 16’? during the
course of [he stud\. on both [heir effective reading
accuracy find compr<henslon
scores. whereas the
plxebo group decre~sed on both composi[e readIWO :roups.
scores, This difference in performance between
:he [IAO[rea[ment groups wos highly sl:nifican[
{eif<c:lw re~ding ~c:ur~c}. r = 3.43. P < 0.001:
In:
tifec:Ive
0.0011.
reading
C<’mpr<hension.
[ = 2.98.
P <
.4 comparison
of composite
and Individual
reading scores reveals that although the placebo
group did incretise in their reading accurac\- ~nti
comprehension
this was accomplished
at [he tx pense of their reading speed which decreased. producing very little effective change in [heir overall
re~ding performance.
The Piracetam group. on the
o[her hand. not only improved their reQding accuracy and comprehension
but also stmul[aneousl:
was able to increase their re~ding r~te. Thts resulted in signific~nt gains in [heir over~il reading
performance.
Fig. 3 shows that on the Free-Writing
Test.
both groups showed an increase in the total number of words written. The Plrxet~m
group Improved
15CC w hereas [he placebo
grouu
sh~~eti
only a 57 yin. ~lthough this difference was not
jt.l[lstlc~ll~ signit’icant. The PIr~( ttam gr~up. ho’+ -
I
I
49
URITING
SA!IPLE
PERW47AGE
OF
(S
sistent ui; h prmious findings. showing no significant m.edl;al abnormalities among the Pir~cetamtrea[ed subjec:s. The double-blind rating of drug
toierance 5> [tie ph>sic:an indica[ed that Piracetam uas udi-mlerated
b} the children (me~n ral ing=l.1 ~= O.I ). 1 excellent. 4 poor). Except for
the onc child who suffered from an asthma attack.
31[ the cl-uldren who u<re treated with Piracetam
remmned heaith\.
MINUTES)
CHANGEFRW WXIIW
1
‘9TAL
urlRDS uR:TTE\
DISCL’SSIOY
PERCENTAGE
SPf.LING
3
~
P:RACE7Af!
:N
= 28)
m
PLACEBC
(h
-
Percen[agc
of change
wnt!en
a~_~percentage
The,< ~<sul[~ confirm st~me of the pret ious findings Of U“l]shcr et al, ( 19641 [hat Piracelam in-
creases [tit ra[t of reading and of writing accurac\.
27)
The amount
from
ba.sehrre fposuest
:es[ scores) made by the Plracelam
nber of words
W
ERRCI?S
minus
and placebo treatment
Jps are shown for [he 5-m]n rree-willng
I
sample. The Imal
m 5 rmn h> each treatment -uoup.
a>
of spelling errors are graphed.
:r. did show significant{ impro~emen[ over [he
cebo group in the accuracy of their spelling
<0.008).
The
Piracetam
I
group decreased [he
-centage of spelling errors (number
of errors,i
al words writ[en) by 4% whereas [he placebo
mp increased
in spelllng errors by otter 77.
ese figures change. however, if oneplacebo’outr’ subject. who scored well above the res[ of [he
jup (83% ). is removed from the analysis. The-n
: placebo group shows only a 4.5% increase in
:Iling errors ( P < 0,02). Nevertheless. [he trends
nain the same. Overall, the Piracetam group not
in their wmting speed. but also
1) increased
proved in their spelling accuracy’. The placebo
xsp’s
Increase in writing speed. however, uas
‘set b} ~ddit]onal spelling errors.
of [he mean change from baseline
%nalysls
.etest-posttest
scores) for each measure in [he
perimental
test ba[te~
for [he Plracetam and
lcebo groups showed that [here were no signlfi
nl differencesfound bc[ween treatmen[ group<
an> ~1([he experlmen~al percep[ud.
memo~ or
IgUJge
mewsures as~en.
R;--’r~ from. la~ura[,>n
e~.alu~llons ~f blood
e r.
hem2tciog1
JrIcl urln~’ .sli uere cc~n-
are
of
found in this presen[
changes
comparable
to
the
stu~:
obtained by Wiisher.
results
In ~“il~h<~”s S-week study. subjec[s improved their
re2ding r~[e b~ 57. The amount of change found
m
In [he prtsent 12-ueek study is proportional
Wilsher”s data with a IOF improvement in reading
rate. This finding. seen in the light of Wilsher”s
pre\]cws data. sugges[s that [he degree of Piracetam-[ nduced Improvement in reading and writing
of [reatment. Howma~ IM reia[ed [O [he tjur3[lon
eve~. Improvement
o\er time was not assessed
direc[l~ in [hc presen[ s[ud}. ,Addi[ional studies
(O ~s[a~llsh the effects of do5e.
wi]] be n~esj~~
ciura[lon.
The presen[ stud) failed [o confirm W’iisher’s
previous findings of drug-improved
reading accuracy, The ;ack of improvement may be due in par[
[o some \ em lorge placebo responders: in fact. [he
Iarges[ lmpro\ emen[ in reJd]ng accurac;
(797)
was f~mnd in J member or’ [he placebo group.
Subsmntlal
changes In reading accuracy and
comprehension
ab]ii[~ occurred over the course of
[he s[u J} ~or m3,n\ of [he dvslc~ic children in bo[h
[he P:nc<:amand plJcebo-treated
groups. This
uas s.~meu h~[ unexpected as [he reJding skills of
d’ sle~]c clmicircn as 3 group are knoun [0 be
in
dtfficuli
[J rernediate. Tncsc marked changes
readtng
su~ges[
pcI>III\t
‘t:niorc:men[
;[udi.
[h~.m
irle:.n,’d.
IO~t:her
I~T:.~.<
:
tha[
wllh
:,ntlr
mtjii~:!,~n,
perhaps
yttn
[he
the t\DrCjsCd
~tJ~in2
.’h;
,+;c~
-LU
a[tcn[]on
~nd
t~~[he chtldren
:wi
i[
“VI
!,,
I
h
Using
c
In ih~
of helpln~
~
)mpr,~itm~n[
Un)due
I
i
t
:
.
---=
m~de.
It IS of constder~ble
in[eres[ [h~t [he Improvements
nod
in the plwxbo-[reo[ed
group
mirror [he instructions given [o them on r~~ding
~nd wrltlng tests,
On the Gllmore reading [est children were [’~id
M
weil
M
[hey could.
.Al!O red the passages
[hough [he children on placebo did improve their
rexfing
~ccurocv
and comprehension.
w }n$truc[ed [o do. [hev did So bv slowlng down th?ir
rtite
of reding
(wer
[ttelr baseline reading
rat<)
[d
whime
[his
improvement.
Thus,
[hey
hod
to lc~je
tn rat< in order [o gain it in accur~cy ~nd
comprehensmn. The dvslexics cm Pirw?[am. t~n
[he other hid.
did no[ need to resor[ [o chls
s[r~[egy to ~chieve lmpro~emen[ in reading dc:uRather. [hey were able [o
racy md comprehension.
ground
slgnifican[ly
their accumcv
increase their reading rate as well M
and comprehension
over thetr ocglnal baseline performance. Tha[ is. they did ao[
have [o lose ground in order [o gain ground. Tncy
gained both speed and impro\ed
wxuracy ~nti
comprehension
over the course of [he j[ud~. The
percentages
of ~ubjects in [he Piruce[am Jnd
placebo [reatment groups showing gains and losses
in reading accuracy and rate ~re shown in Fig. 1.
on [h< writing s~mpie SUbJ~CtS were [old [0
____
90
58
48
20
0
w rite ~~ much M they
I
time-period.
~
could during J specified
The placebo-treated
children did just
[h~t. Th.ty increased [he number of words written
o\er thc:r original baseline performance.
However.
M was iwnd in reding. they made th]s gain Jt the
expense of something else. in this case an increm.ed number of spelling errors. The dyslexics
on pirace[am did no[ show this - lose-to-gain’ pattern. R~[hcr. [hey incre~sed both the number of
words u ri[tcn as well M decreasing [he number of
spelling errors they made. Even though the onlv
significant difference
between groups noted a[
baseline u-as [he number of spelling errors made.
w [th [he Piracetam group making more errors th~n
the placebo group. by the end of the study this
order u as reversed. The Piracetam group made
fewer spelling errors than the placebo group.
Some of the measures in the special perceptual.
memor> and recep[ive language studies suffered
from celling effects. as most of the subjects found
these [es[s m be relatively e~sy. indic~t; ng dequate percepma[. memory and language abilities
for their age. Most of the subjects performed 0[
the top of the scale on all subtests of the Repetition Test as well as on all 5 parts of the Token
and receptive
Test. indicating normal perception
language abilities a[ the onse( of the study. hence
le~ving Ii[tie room for improvement. Only 4 subdeviation
below
jects s<~red at least one standard
the mean on [he Token Tes:. suggesting fha[ Ma[[is ~! al-j (1975)language disorder syndrome wm
poorly represented in this dyslexic sample. Subsubtests of
jects JISO scored highly on perceptual
all 3 Repetition Tests. indicating that they h~d no
difficult} m cfiscriminating between the differen[
audi[o~ or ~isual stimuli. A subgroup of 19 subjects did have difficulty discriminating
between the
t\vo computer-synthesized
speech syllables /ha/
and , da j with 40 ms formant transitions. On [he
Repeunon Test however. perhaps due to the ~ery
small s~mple size. a Xz-test indicated no significant differences between Piracetam and plxebo
groups on this test. Contrary to previous findings
( Dimond. 1975: Wilsher et al.. 1979), subjecl~
[Oklng Pir3cetam did not demonstrate
st~[is[lcall>
jignlfic~n[
lmpro~ements
in [heir short -ttrm ~nd
~erl~l mcm(~ry sk]lls. [email protected] some differences
and verbal stimuli were found.
belween non-serbal
-——..
I
;
;
.
_—-=_
51
sing non-verbal stimuli. trcatmen[ groups showed
~ sisgnifican[ differences on the total number of
,rrect s[imulus series rec211ed in [he audito~
odali[~ of the Repeti[mn
Test. In the visual
odalit>.
subjec[s on placebo
found it easier to
call the proper sequence of the visual nonsense-
aped stimuli. as demonstrated
by their impro~ed
ores for [otal correc[ trials wi(h long 1S1’s. In
could be verbally rewhen
IeSt
items
mlrast.
:arsed. as In the Paired Associate Visual .Memory
:s[.
which
used namable pictures as stimuli. and
the
Pirace[am-treated
e Digit Span subtests.
mean final performance
and change from
IwIce
tha[ of [he placebo
:sc]ine WM dmos[
oup’s
~wp on both [es[s ( Fig. 5). The difference be. een groups. however. was not statistically sigficant in el[her case. These [rends toumi
im-oved memory for verbal]} media[ed ma[erial
Jggest that a significant Improvement in verbal
,emory scores might be realized wi[h a larger
lmple size. a longer dur~tion drug trial. or more
;nT>—- measures, ln addl[ion. pira~e[am”s eff~c[
n.
or: could be mediated by drug-dosage. A
irger (e.g. 4800 mg/’da} ) dosage might produce
gnificant results. since previous findings used a
osage in this range
1
This pat[ern of results calls for a much closer
examination of the differen[ stages of mcmm-y tha[
mav be affected
by Piracetam.
Fu[ure s[udies
should examine possible material-specific
effects
of Piracetam on various memor} components. such
as working capaci[y. rehearsal strategies. re[rim al.
re[ention and recall. In addition. the qu<stions of
dosage-dependent memory effects should be investigated.
1,
I
Subjec[ selection procedures ma) QISOhave important implications for drug studies with dyslex]c
children. Several different subgroups of readingor language-impaired
children. exhibiting different
profiles in the areas of perceptual. memory and
languag~ func[ions. have been described f sce Tallal
and S[arh. 1982. for rmiew). Baseiirw test scores
suggest [hat the majority of re~ding-impaired
children participating
in this stud) did no[ have
signific3n[ perceptual. memory or recep[ive Ianguage deficits assmia[ed wi[h their reading disability. Thus.
I( was difficult
to assess [he potential
I
thcrapeu[lc efficac} of Pimcetam in trca[]ng such
deficits in the present stud!. In order [o better
assess P]racemm”s abili[y lo effect perceptual.
memon or receptive language deficils. it will be
impor[ant
to select a group of resoling- or lan-
guage-impaired
children who show signlficmt def-
icits in these areas
6a.
at baseline [esting. Comparisons between different subgroups of rem-iing-lmpaired children, selected on the b~si~ of specified
behavioral profiles. may be an impor[an[ factor in
assessing the effects of nomropils on le~rning- md
language-impaired
children.
In summa~.
PiracetJm
appe3rs [0 impro\ c?
verbal fluency. as demonstrated bv incrcx+ed rates
of reading and writing accurac\.
These trends
encourage a po[en[ial role for Plrmxt~m in [h<
clinical remediation of dyslexia. d[hough quest tou. <
about drug-dosage. duration of trea[men[.
possible
In[eractlon with other remedial procedures. diiferen[lal effects on various subgroups oi k3rnln:imp3ired
children
remain
and
unanswered.
inves[iga[ed
One
of dru~-response
3re kn:
presenti>,
final
no[e
of c3u:ion
of andl\ses
ptrformed.
tained
be
C.IUIJ
Selcc:i\e
selec[ivi[~
Some of these tjju~>
In[erpre[ecf
repl,c~[]cn
—
some
w
gl\en [he number
oi
:he
Jh.In::
of [hesc flni:-.s:
73u11>
LJb-
.lc:urren~e.
u,:h J
dI’[tT-
I
,
I
~
!
I
I
-.
>.
en[ group
.
.--=
v~lidate
of
dyslextc
these
children
is
necessary
to
‘F
I 19”61 [email protected] Juced
mance
results.
~ controlled
.A(r~ Pwchmf
[mprovcmen[
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102
The Effects of Nootropics on Memory:
New Aspects for Basic Research
(?’
C. Mondadori, F. Petschke, A. Hau.der
Pharmaceutical
Research
Department,
C[BA-GEIGY
Limited,
Bade, Switzerland
NOTICE
TwS MATERIALMAYBE PROTECTEDBy
COP”i~iG};TLAW (TITLE 17, U.S. CODE)
Wirkungen der Nootropika auf das GxMchtnis:
fiir die Grundlagenforsehung
summary
Neue @ekte
The mechanism through
which nootropies of
piracetarnitselfand itsanaloguesoxiracetam,pramiracetam,and aniracetam)improve memory
the piracetam type (i.e.,
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 findings 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
arninoglutethimide and pretreatment with epoxymexrenon,
a potent mineralocurticoid
1memory-enhancing
antagonist,
eradicated the
effect of all four substances.
EsbestehtrtochimmerkeineGewit3heitdariiber, auf weiche Weise die Nootropika des Piracetamtyps
(Piracetam und dessen Analogverbindungen Oxiracetam,
Pramiracetam und Aniracetam) das Gediichtnis verbessem.
Die K&ung dieser Frage wiirde nicht nur einen Formchtitt
bei der Behandlung kognitiver St6rungen darstellen, sondem such die der Gediichtnisspeicherung zugrundeliegen den Vorgange erhellen. Obwohl die groOe Mehrzahi der bis-
lang verfiigbaren
Befunde auf cholinergische
Mechanismen
hinweisen, werden widerspriichliche Ergebnisse erzielt, sobald parallele Experiment mit zwei oder mehreren dieser
Verbindungen
durchgefiihrt
werden. Neuere Beobachtungen scheinen auf Wechselwirkungen mit Steroiden hinzudeuten: alle vier Verbkrdungen sind MI adrenalektomietten
Labortieren unwirksam; sowohl eine chemische Blockiedurch Aminoglutethimid
als
rurtg der Nebennierentinde
such eine Vorbehandlung mit Epoxymexrenon (einem poblockierte die getenten Mineralokortikoidantagonisten)
dachtnisverbessemde Wkkung aller vier Substanzen.
The elucidation
regulation
of biochemical
bases and the
of memory is one of the greatest challenges in neu-
robioiogy. lt is therefore hardly surprising that every year
hundreds of papers are published dealing with some patticuIar facet of memory. Our knowledge of the subject matter increases almost daily, but more in width than in depth. We now
of many transmitters, receptors, and modulators that
play some pan in memory processing; but each new finding is
know
~-=
soon relativized by the realization that it is not generally valid,
but simply sometimes true under certain limiting conditions.
ln 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 prevalent
method in effons to identify the mechanisms and the neuronal
networks operative in memoryprocessingrelieson the testing
of mechanisticallyspecificpreparations for potential effects
on memory in animal models. For example, the NM DA blockers (MK 801, AP5, and AP7) that recently became available
encouraged studies of the influence of NMDA blockade on
Pharmacopsychiat.
@ GeorgThiemeVerlag
22 (1989)
102-106
Stuttgart.
(Supplement)
New York
learning and-tnemory
and speculation
about the possible in-
volvement of this type of receptor in memory processing ( A40rri.ret 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 ( Mon dadotiet al., [989). Thus, while the assortment of transmitters
inwAved 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,
fom’ts of learning and memory ( Mondadori, 1987).
The opposite way of seekin~ insight into the
processes of memory consists in characterizing biochemically
the substances known to affect memory, and then attempting
to comelate certain components of their biochemical profile
with their effect on memory. The memo~-biocking effects of
certain antibiotics such as puromycin, arm.omyein, and cycloheximide, for instance, inspired a very large number of studies
of the possible relations between inhibition of protein synthesis - scientifically the most appealing aspect - and memory
(for a review see, for example, Davies and Squire, 1984). lle
underlying mode of action has, however, always remained
conjectural, because these antibiotics exert many other known
?le Eflects oJ Nootropics on Memo~:
New Aspects for Basic Research
(see, for example, Flexner and Goodman, 1975; Rain>Wet al., 1979) and quite probably just as many other unknown effects that might equally well be responsible for the
disturbance of memo~, or at least contribute to it. The possibility that the known biochemiml effect under scrutiny may
not be responsible for the observed effect on memory, or that
that effeet 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.
~--affects
fiarnracopschiat.
side+ ffects. lle
fact that they have so far been found to dis-
play scarcely 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 structures and mechanisms responsible for
cognitive processes, then the elucidation of their mode of ac-
tion 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 researchand the possibilities emerging from it.
Neuropharmaeologieal ftiiogs
The first experimentally demonstrable effeet
of piracetam, the prototype substance, on the CNS was inhibition of central nystagmus in the rabbit ( Gitugea et al., 1967). In
retrospea, 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 very wide
the disruptive effect of a cerebral electroshock on the orientation of
1972).
rats in a water maze ( Giurgea and Mouravie#_Lauisse,
Many other authors have also observed anti-amnestic effects
of piraeetam 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
anirawtam and piracetam, and by Mondadon” et al. (1986)
after treatment with oxiracetam and piracetam. Sara (1980)
variety of forms. Piracetam, for instance, diminishes
observed similar responses to etiracetam.
Buder
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 ( I’amada et al., 1985;
1980) and oxiraeetam
Wohhuis, 1971), etiracetam (Sam,
(Mondadori et al., !986) were found to exert direct effects on
__aequisition and retention performance in rats and mice in pas“ve- and active-avoidance
paradigms;
pramiracetam
inieased the acquisition rate in a 16-armed radial maze ( Murray
and Fibiger, 1986) and in a place navigation test (Morris maze)
( Poschelet al., 1985); positive effects of aniraeetam were demonstrated in matching-to-sample tests (Porrrecorvoe[ al., 1985).
AI] these findings are supplemented and indirectly supported
by observations of a facilitating effect of piracetam on inter-
103
hemispherical transfer (Buresova
and Bures, 1976), on
augmentation of paradoxical sleep in rats ( Wetzel, 1985), on
increased theta power in the hippocampal EEG, and on a reduction in the power of cortical slow waves (Poschel et al.,
1985).
Interesting and biochemically inexplicable observations indicate that both piraeetam and oxiraeetam intensify the anticonvulsive effects of anti-epileptics such as carbamazepine (Mondadori
et al., 1984; Mondadori
and
Schmurz, 1986; Hawkins and Melhnby, 1986).
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
on various manifestations
of memory, yet provoke few or no
22 (1989)
B*mieal
effects of piraeetamIike nootropies
biochemical
There are relatively few data available on the
effects of the piracetam-like nootropics. For a
long time, the observation by Nickolron and Wolthuir (1976)
that piraeetam stimulates adenylate kinase activity was the
sole measured biochemical effect. Woefk ( 1979) then showed
that piracetam increased the inemporation
of 32P in
phosphatidylinositol and phosphatidyl chloride in glia W1lS
and neurons. Grauet al. ( 1987) repotted an increase in glucose
utilization under hypoxic conditions and accelerated recovery
of the EEG. Poschel et al. ( 1983) demonstrated that neither
piracetam nor pramiraeetam bound to muscarinic cholinergic
reeeptors; nor did binding occur in a dopamine assay with
halopendol. The uptake of GABA and serotonin was not affected by piracetam or by pramiramam. l%gsley et al. ( 1983)
found no evidence of activity in traditional pharmacological
assays. No effects were detectable on the concentrations of
not-adrenaline, dopamine, 5-HT, or 5-HIAA in the cortex or
midbrain of the tat. At very high doses (200 mg/kg i.p.),
piraeetam increased striatal HV without affecting DA levels,
indicating
that it augments
the turnover of DA. Pramiraeetam,
however, did not increase DA turnover. Receptor assays revealed no afiinity of either piracetam or pramiraeetam for DA
muscarinic, alpha 1,2- and beta 1,2-adrenergic, 5-HTl -, 5HTz-, GAB~ adenosine, and beruodiazepine
receptors. On
the other hand, it was shown ( /%gsley et al., 1983: Shih and
F%gsky, 1985) that pramiracetam increased high-affinity choline uptake into hippocampal synaptosomes. The effective
doses were 44 and 88 mg/kg i.p.: neither higher nor lower
doses were active. Surprisingly enough, piracetam at 100 and
300 mg/kg and aniracetam between 10 and 200 mg/kg both
had no effect on high-affinity choline uptake. These results
with piracetam are slightly at variance with the observations
reported by Peda[a et al. ( 1984). These latter authors found
and piracetam
exerted positive effects on
that both oxiracetam
high-affinity
choline
uptake
in the rat cortex and hippocampus. The discrepancy may have been due to the timing of the
determinations.
The above cholinergic effects are supplemented by findings made by .Spignoliand Pepeu ( 1986) which
demonstrated that oxiracetam prevented the decrease in the
aeetylcholine content of the cortex and hippocampus induced
bY cerebral electroshock treatment (piracetam was inactive).
Further
obsenations
show
that
piracetam
reduces
scopolamine-induced
amnesia ( I+ercey et al., 1987) and, according to one interesting report (Pdch and Mtiller, 1988), elevates the muscarinic cholinergic receptor density in the frontal
cortex of aged rats.
I
I
I
Pharmacopsychiat.
____
22 (1989)
Taken as a whole, this selection of findings
migh[ at first glance give the impression that the piracetam-like
nootropics act by way of cholinergic mechanisms. This conclusion is all the-more plausible b&ause there is a vety large
body of literature on the significance of cholinergic mechanisms in learning and memory (see, for example, Druchman,
1978; Barms, 1980). On closer scrutiny of the available results,
however, it becomes plainly evident that there is not one single
report in which several piracetam-like nootropics tested wmcurrently have actually been found to prodrm the same effects. ‘l%e observed effects, insofar as they have been studied,
are not common to all nootropics (Shih and ~gsfey, 1985;
Spignofi and Pepeu, 1986). Considering
their similarity in
structure as well as in their pharmacological profiles of activity
on learning and memory, it seems quite likely (or at Iewt quite
possible) that all representatives
of this class modulate
memoty 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 substancesbelonging to this class.
C. Mondadori, F. Petsch&, A. Hausler
nenolone), and 11-hydroxylation (i.e. glucocorticoid biosynthesis) (for a review see Santen et al., 1981). Exactly as
adrenalectom y, this pretreatment
rendered
the
piracetam-like nootropics inactive. Aminoglutethimide
had no effects on the retention
data provided
performance
the first indication
ucts of the adrenal
of the mice. These
of the involvement
cortex in the mediation
four
itself
of prod-
of the effects of the
nootropics. It must be conceded that aminopiraeetam-like
glutethimide is not entirely devoid of effects on the adrenal
medulla: increases in catecholamine levels have been observed (Ducbvorth and Kirabchi, 1971). To exclude this possi-
pretreated with epoxymexrenon.Pretreatment with this specificmineralocottieoidantagonist(de Gz.r-
bility, mice were
paro et al., 1987) gave similar results: the memoty-enhancing
effects of the piracetam-like nootropics were completely
blocked; and again the drug itself had no effect on memory.
These tindings prove that steroids cart play a role in the mediation of nootropic effects. Furthermore, these were the first
phartnacdogical experiments in which all four prototype substances behaved in exactly the same way. ( Mondadon” et al,
1989, in press)
Aresterokis
invohed in the mediation
Even if allowance is made for indi”’idual variations dependent on their particular pharmacokinetics, it is still
true to say that whenever neuropharrnacological
agents are administered systemically the brain is flooded with active sub-
It 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 (A4am”nezetal., 1980) and vasopressin (Borellet al.,
1983). However, the effecls of these drugs appear to be dependent on the function of the adrenal medulla.
stance. 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 physiologi-
Although autoradiographic studies of the rat
brain give the impression that oxiracetam does not readily
penetrate the blood-brain barrier (Mondadoti and Pefschke,
of nootropic effects?
cal 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 deserve to be regarded as
potential targets for pharmacological
interventions. In 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 futier
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 emotional states, it
seemed important to find out whether piracetam-like nootropics retained their activities in adrenalectomized animals. They
piracetam,
aniracetam,
and pradid not: oxiracetam,
showed
no memory-enhancing
effects in
miracetam
1987). A
adrenaleetomized mice ( Mondadori and Petdke,
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
(Mondadori,
Ducre[ and Perschke, 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-
1987), the above-mentioned
findings as a whole cannot be
taken as evidence that the piracetarn-like nootropics act peripherally. Amongst various other possible mechanisms (see
also Afondadoriand Petschke, 1987), itis conceivable that activation
of steroid
receptors
in the brain may be a prerequisite
for the effcacy of the piracetam-like nootropics; in other
words, steroids may mediate the action of nootropics on
memory. The convene 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 Kloet, 198 1). A new facet
emerging from the authors’ experiments is that aldosterone-receptor-mediated
activity may play a part in memory processing orits 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
demonstrated that in various organs steroids affect specific
gene expression by mod ., ing the rate of transcription of A
specific set of genes ( Yamamoro, 1985; Schtitc, 1988). It
would therefore be extremely interesting to know whether
piracetam-like nootropics can exert direct effects on gene trarrscription, or modulate the action of steroids on gene transcrip
tion. There are already a number of publications or-ithe effects
of steroids on protein synthesis (Arenander and Vallis, 1980;
E{gen et al., 1980; Nesfleret al., 1981; Mikusnic et al., 1986).
Since it is known that protein synthesis plays an important part
in the formation of memory traces (for a review see Davies and
The Eflects of Nootropics on Memory: New Aspectsfor Basic Research
1984), it is conceivable that nootropics may improve
,emory via modulation of protein synthesis.
+—=quire,
The present observations, which suggest that
steroids may be involved in the mediation of the nootropic action of the piracetam derivatives, do not contradia the reported findings on their cholinergic effects, since the possibility that steroids may interact with cholinergic mechanisms
cannot simply be dismissed.
Referessees
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their Modulation by Hydrocortisone. Brain Res. 200(1980) 401419
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New Epoxy-spironolactone Derivatives: Characterization in VIVO
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-—a- tions. Drug Develop. Res. 2 (1982) 441-$46
Irgea, C. E., F, Moyensaons,
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Glucose
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Mondadori, C., W. Clossen, J. Borkowski, T. Ducret, H. Buerki, A.
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Stand. (SUPPI. 109)74(!
Mondadori, C., F. Petschke: Do Piraatam-tike Compounds Au Centrally Ma peripheral Mechanisms? Brain Res. 435 (1987)3I&314
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MondadorL C., A. Bhatnagar, J. Borkowski, A. H&der: Involvement
of a steroidal components in the mechanism of action of
piracetam-Iike nootropics. Brain Rev, in press
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Morris, R. G, M., E, Anderson, G. S. Lynch, M. Baudry: Selective Impairment of i-earning and Blockade of Long-terns Potentiation by
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Mumay, C. L.. H. C. Fbiger: The effect of Pramiracetam (C I-879) on
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Pedafu, F., F. Moroni, G. C. Pepeu: Effect of Nootropic Agents on
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I )( 1984) 772
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Mice. Psychophamnaco10
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74-78
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ing-to-Sample
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Behav
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853--S7l
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Tlserapeutic
Wrdow
of Pramiracetam
Demonstrated
in
10S
I
.
.
.
106
.-..
;-.
l%armucopsychiar,
C. Mondadori, F. Petschke, A. Hausler
22 (1989)
Behavior,
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Latencies for Passive Avoidana Respomses in Rats Treated with
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Dr. C. Mondadori
Pharmaceutical Research Department
CIBA-GEIGY Limited
CH4302 Bad
Switzerland
.
Life Extension Foundation Offshore Drugs
Page 12 of 13
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 really a vitamin-like compound
consisting of a niacin analog (n-nicotinoyl) uniquely bonded to GABA
(gamma aminobutyric acid), When niacin is bound to GAB~ it creates a
molecule that readily penetrates the blood-brain barrier to enhance cerebral
and peripheral circulation, What enables picamilon to work so well is the
synergism bet ween 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.
,,,,,
P] RACET.4 X1
L, . . .
.&
.J:
Piracetam is a derivative of the amino acid GABA that increases the
sensitivity of receptors in the brain involved in memory 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
processing ability, concentration, memory, and creativity, It has been shown
to harmonize and synchronize the spheres of the brain by anchoring
information within the brain,
-a, .:-r
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Suggested dose: Piracetam should be used in doses ranging from 1600 to
2400 mg a day taken first thing in the morning.
Retin A is a highly publicized vitamin A derivative that stimulates skin cell
renewal, increasing the creation of youthful cells at the skin’s surface. Retin A
may produce side effects such as minor irritation, People using Retin A
should stay out oft he sun and use a sunblock for normal sunlight exposure,
because Retin A increases skin sensitivity to sunlight.
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3/10/98
EROWI’D - NOOTROPICS
: PIRACETAM
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FAQ
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TITLE:
Piracetam-induced changes in the functional activity of neurons as a
possible mechanism for the effects of nootropic agents.
AUTHOR:
Verbnyi YaI; Detzhiruk LP; Mogilevskii AYa
AUTHOR
AFFILIATION:
Physical-Technical Low Temperature Institute, National Academy of
Sciences of Ukraine, Khar’kov.
SOURCE:
Neurosci Behav Physiol 1996 Nov-Dec;26(6):507-15
NLM CIT. ID:
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
60-70V0 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
voltage-current characteristics of neuron membranes, and the appearance
of piracetam-induced transmembrane ion currents. Nifedipine and
cadmium ions, both of which are calcium channel blockers, generally
reversed or weakened the effects of piracetam on the changes seen in test
cells. This indicates that the effects of piracetam mxwdtfrom its action on
calcium channels; selective changes in calcium channels may determine
which piracetam-induced elTimtsappear at the cdtular led It is
hypothesized that the piracetam-sensitive celhdir plasticity mechanisms
may make a significant contribution to its nootropic action at the
behavioral level
MAIN MESH
SUBJECTS:
Lymnaea/*PHYSIOLOGY
Neurons/*DRUG EFFECTS
Nootropic Agents/ANTAGONISTS & 1NHIW*PHARMAC0L0G%
Piracetam/ANTAGONISTS & INHIB/*PHARMACOLOGY
j,l
[,’98 1206
pM
,
-.
_-
ADDITIONAL
MESH
SUBJECTS:
Animal
Cadmium/PHARMACOLOGY
Calcium Channel Blockers/PHARMACOLOGY
Electrophysiology
Ganglia, Invertebrate/CYTOLOGY/PHYSIOLOGY
In Vitro
Membrane Potentials/DRUG EFFECTWPHYSIOLOGY
Nifedipine/PHARMACOLOGY
Parietal bbe4CYTOLOGY/DRUG EFFECTS
Patch-Clamp Techniques
PUBLICATION
TYPES:
JOURNAL ARTICLE
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Calcium Channel Blockers)
O(Nootropic Agents)
21829-25-4 (Nifdipine)
7440-43-9 (Cadmium)
7491-74-9 (Piracetam)
❑
.-.
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2of2
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TITLE:
Nootropic drugs and brain cholinergic mechanisms.
AUTHOR:
Pepeu G; Spignoli G
AUTHOR
AFFILIATION:
Department of Preclinical and Clinical Pharmacology, University of
Florence, Italy.
SOURCE:
Prog Neuropsychopharmacol Biol Psychiatry 1989;13 Suppl:S77-88
NLM CIT. ID:
90139561
ABSTRACT:
1. This review has two aims: firs~ to marshal and discuss evklcnces
demonstrating an interaction between nootropic drugs and ,brain
cholhergie mechanisms; second, to define the relationship between the
effds on cholinergic mechanisms and the cognitive process. 2. Direct or
indirect evidences indicating an activation of cholinergic mechanisms exist
for pyrrolidinone derivatives including piracetam, oxiracetam, aniracetam,
pyroglutamic acid, tenilsetam and pramiracetam and for miscellaneous
chemical structures such as vinpocetine, naloxone, ebiratide and
phosphatidylserine. All ttwe drugs prevent or revert seopolamin~induced
disruption of several learning and memory paradigms in animal 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. Phosphatidylserine restores acetylcholine synthesis
and conditioned responses in aging rats. 4. The ~
through which
the action on cholinergic systems might take place, including stimulation of
the high affinity choIine uptakq 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.
MAIN MESH
SUBJECTS:
Acetylcholine/* METABOLISM
Brain/DRUG EFFECTS/* METABOLISM
Psychotropic Drugs/’PHARMACOLOGY
3/ 10/’98 4:39 PM
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ADDITIONAL
MESH
SUBJECTS:
Animal
Receptors, Cholinergic/DRUG EFFECT!VMETABOLISM
Scopolamine/PHARMACOLOGY
Synapses/DRUG EFFECT!WHYSIOLOGY
PUBLICATION
TYPES:
JOURNAL ARTICLE
//t#-UUU
lWLV1%llGI1l
!,&JU>+
T UUUS1l T 1
REVLEW
REVIEW, TUTORIAL
2 of2
LANGUAGE:
Eng
REGISTRY
NUMBERS:
O(Receptors, Cholinergic)
51-34-3 (Scopolamine)
51-84-3 (Acetylcholine)
3;10/98
4:39 PM
~
k
—_
1of2
TITLE:
Piracetam elevates muscannic cholinergic receptor density in the frontal
cortex of aged but not of young mice.
AUTHOR:
Pilch H; Muller WE
AUTHOR
AFFILIATION:
Psychopharmacological Laboratory, Central Institute of Mental Health,
Mannheim, Federal Republic of Germany.
SOURCE:
Psychopharmacology (Berl) 1988;94(1):74-8
NLM CIT. ill:
88158509
ABSTRACT:
Chronic treatment (2 weeks) with @[email protected]@Wentwdaiiy [email protected]
ekwated m-tholhmceptor density in the frontal cortex ofaged (18 months}
female mice by abut_
~ut had no effbct on m+wlinoceptmr
density k tlie fkmtal cortti of young (4 weeks) mim T’keeffect of
piracetam on m-choiinoceptor density as determined by the specific
binding of tritiated QNB was ❑ot affected by concomitant daily treatment
with either choline (200 mg/kg) or scopolamine (4 [email protected]). It is concluded
that the effectaf phcetam on m+mIinoceptor deasity could ex~n the
positive effkcts which have been reported for combinations of cbolinergic
precumor treatment with piracetam on memory and other cognitive
functions in aged experimental animaia and patienta and could aJso
represent part of the possible mechanism of action of piracetam alon~
MAIN MESH
SUBJECTS:
Agin~METABOLISM
Cerebral Cortex/DRUG EFFECTS/* METABOLISM
Piracetam/*PHAR.MACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Receptors, Muscarinic/*DRUG EFFECTS
ADDITIONAL
MESH
SIJBJECTS:
Animal
Atropine/PHARMACOLOGY
Female
Male
Mice
Oxotremorine/PHARMACOLOGY
Quinuclidinyl Benzilate/PHARMACOLOGY
Scopolamine/PHARMACOLOGY
3/10/’98 4,40 PM
http://l3O. 14.32 .47/cgi...client?23694+detail+l+
-.
2of2
1
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)
http://l3O.
14 .32.47 /cgi-bidIGMdient?23694
+detail+ !
3/ 10!98 4:40 PM
nlLp. // 1 XJ.
14. JA.40/C~l-OWIUIVl~
llmlf 1Y5 lYWMWLII*/
National Library of Medicine: IGM Full Record Screen
.-.
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PI
h
TITLE:
Treatment of acute ischemic stroke with piracetam. Members of the
Piracetam in Acute Stroke Study (PASS) Group.
AUTHOR:
De Deyn PP; Reuck JD; Deberdt W; Vlietinck R; Orgogozo JM
AUTHOR
AFFILIATION:
Department of Neurology, Middelheim Hospital, Antwerp, Belgium.
SOURCE:
Stroke 1997 Dec;28(12):2347-52
NLM CIT. ID:
98074088
3/1198
[I:59AM
ABSTRACT:
MAIN MESH
SUBJECTS:
BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with
neuroprotective properties, has beenmported in pilotstndies ti Aocuuwe
compromised regional cerebral blood flow in patients with acute strdw’
and, ~
seun after onse~ 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 O~ogozo scale. Functional status at 12
weeks as measured by the Barthel Index was the major secondary
outcome. CT scan was performed within 24 houm 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 treatment within 6
hours of the onset nf stroke but subsequently redefined as less than 7 hours
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 Batihel Index after 12 weeks:
piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (1 11/464)
in the piracetam group and 19.2°/0 (89/463) in the placebo group (relative
risk 1.24, 9!Y%confidence interval, 0.97 to 1.59; P = .15). Deaths were
fwer in the piracetam group in those patients in the intention-to-treat
population admitted with primary hemorrhagic stroke. Post hoc analyses
in the eariy treatment subgroup showed dflerences favoring piracetam
relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam
60.4, placebo 54.9; P = .07) and Barthel 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
Orgogozo scale score< 55), showed significant improvement on piracetam
in both outcomes (P < .02). CONCLUSIONS: PMmetam did not Whence
outcome when given within 12 hours of the onset of acute ischemic stroke.
Post hoc anatyses suggest that piracetam may confer beswf5twhen given
within 7 honrs of onseQ particularity in patients with stroke of moderate
and severe degrea A randomized, placebo-controlled, multicenter study,
the Piracetam Acute Stroke Study II (PASS II) will soon begin.
Cerebral Ischemia/*DRUG TIIERAPY/MORTALITY
Cerebrovascular Disorders/*DRUG THERAPY/MORTALITY
Neuroprotective Agents/ADVERSE EFFECTS/*THERAPEUTIC USE
Nootropic Agents/ADVERSE EFFECTS/* THERAPEUTIC USE
Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
_&=%
2of3
3!11198
11:59AM
....y. $
_-
3of3
ADDITIONAL
MESH
SUBJECTS:
Acute Disease
Aged
Aged, 80 and over
Doubl&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)
.“./.
.
,..,
W,
,“ew
6.
-“”. -...
w..- .. . . . . . . .
“--.5,
3:1 1/98 1 l:59AM
___
TITLE:
The effects of piracetam in children witmdyslexlw
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
6
ABSTRACT:
____
2vf3
Following previous research which suggests that piracetam improves
performance on tasks associated with the left hemisphere, a 12-wee~
doubleblind, placebo-controlled study of developmental 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 nor emotionally
disturbed. Piracetam was found to be well tolerated in this study
,. .,.
.
populatio~~~wit&~~
~,~~0
,,other effects Onreading were obse~ed. ~ addition,
~~w
observed in
those piracetam-treated patients who show~ relatively poor memory at
ttreatment with piracetam may
~$,
:
::,,-’:
,;
,
result in ad
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
PUBL1CATION
TYPES:
CLINICAL TRIAL
CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE:
Eng
kEGISTRY
NUMBERS:
OxPyrrolidinones)
7491-74-9 (Piracetam)
3/10/98
3.54
PM
A
TITLE:
Piracetam [email protected] 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:
Previous research has suggested that ~
[email protected]@[email protected]
have
shownimprovcnuuts in rwadiag skil&vulrd [email protected] S* vedd
~a,
fuiumanabdw=d
proadngofktteF4i&
‘e*wo
hundred twew-fi’e 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~ double-blind, placebo-controlled study. Children of below average
intelligence, with abnormal findings on audiologic, ophthalmologic,
necrologic, psychiatric, and physical examination% who were emotionally
disturbed or educationally deprived and who had recently been treated
with psychoactive medication were excluded from the triaL~
wwetl ~tcd,
with no serious adveme clinical [email protected]&ta
.,.
.... .
ub&@c8nt
hqpwements in
~trkated
cWbulmw
reading &I& (Gi’ay WarR&diig Tii)’an(h’[email protected]
com#m6imaioa
(GiImore 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/* TIIERAPEUTIC 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)
310.983
:5.3
PM
.
b~
---—
‘F
~
TITLE:
An overview of pharmacologic treatment of agnitive decline [email protected] aged.
AUTHOR:
SOURCE:
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 neurotransmitters.
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 Disorders/*DRUG THERAPY
ADDITIONAL
MESH
SUBJECTS:
Anticoagulants/THERAPEUTIC
_—-
fi
b
USE
Clinical Trials
Comparative Study
Dihydroergotoxine~HERAPEUTIC USE
Human
Hyperbaric Oxygenation
Methylphenidate/THERAPEUTIC USE
Parasympathomimetics/THERAPEUTIC USE
PeptidesflHERAPEUTIC USE
Piracetam~HERAPEUTIC USE
ProcaineflHERAPEUTIC 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 (Gcrovital H3)
59-46-1 (Procaine)
7491-74-9 (Piracetam)
—--
2of2
3110/98 4:06 PM
National Library of Medicine: IGM Full Record Screen
k
TITLE:
Profound effects of combining choline and piracetam o~~!
~~d
cholinergic function in aged rats.
AUTHOR:
Bartus RT; Dean RL 3d; Sherman KA; Friedman E; Beer B
SOURCE:
Neurobiol Aging 1981 Summe~2(2): 105-11
NLM CIT. ID:
82058347
.-.
.——...
—
1 et-3
3/10/98
3:50 PM
1111~.,1 lJV.
l?.
JL. +Lrb&l...lV1%llGl
ABSTRACT:
_—_.
---
_——..
MAIN MESH
SUBJECTS:
2 of3
il! lVI.)OTUCUII1
‘Z
1111P.,, lJU.
i*, JL. *Lib~l-VUU
IUIV1%ltGll
L: lV1.10TtlGliU1~L
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 acetylcholine levels in hippocampus, cortex and striatum. Previous
research has shown that rats of this strain suffer severe agereiated 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.
[email protected]#[email protected]@g-)
~w&@@[email protected]
~#HW~
Wruti gJven’th;”pWttti’rnA!W?MaWr?W&Wn
,([email protected]@[email protected]
mtentlon ucorM wwra!timw(better~
~~~:In a s~ond study> it W= ShOWnthat twice the
~oie 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 area. 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 administration were observed in the
hippocampus. However, piracetam alone markedly increased choline
content in hippocampus (88°/0) and tended to decrease acetylcholine levels
(19?40). 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 subjeck ~
“ demonstrate that the effects ,of
combining ch~ne mfll pfiracetam an quite-different tin ‘fiose o%tained
with either drug alone and support the notion that in order to achieve;
substantial efficacy in agfd subjects it maybe meemary to reduce multiplw
interactive
neurochem~ctions
in the b~er
affect activity in;
more than one parameter of a deficient metabolic pathway.
*Aging
Choline/ANALYSIS/* PHARMACOLOGY
Memory/*DRUG EFFECTS
Parasympathetic Nervous System/* PHYSIOLOGY
Piracetam/*PHARMACOLOGY
Pyrrolidinones/’PHARMACOLOGY
310!)8
3.50 PM
llLL~.// 1JU, l+, JA.+z/U~l
A
_n
3o1-3
. ..1Vl%1lml1
! 1(/ / .) OWJISL211TL
ADD1TIONAL
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)
llLL~. /f lJU.
L*. -JL.*4L++-UUU
lULV1%IIU
IL: lV
120
ULLU1l I /.
ntlp.(f i.w. i4.3z.4z/cg]...
M<llenI?
l~6+aemll*l*
1
IllLp:/! I.)U. 14. J4.4Z/Ugl-DUU l\JIVl%IIC[lL! IU I JO 7UCUIII
- 1
National Library of Medicine: lGM Full Record Screen
-=
_-—
.:.oa.:
la
-mm==
;:.:
W==
.....E*N1*.;.:;: -_ amwa‘
*m~”w
,:!: .’~:,?mm
ta Wsutts .semk scmm. ::.:..:.::.:..tmm.
:
E
&
_&”%
lot-2
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 effect 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 functionally 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 unaff’ted but that the secondary trace (in the
ipsilateral hemisphere) was considerably improved and almost equalled the
primary one (savings increased from 20-30V0 to 50-60VO).Learning with
uncrossed optic fibers was unaffected by the drug. Interhemispheric
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
Iateralized 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 mechanism: of
redundant information storage which improve Iiminal or subnormal
learning.
3/10 983:51
PM
MAIN MESH
SUBJECTS:
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
.n
Form Perception/*DRUG
_—.
20s2
3110983:51PM
imp.,,
,2”.
,-l,.l,i,
-?L( be,., .,v,-blmlt!
Iv , Jo ruGlall
- 1
11,(p.. ! ,.7”.
I-r. J/-. -?#””u””u
.LJL”. -V,,*LLL, , “ , J“
“*WI,,
E:
—-<
.-—
<
TITLE:
Some effects of~iracetam (UCB 6215, Nootropyl) on dbu?nicSchizopbrenk:
AUTHOR:
Dimond SJ; Scammell RE; Pryce IG; Huws D; Gray C
SOURCE:
Psychopharmacology (Bet-l) 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 cerclwal tort-astieir
target Chronic schizophrenic patients on the
drug showed’impmwement in object namingandiu tm&tiere the patient
was required to indicate the number of times he had been tapped.
Improvements were also noted in=
ad ~~
b dichotic
listening the patients showed a reduction in the amount of incorrect verbal
responses producedW= [email protected]
~rdnfpm
socid.behaviour~These
results suggest some cognitive improvement
IM llttfe 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 Lktening 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
.—.
2of2
3/10/’98
3:57 PM
,
‘C.y,?r
,./”.
L*.
J-.
T&,
k~,.
,.,,,
%,,
Q,,,.
‘“,
J“
,Ucla,,
~
Uup.,
I
,.)”,
L-f,
J&,
-?*/
&&-”u.
,V,”,
-W,,
Q,l,
.
,
“
J ,“
Uuul,,
National Library of Medicine: lGM Full Record Screen
000
00000
E
&
TITLE:
Increase in the power of human mcmorj in normal man through the use
of drugs.
AUTHOR:
Dimond SJ; Brouwers EM
SOURCE:
Psychopharmacology (Berl) 1976 Sep 29;49(3):307-9
NLM CIT. ID:
77079535
ABSTRACT:
Nootropyl (Piracetam) a drug reported to facilitate learning in animals
was tested for its effect on man by administering it to normal volunteers.
The subjects were g&cn 3x4 capmdca @ 400 mg p [email protected] a double blind
study. Each subject learned series of words presented as stimuli upon a
memory drum. No effects were observed after 7 days but aflkr 14 dayg
verbal teamrnghad signifhntly incrwsexL
MAIN 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
_—–—
lofl
3/10’98
3.58PM
-
National Library of Medicine: IGM Full Record Screen
•1
_&-.
Onu
00000
f
~
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 (Bed) 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]@cd
animals had sijpdfkautiy shorter response htcxmks than satiacdrcatdl
uhubg~,q;~.adts
= rnteqwaed 8s s’fhcMati9n<[email protected] .pIweases
af$cr f~e$tfi& 7he 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
.-.
lofl
3/10/984:1 I PM
[ll[~,,;
lJU. 1+.JL. +U/L~l... %l1G11L!lYO1>~&Ulll
TJJ
lILLP.,( I.IV,
4V.
-J&.
WJlb)51-UUU
LULV1%llC.
ILL;
, 7017
, UGklll
T J.)
E2
.-w
_-—
~{
w
TITLE:
Piracetam impedes hippocampal neuronal loss during withdrawal after
AUTHOR:
Brandao F; Paula-Barbosa MM; Cadete-Leite A
AUTHOR
AFFILIATION:
Department of Anatomy, Porto Medical School, Portugal.
SOURCE:
Alcohol 1995 May-Jun; 12(3):279-88
NLM CIT. ID:
95367208
ABSTRACT:
In previous studies we have demonstrated that prolonged ethad
consumption induced hippocampal neuronalloss. In addition, we have
shown that withdrawal after chronic alcohol intake augmented such
degenerative activity leading to increased neuronal death in all subregions
of the hippocampa.1formation but in the CA3 field. In an attempt to
reverse 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 agent. The total number of dentate granule, hilar,
and CA3 and CA1 pyramidal cells of the hippocampal 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 withdmwaLTbesc data suggest that ph’acetam treatment
imped~ during witbdrawa~ the pumdng of aearwnal degeneration.
MAIN MESH
SUBJECTS:
Ethanol/* ADVERSE EFFECTS
Hippocampus/*DRUG EFFECT!VPATHOLOGY
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)
-=
-—
20f3
.
3/11/98 12:03 PM
F!l
.-. f
x
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. H):
75201625
ABSTRACT:
A double-blind, intra-individual cross-over comparison of the effect of
piracetam on retrograde memory impairment as measured by the KS
memo~ 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 visuaIIy and the
post-ECT confusion time was measured. Piracetam waa given orally in the
dose of 4.8 g/day for 3 dam No significant effects were obtained on memory
scores, electrical stimulus duration, EEG pattern or post-ECT confusion
time. The fmdingg.maghukk41Uk_ed&4.of.piracetam
shown k animal ektrocmvuslive stimulation (ECS) is due to a
is
mmtemdm
of the disturbing&&of
hypoahon memdpfhnct.ionwlt
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
~, y
LANGUAGE:
201-2
3;1oI98 4.25 PM
n
TITLE:
. A= T
i
-
2of2
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
SOURCE:
Clin Neuropharmacol i 986;9 Suppl 3:S27-38
NLM CIT. ID:
87244092
ABSTRACT:
The effects of oxiracetam
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. Stepdown 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 piracetam showed no effect at 100 mg/kg i.p.
and piracetam
MAIN MESH
SUBJECTS:
Avoidance Leaming/*DRUG EFFECTS
Memory/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidines/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL
MESH
SUBJECTS:
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)
~
3/’10/98 428
PM
A. INGREDIENT NAME:
UINACRINE HYDROCHLORIDE
B. Chemical Name:
3-Chloro-7-methoxy-9-(1 -methyl-%iiethykuninobutylamino)acridine Dihydrochloride;
Mepacrine Hydrochloride; Quinacrinium Chloride
2-CMoro-5-(Omega-Diethylatino-Npha-Methylbutyltino)-7-MethoWacfidine
Dihydrochloride
3-Chloro-9-(4’-Diethylamino- l’-Methylbutylamino)-7-Methoxyacridine Dihydrochloride
6-Chloro-9-((4-(Diethylamino)- 1-Methylbutyl)Amino)-2-Methoxyacridine
Dihydrochloride
3-Chloro-7-Methoxy-9-( l-Methyl-4-Diethylaminobutylamino)Acridine Dihydrochloride
2-Methoxy-6-Chloro-9-(4-Diethykirnino- l-Methylbutylamino)
c.Common Name:
_——-_ Acrichine, Acriquine,
Akrichin (Czech), Arichin, Atabrine, Atabrine Dihydrochloride,
Atabrine Hydrochloride, Atebrin, Atebrine, AtebrinHydrochloride, Cherniochin, Chinacri~
Chinacrin Hydrochloride, Crinodor~ Dial, Erio~ Italchin, malaricid~ Mecryl, Mepacrine
Dlhydrochloride, Mepacrine Hydrochloride, Methoquine, Acridine Dihydrochloride,
MetochiL Metoquin, Metoquine, Palacri~ Palusan, Pentile~ Quinacrine Dihydrochloride,
Quinacrine Hydrochloride
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay: 100. 12%40
98%
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.
A==%
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
H. Information about dosage forms used:
Tablets
I.
Information about strength:
100mg - 900mg
J. Information about route of administration:
orally
K. Stability data:
-=.
Melting Point: 257 C (DEC)
Incompatible with alkalk, nitrates, and oxidizing agents.
L. Formulations:
M. Miscellaneous Information:
____
Page -2-
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JIJwE ‘ Zc)ol
JLLY’27
RESULTS OF ANAL~sIs
_-
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;
-
71w o~kion
SEF’ 24 ’97
—g =–
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-..>==
Is in ror~ect of Itw tasts carried UUI and rnumioned above.
09:14
P9GE. 0a2
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—. —---
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.-—.
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. . .~-~~=.. .
.
. -:---:==-=
--
L-A +-::..-,
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--------,. -~..-—
.,. -.--.
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--—-—-——————.
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WIC-.--.-.=M+5+
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-- ‘———-:~---—~n~—-..n.—p—==.
---- .:. ---> 4-
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...-.*
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.
QUALITY
CONTROL
REPORT
CHEMICAL NAME. :QUINACRINE HYDROCHLORIDE USP
MANUFACTURE
LOT NO. :025
PHYSICAL
sncIFIcATIoN
=
~
~ST
STANDARD.
TEST
:USP — /BP_/MERCK_/NF_/MART,
— /CO.SPECS.
l)DESCRIPTION .:
BRIGHT YELLOW, CRYSTALLINE POWDER. IS ODORLESS AND HAS A BITTER
TASTE.
2)SOLUBILITY.
:
SPARINGLY
3)MLTING
SOLUBLE
IN WATER;
SOLUBLE
IN ALCOHOL.
POINT.:
MELTS AT ABOUT 250 DEGREES WITH DECOMPOSITION,
.-.
4)SPECIFIC
GRAVITY.
5)IDENTIFICATION
A)COMPLIES (A)
B)COMPLIES (C)
C)A SOLUTION 1
PASSES.
:
.:
AS PER IR SPECTRUM USP XXII.
AS PER USP XXII.
IN 100 HAS A PH ABOUT 4,5.
:
FAILS
.:
COMMIZNTS.:QUINACRINE DIHYDROCHLORIDE IS ALSO KNOWNAS QUINACRINE HCL.
ANALYST
SIGNATURE.:
PREPACK
TEST.:
RETEST.
-.—.
:
DATE.
DATE.
DATE.
:
:
INITIAL.
INITIAL.
:
:
:
—
.
~
------------------ IDENTIFICATION
------------------PRODUCT # 22299-2
NAME QUINACRINE DIHYDROCHLORIDE
HYDRATE,
98%
CAS #
69-05-6
MF C23H30CLN30
smoms
ACRICHINE * ACRIQUINE * AKRICHIN (CZECH) * ARICHIN * ATABRINE *
ATABRINE DIHYDROCHLORIDE
* ATABRINE HYDROCHLORIDE * ATEBRIN *
c{
?
@(
ATEBRINE * ATEBRIN HYDROCHLORIDE * CHEMIOCHIN * CHINACRIN *
CHINACRIN
HYDROCHLORIDE *
2-CHLORO-5-(OMEGA-DIETHYLmO-ALPHA-METHYLBUTYLAMINO)
-7-METHOXYACRIDINE
DIHYDROCHLORIDE
“~
3-CHLORO-9-(4’-DIETHYLAMINO1‘METHYLBUTYLAMINO)-7-METHOXYACRIDINE
DIHYDROCHLORIDE
*
6-CHLORO-9-((4(DIETHYLAMINO)-I -METHYLBUTYL)AMINO)-2-METHOXYACRICMN13
DIHYDROCHLORIDE
*
3-CHLORO-7-METHOXY-9-(1
DIHYDROCHLORIDE
-METHYL-4-DIETHYLANUNOBUTYLAMINO)ACR.IINNE
~CRINODORA
MECRYL * MEPACRINE
* DIAL * ERION * ITALCHIN * MALARICIDA
DIHYDROCHLORIDE
* MEPACRINE
HYDROCHLORIDE
METHOQUINE ~
c
2 [2-METHOXY.6-CHL0RO-9-(4-DIETHYLAMIN0-I-METHYLBLJTYLm0)
J
ACRIDINE DIHYDROCHLORIDE
* METOCHIN * METOQUIN * METOQUINE *
PALACRIN
bc
* PALUSAN * PENTILEN * QUINACIUNE DIHYDROCHLORJDE
* QUINACRINE
HYDROCHLORIDE * 866 R,P. * SN 390 *
------------------ TOXICITY HAZARDS ------------------RTECS NO: AR7875000
ACRIDINE, 6-CHLORO-9-((4-(DIETHYLAMINO)-1
-METHYLBUTYL)AMINO)-2METHOXY-, DIHYDROCHLORIDE
TOXICITY DATA
ORL-RAT LD50:660 MG/KG
IVN-RATLD5029
MG/KG
IUT-RAT LD50: 100 MG/KG
ORL-MUS LD50:557 MG/KG
IPR-hfUS LD50: 189 MG/KG
SCU-MUS LD50:212 MG/KG
JPETAB 91,157,47
JPETAB 91,157,47
IJEBA6 16,1074,78
JPETAB 91,157,47
JPETAB 91,133,47
ABEMAV 1,317,41
*
*
.-.
IVN-MUS LD50:38 MG/KG
ORL-RBT LD50:433 MG/KG
IVN-RBT LD50:9 MG/KG
JPETAB 91,157,47
JPETAB 91,157,47
JPETAB 91,157,47
IVN-GPG LD50: 14 MG/’KG
JPETAB 91,157,47
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 (FLACCHl 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 FERTILITY (FEMALE FERTILITY INDEX)
EFFECTS ON FERTILITY (PILE-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
.-.
n
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 -------------------,t
w
MELTING PT: 257 C (DEC)
APPEARANCE 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-CONTMNED 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
NIOSHM4SHA-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 GULDE 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
. -=”-.
WSITED ST.\TES OF .4MER1CA
1/
Packaging and storage-Preserve
from light.
CmEGom-Pharrnaceutic
P?mxylin
loosely packed in cartons,
protected
necessity for COLLODION.
Quinacrirte
r[
,599
..—
.—
Hydrochloride
4
QL~NAcRIXE.
HYDROCHLORIDE
----.—.
——&Chlom7-me~o~-Ml-me[
hl-l=ethylamkobuty lamino)acntioe
D=ydrochloride;}[eparrine~ydr~hloride; Quinwriniurri
Chloride
@/“
r
~H—CIi(CH3)-CH2
CH2CH2-N
H+
(C2H5)2
[email protected]’&
L
C=H30ClN302HC1.2HZ0
I
e=,
Sotl:l
LIN
)ttorl
he action of a mixture
of nitric
s chiefly of cellulose tetrmitrate
●
, matted mass of fdamenta, resembling
e touch. [tisexceedingly $arnmable.
titha luminous flame. When kept in
is decomposed with the evolution of
ue.
xvly
“
but completely
in 25 partsof a
falcohol.Itissoluble
inacetoneand
n thesesolutions
by water.
ut 500 mg. of Pyro lin,accurately
Id water, and ignite %
t e Pyroxylin at
]t the &ah to redness, and cool: not
lm. of Pyroxylin with 20 ml. of water
not have an acid reaction to litmus.
on a steam bath, and dry the residue
of residue remains.
Mo1. wt. 508.94
contains
not [ess than 98 per cent
of
CasHwCl?JoO2HCI ‘2Ha0.
,.
“nacrine [email protected] a brt~
or em and luwa b[tter taste.
nacrmem}-drochfotidecfissolvesin about 35 m]. of water.
De-scri tion
—r_
2H20
J
H
Quinacrine Hydrochlonde
2C1-.
lt is solublein alc$ol.
ldentitkatioa.1: TO 5 ml. of a solution of Ouinacrine Hydrochloride (1 in 40). add a slight excess
of ammonia T.S. : a y~llow to oran-~, oily precipitate of quinacri~e base is
formed which adheres to the wafl of the vessel and ia 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 c~stdine
precipi~te is formed.
C: To 5 rrd. of a solution of Qu.irmcrine Hydrochloride (1 in 40), add 1 ml. of
mercuric chloride T.S.:
a yellow recipitate is formed.
D: The filtrate from the precipitate, o[ tained in Identification test A, aciditied
with nitric acid, responds to the tests for ChZoride,.page901.
pH—The
pH
Water,
page
of a Solution of Quinacrine Hydrochloride (1 m 100) is about 4.5.
942-Determine
the water content of Quinacrine Hydrochloride by
drying at 1050 for 4 hours or by the Karl Fischer method: it contains not lew than
page 9
12—T r e residue
on lgmt~on
Restdue
‘“wr cent”md”not
on [email protected],
‘ore
‘bans
‘n’ ‘f ‘awr”
“ “ of 200 mg. of Quinacrine
Hydroddonde is negligible.
Assay—Transfer to a 100-mL volumetric tlask about 250 mg. of Quinacrine Hydrochloride, accurately weighed,, disscd~e it in 10 ml. of water, then add 10 ml. of a
solution Prepared by diseohnng 25 Gm. of sodium acetate and IO ml~fi$~$l
acetic acid in water to make 100 ml. Add exactly 50 ml. of 0.1 N
chromate and water to make ltN ml., stopper the flaak, mix thoroug G y, and filterthrough a dry filter
per into a dry tlaek, rejecting the first 15 ml. of the filtrate.
Measure 50 ml. of 8 e subsequent IHtrav [email protected] a glsas-stoppered fhdr, add 15 ml.
of hydrochloric acid and 20 ml. of
contents gently, and allow to stan #’m’u
m the dark‘OddeT”s”’
for 5 uunutea.
‘@pR~h~.5W!o*a$~
and titrate the liberated iodine with 0.1 N wdium tbioeulfa~~ adding starch T.S~
as the end-point is neared. Perform a blank determination w]th the same quanti-
*
600
THE
t.ieaof the same reagenta and
832). Each ml. of 0.1 ApotiuM
CIXtO 2HCI .2H*0.
Packaging and storage—P~e
PRARMACOPEIA
OF THE
(see Re-mikd Tif.rutkmu,
bichromate is equivalent to 8.482 mg. of & P ~m
in the same manner
Quinacrine
Hydrochloride in tight, light-resistant
containers.
CATEGoRY-Anthelrnintic;
DOSE —USUAL—SUpptiV&
antima]aria];
Antimalarial-l(Xl
Therapeutic-
antiprof,ozoan.
mg,
mg. every 6
and antiprotoaoan-200
hours for 5 doses, then 100 mg. three times a
day for 6 days.
mg. with 500 mg. of sodium
Antllelmintie-500
material.
p]et,elywith
-t
~tton
Make the e
aucce.saive
is colorless. I
moistened with
2m&uRdknPs
cbath until the q
pletily with the aid of 2
prweed M directed in I
fig with “then add 101
iS equivalent to S.482 n
Packaging and s[orage--
Ant&n&uial
bicarbonate
Quinacrine Hydrochloride
Q~XACRIAm
Ta%&[email protected]
following amounts of qu
DOS
CATEGORY and
in a single dose.
Tablets
Q
HYDROCHLORIDE T.4BLETS
Quinacrine Hydrochloride
Tablets contain not less than 93 per cent
and not more than 107 per cent of t}le labeled amount of CSsHwCINT~O. -
[Cl
2HC1.2H,0.
ldentification—
.1:
Powdw a sufficient number of Quinacrine
H~drochlonde
Tablets,
to about 250 mg. of uinwrine hydrochloride,
and extract with
CH30
,1
equivalent
two 15-ml.
T05 ml. of theextraet
portions of hotwamr,%l~nngdkrwhw
tmction.
add ammonia T. S., and remove the oilv precipitate so formed by extraction
with two ] O-ml. portiona of ether. The water layer, acidified with nitric
acid, responds w the teats for Chforids, page $01.
tzd A
B: To the remaining portion of the water extract obtained in [email protected]
add 2 ml. of ammonia T. S.: a ~ellow, oifv precipitate forrna. Shake the
mixture with several ]o-tnf. potions of chloroform until the water layer iE
practically colorkaa, Evaporate the combmed chloroform solutions on a
gteam 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 beaker with
the liquid and stirring with a glms rod. .4110wto stand for 30 minutes, then
filter, wash the crystals with ice-cold water untif the last washing is practically
neutral to litmus, and dry at 10.50 for 2 hours: the CryBW)B so obhined
respond to [email protected]
.ta.h B and C under Quiruxriw
Hydrochlortiie,
page 599.
Disintegration--Quinacnne
Hydrochloride Tablets meet the requirements of the
Lkintegration
Test jar Toldeta, page 936! in not more than1 hour.
\\’eight
varia[ion-Quinacrine
Hydrochloride
TableM meet therequirements
of the
lFcight Vatition Te.w jar Tob&a, page 945.
.Assay—JVeigh
a countednumber ofnotleasthan 20 Quin.acrine Hydrochloride Tableta, ~d reduce them to a tie powder without appreciable 10SS. Weigh accurately
a Potion of ~he powder, equydent to about 20+3m . of uinacnnehydrochloride,
and place lt m a separator wrth 25 ML of water an 3’/3 m . of dduted hydrochloric
acid. Extract the suspension with two 15-ml. portions of chloroform, and wash the
chloroform extracta in a ~econd separator with 10 ml. of water. Discard the washed
chloroform, and add the water in the second separatm to the suspension of tablet
,
(C20H24S202)2
Qujnidine
H2s04
Sulfate
species of Cinchona
Fluckiger (Fare.
Descrip~on+titi&e
i:
a
Rubi(
S
cohering m masses. It
Ita solutions ~
w [email protected]
Volubility-one
Gm. of t
about IO ml, of alcohol.
ldentification—
.>:
Acidify a solution ~
ing solution has
B:
TO
5 ml. of a soiu~
mine T. S., and t;
green color due 1
5 m],
of a aolut]
T. S., and @ ~
interval (dxwinc~
D: Quinidine
Sdfate1
Specific rotation, page 80’.
the an+ydrous b~~, d
Qtimdlne Su]fate in -c
C:
TO
Amopyroquine/
]378-W
chloroquine base. Soluble I in 5 of water: practically insoluble in alcohol, chloroform, and ether.
A 1%
Protect
C,4.$ — 14s94-33-3.
,4 yellowcrystalline powder
UaeS.Cyclcquincr=cmbla chlomqttine
in ita action and
IUS been ussd in the USSR for the supprcasion and
[~tment
of malaria. A d~
of 300 mg has bun given
weekly for the suppression of malaria and 3043mg has
keo given daily for thrcx days in the !rcatment of acute
macb.
I 379-e
Bif-yidspsotte.
DFD:DFDDS: Diformyldiaminodiphcoylsulphone.4,4’-Sulphonylhisformaniiide.
C,, H,#J10,S=304.3.
CAS— 6784-2S-4.
A crystalline solid. M.p. 267* to 269”. Practically imokubkc in watec soluble I in about 200 of dimcthyl sulphoxide. It is moat slable at pfi 6.
UseS. Diformyldapsone
has been used as an antimalarial
in dcsc.s of 400 to 800 mg weekly, but is given with
chloroquinc., primaquine,
or pyrimethamine,
since it has
no action on gamemcyta.
Diformyldapsonc
had an a proximate
half-life
of .84
hours.—W. Peters,Po$rrra 1 wed. J., 1973.49.573,
Oiformyldapsonc in d~-s of 3.2g twice weekly for 4
weeks damaged the rest blood calls in 25 subjects,
Smaller doses did not smear LOcause haemoivs,s.— S.
A. Cucimcll c1 al,, J. cli;.’ Pframvuc., 1974, 14, 3 I,
Udzriu.
Diforrnyldapaonc
was .mnsidersd
to protect
volumccra more effectively against the Vietnam Smith
swain of P, falciponcm than against the Chcssrm strain
~~
v~vax. There
were no repona of met.
~blnaemia in patients receiving diformyidapaonc
in conjunction with chlomquine.—
Clyde. D.F.
ai
tl & ,iiiit. Med., 1971. 136, g36. per Trop. Dis, BuII,.
1972. 69. 593. Sce also idem, Milit. Med.. 1970, 135,
527.
Diformyldapsone 100 to 800 mg weckl y given with cbiorcquinc alone. or with chlorcquine and primaquinc, sup.
prased the Smith strain of falciparum malaria in 41 of
45 men and the Brai. strain in 9 men. The mmbhsatiort
appeared to ~ ,rnoreeffective than trsatmcnt wi~h chloroqumc and prlmaqu]ne, or than pyrimcthamine
25 mg
weekly which su pressed {he Brai. but not the Smith
strain.D. F. $Iydc e, d., Arm 1. wop. h4ed. Hyg..
1971, 20, 1, per Trop. Dis. Bull,, 1971, 68. 1153.
weekly
with
Diformyldapsonc
chloroquinc
given
protected 5 of $ voluntccra against falciparum malaria.
Better results were noted when voluntcera were given
dapsonc daily with chloroquinc or chlorcquinc and primaquine weekly. — D. Willeraon, ,4m. J, trop. ,Mcd,
ffyg.. 1972, 21, 138, per J. Am. med. ,4$s., 1972, 220.
1382.
Diformyldapxonc,
4011 to 800 mg with pyrimcthaminc
25 mg, both given weekly, was considered to prowde
effcctivc prophylaxis against chlorcquinc-rcaistant
P Jalctparum and against P. wvax. No toxic side-effects were
noted. — D. F. Clyde er al., Milit Med., 1973. 138.
418, per Trop. Dis. Bull., 1974, 7/. 15.
1380-b
Flydroxychloroq uine Sulphate /B.P. )
sulfate
(LL.S.P.);
Oxichloro-
2-(/v’- {4-(7 -Chloro.Sulptrate:
Win
1258-2.
Lquinolylamino) pentyl]-jV-ethy lamino]cthanol
>ulphate.
C,,8H&lN30,
H1S04=433.9.
~hin
C 4s — I IS4P-3
(hydroxychloroq
vulphnLej
PA=
“,W,m,
[n B, and us,
equivalent
~ pH
of 3.5
Effects, Treatassen~ Precautio~
Resistance. As for Chlorequine, p.395.
uini):
to
77 mg
of
hydroxy
Ocular toxicity in 3 of 99 patients
ment with hydroxychloroquinc.—
Ar(hm”ti$ Rheum., (979. 22.832.
after lon~te~
R. I. Ryncs
[rc..[.
ef al,,
PorpAyria Hydrox ych loraquinc, 4C41mg wcekl y for scvcra[ months. had been repmwd to be safe and effective
in the treatment
of porphyria cutanca tarda.— F. Dc
Mattcis. Br. J. Dcrm,, 1972, 87, 174.
Throm60-em60tic
disorders. Of 565 patients who under.
wem $urgcry 284 rccewd
an inlec(ion of hydroxy chlorcquine
sulphate X43 mg with their premeditation
and then 200 mg etght-hourly by mouth or by injection
unt!l discharge
from
hospital.
From
postoperative
that
observations
and
by phlebgraphy
it appeared
hydroxychlorcquine
could t-c useful in reducing
the
incidence of deep-vein thrombosis and pulmonary emtdtsm,— A. E, Carter t! al.. Br. med. J.. [971, [. 312.
The incidence of deep-vein thromtoxis after surgery was
5% in 107 patients given hydroxychioroqume
sulphate
compared with [6% !n 97 conlrols. The dose was 1.2 g
by mouth in 3 divided doaa In the 24 hours before
surgery followed by 400 mg every 12 hours after surgery
umd diachargc. — A. E, Caner and R. Eban, Br ntrd
J, 1974. 3, 94.
Hydrochloride.
—
53230-10-7
(mej70quine);
reported after doses of 1 g, and nausea and dizziness after doses of 1.75 or 2 g.
UaeS. Mcfloquine
hydrochloride
is a 4-quinoIinemethanol
compound which has schizonticidal
activity
againat malaria
parasites.
It is active
against chloroqtaine-resistant
falciparum
malaria.
$fafaria A preliminary study in 17 subjects of the usc
of mcfloquine hydrochloride in single I-g doses as a
fp&&ctic
against drug-raistam
malaria, — K, H.
nn et al., BuII, W[d Hlth Org.. !974, 51, 37S.
Thirty-rive non-immune volunteers infected with I of 3
strains of Plasmodium /a/ci~m,
2 of them drug- rcais tant, were treated with a single oral do$a Of mefloqujne
hydrochloride 0.4, 1, or 1.5
The infection was cured
in 2 O( 12 given 0.4g, 13 0 ? 15 gwen [ g, and 8 of 8
given I.5 8. In 5 partially-immune
volunteers infected
with P. viwv.s cures were achieved with single dmcs of
0.4 or I g in two, but infection
rcappsarcd
in the
remaining 3 subjects and was subsequently cured w[th
cldorcquoae and primaquine.— G. .M. Trenholmc cf al.,
Science. 1973, 190.792.
None ~ 21 volurttma
bitten by 10 to 15 mosquitwx
heavily infected with P. falctpurum
developed malaria
when given mefloquinc
hydrochloride
250 or W3 mg
weekly, 5tX3mg every 2 weeks, or 1 g every 4 weeks.
h
of 250 mg weekly suppraaed
P, vivax infections
during dmg administration
but malaria appeared when
treatment ceased.— D, F, Clyde ●t 01,. Antimicrob,
Ag.
Chemothtr,, 1976.9, 384.
Of 39 patients with chlorcquine-rcaiscant
falciparum
malaria, 36 (92%) were clcsred of infection with no
rccrudcacencs zfter treatment with quinine. sulfadoxinc,
and pyrimethaminc,
by the regimen of A.P. Hall (Br.
med. J., 1975. 2, IS. ace under Quinine, p.405), while
all of 35 were cleared by treatment
with quinine followed by a single dose of meftoquine hydrochloride
1.5 g
(OOC patient received only 1 g). Side-effects in 40
patients given mcfloquinc were abdominal pain (7).
anorexia (6), diarrhoea (6), dizziness (9), nausea (3),
vomiting (9), and wcaknas (3). Side-effects were minimal or absent if at least 12 hours clapaccf after the last
dose of quinine.— A, P. Hall cr a/,, L?,. med. J,, 1977.
1, 1626.
Ammcal studia of the antimalarial
activities
of 4-quin&
and a report of the
lincmcthanoka
including
mclbquine
US Amry Malaria Research Program.—. L, H. Schmidt
#l al., Amimicrob. Ag. Chemothcr
1978, 13. 10 I I.
Of 37 patianca with chlorc=qumc. raistant
faiciparum
malaria all were radi$.ally cured by a single dose of
mcfloquine
hydrochlond~
1.5 g. S,de.effects
(nausea.
vomiting, diarrhocct, diazm~,
headache) could probably
~ reduced by a fomrulahon
dcs,gncd W, SIOW atJSOP
E. B. Dobsratyn et al.. Bull W/d HIth Org..
tlon.—
i979. 57. 275.
hfctabo(i$m.
Preliminary
s!udy in 1 s:b]ect given a sin.
gie dOf Mcf30yJi~c l~dlcstd
titlvcly
rapid absorp.
uon, extesxswe dt.strsbutlon. and prolonged
elirrri”atlon
phases. Mcflcquinc
was reported to be extensively bound
to plasma proteins and to be concentrated
in erythr~
CVSes.— J. M. Grindel ●t a!.. J. pharm. Sri., 1977. 66.
834.
The kinetics of mefloquinc hydrochloride.—
R. E.DCSjardins ●t al.. Clin. Pharmac. Thcr.. 1979, 26, 372.
1382-g
sulphatc
fB P I. T~bkfs
conmin!ng
They arc sugar-coated
Plaqucrail ( 14’imbrop, L’KI H>dro.vchloroqu\ne sulpham,
os rtble!s
ui
ovailablc as
200 mq.
(AISO
Plaquenll
)n ..tust
.AurJrai
Belg Canad Denm., Fin
Fr Ice/and. lral,. .Ytrh .vcrn
.Swed,, .Swtt:,. L’.sA).
JVa IIJOIC
Other Proprietary
Names
Ercyu,
n :Darm
VOW .’iwt-d $. ~uen$yl
Ger I
S1 773-92-3
Adverse EITeets. Epigastric discomfort has been
Mepacrine Hydrochloride
hydroxychlorcqulnc
142490.
(hydrochloride),
Preparations
Tablets
WR
( * )-a-[ 2.8-Bis(trif3uoromethy
l)-4-quinolyi]-a(2-piperidyl)methanol
hydrochloride.
C,,,, H,... F6N20.
HCI-414.8.
.
For dlscusstons. $ee A. S Gtllus and J. Hirsh. Drugs.
1976, /2, 132. A. G. G. Turplc and J. Hirsh. Br med.
14u//.. 1978, 34. 183,
( U S. P /
399
1381-v
Mefloquine
CAS
of systemic and discoid lupus erythematoaus and
rheumatoid arthritis. Treatment
is usually started
with about 400 to 800 mg daily in divided doses
with meals and the dose is reduced to about 200
to 400 mg what a response occurs. In malaria. a
suppressive dose of 400 mg every 7 days is used,
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 equivalent to 5 mg of base per
kg body-weight,
while for treatment
an initial
dose of IO 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
200 mg thrice daily for 5 days.
Hydroxychloraquine
sulphatc has been used in
the treatment
of polymorphous
light eruptions.
The dose is as for rheumatoid arthritis,
Tablets
Hvdmxychloroquine
hydroxyhloroqu,
ne sulphatc
-
and
Uses. Hydroxychloraquine sulphate has an antimalarial
action simdar to that of chloraquinc
(see p.396) but it is mainly used in the treatment
conla!nmg
747-36-4
to 5.5,
Hydroxychlorcquine
was given in an aver-age dose of
800 mg daily for up to 4H ycsfi to 94 patients with
]upus
erythcmatosus,
rheumatoid
aflhritis.
or SCIe.
rodcrma. The patients had not previously received chls+
roquine, amceJiaquine. mepacrine, w quinine. Corned
deposition occurred in 26 psticnw
it was reversible in
20, pcraistcnt in 3, and 3 were lost to follow-up. There
wsa a rapid rise in incidence after i SO g had been given.
One patient who had received 770 g -r
26fi months
developed t-etinopihy.
A second case of probable rctin~
psthy was subsequently seen in a further patient — R.
V, Shearer and E, L. Dubois, Am. J. Ophrhaf
1967,
64, 245.
Hydroxychloroquiare Sulfate Tablets
+
.e or 31mosc
white
odourless
crystalline
powder
with J bitter
taste.
There
Ire 2 forms.
one meltlng
at about
19t3° and the other
at ~bout
240°.
Hydroxychiorquine
suipha:e
100 mg is
Jpwximately
has
Adverse
with a bitter taste. Practically imvlubla in water: readily soluble in dilute acids;
,@lublc in dilute alkalis. Protect from light.
Hydroxyctrloroquinc
solutiott
in water
from light.
?vfepacrine
(B.P., Eur. P.).
Mepacnni Hydrochloridum:
Acrinamine;
Qurnacnnc Hydrochloride
(U. S. P.); Quinacrinium
Chloride; Acrichinun]; ,4ntimalarinae
Chlorhydras: Chinacrina. 6- Chloro-9-( 4-diethylamino-l
methy’lbutytaml no)-? -methoxvacndine
dihydroch lorlde dihyarate
C:IHlOCl\lO.
2HCI.
?H10=508.9.
C,-SS — w-89-6
(mepacrirrel:
69-0 S-6 (dihydrcxhlortde.
anhvdrnu.r\:
6iS1-30J3
(dihydroch [ortde. dihvdratt-j
Chloroquine
400
Iy
~s
F
k
and other Antimalarial
Pharmacopoeias
1n Arg., Belg.. Br Bra:., Eur.. Fr.,
Ger., Hung., Irsd., lm., It., Mex,, .Velh., .Nard., Po[.,
Rus., Span., Swiss, Turk,. and L.’s.
A bright yellow odourless crystalline powder with
a bitter taste. M.p. about 2>0’ with de~mposition. Soluble
1 in 35 10 40 of wateq soluble in
qlcohol:
sllghtly soluble in dehydrated
alcohol;
‘cry slightly soluble in chloroform;
practically
insoluble in acetone and ether. A 2% solution in
water has a pH of 3 to 5. hreompatibk
with
alkalis, nitrates, and oxidising a~ents, Store
in
awtlght containers. Pro~m from hgfit.
lncompstihiiity.
Mcpacrine hydrochloride
was incompatible with amararrlh.
bcnsylpen!cdlln,
sod!
~iginate,
sodium
sodium
amirroaahcylatc,
sodnsm
Iauryl
sulphatc.
and
=rtixy.mclif,lccllul~,
thiomeraal.—
J,
Am.
pharm. Ass., pracr, Pharm. Edn. 1952, 13, 658,
Adverse Effects. Minor
effects liable to arise with
ordinary doses arc dizziness,
headache,
and mild
gaatro-intestinal
disturbances.
Moat patients develop a yellow
disuxloration
of the skin.
Large
dosea may give rise to nausea and vomiting
and
occasionally
to transient
mental
disturbances.
A
fcw
patienta
develop
chronic dermatoaes after
prolonged administration
of the drug; these may
be either lichenoid, eczcmatoid, or exfoliative in
type. Deaths from exfoliative dermatitis and from
hepatitis have hen reported. The use of meptscrine over prolonged pericds may give rise to
aplastic anaemia.
Adverse cffecta of intrapleural
instillation include
fever and cheat pain caused by the inflammatory
react ion.
The toxicity arising from pro}onged administration has contributed to the decline in the usc of
mepacrine in malaria.
Two patienss had cavutsiom a few hours afier Ihe
intmpleural
administration
of mepacrinc
bykochloridc
400 mg for malignant
effusions,
Orre dcvetopad status
epilcpticus
and died: the other was wscccasfully controlled with phenobarbitone
intravenously msd phcnyroin
by mouth.— 1. Borda and M. Krant, J. Am. med. Am..
1%7, 201, 1049.
Mepscrirte
hydrochloride
100 mg
daily
had
been
.-eportcd
to csusc hacmalytic
anaemia
in cersain indivi~alc with a deficiency of glucose-d-pbapbate dehyd.0 crsase.The reaction was rsm considered ctinieally sigm/ lam under normal circumstances (e.g. in the absence
of infection).— E. Bcutkr, Pharmac. Rev.. t%9, 21. 73.
A patient with rheumatoid arthritis treated with mcpacrinc hydrochloride
for about 20 years had developed a
blue-black discoloration
of the hard patate, the nail
beds, and the skin over the shins, The colour diaap
pearcd when mcpacrine was stopped and reappeared
when it was restarted,—
M. J. Egorin ●f al., J. Am.
med. Ass.. 1976, 236, 385.
Trestment
of Adverse Effects. As for
Chloro-
quinc, p.396.
Precautions. Mepacrine enhances the toxicity
‘
~~v
of
the B-aminoquinoline
derivatives such as primaquinc by inhibiting their metabolism.
Mepacrinc might interfere with fluorimctric estimations
of plasma hydrocortisone.— J. M illhouxc, Adswrst Drug
Rcacl Bull., 1974, Dec., 164.
, ~ Absorption aod Fate. Me~crine
is absorbed from
] the gastro-intestinal
tract
and
ap~rs
in the
~blood within 2 hours. Itbecomes eorrccntrated in
liver, pancreas, spleen, and lung, and higher concentrations
occur
in red and white blood cells
than in plasma.
but it also permeates
into all
body
fluids
and, crosses the placenta,
It has a
biological
half-hfe
of about
5 days
and
is
excreted
only ver! SIOWIY in the urine and faeces.
Mepacrinc
hydrochloride
wss bound to serum protcim
in vilro.— G. A. Lutty, Toxic appl, Wrarmac.,
1978,
44, 225.
?2,--
Uses. Mepacrine
was formerly widely used for
the suppression and weatmcm
of malaria bul it
has been superseded for these tmrooses bv chlorw
quinc and &her more recentiy ~ntrodu~ed” a-ntimalarials.
Doses ranged from
suppression and from 900
g reducing
to
*:;
for
‘uily
tscd
treatment.
In the [reatment
&crnc-fiyd~~hloi~Z
of glardlasls:
is
ICQ mg thrice
daily for 7 days is usually cffccuve.
though
relapses may occur,A suggeweddose for children is 2.7 mg per kg body -weigh[ thrice daily.
It has been used for the expulsion of tapeworms;
100 mg is given at intervals of 5 minutes until a
total dose of 1 g is reached.
Instillations of mcpacrine hydrochloride or mesy latc arc used in the symptomatic
treatment
of
neoplaatic effusions in the pleura or peritoneum
but the treatment
is associated with a high frequency of toxic effects.
For tJsc use of mepacrine as an anthclmintic,
see A.
Davis, Drug Treatmenr
in intestinal
He[mtrrlhiases,
Geneva, World Health Organization. 1973.
Giasdiaxia. Mcpacrinc 100 mg thrice daily for 5 to 7
days was usually effective in the treatment of giardiasis,
although a sccmzd course might Isc required. The dose
for children under 4 years old was oncquarter
of the
adult doac.— fJr. med. J., 1974, 2, 347.
A 95% cure-ra!e was obtained in giardiasis after treatment with mepacnnc hydrochloride
100 mg thrice daily
for 7 days. Dosages in children were: under I year,
33 mg thriec daily; I to 4 years, 50 mg twice daily; 4 to
8 years, 50 mg thrice daily over 8 years. 100 mg thrice
daily, all for 7 days — M. S. Wolfe. J. Am. med. Am.,
1975, .733, 1362.
Further rcfcrcncc.s G. T. Moors ●! al., New Engl. J.
Med., 1969, 281. 402; Med. Let(., 1976, 18, 39; R. E.
Raizman, Am. J. djg. Dis., 1976, 21, 1070.
Maliguat
cfiusissrxs. The value of local instillations of
mepacrirte in controlling cffusions in advanccxl disseminated ncoplastic disease was studied in 60 patients, For
plcctcal cffusions,
followed
by 200
an initial
doss of
to 400 mg daily
50 to 100 mg was
for 4 or 5 dayx
patients with ascitcs rcccivcd IW to 2CQ mg followed by
400 to 800 mg daily for 3 to 5 &ys. The mcpacrinc was
[email protected]
in 10 ml of the cffasion fluid which was then
rc.mjectcd.
Of 33 patients cliniedly
evahsawd for 2
months or more, objective control of the cfftssion was
maintained
in 27 for 2 to 26 months.
Fever, often
accompanied
by Icueocymais and persisting for a few
hours to 10 days after completion of treatment.
was
noted in about half the patients.— J. E. Ukmann et Izf,,
Cancer, 1963, 16.283.
Thirteen patients with ncoplastic effusiom were treated
with mepacrinc
hydrochloride
in dmcx of I MI to 2C0 m
daily by local instillations for pleural effusions, and 2d
to 400 mg daily for ascitea, usually for 3 to 5 days
Clinical benefit with favourablc objeetivc changes in all
measurable criteria of the disease was seen in 9 patients
for periods of up to 27 months. Mild Icd
toxicity was
frequccu but hacmatopmc:ic
depression did not @cur.
No consistent cytoly!ic
changes of tumour wlls were
observed and response was a!trihutcd
10 the inftamma.
tion and fibrosis produecst.—
M. R Dollingcr
el al.,
Ann. im. m. Med., 1967, 66, 249.
There was a response in E of 12 patients with malignant
pleural cffusions given mepacrinc by Instillation in small
daily doses, and in 19 of 27 given mcpacrinc as a single
dose through a \horacoatomy
tube. More disturbin
and
serious toxicity occurred in the xomnd group.— fi R
Borja and R. P. Pugh, Cancer, 1973, 31.899.
A beneficial effect (less than S00 ml fluid drawn at
each plcurrrccntcsis in 3 months) was achieved on 9 of
14 occasions after the instillation of mcpacrinc
(100,
200, and 200 mg respectively on 3 occasions in 1 week).
on 4 of 15 ocasions after thioteps (20 mg ~r instil)aalone.
uon), and on 1 of 9 occasions after pleurocenwsis
Fever and cheat pain were limiting factors: mcpacrinc
was suitable if tbc patient’s condition and prognosis was
good;
otherwise
thlotcpa
J. McJcr er al..
prefcrred.—
or
plcuroecnmais
Scarrd J. resp Dis.,
were
1977.
S8. 319.
Furtbcr references: J. A Hickman and M. C. Jones.
Thorax, 1970, 15. 226; M Lee and D A. Boycs. J.
Obswr. Gynocc. Br. Commonw., 1971, 78, 843.
Prwnsorfsorax A patient with cystic fibrosis was treated
for pneumothorax
on the Icft side by the instillation of
mepacrinc hydrmhloride
100 mg in 15 ml saline into Lhe
intraplcural space on 4 corssecuuvc days This procedure
was repeated 12 months later for pneumothorax
on the
right. There was no recurrence of pneumothorax
on
either side before the patient died 1I months after the
second treatment
after several relapses of chronic pulmonary disease — J. Kattwinkcl e( al.. J. Am mrd
ASJ, 1973, 226, !!? Srx also R E Jones and S T
Giammona, Am J Dis. Child, 1976. 130, 777.
Tubal accfvsion
sion
of
mepacr]nc
T*o
104 ml of a 30% aqueous suspeninstlllcd transvaglnally
hydra-chloride
once in the immediate
cutive cycles induced
postmenstrual
phase of 2 consetubal occlusion in 93’% of 134
warner, — Advances lr Methods of Fe.rtiiit~ Rcgulat\oP.,
TtciI Rep .% W/d Hlth Org ho. !27, 1973
SIXI!
women
desiring
s~erilisat!on were Ircawd b] tnc
within the uterus. of I ~ or
suspended
In 7 ml of slcplic
wa~er Of S2 avaiiabie for cxam!nation 4 montns Iz!cr,
22 nad bilateral tubal patency and 3 uniialcral paumc!,
a further 6 were prxgnanl. The low success-rate o! ~
smglc application
\ridicatcd
hmlted
usefulness — c
Israngkun et al., Contraception,
1976, 14, 75.
b) cannuia
hydrochlor]dc
appll:auon.
mcpacrme
Sf’’arrs. A local injection technique was used in the treat.
mcm of warrs in children. A 4% solution of mepacrl”c,
in doss of 0.1 to 0.2 ml. was injected mto the health,
skin al the base of the wart, 3 to 6 warts being Iream,j
a! each session. The injections were repeated tu wc if “o
response followed the first injection
The trc.almen! Ua$
successful in 97 of I 12 patients
It sometimes caus~
slight ~ransicnt pain.— A. 1. Lopatin. Pcdiav!}a,
1966,
45, 71, per Ab$!r. W/d Med., 1966, 40, 446
Preparatiorsa
Mepaccinc Tabkta (B.P.). Tablets Containing mepacnnc
hydroch16rid~o!cct
from ~.
Quirracrissa Hydroelrloride Tablets (L’.S.P.). Tablets con.
taining mepacr’inc hydroch~
Slore in ainighl con.
tainers.
Proprietary Names
Atabrme
~~!~,
(~inrhrop,
USA),
Carrad.):----Atabrine
.._,
Hydrochloride
-.
Mepacrinc
hydrochloride
was formerly
markelcd
In
certain eountrics under the proprietary name Qulnacrinc
(Mtr) & Baker).
1 3B3-q
Meptscrine Mcsyiate. Mepacrine Mcthancsulphonate
IB.P. C 19631.
C11H;OClti]0,2CH,S01
H, H20-610.2.
CAS — 316-05-2
(arth~drous)
Bright yellow odourkss crystals wi~h a bitlcr taste.
Mcpacrinc meaylate 120 mg is approximately
quivalcn!
to 100 mg of mcpacrtne hydrechloridc. soluble 1 In 3 of
waler and I in 36 of alcohol. A 2% solul ion in water
has a pH of 3 to 5. Protect from light Solutlons should
not be heated, or stored for any Icngth of time
Uses. Mcpacrine mcs} Ia!c has actions similar to those O(
mepacnnc hydrochloride,
but as IL is more soluble than
the hydrochloride
It has been administered
b} !n:ra.
muscutar injection in the treatment of severe malaria A
dose of 360 mg has been given in 2 [o 4 ml of Waler
for In!cct ions.
It w gwcn by imraplcural
or lntrapcritoneal
)ns[illa~lon
in the treaimcn! of ncoplastic cffuslons.
Preparations
Mepacrine Mettxancmdphosmte injection (B.P C /963/
Mcpacrine
Mcsylatc
lnJection.
A s~crtle solut!on of
mepacrinc mcsyiaw in Waler for Injections, prepared b)
dissolving, immediatcl} before USC.the sterile contents of
a sealed container in U:atcr for Injections
Mcpacrinc mcsylate was formerly
countries
under
the
proprietary
Soluble (May & lhdw)
marketed
name
In ccrtaln
Qulnacnnt
1384-p
Pamaquin (B.P. /9531 Gamctocidum:
Pamachini
Pamaquinc Embonate. Plasmcqujnum:
SN 971 8-(4.
Dieth!lamln*l-mcth>
)butylamino)-6-mcthoxyqu]nol!nc
4.4’-merhylenebis( 3-h> droxy-2-naphthoa [e)
C,: H4. S307-703.8
CAS — 49/-92-9
(base), 635-03-2
rembona(e)
A yellow [o orange-}cllow
odourless powder with a btl.
tcr taste Practical}
insoluble in water: soluble 1 In 20
of alcohol.
USCS. Pamaquin
was formed~
used In the trea!mcn!
of
malaria but has been superseded b) prlmaqumc phos~
hate
~
A. INGREDIENT NAME:
SILVE R PROTEIN MILD NF
B. Chemical Name:
c.Common
Name:
Argentum Creole, Collargol (9CI), Colloidal Silver, Stillargol, Vitarg6nol, Aust.:
Coldarg~ Fr.: Pastab~ Ger.: Coldargaq Ital.: Arscolloid, Bio-Arscolloid, CortiAscolloid, Rikosilver, Rinatipiol, Rinovit Nube.
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay: (tier ignition)
([email protected]@
(Results)
19.0-23 ,()~o
19.74?40
—_
E. Information about how the ingredient is supplied:
Browq Dark-Brown,or almost black, odorless, lustrous scales or granules, somewhat
hydroscopic, and is affected 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 of the eye in ophthalmic
surgery. II. Effectiveness of mild silver protein solution. Archives of Ophthalmology, 1983;
101(5): 764-765.
Apt, L. and Isenberg, S. Chemical preparation of skin and eye in ophthalmic surgery: an
international survey. Opthdmic Surgeryp 1982; 13(12): 1026-1029.
_-—=
_—
H. Information about dosage forms used:
Liquid
1.
Information about strength:
1-20%
J. Information about route of administration:
Nasal
Opthalmic
K
Stability data:
L. Formulations:
M. Miscellaneous Information:
-
Page -2-
‘“”\.
..+
..
.-%
CERTIFICATE OF ANmYSIS
-------.------------- --
LOT #
:B6169sG18
SPECIFICATIONS
------------ --
1.
DESCRIPTION
2.
Identification
3.
Volubility
4.
Assay
5.
Ionic silver
6.
Distinction from strong
silver protein
Black granules
TO pass test
Date
TONY
:06/23/97
NO turbidity
Conforms
pass test
Passes test
10762
..-—.
HATCHETT
prepared by
..
A. HAZARI
Approved
/’
...
./
Conforms
1~%
__—_
ATTENTIoN:
RESULT
----- -
Passes test
19.0 - 23.0%
TO
GRADE:NFXIII
CODE:DS78S
Passes test
TO pass test
(after ignition) ~
QL ,3
d lfflyq
PRODUCT: SILVER PROTEIN MILD
RELEAsE #: N
.
y~”
by
QUALITY
_—_
—
NAME. :SILVER
CHEMICAL
MANUFACTURE
LOT
NO.
CONTROL
PROTEIN MILD
REPORT
NF
.4
:C64O51D1O
PHYSICAL TEST
SPECIFICATION
l)DESCRIPTION
TEST
STANDARD.
/BP
——
/MERCK
/NF
——
/MART.
— /CO.SPECS._.
.:
c{
5
:USP
BROWN, DARK-BROWN,OR
GRANULES;
SOMEWHAT
ALMOST
BLACK,ODORLESS,
LUSTROUS
HYGROSCOPIC,AND
IS AFFECTED
BY
SCALES
LIGHT.
OR
2)SOLUBILITY. :
FREELY SOLUBLE IN WATER. ALMOST INSOLUBLE IN ALCOHOL,CHLOROFOP.M
AND IN ETHER.
3)14ELTING
.~.
.—
POINT.:
.
4)SPECIFIC
GRAVITY
5)IDENTIFICATION
A)COMPLIES
B)COMPLIES
PASSES.
..4.
.:
(B) AS PER NF 10th
(C) AS PER NF 10th
EDITION
1955,
EDITION
1955.
FAILS .:
:
CCM4ENTS.
:
ANALYST
SIGNATURE.
PRIZPACK
TEST.:
RETEST
.:
.:
DATE .:
:
DATE
DATE.
:
.:
INITIAL.
INITIAL.
:
:
------------------ IDENTIFICATION ------------------PRODUCT #: 29824-7
NAME: SILVER PROTEIN, MILD
CAS #: 9015-51-4
SYNONYMS
~
ARGENT~
CREDE * COLLARGOL (9CI) * COLLOIDAL SILVER *
------------------ TOXICITY HAZARDS ------------------RTECS NO: VW3675000
SILVER COLLOIDAL
TOXICITY DATA
ORL-MC.JSLD50: 100 MG/KG
JPPMAB 2,20,50
REVIEWS, STANDARDS, AND REGULATIONS
ACGIH TLV-TWA 0,01 MG(AG)/M3 851NA8 5,529,86
MSHA STANDARD-AIR: TWA 0,01 MG(AG)/M3 DTLVS* 3,231,71
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 FLUSH EYES OR SKIN WITH 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 CHEMICAL POWDER OR APPROPRIATE FOAM
SPECIAL FIREFIGHTING PROCEDURES
n
.—’+.
_-
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHTNG
TO
PREVENT CONTACT WITH SKIN AND EYES
UNUSUAL FIRE AND EXPLOSIONS HAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS
------------------- REACTIVITY DATA ------------------INCOMPATIBILITIES
STRONG OXIDIZING AGENTS
PROTECT FROM LIGHT
ACIDS
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
TOXIC FUMES OF
CARBON MONOXIDE, CARBON DIOXIDE
--------------- 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 --WEAR APPROPRIATE NIOSHM4SHA-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.
AVOID CONTACT WITH EYES, SKIN AND CLOTHING,
AVOID PROLONGED OR REPEATED EXPOSURE.
WASH THOROUGHLY AFTER HANDLING,
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
.n.
POSSIBLE)
WEAR SUITABLE PROTECTIVE CLOTHING, GLOVES AND EYWFACE
PROTECTION.
REGULATORY INFORMATION
200?40SILVER COMPOUND
THIS PRODUCT IS SUBJECT TO SARA SECTION313 REPORTING REQUIREMENTS
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
Sanguinaria/Slipper-y Elm
gmy discoloration,
Silver is used a.ra cOiis nrgyriz a general
of confectionery. It i3 ak.o used
ouring agent for some rypx
m Afsenmm Metallicum in homeopathy,
Numerous salts or comprnmds of silver have been employed
for various therapeutic purposes, including silver acetmc
(P. 175 I). siIver allantOinate ~d silver zinc allmtOinate, silver
borate, silver carbonate, silver chloride, silver chromate, silver glycerolam, colloidal silver iodide, silver Mate, silver
marrganite, silver nitcme (p. 175 I ). silver-nylon polymecs, silver protein (p. 175 1), and silver sulphadiazine (p.273).
A repoet of reversible neuropathy associated with the absotp.
tion of silver from an acthroplzwy cement. ]
1. Vik H, ef cd. Neuropathy caused by silver absorption from arthroplarly cement. J&w-et 1985: i: 872.
Cuating catheters with silver haa been repotted to reduce the
incidence of catheter-associated bacteriuria, 1,2but other studies have cqmrted increased infection.3
1. Lundebmg T. Prevention of cathcler-associated urinary-tract
infections by usc of silver-impregoratedcatheters. Lancer 1986.
ii: 1031.
2 Johnson JR, et al. Prevention of cathctcr-asswiated urinary
watt mfechons wilh a salver oxide-coaled urinary catheter:
chmcal and microbloioglc correlates. J Infrc! DiS 19W, 162
1145-50.
3. Riley DK, er al. A large randomized clmcal rrial of a silver-
imprcgna[edunnaV catheter lack of efficacy and srspbylmoccal su~rinfcction. AmJ .Ued 1995, 98: ?-49-56.
Preparations
Names of preparations are fisted bslow; derails am given in Pan 3.
Pmptietsry Preparations
Awmat.: Micmpun Canad: Tabattil; Gcr: Dulcargatrt; Silafgcltent.
Multi-ingredient
preparations.
Amrnd.: Sims-Varix Bartdaget; Stmanitet; Fr: St&ilet T au Cuiwe Argemt; Gen: Adrorgant: Grfhte Salbc ‘Schmidt” N; }rd.: Ac!isorb Phrs; Agipiti
Katodenm Kamxyn; Nova-T Silver-Nova T?: Spnin: Argentmo; UK: Acrisorb Plus.
Silver
Acetate
(5319-P)
~cial
Preparations
f7SNF18; Pharmaceutical Glaze
Siam
Benzoin
A bshrrric resin from Styur mrkuzerui$
(Styracaceae) and
containing not more than 10% of alcohol (90%)-insoluble
matter,
yellowish-brown
to rusty brown compressed pebble-like
tears with an agreeable. balsamic. vanilla-like odour. The
and brittle at ordmr-y temperatures, but
s
n used similarly to Sumatra benzoin
en used as a preservative and was forat]on of benzomated Isrd.
~m. \
isted bdou,, details am given m Pact 3.
Officia
USP 23: Co
Cd Solution.
Tmcmre; Podophylhrm Resin Topi-
Sore Lotio”t; )ra!. CJ”d
in; Vafrm Batsamicost.
,-.
Silver
f5316-v)
\
\
E174.
‘%=
107.8682.
: — 7440-22-4.
JrmOCopoems,In SWISS. \
&
#~ ~Pure white, malleable and du~
kbher as the metal m as silver Salt
“’fhe sym~l
7:535-40.
?. Gourlay SG, McNeill JJ Amismokmg products Med J
Preparations
of preparations are listed below:
Natrres
Bqoin du Laos; Benzoe Tonkmensis.
Phormacopoeios. In Au.eL,Chin., Fr.. /L, and Swms.Also in many
pharrmacopoe{as under the title benzotn and should not be
confused wflh Sumatra Benzom. Hung.,Jpn, and US allow both
Sam benzom and Sumatm benzom under the title Benzoin.
on frscrure
softe
References.
1. Jensen EJ, e! al. Serum concentrations and accumulationof silver in skm dwing three months’ trmtmem with an anu-smok
mg chewing gum confammg silver acetate. Hum TOXICO11988;
Ausr
1990, 153:699-707.
(273-c)
t denotes a preparation
Id is used topically
pt absorbed to any
d with the met.d
dchils are given in
Uses and Administration
Silver nitratepossesses
disinfectantpropertiesand is used in
mstry countries ss a 1% solution for the prophylaxis of gnnocd
ophthalmia nemtaromm (see Neonatal Conjunctivitis,
when 2 drqrs arc instilled into each conjrmctivaf sac of
the nconste. However, as it csn cause irritation, other agents
are often used
In arick fomt it Irss been used as a cauatic to destroy wsmr and
other sma31skin growths. Compresses soaked in a 0.5% solrttion nf silver tdusdc have been applied to severe bums to reduce infection. Solutions have also been used as topical
diainfectarrts and astringents in other conditions.
Silver nitmte (Argerrrum Nitcicum; Argent. Nit.) is used in ho
mceopmfric medicine. It is also used in cosmetics to dye eyebrows and eye lashes in a concentration of not more than 4%.
p.151)
Preparations
of preparations art listed below; derails are given in Part 3.
Names
Officist
Prepsntfom
UW 23: Silver Nimue Ophtbafmic Solution; Toughened Silver
Nitrate,
Pmprietsry Prepsrstions
Atmraf.: Howe”s SoIutiont: Quitt; Ger: Mova Nitnt; Pluralane:
Spain: Arpcnpal.
Multi-ingredpreparations. AusrraL: Super Banish; Spain:
Argentofenol; SWirL:Grafco: UK: AVOCA.
Pan 3.
PrOprieeary Prepvations
UK Tabmint.
silver Nitrate
Pharrnacokinetics
Silver nitrateia ncxreadily absmbed.
1987: i: 304-6.
Silver acetste has been used simikar]y to silver nioafe ss a disinfectant. [t has also been used in amismoking preparations.
. ~’eparations
Names of preparations are Iiwed below: demils me gwen in ParI 3.
Silver nitrate from a stick containing 75% was applied to the
eyes of a newborn infant instead of a 1% solution. 1 After 1
hour there wcs a thick prtmlent secretion, the eyelids were red
and oedcnratous, and the conjtmctiva markedly injected. The
corneas had a blue-grey bedewed appearance with areas of
wmeaf opacification. A& treatmentby Iavage and topicsf
applic~,on Of antibiotics snd homatropine 2% there war a
marked tmprovernent and after I week topicaf application of
corticosteroids wss sinned. Residuaf damage was limited to
slight corned opacity.
1. Homblass A Silver nitrate Dculardamage in newborns. JAMA
1975:231:245.
Cystitis. Comment on sifver nitrate irrigation having limited
vafue in the trrsnagemem of hemorrhagic cystitis after radiotherapy. i
1. AnDDynrous. Hscmorrhagic cysti!is after radiotherapy. Lancef
Argenti Acetas.
CH3COOAg = 166.9.
CAS — 563-63-3.
Phorr-nacopoeios.In AtiL and Hung.
ge,
1751
Chronic application to the conjunctival, mucous surfaces, or
open wounds lads to at’gytia, which though difficult to treat
is considered to he mainly a cosmetic hazard, see under Silver
(above).
Absocpdon of nitrite following reduction of nitrate may cause
metfraemoglobitraemi~ There is also a risk of electrolyte disturbances.
Treatmenl of rbese adverse effects is symptomatic,
(5321.h)
Silver
Protein
(5322-m)
Albumosesilbec Argentopmteinum: Argentum Prntemicum;
Protsrgolum; Prote!nato de Plata: Proteinato de Praw Strong
PrOrargIrTStrong Protein Sdvec Strong Silver Protein.
CAS — 9007 -35-6 (colloidal silver).
Argemi N!tw Nm_ato de Plata; Nitrato de Pi-m
NOTE.Synonyms for mild silver protein include: ArgenroproAgN03 = 169.9.
teinum Mire; Argetrtum Vklinicum;
Mild Protargin; Mild
C/U – 776 I-88-8.
Silver Proteimue; Silver Nucleinate; Silver Vlte]lin;
Pharmacopneios. In AWL, Belg., &., Cz., Eur., Fr., Ger., Hung.,
Vdelinato de P1am and V}relinato de Pcata
/rIL, IL,Jpn. Netft., porn, Swu’s,and US.
IL, and/pn.Many
The standards of Ph. Eur.aDDIY
,,, to those countries that are Dar-~ -Phomrocopekm ln~G.,Fr.,H.rrE.,
ues to the Convention on the Elabomtion of a European Phar-’ of these pharmacopoeias include monogmphs on mild silver
protein ~ well as o’n collotdal silver.
macopoem, see p,xm,
Silver prolein solutions have antjbaiteriaJ properties, due to
Colorless or white lransparem crystals or crystalline cdourthe presence of low concentrations of ionised silver, and have
Iess powder. On exposure to light in the presence of organic
been used as eye drops snd for application [o mucous memmatter, silver nitrate ~cnmes grey or greyish-black.
branes. The mtld form of silver protein is considered to be less
Soluble I in 0.4 of water and I in 30 of alcohol: its volubility
irritstmg. but less active.
is increased in baling water or alcohol: slightly soluble in
Colloidal silver which is also a preparmion of silver in comether. A solution in water hzs a pH of about 5.5.
bination with protein has also been used mpically for its antiSilver nitrate is incompatible with a rangeof subsrsnces.
Albacterial activity.
thoughit is unlikely that there will be a need to add any of the
interacting substarrces to silver recrate solutions considering
Preparations
m current uses. pharmacists should be aware of the potential
of prqar’auons srr lis~d below: dewds are given In Pan 3.
Names
for incompatiblbty. Stem m aimght nrnr-metaflic containers.
Proprietary
Preparations
Protect from light.
L
FE: S~
The reported yellow-brown dlscolormion of samples Of sih er
Multi-ingredient
preparations.
Aurt.: Coldangam Fr: Pasra-L-faz GeK: Coldmgan+: Ilal.: ArsCDlloid:Bio-Arscollo]d; Cort-AInirrme bladder migation ( 1 m 10 000) probably arose from
scolloid;
Rikosilven
Rirtamipiol;
RinovI[
Nube.
the reaction of the silver nitrme with alkali released from the
)
glass bottle wh]ch appeared m be soda-glms.!
I PSG8 Lab R,f)orl P/80/6 1980
Slippery
Elm (5458-[)
Adverse
Effects
Symptoms of poisoning stem from the corrosive action of silver mrrme and include pain in the mouth. sidorrhoea, diarrhoea, vomiting, coma, and convulsions.
A shon hved mmor conjunctivitis is common in mfams given
silver mtrate eye drops: reptmed use or the use of high conccmrations prnduces severe damage and even blindness
~er actively marketed
Elm Bark Shppery Elm Bark Ulmus: Ulmus Fulva
Phormacopoe#os In US.
The dried inner bark of Ulmusfulvcr (=U. rubra) (Ulmaceae).
Shppery elm comains much mucilage mrd has been used as a
demulcenr.
942
-.
Metals
and some Metallic
Salts
Epidrrmrd nrcroiysis. Based on (he treatment of 10
cases. the following was suggested as mcatmcm for toxic
epidermal
necrolysis: continuous
moist compresses
of
silver nitrate solution 0.25 to 0.5%, with generous wrapping to prevent
excessive coahng
dady electrolyte
estimations
and daily debridement:
after about the
fourth day the compressca could be replaced by dexamethasonefncomycin spray followed by inunction of wool
alcohols ointment. A penicillin should be gi~en routinely
and steroids if vasmlitis was present.— P. J. Koblmzcr,
Archs Derm., 1967, 95, 608.
Fferpm simplez
Silver nitrate I% had little cffeet in
vimo or in viro against herpes simplex vims type 2.—
V. R. Coleman et al., Amimicrob.
Ag. Chemother.,
1973.4, 259. A further study.— F. Shimizu et af., ibid.,
1976. fO, 57.
Hydetid CYSIS. Intrahepatic cysts of Echinomccus granufosus were treated with excellent results in 20 patients
by freezing tbe operation area then administering
silver
nitrate 0.5% to destroy tbe scolima.— 1. Nazarian and
F. Saidi, Z. Trapenmed. ?arasit., 1971, 22, 188, per
Trop. Dis. rYufI., 1971, 68, 1356.
become grey or greyish-black
on expmtre
to light.
Freclv soluble in watec sparingly soluble in alcohol.
Prote~t from light.
A similar preparation is included in several pharm~cupoeias.
Toughened Silver Nhte
(U.S.P.J. Contains not leas than
94.5% of AgNO1, tbe remainder
consisting of silver
chloride. Store in airtight containers. Protect from light.
Creanss
Silwr Nitrate Cream. Silver nitrate. 0.5 or 290, Xalitin- 15 20%, water to 100%. The cream was stable with
onlv sliebt discoloration when scored for 4 weeks in the
da~k ‘at” rcom Iemperaturq
at 0° to 4° there was no
discoloration.-Pbarm.
.%x. Lab. Rep. P/68/ 15.1968.
Eye-strops
Ocrdoguttae Argend Nitratks pro Neorratia (Da..
Silver nitrate
670 mx, ootassium
nitrate
1.2
Water for Injections. $8.13 g.
A similar preparation is included in F.N.Be4g.
Silver Nitrate Eyedro
nitrate
Nit. silver nitrate 0,5~ ~~~C. pmasaium
1954) Gutt.
w/v. in Sofution for Eye-drops,
Nerd. P. hasI% w/w with potassium nitrate I%
Water for Injcctiona.
Disp.).
g. and
I .33%
Ar8ent.
Preparations
‘k&
silver Protein Eydropa
(B.P.C. 1963). t$
rot. A solution of silver pro~cin 5%, with ,
acetate or nitrate 0.002%. m water.
f’f%?
ving, aseptically. the silver protein in ,$
solution of pbenylmercuric
acetate or it..,
ferring to the final sterilised cmrtainerF
must be freshly prepar~. They are a~,~
by alkali. Protect from hght.
-SF
-4
Proprietary Names
:*
Stillargoi (Mayoly-spindler,
Fr.).
.7 &
Mild Silver Protein (B.P.C. 1968). A&
Mite; Argcntum Viteilinicum; Mild SilvesJ
Silver Nucleinat< Silver Vitellin; Mild pm.
nato de Plats; Vitelinato de Prata.
“’”-~
?
NOTE.Tbe name Mild Silver Protein fi
compound because ii is lma bactericidal’~
than Silver Protein, though it contains nto.,
Ophthalmia rreonutorum. In a study of the incidence of
ophthalmia neonatorttm in 220000 births, it was found
that in 92865 cases where preparations other than silver
nitrate were used the fr ucncy of gonomccal ophthalmia nemrator.m was 0.0% wh.xem where silver nitrate
was used the rate was O.I%. Silver nitrate did not
always suppress the development of the condition and
seemed no more effectwe than other agents. While a
drop of I% silver nitrate solution did no harm, there
~3 ;i#e
evidence that it did any goad.— Lacer,
1949.
Nitratia Cmrrpoaitam.Compound A bydroacopic brown pawder or nearf y-$
“1
Silver Nitrate Ointment. An ointmentwith this title is granulca with a slight odour and taste. u
Of the 49 states of the
tions rquiring
routine
eyes of newborn infants,
applications: No eyldencc
Opbtbalmic SoIrrtiosra
silver Nitrate Ophthalmic SoIrstkon (U.S.P.). A solution
of silver nitrate 0.95 to I .05% in an aqueous medium.
pH 4,5 to 6. It may cmrtain sodium acetate as a buffer.
Store in singiedoac mntainera. Protect from light.
USA which had made reguksprophylactic
treatment
of the
22 had specified silver nitrate
had been found to contra. indi-
w/w in
Pharmacopoeias.
In Arg.. Be[g.. Fr.: I&
> :.,tj
Roum.. Span.. Swiss, and Turk.
Obmrserrta
Lfngrsesrtum Asgenti
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 wool
fat.
~~dl~% ~y~d$~$~~r~fie~$ea~~Z~~id~$~~
gonorrh~
had rendered continued routine prophylaxis
neceaaary.-P.C.
Baraam, New Engl. J. Med.. 1966,
274, 731. Fewer local reactions accrwred with penicillin
than with silver nitrate eyedrops. Penicillin for neonatal
prophylaxis should not be abandoned. since it did not
appear to Sensitise infants.<.
Natherwon (letter), ibid.,
275, 280. Eye-drops containing la
than 2% of silver
nitrate were considered to be ineffective. Treatment was
effective if applied early and prophylaxis was advised
only in infants whose mothets were known or suapcctcd
to be in fected.— E. B. Shaw (letter), ibid.. 281. See
also P. Kober, hfedsche Klin., 1967, 62. 424.
To prevent gonorrhoeal ophthalmia
neonatorum,
a 1%
solution of silver nitrate was instilled at birth. The
chemical conjunctivitis
caused by silver nitrate was of
shart duration.— P. Tb ygmon, J. 4m. med. Ass.. 1967,
20/, 902.
For reparts on the chemical conjunctivitis
associated
with instillation of silver nitsate eyedro~
and recommendations for reduction of the incidence, see Adverse
Effects (above).
Sofutioru
Ammoedac8f Sklwr fWtrate SoIutkm
(U,S.IV,F. XII,
19651. Ammoniacal Silver Nitrate, Howe. A solution of
diamminoailver
nitrate was prepared from silver nilrate
704 g. water 245 ml, and strong ammonia solution to
dissolve ail but the last traa
of precipitate
(abaut
680 ml).lt contains 28.5 to 30.5% w/w of Ag and 9 10
9.7% w/w of NHY Store in small glasa-stoppercd container or in ampmk.
Protect from light.
This solution has keen employed in dental surgery to
deposit silver in exposed dcntine or to till up small crevices in the tcetb. After the solution had been applied to
the toath it was followed by a reducing agent such as a
10% formaldehyde solution or eugenof to cause a depaait
of metallic silver. The solution has also been employed
in the trcatmmt of fungous infections of the nails.
Sobrtio kgenti
Nitratis
cum Tehmdrto
(Nerd. P.).
Silver nitrate 200 mg. amcthocaine nitrate 100 mg, and
water 99.7 g.
[1
Prrermrothorar. Spontancoua pneumothorax
was sucmsafully treated in 132 patients by pleurodeais induced with
silver nitrate repeated pleurodeais was nexsaary in only
2 patients. It was suggested that this therapy should be
used for patients with only small or no blebs visible on
thoracosmpy,
or with on] mild pre-existing
lung disease.1. Anderson and k. Niasen, Dis. Cfrcst, 1968,
54.230, pcr J. Am. med. Ass., 1968, 2~. 68 [.
Mova Nitrat
Wowrds. Silver nitrate solution 0,5% was more effective
against Gram -positive than Gram-negative
bacteria’ in
the treatment of nontbermal war wounds. The solution
did not hinder wound healing or epithelialisa!ion
of split
thickneaa skin grafts.— J. P. Connors ef al.. Archs
Surg., Chicago, 1969. 98, 119, per J. Am. med. Ass.,
1969, 207, 580.
ncwwxcn-ttt
LGr
I or.
Pippette
un.ucnm.1, up=. I u--in.
(Lisrdopharm, Ger.).
u.
silver protein (B.P.C. 1968). Argentoproteinum;
Strong Protein Silver Strong Rotargin; Argentum
Rotcinicum:
Albumoaesilbcn
Protargohmu Protcinato
Plaw, Proteinato de Prata.
de
7.5 to
8.5% of Ag.
Preparation
Mitigated Sil:er Nitrate (ff.P.C. /968}. Argenti Nitras SlowIy soluble 1 in 2 of watcc very slightly soluble in
Mitigatus; Mitigated Caustiq Argenti Nitras DiIutus. alcohol, chloroform, and ether. A solution in water is
neutral to litmus. Scdutioos may be prepared by shaking
Silver nitrate I and patassiumnitrate 2, fused together
and suitably moulded for application
as a caustic 10
warts and condylomas. Protect from light.
A similar preparation is included in several pharmacopoeias.
Sliver Nitrate Stair! Remowr (Unis. of fowa). Thiourea
(N H,. CS.NH2-76.
12) 8 g, citric acid monohydrate 8 g,
w?.ter to 100 ml. It should he freshly prepared.
Toughened Silver Nitrate (BP.). Argmti
Nitras Induratus; Toughened Caustic; Fused Silver Nitrate.; Lunar
Caustiw Mouldcd Silver Nitrat% Stylus Argenti Nitrici.
Silver nitrate 95 and potassium nitrate 5, fused together
and suitably moulded.
White or greyish-white cylindrical rads or cones, which
tbc powder over the surface of cold water and allowing
it to dissolve slowly, or by triturating
the puwder to a
cream with water and diluting. Solutions are transparent
and not msgulated
by hear. nor precipitated
by the
addition of alkali, alkali sulphidea, alkali salta, or albumin; they are relatively non-stainin8. Store in airtight
containers. Protect from light.
Adversa Effects. As for Silver (above).
Uses. Silver
ties. due to
silver, and
mnjunctivitis.
they contain
Preaut
Uaea. Mild silver protein solutions .hav
‘!!
properties similar to those of silver prot~n~
they mntain even lower mncmrtrations:tii
and arc consequently
leas irritant to fig
silver protein may be uaesk. therefore, ietth
trationa than silver protein, particularly~
important
to avoid irshation
of mttcov
Mild silver swotein. usually I to 5%, ia,w
nconaiorturp
.,r$l
-m
Rkinitis. Mild silver protein (Argyrol) hash
many years in children with chronic pu~
and bas some value in encouraging n% ~
main disadvantage
is the irreversible $tmm
kerchiefs and pillows.— D. F. N. Harriaon~
Pharmacopoeias.
in Arg., Ausr., Be[g.. Cz.. Fr., Hung..
lnd,, lrv.. II.. Jap., Po!.. PorI.. Roum., Span.. and Turk.
powder containing
sod
‘]*?
,4rgyria
Argyria developed in an efderl~
prolonged use of mild silver protein lM,!
W. A. Parker, Am. J. Hosp. Pharm.. 1~7’7
the pripbylaxis of ophthalmia
solution to mrneal ulcem.
CAS — 901 S-51-4.
hydroscopic
.4s
Adverse Effeet.% TreatnssrsG
Silver (above).
.JwrI./u
5322-m
A brown cdourlcsa
SwIubk slowly bu{ completely in wi~
soluble in alcohol, chloroform, and ctl
~
to Iigbt it is incompletely soluble in tii~
solution in water is isrm$motic with serum. ”1
with cocaine hydrochloride,
bat cortspati~
atropine sulphate solution. Incompatible,~
acids, alkalis, tannins, and oxidising ~g
airtight containers. protect from fight. .Wj
i
[email protected]
fiestwatiw
for
eye-drop$.
0.005% was a suitable
prcaervative”~~
protein eye-drop
sterilised by heating at
~
for 30 minutes.— M. Van Ootegbem; Phars
protein solutions have antibacterial
properthe prcsencc of low concentrations of ionised
are used as eye-drops in the treatment
of
Solutions are relatively non-irritant
unles
more than 10% of silver protein.
Preparatiwna
‘ .$
Mild Silver Protein
Eye-drops (B.P. C.’.,.,.
Argentoprot.
Mit. A solution of mild silver, 1
with phenylmermric
acetate or nitrate 0:
Prepared
by dissolving,
aseptically,
the A
protein in a sterile 0.002% solution Of ph
acevate or nitrate and transferring to thq, ~,.
container. The eye-drops must be freshly-p
$
are adversely affected by alkali. Protect from
A.P.F. (Mild Silver Protein Eye-Drofs) h~~
protein
20% and phenylmercuric
nitmt~,
Water for Injections.
.~:$ r ~
Silver Protein and Ephedrine Instillation(A~~
Proteinand EphedrineNasal Dropa. MM I
5 g, ephedrine 500 mg. phenylmercuric~
freshly boiled and ceded water to 100 ml. ~
should bc recently prepared. Protect from fi~
?~
Proprietary Preparations
.Argotorra (Rorra, UK). Contains mild sifver:fJ!
and ephedrine
hydrochloride
0.9% in O
chloride solution, available as Nasal I
Ready&pray nasal spray in pimtic atomise
i
Other Proprietary Names
Arginmlor (Fr.); Argirol (Spainfi vitarg~nol 1
y
THE NATIONAL FORMULARY
ULARY
with 50 ml. of water, and add sufficient of the water to make a volume of 200 mf.;
add 10 ml. of sodium sulfide T.S. and 20 ml of a solution of sodium hydroxide(4
in 10). Connectthe flaskh a condenser,
the ~oweroutlettube of which di s
ghly with hot 3 per cent hydro~ight of the precipitate so obtained
&
Iodide in tight,light-resistant
TRATE SOLUTION
Lmouiacal
Silver~ltr~te,Howe
a soIuticm of silver diammino
quivalent of not less than 28.5
and not less than 9.0 Gm. and
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . .
..
beneath the surface of 50 ml. of 0.5 N sulfuric ac~d contained in a receiving flaei .
Distil the mixture until about 100 ml. of distillate hsa been collected, add methyl
Each ml. of
red T. S., and titrde the excess acid with 0.5 .V sodium hydroxide.
0.5 N sulfuric acid is equivalent to S.516 mg. of NHi.
The ratio between the percentage of ammonia and the percentage of silver
closely approximates 1 to 3.16.
Packaging and storsge-Preserve Ammoniacal Silver Nitrate Solution in small glasestoppered, lightiresistsnt containers, or in Iightiresistant ampuls.
FOR TOPICAL usE—Jlix Ammoniacal EllverNitratesolutionwith a reducing agent, such as formaldehyde (1 in 10) or eugenol, to deposit
the metallicsilver,
in a stateof finesubdivision,inthe desiredarea of the
tooth.
‘.
-,
CATEGoRY—Protective (dental).
Silver Protein, Mild
704 Gm.
245 mf.
6s0 ml.
MILD SILVER
&entum ProteinicumMite
1000 ml.
]rtar and dissolve it in the [email protected] m temperature and add
e~. . all but the last trace of
lis last trace of precipitate from
ionisa ciear,
colorless,
afmoe.t
odorless
ectedby light.Itsspecific
gravity
is
ke Solution (1 in 10) responds to the
ate, page 683.
Solution add a few drops of formaldereci~itate is immediately formed (dis-
nonkm nitrates).
Silver Nitrate Solution (1 in 10) add
filter, add 5 ml. of sodium hydroxide
itmus blue.
remains free from even a transient biue
tiacal Silver Nitrate Solution add 3 mf.
;he clear dltrate tested in a flame on a
~fsodium or potassium (distindion from
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 -4g.
ut 1 rnf. of Ammoniacal i%lver Nitrate
e sample ta a Kjeldahl distillation tlaak
519
PROTEIN
lMiid Protargin
Mild Silver Protein is siiver 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.
Solulion8
ojMildSilver
Protein
should
bejreshl~
prepared
OT
Caution:
a suitable stabilizer, and should be dispensed in amber-colored
bottles!
contain
Description-Mild
Silver Protein occurs as dark brown or almost black, shining
scafes or grmules.
It is odorless, is frequently hydroscopic, and is affected by
light.
Volubility-Mild
Silver Protein is freely soluble in water, but almost insoluble in
alcohoL in chloroform and in etherl
Identithtion—
A: Heat about 100 mg. of Mild Silver Protein in a porcelain crucible until all
carbonaceous matter is burned off, warm the residue with 1 ml. of nitric
acid, dilute with 10 ml. of water, and add a few drops of hydrochloric acid:
a white precipitate is produced which dissolves in ammonia T.S.
B: Ferric chfonde T.S. added to a solution of Mild Salver Protein (1 in 100)
discharges the dark color and a reci itate is gradually produced.
ver ~ rotein (1 in 100) add a few drops of
To 10 ml. of a solution of Mild S1“1’
a white precipitate is formed and the supermercury bichloride T.S.:
natant liquid becomes colorless or nearly so.
Ionic silver—To 10 ml. of a solution of Mild Silver Protein (1 in 100) add 2 ml. 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, afl at once, 7 Gm. of ammonium suffate., and stir occasionally
for 30 minutes.
FWer through
uantitative filter paper mto a 50-ml. Nessler
tube, returning the first portions o? the filtrate to the filter, if necessary, to secure
a clear filtrate, and allow the filter and precipitate ta drain. Add to the clear
filtrate 25 ml. of a solution of acacia (1 in 100). IrI a second 50-mf. [email protected] tube
dissolve 7 Gm. of ammonium sulfate in 10 ml. of water, and add to thm solution
To each tube
25 ml. of tbe solution of acacia and 1.6 ml. of 0.01 N silver nitrate.
C:
I
,
I
I
Page Number
: 1
---
Database:
Medline
<1966
to
present>
<1>
Unique Identifier
83203583
Authors
Yoshimuri R.
Isenberg S. Apt L.
Title
Chemical preparation
of the eye in ophthalmic
surgery. II.
Effectiveness
of mild silver protein solution.
Source
101(5):764-5,
1983 May.
Archives of Ophthalmology.
Abstract
Although a mild silver protein solution
(Argyrol) has been
used for a number of years and is still used by many
as an antibacterial
ophthalmic
surgeons, its efficiency
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
analysis,
the mild
in a masked fashion. By bacteriologic
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.
<2>
Unique Identifier
83142687
Authors
(1 &z
Isenberg S.
Apt L.
~/
Title
i
Chemical preparation
of skin and eye in ophthalmic
surgery:
an
international
survey.
k/
+ource
13(12):1026-9,
1982 Dec.
Ophthalmic
Surgery.
G
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
Almost
a quarter
used mild silver
by the respondents.
Page Number
,
protein
(Argyrol) on the conjunctival. Most of the
preparation
is performed by the physician
rather than the
Review
of
the
advantages
and
pitfalls
of the agents
nurse.
reported should cause the ophthalmologist
to reconsider
these agents for their effectiveness,
spectrum, and
duration of action.
—...
___
: 2
through the Copyright
NOTICE
~
7H!S MATERIALMAY’BE PROTECTEDBY
COPYRIGHT LAw(TITLE17,
COD4
Clearance Center
Uss,
Chemical Preparation 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 solutlon (Argyrol) has been used for a number
of years and is still used by many ophthak
mlc surgeons, its efftclency as an antibacterial agent on the conjunctlva 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 bacteriologic
analysis, the
rnlld silver protein solution was found to
be no more etfecttve In reducing the
number of species and colonies in the
treated eye than In the untreated eye.
While the mild silver protein solution does
stabi mucus and other debris on the eye
to facilitate irrigation, this study did not
demonstrate
a significant bactericidal
effect.
(Arch Ophthalmol
1983; 101:764-765)
Therapeutic properties of silver and
Its salts were recognized as early
as the Roman Empire period. Jablr
ibn Hayyan Geber, an Arabian 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
1S84. After that, silver nitrate
was
used for other ophthalmic disorders,
but it was found occasionally to cause
Accepted for publication Ott ’22,1982.
From the Departments
of Ophthalmology (Drs
Isenberg and Apt) and Pathology fDr Yoshimuri), Jules Stein Eye Institute and Harbor-LTCLA
Medical Center, UCLA School of Medicine.
Reprint requests to the Jules Stein Eye Institute, UCLA Srhool of Medicine, k Angeles, CA
90024 (Dr Iaenberg).
764
Arch
Ophthalmot-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
conjunctival,
corneal
opacificatioq
and symblepharon
occurred. In an
attempt
to reduce these problem%
Albert C. Barnes, MD, and Hermann
Hille, in 19X? developed a combination of silver nitrate and grain protein
(Argyrol).’ However, this drug also
caused complications. In 1980, Spen-
cer et al’ reported the clinical and
histopatholcwic findings in one patient ‘who dr;nk this mild silver p%
tein 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 classifiedin 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 [email protected]
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
ophthal-
mic 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 inferonaaal or inferotemporal
conjunctival fornix of one eye and a second
swab waa 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
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
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. The
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 knowiedge 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 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—lsenberg
et al
1:
Table
1.—Mean
Number of Calories
.—— =.
and Species
I
of Sacteria
Isolated per Subject
Mean t SO
After
% of
Preparation
Before
Preparation
Increase
Untreated
1S3 ? 425
284 ? 571
55
MJd silver protein-treated
231 t 6S7
323 k 750
40
Untreated
l.oa
t 0.s3
1.41 * O.ea
33
Mid silver Drolein-treated
1.CM * 0.75
1.31 * 0.77
24
Eye
COtnrries
Species
Table 2.—Number
I
I
in whiih Culture Was Sterile
of Eyes
No.of Eyes
Before
Preparation
Type of Eye
I
Thet Were Sterile
Afhr
Preperetion
I
No. of Eyes
That Remained Sterile
Untreated
s
4
2
Mild silver protein-treated
7
5
1
glass rod. The blood agar plates were incubated for seven days at 35 ‘C in an
anaerobic jar with a gas mixture of SO%
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
differentiated and enumerated by standard bacteriologic procedures.
.P
RESULTS
able
1 gives
the mean
number
of
colonies and species per subject isoand experimenlated from untreated
tal eyes before and after instillation
of this mild silver protein solution.
Although the number of coloniesand
specieswere greater after the preparation than beforein 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.
The pattern
of sterile cultures
before and after chemical preparation
of the eye is given in Table 2. Of all the
three of the 15
eyes in this study, only
that were sterile before preparation
remained sterile after preparation.
The organisms cultured were diphtheroids, Staph @coccus qnd.emnidia,
Propianibacterium
acn.es,
albicans, and Klebsidla sp.
_——_
Candida
COMMENT
“’his mild siIver protein solution
ginally was intended ta be an antimicrobial agent. The colloidal suspension liberates silver ions that alter the
protein in the bacterial cell wall. It
:~~kch Opfrthalmd-Vd
101, May lW”
that silver
interferes with essential metabolic
also has beeri suggested
activity of bacteria.’ The silver in this
mild silver protein solution ionizes
poorly, and thus causes less irritation
than siher nitrate. However, its germicidal
effectiveness
is also decreased. Pharmacologists
have written that “colloidal silver preparations
are now in a desewed
oblivion.’”
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.”5 None of these
authors cited a controlled study on
humans to support their assertions.
Despite
these
negative
opinions,
almost a quarter of the 214 ophthalmologists surveyed in a large 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 to verify
that the application of this mild silver
protein solution on the eye in vivo was
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 irrigate
any remaining
mucus and debris from the eye.
Indee& in the international
survey by
Apt and Iaenbergj8 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
flora
by the increase in bacterial
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
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 @out the effectiveness of
our tesfed mild silver protein solution
should have been raisedat 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
fashion.
‘ii
~,.,
,
“’$
,......
References
Foundation ~Ophthalaad
Hereditfr, Pa.tholopp, ~
1. Antieeptica,
_.
Therupeutiq vol 7, in Duke-Elder
~ @-%oJmoloPP.
St I-oai% W
p 635.
Z .!khset
.
in The
W A~I
S (sol) [email protected]
Moeby Co, [email protected]
and a byprcduct, in Art
1S60, pp
and Ampro4 New York Yoeeloff CQ
47-52.
3. Spencer WH, Garron LK, Contreras F, et ok
Endcgenrxrs and exngenoua ocular and systemic
deposition. Trana OpMhabnoJ Soc UK
1980-Jw.t71
-17a
4. HarveySC Antiwptics and disinfectan~
fungicid%
ectoparaaiticides,
in Gilnmn AG,
Gmnfman LS, Gilman A (eds): T& Phw—wcQ&
id Bmis o.f Therapeutics, ed 6. New York,
Macmillan Publishing Co Inq 1SS0, pp W&W?.
5. Havener WH Germicides, in Ocsdar [email protected] ed 4. St kuis. CV Mosby Co, 197S,
silver
p 425
6. Thompson
R, Iaaace MI+ Khoram D A
laboratory study of some antiseptics with reference to ocular application. Am J Ophthubrsd
19372SllfB7-lo9a
7. IQ
~
Wadsworth JAs2 An AfJas qfOphtklrrsic SUZWM ad & Phi1adelph14 Harper &
, -’
Row Publishem Inq 19S1,
p 9.
R Apt I+ Iseabers & Chendcal preparation of
akin and eye in ophthalmic surgery An international snrm.
OoMAatmic Sum lSXkl&lO%
.,
.._.
f?eprintetj with permission
through the Copyri~[]:
of Skin
and Eye in Ophthalmic
Surgery:
An International
Survey
~hemical
I
Preparation
Leonard
Apt, M.D.
Sherwin
Isenberg,
Clearance
~efi j:.-
NOTICE
MAY 8E PF?OTECTED BY
COFIYWGHTLAW (TITLE 17, U.S. COQE)
THIS MATERIAL
M.D.
I
1
I
SUMMARY
We surveyed
chemical
ophthalmologists
preparation
of agents
was reported,
the skin
Theconjunctiva
Almost
advantages
reconsider
these
of the
agents
agents
for their
ignored
of preoperatwe
popular
orrinsedwitha
(Argyrol)
rather
reported
effectiveness,
methods
was the most
by the physician
pitfalls
thetr
rate was achieved.
A 96.8°6 return
used mild silver~
is performed
and
to learn
povtdone-iodine
usual lywaselther
a quarter
of the preparation
I
worldwlde
of eye and skin.
diversity
respondents.
I
214
the nurse.
cause
spectrum,
a wide
applied
saline solution
on theconjunctiva
than
should
While
agent
the
to
by the
Most
Review
of the
ophthalmologist
and duration
to
of action
J
I
s
Ince
the
have
known
sweat
glands,
studies
in gauze
preoperative
for
968°4.
surgeons
half
in hair follicles,
Today,
at
percent
of the
known
ophthalmic
and deeper
acid In spray
Subsequently,
asepsls
other
of the
layers
!echniques
operative
field
many
of tralnlng
dtfferent
reasons
given
for
ophthalmologists
exists,
whether
answer
choice
or
using
a certain
of the eye.
regtmen
throughout
the
survey
world,
on a specific
are
Thlsinformatton
The survey
defln!tlvely
about
and
to
!s not found
the best
method
to
and
of agents.
Quest lonnalres
application.
The
third
question
done
Finally,
rhe
This return
of
rate IS
.-.
Requests
Jules
for reprints
.SVevr Eye Inst/rure.
Ca/iforn/a
1026
School
90024
of
Ophthalmology,
of Medicine.
shou[dbe
UCLA
Jules
Los Angeles.
addressed
School
Stetrr
[o Leonard
of Medic(ne.
Eve
California
Apt, M D.,
Los Angeles,
by widel
Canada,
asked
to the skin,
of
the
series
asked
what
German,
concerned
th
the duration
face
:
receiving
Ib
dealt
wlt
of questions
proportion
by a phystcian,
nurse,
comments
of the
or other
were
preparatlo
nonphysicla’
requested.
RESULTS
There
was
considerable
of agents
In the preparation,
disparity
placed
were
Deparrmenl
UCLA
second
respondents
ophthalmologists
Argentina,
area
Isodlne,
to 221
answered
such forelgncountr!esa
questions
67 5% of the
and returned
were
applied
the
additional
somewhere
regimen
of all,
povld~ne-iodine
alcohol
The
lactated
product
Ringer
(Figure
the
types
Septodyne)
hexachlorophene
iodine
in the preparation
ar
1 ). Howeve
used povidone-lodlne
prepodyne.
while
In
on the skin (Table
by 16 5°6, and aqueous
126°4
From
of
(as Betadine,
mailed
aboL
well-know
solutlons
intentionally
placed on the conjunctival,
duratlc
of application,
and what was used as the rinsing agent Tb
used
/nst(rufe.
series
of solutlons
METHODS
answered
to
and Switzerland.
and
sequence
AND
214 were
first
Japan,
sample,
sent
institutions
and half t
of ophthalmology,
Te
surge onsfrom
application,
was
regtmen
was not Intended
The
were
questionnaires
Belgtum,
Britain,
sequence
of effectiveness.
A scientific
To learn the preferences
of
literature
questions
MATERIALS
which
preparation
a consensus
we undertooka
in the ophthalmic
surgery,
one often sees different
chemtcal
and the Impression
rarely is mentioned
determtne
In ophthalmic
institutions,
a representative
surgeons
at academic
private
practitioners
Mexico,
Great
}n preoperative
main
to obtain
questionnaires
and laid on the skin, was the first attempt
in the course
tradition
rationale
the
ophthalmic
prominent
preoperative
vlsltlng
techniques
In order
of
or
carbolic
evolved
when
The
in 1875,
are found
form,
Lister’s
antisepsis.
achieving
have
Eberth
and in both the superficial
of the skin.1 Joseph
soaked
of Carl
thar bacteria
produc
somewh~~
(p Hiso Hex) w:
solutlon
The
was
most
used t
freque’
used by a third of the respondents,
w:
solution
on the skin followed
by a rinse
term
“rInse”
solution,
1). Half
Includes
saline,
sterile
wate
balanced
salt solutlon,
or simll:
of the respondents
used a sing
DECEMBER 1982, VOL
3, NO
...
—,. . .. .-
— .——
. . - .. .. . . ..
.
—
.—=
—
TABLE
1
ROUTINE OF CHEMICAL AGENTS
USED FOR SKIN PREPARATION
[n=196)
Multlple
Agents
Percent
I
Povldone-loclne
soap – rinse”
Povldone-(odlne
soiutlon
-
= alcohol
Povidone-lodlne
: rinse or alcohol
Hexachlorophene:
- Povldone.lod{ne
Soap=
150
solution
Soap - rinse -
73
alcohol or rinse
z alcohol or rinse
7,3
rinse z alcohol = rinse
40
Soap I rinse z Iodine = alcohol
39
Hexachlorophene
- rinse - Iodine = alcohol
24
liexachlorophene
- rinse
Powdone-lodlne
Alcohol
-
- rinse
Powdone
Single
-
15
mer!h!ola~e
10
– Iodine
Agents
-
Rtnse or Alcohol
FIGuRE
325
Powdone-lodtne
lodine
10
1.0
Alcohol
10
Don’t know
10
=
saline
solut(on,
srer!le
water,
or similar
salt solut)on,
balanced
CHEMICAL
Iactafed
AGENTS
INTENTIONALLY
20
o
a0
PLACED
10
I
—
Saline
345
267
= rinse
salt solutton
53
Belad!ne
solution
24
Neosporln
(dllutedl
20
15
10
10
10
10
05
05
05
= r!nse
solu[!on
Chlorhexldlne
waler
Chloramphenlcol
bichloride
.Garjamycin
Gentamycln
mix
t know
8 deterred
OPHTHALMIC
or dld nor answer
SURGERY
%,
223
Balanced
I
().J
Percent
Agent
Mercury
-. a
Ringer
2
Nothing
Argyrol
usino
preoperatwe
producr
(n=206)
Sterile
of the
30
ON THE CONJUNCTIVAL
Ringer
of respondents
as parr
1
I&
TABLE
Normal
Percentage
on the skin
preparation
24
Merthtolate
Chemical
agent
29
1%
Merfen
soiur!orr,
chemical
43
Ira n
Iorhexldene
‘Rtnse
7. {AD( and lsenberg)
particular
4.8
1%
Hexachlorophene
_=~~ph
“%
10
Iodine
—
——
,,,
FIGURE
2 (Apr arm tsenoerg]
par f!cutar
chemmai
preoperative
primary
agent
t’ercenrage
on
rhe
Or
respondents
con)uncffva
as part
using
of
a
the
prepararton
agent
or a povidone.
while
-
half
(such
iodtne
as aqueous
product)
used a combination
The amount
oftlmetha[
skin varied from
variation
In the
Iodtne,
hexachlorophene,
followed
by a rlnseor alcohol,
of prtmary agents (Table 1 )
these
agents
were applied
lo the
one second to several mlnu; es So much
length
of time was reporfed
as [o make
1027
CHEMICAL
PREP OF EYE
-N-’%
‘/. PHYSICIAN
‘la NURSE
O
50
50
100
100
0
J
FIGURE
3 (Apt andlsenberg).
Relative
proportion
of physicians
compared
with nurses
performing
preoperative
TABLE
HOW
MUCH
3
IS DONE
RELATIVE
dents
preparation.
Indicated
tion,
BY PHYSICIAN
while
reported
and nurse
and Figure
Physlclan~Nurse
Sixty-two
that
of the eye.
percent
of the respon -
does the entire
the
nurse
The rest of the respondents
physician
(n=205)
preparation
that the physician
29°A
preparation.
TO NURSE
preoperative
does
preparathe
answered
entire
that the
each do part of thepreparation
(Table 3
3).
Percent
COMMENT
100”6 /
o
98°’0/
620
10°6
90°6
80°’0,’ 20°6
75%.’
25°6
validity
spectrum
spectalists
and
and
50°6
75%
15
tory rate of returned
20%
80”6
05
05
the valldity
44
preparation
0
100%
While
294
recent
05
all
difficult.
universally
The facial
the forehead,
areas
treated
both eyelids,
were
the cheeks,
and the
Some
on the
quarter
.-=.
ophthalmic
confunctlva
surgeons
while
Intentionally
others
of the respondents
do not (Table
place
ophthalmologists
what
agents
noth!ng
a
balanced
salt solution,
Ringer solutlon,
or
Only
31°6
use a solutlon
bearing
any
IS by far the
In general,
1028
properties
more
Of the
most
latter,
frequently
physicians
the
About
percent
antimicrobial
rinse
2)
on [he conjunc-
saline
sterile
(Argyrol)
great
this
solutjons
tival. Forty-two
solution,
water,
simply
place
than
conjunctlva
mild
used
nurses
silver
with
protein
(Figure
perform
the
also
topic.
were
of this
found
saline,
either
lodlne,
and hexachlorophene
benzalkonlum
our survey,
techniques
experimentally
11
The
scientific
advent
of
and then
DECEMBER
: ‘eld
tha!
soap and
or aqueous
followed
by either
and alcohol
still
clinically
VOL
Ir
used one of
povidone-iodine,
1982,
In
five
by merthiolate
of the respondents
agents
compared
were
iodine
the
The
Interest
the opera!
techniques
and saline
in the 1960s
nurse
In the chemical
or aqueous
VO
had to obtain
surgical
and Michler
or followed
chlorlde
about
the
study
five
not know
of theoperativefleld
for sterilizing
These
wasexhlbltedby
that theydld
a lack of recent
Maumenee
chemlcai
has been little
in the ophthalmic
surgeons
usually
in this
popular.:
alone
these
others,
techniques
then
subject
replied
of
there
used inpreparatlon
Indicates
In 1951,
a form
in this subject
who
survey,
disparity
different
these
2).
or study
A lack of interest
from
and
satisfac-
(96 8°6) also attestsio
use
this
foreigners.
survey.
some
chosen
nose
questionnaires
sub-
academicians
The highly
surgery,
were
by the broad
including
and
ophthalmologists
information
almost
Americans
for the eye prlorto
mention
To answer
conclusions
enhanced
contacted.
ophthalmologists
of this
literature
or d!d not answer
was
ophthalmologists,
ians,
and senior
25%
Not known
survey
general
nonacademic
younger
29
of this
of ophthalmologists
So”b.
15°6,85”6
1006,’
90°6
9 deferred
The
05
05
10
10
2%
firs~
In the early
13, NO
12
J70s,
gists
changed
1-’ In fact,
currently
the
this
the single
preparation
techniques
survey
most
of the skin
of
showed
popular
prior
many
that
surgery.
ophthalmolo-
povidone-iodine
agent
is
for use in chemical
to ophthalmic
surgery
in this
factant
(polyvinylpyrrol
properties
two thirds
IS slowly
that
released
can
idone)
toxicity
But if Iodine
IS combined
shown
solutions
to
be
within
and enough
against
and spores
There
is more
regard
to the
ignore
conjunctlva
the
31
would
not bear
of the
YO
some
ophthalmologists
-~the
two thirds
or
patible
with
dtrect
contact
are
should
effectiveness,
Some
even
chemical
conjunctival
irrigate
or
it
other
to surgery.
have
used
Only
mined
that
buckle
on
.ctive
growth
of resistant
conjunctival
bacteria
controversial.
If
” Argyrol
on the conjunctival
at the
ttme
was
debris,
which
used
as povldone-lodlne,
one
these
chemicals
the
and possible
soap or detergent
more
hemorrhage
a vasoconstrlctor
preparation
to
this
such
as phenylephrine
while
such
as naphazoline
to know
Important
that
phene,
as used
actlvl[y
To be maximally
:~pplled
by some
than
gram
a single
al least dally beglnnlng
3
4
of
dilation,
and
IS more
-nega[lve
has Ilttle
5
from
scleral
and
found
was
implants.
was
contamination
the
and
bathing
Implants.
g In
Kreissig
the
infecting
felt
that
at the site
the
I
of the
should
be placed
Sterilization
of the
the
I
intra -
usually
decrease
I
deter-
on routine
more emphasis
might
nor
ro They
conjunctival.
I
did
incidence
of
endophthalmitis.
the
C. VIrchows
Arch.,
,
Bd 52, 1875 AS quoted m Wheeler
of ant!septtc
surgery
1974,
Am J Surg
I
Maumenee
AE,
after
surgery
ocular
Mlchler
RC
Sterihty
Trans Pacific
of the operative
Coasf
f!eld
0toZ5ph(/rah-no/
SOC
6
It IS
should
Ha!taway
AC Powdone-iodlnea
Saggers
PP
1970,
6A,
sanophthalmlc
1966,17434-436
Surg Forum
RC, EIIIs
Iodophosphors
and skin
asepss
Ann
12312-317
Stewarl
GT
Polyvlnylpyrroltdone
of anti-bacterial
Fahmy
JA
Effects
of topical
Acts
Browntng
1955,
Bacterial
actlwty
flora In relation
antiblottcs
-lodlne
./ Hyg (Carob)
Ophthalmol
1980,
an
I
1964,
Desk
Economtcs
Co , 1980,
9
L!ncoff H, Nadel A, O’Connor
Infected
10
Hahn
extraction
V
con]unctlval
58567575
keratn, s Arch Ophfha/mo/
,,
,,
,:
53817-824
Phys/cian’s
-
toca[aracl
on the preoperatwe
CW, Llppas J pHlsoHex
8
effecttve
anttmlcroblal
GTJr,
Chase
flora
7
pupil,
of hexachloro
Klffney
62509-518.
vaso -
five to seven days prlorto
Eberth
assessment
and after
bacteria
hexachlorophene
Iavage,
Lincoff,
culture
Perhaps
Ophthalmol
lead to
Some
dilate
ophthal-
soap scrubs,
chloramphenicol,
organism
ultimately
antiseptic
not
application
surgeons,
effective,
will
will
IS bactertostatlc
gram -poslflve
problem.
coworkers
preoperative
scleral
of
and
preoperative
1951,32172-179
One could
before
to
to avoid
127.573-579
2
either
entry
result
is inc!sed
regard
of any preoperative
rate of infected
ES The development
or simple
this could
on the conjunctlva
minimize
Hexachlorophene
could
Potentially
constrictors
against
IS used,
Vascular
damage
If the conjunct!va
1
of practical
conjunctival
corneal
in
agents
REFERENCES
that
of chemicals
agent,
organic
used
properties.
Inadvertent
infected
infectious
and other
to avoid
with
i
-
is used
of action
Lincoff
saline
Lincoff,
same
sterilization
bylrrlgation,
comments
antimicrobial
Instillation.
place
removed
If a soap or scrub
be careful
onto
mucus
combinations
some
another
should
others
the
is
agents
commented
of its antimicrobial
skin,
are indicated
hyperemla,
individuals
different
the
used,
most commonly
it stains
because
the
to sterilize
soap,
the
Some
is
used antimtcroblal
then can be speclftcally
reviewing
importance
who
because
and not necessarily
In
drug
was the agent
by those
of surgery
Argyrol
used
bacteriostatic
a
of the
the
operation.
in the days preceding
surgery. Whether
truly sterilizes
theconjunctiva,
or permits
three
with
their
Hahn,
of infection
practice
eye.
that an extensive
conjunctival
in
source
conjunct;va
original
alter
operative
of the
preparation,
study,
agent
antibiotics
or regrowth
other
often
activity
duration
in
bejlzyl
use multiple
as to the efficacy
implants
a later
‘atter
bacteria
who
-
is incom-
not be placed
which
Individual
including
Iavaging
significantly
However,
topical
mic preparation,
powdone-iodine
use of an antimicrobial
prior
in one study
and
but
exists
preparation
either
Irrigation
action.
doubt
of the
debris,
antimicrobial
the
may
preparation
mucus
just
In
of the respondents
chloride
by blood,
material
and
I
palpebral
epithelium,
overlap
proper
ophthalmologists
their
the
should
inactivated
spectrum,
not be
on skin ‘ In addition,
Ophthalmologists
reconsider
entering
to the corneal
therefore
and cotton
its application.
produced
should
Care should be taken
from
it, even
is
then
Alcohol
benzylkonium
and
with
soap,
has
that
iodine
chloride
material,
dilute
the
it IS effective
merely
indicated
on the
time,
among
significant
reports
agent
In
Given
effects
it is injurious
noted
ISENBERG
hexachlorophene
hexachlorophene
It has been
found
remove
any
problems
of
the hexachlorophene.
because
konlum
corneal
viru~idal
‘
preoperative
than
solutions
and
these
vitro
contact
immediate
More
and
Povidone-iodine
and
in
About
in the conjunctival.
povidone
consensus
conjunctival
presumably
skin
bactericidal
concentration
fungi
Aqueous
the
sur-
state
to
magnitude
minutes
Iod!ne
acttvity
changes
with
and of lesser
with
with
in the elemental
for antibiotic
cause
and Inflammatory
been
easily
remains
eplthellum,
less common
is a polymer
combines
of the iodine
iodine
would
to prevent
fissure
Povidone
film
its antimicrobial
used to remove
country
of
The
enhances
APT&
scleral
YS,
Implantation
Reference,
7
Oradell,
Medtcal
p 1859
Implant
Ltncoff
ed
A, Llncof{
for scleral
P Thechanglng
character
Arch Ophtha/mo/1970,
H, er al
buckling
Am
Infect{on
oflhe
,1
84421-426
after
J Ophrhalmol
II
sponge
1979.
I
87180-185
.1
I
,1
OPHTHALMIC
SURGERY
1029
I
I
1
I
I
GREDIENT NAME;
●
THYMOL IODIDlj
B. Chemical Name:
Dithymol Diiodide, Iodothymol
C. Common Name:
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
(Specijlcatiorq)
43.0’%0min.
(Results)
44.08%
E. Information about how the ingredient is supplied:
Reddish-browq tasteless powder
.~
F. Information about ‘recognition of the substance in foreign
pharmacopoeias:
port. and $viss.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
IL Information about dosage forms used:
It has been used in dusting powders and ointments, and in dental root filling.
I.
.—.
Information about strength:
J. Information about route of administration:
i
-
K
Stability data:
Stable
Loses iodine on prolonged exposure to light.
Gives off purple iodine vapors when heated above 100°
L. Formulations:
M. Miscellaneous Information:
—_
Page -2-
CERTIFICATE OF ANALYSIS
------------------
PRODUCT: THYMOL IODIDE
lU’LEXE #: 102161
-----
POWDER .
LOT #
:B60244A02
.
SPECIFICATIONS
--------------
RESULT
------
1.
DESCRIPTION
REDDISH BROWN POWDER
CONFORMS
2.
Identification
To pass test
Passes test
3.
Alkalinity
To pass test
Passes test
4.
Solubi&
1.5% max.
0.9%
5.
+say
43.0% min.
44.08%
6.
Volubility
To pass tests
Passes tests
3% max.
0.2%
.,
Halides
7_w Loss on drying
( 4 hrs./sulfuric
acid)
..
.“
-.
.
.
.
ATTENTION:
Date :02/13/97
.,
TONY HATCHETT
-.- Prepared~&.~:
.,
J.PATEL
&/k
QUALITY
CONTROL
REPORT
NAME. :THYMOL IODIDE PURIFIED
CHEMICAL
MANUFACTURE
LOT
No. :B62871M05
PHYSICAL
SPECIFICATION
TEST
STANDARD .:USP_/BP_/NF_/WR=_/_T
TEST
._/CO.SPECS.
l)DESCRIPTION
.:
BULKY POWDER; SLIGHT AROMATIC
REDDISH-BROWN OR REDDISH-YELLOW,
ODOR; LOSES IODINE ON PROLONGED EXPOSURE TO LIGHT.
/<
2)SOLUBILITY. :
INSOLUBLE IN WATER, GLYCEROL, ALKALINE SOLUTIONs; READILY SOLUBLE
IN CHLOROFORM, ETHER, COLLODION, FIXED AND VOLATILE OILs,
USUALLY LEAVING A SLIGHT RESIDUE; SLIGHTLY SOLUBLE IN ALCOHOL.
–—_
‘6
3)MELTING
GIVES
POINT.:
OFF PURPLE IODINE VAPORS WHEN HEATED ABOVE 100 DEGREES.
r’
4)SPECIFIC GmvITY.:
5)IDENTIFICATION
.:
FAILS
PASSES .:
.:
cOFmENTs .:
ANALYST
SIGNATURE.
PREPACK
TEST.:
RETEST .:
DATE.
:
DATE.
DATE.
:
:
INITIAL.
INITIAL.
:
:
:
_.
---
------------------ IDENTIFICATION ------------------PRODUCT #: T2763
NAME: THYMOL IODIDE
CAS #: 552-22-7
------------------ TOXICITY HAZARDS ------------------DATA NOT AVAILABLE
------------------ HEALTH HAZARD DATA ----------------ACUTE EFFECTS
MAY BE HARMFUL BY INHALATION, INGESTION, OR SKIN ABSORPTION,
MAY CAUSE IRRITATION,
THE TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY
INVESTIGATED.
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, 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 -------------------APPEARANCE AND ODOR
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 ------------------STABILITY
STABLE
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
CARBON MONOXIDE, CARBON DIOXIDE
~—
.n
_—_
HAZARDOUS POLYMERIZATION
WILL NOT OCCUR
--------------- SPILL OR LEAK PROCEDURES -------------STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
WEAR PROTECTIVE EQUIPMENT
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 MOSI-UMSHA-APPROVED
RESPIRATOR
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE CLOTHING
MECHANICAL EXHAUST REQUIRED
CAUTION
AVOID CONTACT AND INHALATION
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
F
“r
J
at ~
merh
-me.
w -2-S
w
Jt-f
b
%
1!
oh
Ian
)m
b
nti
un
“00
a
itb
al.
Sal
Thiomersal/Triclosan
,,i iurtgous skin infections
~h}m~l
(0.01%)
is added as an antoxidarrl
~Jiothane,
‘- .+
-..broethylene.
trichloroethylerte,
Thvmol,
and
10% in isomotwl
..
2292-1
10
[etra-
alcohol.
Dithymol
Di.iodide.
.S,.$’.Bis(icdc-trxy)-
5.5’.disopr&r&
pyl-2,2’-dimethyl- 1,I’-blphcnyl.
C20HN[:O:-5513 2
/“”
CAS — 551-22-7
!~~ been used to preserve urine.
f\\mOi had only a 10* volubility in waler and was a
22
e
/
~l,; bactcmcidc. 1[s usc as a disinfectant even for clinib
A
.ai [hcrmometsm was not recommended.-Rcport
by th
Thymol I “ (B.P.C’ f 949~Di!hvmol
Diiodide
elt’
Timol bduro. A mlxiurc o! lM1ne deravatp:aitc Heal(h Laboratory
Service Committee
on
ymol.
chiefly
dithymoi
di.
iodide,
containing not
r~(lng and Evaluation
of Disinfectants,
8r me
J.,
e-w than 43% of icdine.
@
1.26$, /. 40$.
NOTE. The name iodothymol is .aIao applied [o In
.W+WS. Fifteen Pstienu
with herpes of the genitalia
anth , ~ic
compound (see p,94 ).
*CC trealed topically *tth thymol (ss Lismine) twice
Pharmacopoeias,
In PorI, and SWISS,
L,I} Symptomatic
relief was obtained in 14 days with
—F
A
reddish-brown
or buff-coloured.
almost tasteless
pduai
healing of the lesions. There had been one
bu[ky, [email protected]
a sl$ht ‘aKXt’sati.O&XK.
murrence in 8 monthsH. M. Radman. Md St. med.
lyceroi, and sodkm
Practical y itaso
j !978, 27. 49. See 3iS0 V Knight and M. W. NosII 6 hydroxide ~l”[iw:
a[i~~tlywti~ble
in alcohol; soluble in
,k!:cr).
NCIU EngI. J. Med.. 1976, 294, 337.
~M in ~~.
The Focal Additives and Contaminants
C~mmittec rccOmmendcd that, on the grounds of safety,
lh~ mol could continue 10 be used as a stabiliser for
AX,ents used m focal.— Rcpor( m fhc Review of Sol.
Mmr In Food. FAC/RE P/25, Ministry of Agriculture,
fimcri~
and F~,
L~ndon. H M Stationery Office R+
19-3
chloroform. ether. aoft parafflr, and fixed and volatile
oils. usually leaving a siight residue. [acoaspadkka with
alkaiia, mercuric chloride. and metallic oxides. Protect
from light,
Thymol iodide is insoluble and has little or no antiseptic
action but
es as an absorbent and proin ~ng-powd
ers and ointments. and
t has been u
““ Idlmg prepara~
in
rcot
Preparations
:.
r.
r.,
:r
d
s
A
IS
i
I
1
s
[
[
CompoundTIsYmol ClyCeriSS(BP L Glycerinum Thymohs
CJmpositum. Thymol 50 mg, sodium bicarbonate 1 g.
torix 2 g, sodium bcnzoate 800 mg, sodium saiicylate
!:0 mg. menthol 30 mg. cinmle O.13 ml, pumilio pine
mi 105 ml, methyl salic!late 0.03 ml, alcohol (909.) (or
inauitrtai methylated spirit, suitably diluted) 2.5 ml.
gl)ccrol 10 ml. sodium metabisulphite
35 mg, carmine.
(W grade of commerce. 30 mg, dilute ammonia soluuon 0.075 ml, water to IW ml. pH 7.1 to 7.6. To be
diluted with about 3 times its vol. of warm water before
Ase: dduted solutions should he prepared immediately
‘ iore use.
odificd fwmnia.
Fadusg and dkcraloration
of Compound Thymol Glycerin during storage muld be minimsed by increasing the scdium metabisulphite
to 50 mg
per 100 ml and by proteftlng
from light. —Pharm. Sot.
Lab. Rep. No. P/69/33,
t969.
Ke~rts
of comaminauon
of Compound
Gl}ccrin.—
M. H. Hu8hcs (letter), Loncer.
110, T A. Rees (letter), /btd., 532.
Thymol
1972, 1,
A ,[udy suggesting that phenol might & worth investi.
ga~lng as a potential prrs-ervative of Compound Thymol
Gliccrin.—
Pharm, SW. Lab. Rep. P/78/9,
i 978. Confwmauon that phenol 0.5% was physically compatible
with Compound
Thymol Glycerin. Initial studies also
sugge.ted that cinnamon oil and citral appeared worthy
of f“r~her inveatiga[ ion as preservatives. — Pharm. SOC
L3b Rep, P/80/3,
1980.
Compound Thymoi %lourb-wsab (B, P.C. /949). Coilut.
Thy mol. CO, Thymol 10 mg, liquefied phenol 0.52 ml,
Wtasslum hydroxide Solutlon 0.52 ml, methyl salicylatc
O01 ml. peppermmt
oil 0.01 ml. bordeaux B solution
1.04 ml. water to ltM ml. To be diluted with 3 times its
vol. of warm water &fore use.
Amended Jormsda.
Thymol
30 mg, liquefied
phenol
0,52 ml. paaswum
hydroxide solution 0.52 ml, methyl
Salicylate 0.01 ml, peppermint
oil 0,01 ml, amaranth
Solu(ton I ml, waler 10 100 ml. —Corrrprndiwr
0/ Pasl
Formu/ae /933 10 /966, London, The National
Phar.
maceutlcal Umon. !969.
Compound Thymol SoIurioas-tsblecs /B.P C. [963/, Solv.
Th>mol. CO. Each conta]ns thymol 3.24 mg, sod[um
blcarhonate 324 mg. borax 324 mg. phenol 32,4 mg, xnd
~maramh 650 ~g. One solution-tablet
to & dissolved in
$0 ml of warm water.
“VlnOl
Mouth-wash
Corr~ursd
(A,) F }, Col]u!. Thv.
\lb : Llq. Thymol. Co Thymol 150 mg, menthol
J me. hnzo!c ~cld 8(M mg, methyl salicy late O 05 ml,
oneotc 0,05 ml. glycc rot 2 ml, alcohol (90%) 20 mi,
water 10 100 ml. Dilute with 7 vol. of water for use M J
~~rgle or mouth-wash.
2284-1
Tribromometsscresol.
2..t,6-Trlbromo-rrr-cresol;
2,4,6-Tribromo-3 -methylphenof.
C7H$BrJ0-344.8.
CrtS — 4619-74-3.
Tribromome(acresol
is an antifungal agent used in the
treatment of dermatomycoaea.
[t is applied topically JS
an aerosol spray containing
2%, [t should be applied
with caution to suppurating
mycoses: it should not be
aPPii~ near the eyes or mucous membranes.
proprietary %saas
Triphysan
13rrrm./;
Tn- Physol
(Sigma.
(Lhmrex,
Aumraf. /.
577
Adverse Effects and Precautions. W’hen subjected
to prolonged high temperatures
triclocarban
can
decompose to form toxic chloroanilines,
which
can be absorbed through the skin.
Mild photosensitivity
has been seen in patch testing.
An outbreak of methaemoglobinaem!a
in 18 infants (12
premature) in a nursery in a S-week period ceased when
!he laundry process applied to clothing and napkins was
rcvraed. The process had involved washing in detergent.
blucing. a chemical rinse ~ntalnlng
trlclocarban
2%,
neutralizing. dr}!ng and autoclavlng. — R. O. Fisch a
al., J. Am. med. ASS., 1963, 185. 760
Eight patients
developed
mc.thacmoglobinaemia
af[er
receiving an enema prepared from soap containing about
2% of triclocarban. Three days prior to the incident the
proczdure for preparing the soap gel had been changed
[O include heating
near to boi]ing. point for several
bout% Laboratory tests showed that tmiling reduced the
triclocarban content of the soap gel (oH 9,5) and Icd to
the formation of primary am;n&-”’
R, R. Johnson e!
al.. Pediatrics. 1963. 3/. 222.
cu~ncous
and mucoaal
apcutique. 1973, 49.685,
lesions,—
H.
Barri?re,
Thcr-
Uses.Triclocarban
ia a non- henolic disinfectant,
[t is bacteriostatic
against gram-positive
organisms in high dilutions but is less effective against
Gram-negative
organisms and some fungi. It is
used in soaps, usually in a concentration of 2%,
for similar purposes
to hexachlorophane,
and has
been applied in solutions, powders. and ointments
for the control of skin infections.
A review of antimicrobial
agents, including miclocarban,
used in cosmetics.— [. R. Gucklhorn. .lfJg Cherrr.. 197o,
41 ( Feb.), )0.
Proprietary
Preparations
Cwti$sa IMorrtrtdale Phormareurica[s,
CK. Farillon,
fJKL Triclocarban, available as Oinmwsst containing 2%.
as Powder containing
l%, and as Solution containing
l%. For infected skin conditions. leg ulcers, find burns.
(Atso available as Cutisart in Fr. ).
TCC (Monrarrm. UK). A brand of triclmarban
Other Proprietary Names
.4rg.-Ungel;
fle/g.-Solubactcc
von-f-avril, Solubacter.
Fr. —Xobactcr,
Septi-
A preparation containing triclocarban was also formerly
marketed in Great Britain under :hc proprietary
name
Crinagen (Pharmax).
2285-y
Triclobisonium Cbforide. Hexame[hylencbis{ dimethyl[l-mcthyl.3 -(2.2 .6-{rimethylcyclohexy l)propyl]amm&
nium chloride 1.
C,6H,,CIZN:=605.9.
CAS — 7187-64-5 [tric/obtsonium/,
79-9&3 [chlorrdel
2287-z
Triclosan.
Cloxifenol; CH
(2,4-dichiorophenoxy )phenol.
CIZH7CI,01=
289.5.
A whne or nearly white. almost tiourless, ct-ystallinc
powder, M .p. about 243”. Freely sokuble in water, alto.
hoi. and chloroform;
practically
Insoluble in ether
Protect from light,
A white to off-white
Triclobisonium
chloride is a quaternar> ammonium compound with properwa and uses simtlar to those of other
cationic surfactams as described under Cctrimide. p.55 I
It has been reported to have activity against Carsdida
ulbicans and Tnchomomrs vagirsa/1$,[t has been applieo
topically as a O.1% otntmcnt or cream In the vestment
of skin Infecuons and as a O.I % cream or pcssaries m
the treatment of vaginitis.
Adwxae
sionally
2286-j
Triclocarban.
3,4,-t’-Trichlorwarbanilide. I(4-Chiorophenyl) -3-(3,4 -dichlorophenyl) urea.
C,3HqC13N10=315.6.
CAY — 101-20-1.
A fine white odourless powder. M.p. ?50° to
256”. Practically
insoluble
in wamr: soluble I in
25 of tcetone,
I In 100 of prop} iene glycol. mtd
I in 100 of dimethyl ph[halo[e. wluble I In 10 to
I In .S of mzcrogols.
Vacrogol LOO monolaurate
!r!crcmea (he >o{ublii[y of
lrlclmar~ an, resultln~ \n (ncrmsed ,acterlcd~l aCl[b[TV— J.. E Elkhou[\ ~na R, C S Wmuroife.
J appt
t7&-1
!9-:.
-?6, ;8-
3565.
5-Chloro-2-
CAS — 3380-34-S.
powder or soft
crystalline
agglomerates
with
a slightly
aroma!ic
odour,
,W.p. 55° to 57 °. PracticalIy
insoluble
in water;
very soluble in most organic solvents: soluble 1 in
3 of 47. sodium hydroxide solution. Protect from
light.
Effects. Contact
been reported.
dermatitis
has
occ~-
From studiezon [be percutaneousabsoqmon of triclosan
in rar$, ii was calculated that the absorbed dose from a
shampoo preparation (0.05% tnclosan) In a Woman
Would be about 4.8 #g per kg body-weight and from an
acrmol (0.1% trlcl~n)
24.9 ~g per kg. These doses
were considered tO have no effect m humans. — J. G
Black and D. HOWCS.J SOC cosrnerChem
1975, 26,
205.
Use% Triclman is bacteriostatic
agains[
Grampositive and most Gram-negative
organisms,
It
has little actlwty
ag~inst
Pseudornorrus
spp..
yeasts. or fungi. [t is used in surgical scrubs.
soaPs. and deodorants in concentrations
of O.OS
co 2%.
Rmcw
of propcrl!es and mrcrob[oloS[cal ac[,vl(} — T
E. Funs and \ (i Schcnkel, Soup <hem Spec., 1968.
<4 (Jan ), 47
Handwzishlng
(or 2 minutes
t!osan O 75F. WS, 1.ss effective
wllh
,oap
conu]n]ng
(r].
$kln o~ctcrld
)n :emoblng
,.han w,sh, ng w!th map wnmlntng hex~chlorocmnc :’7
I
‘“----’yf
,//------”
.: ~’
~ORMUIARY
~HE NATIONAL FORMULARY
613
f;;
.otata-y,
but the angle of rotation in .S
yme f)d is not kas than 1.4950 and not
“
,, .
me Oil with 10 ml. of hot water, and
\ moistened filter: not even a transient
b upon the addition of 1 drop of ferric
Oil into a cassia ~k,
add 75 rd.
i:s:ss?s%:$:%
in tight, light-resistant
CA’rEGoRY-ktifungd;
into three doees.
~~
ThymolIodide
T’IIYIUOL IODIDE
DescriptionTThymol
-
OL
H
H,
CH,
Mol. wt. 150.22
t+, often large, or as a white,
cry+.
~;~;;n~;ifi~b~
~$;%$i$,
91solution is neutral to litmus.
about 1000 ml. of water, in I ml. of
f ether, and in about 2 ml. of olive oif.
i or volatile oils.
1 weight of camphor or
menthol:
the
1 iII
1 [email protected],cialUet,ic
acid,
~d ~d
acid:
}fnitric
the Iiqtid shows a deep
tlected light.
tube in a water bath with 5 ml. of a 10
!: a clenr, colorless, or paIe red solution
Without
the se aration of
n standing,
‘e~ drops of chloroform to&s SOIUtiOII
tcolor is
Id 51°,
S91.
_n._
produced.
but when melted
anthelmintic.
2 Gm. (approximately 30 graine) divided
Thymol Iodide ia a mixture of iodine derivatives of thymol, principally dithymol diiodide [[email protected]~(CHa)(01) (CJH7)-1,3,4]~, containing,
when dried over sulfuric acid for 4 hours, not less than 43 per cent of 1.
containers.
y 1 1/2 -).
4
antibacterial;
USUAL DosE—&Itheknidic,
of
me clear, ad]wt it h the tern mture
VOiae of the residual liqui~
This
le presence of not less than 40 per cen~
Non-vofatile residue-Volatilize
about 2 Gm. ofl’hymol,accurately weighed, on a
water bath, and dry at 100” to constant weight:
not more than 0.05 per cent of
residue remains.
Thymol in tight, Iighkreeistant containers.
Packaging and storage-Prese=
[email protected]
occurs as a rcd~
brown or @dish
yellow, bulky
ty-Thymol
o&de IS freely soluble in
cNoroform, III ether, in collodion,
emfiaveTsl’dt’mm’cdOr”
‘t”dwMby”’@t”
and in fired and volatile oils, usually leaving a slight residue.
It is slightly mluble
in alcohol. Thymol Iodide is insoluble in water and in glycerin, and in cold and
in hot solutions of the fi..ed alkali h droxidee.
Identi5cation-Heat
about 100 W. o [ Tbmol Iodide with 2 ml. of sulfuric acid: it
decomposes with the separation of iodine.
Loss on drying-D
Thymol Iodide over sdfu.ric acid for 4 hours: it bee not more
than 2 per cent o7“ Its weight pa$e 690.
Residue on imition-llwmol
~odi e tieJds not more than 1.5 ~r cent of residue on
ignition, +ge 711.
Soluble hahdes-Digeet
100 mg. of Thymol Iodide with 50 ml. of warm water for
10 minutes, filter, COOIand add 5 drops of diluted nitric acid and 1 ml. of silver
nitrate T. S.: anY turbidity produced is not greater than that in a control test
containin 2 mg. of PO-rim
iodide.
MkaIinity&ake
500 mg. of Thymol Iodide with 10 mf. of water, and filter the mixture: the filtrate is not alkaline b litmus.
Iodine-Shake
500 mg. of Thvmol Indde with 10 ml. of water, 61ter the mixture, and
add a few drops of starch ~. S.: no blue coIoris pro+ced.
Aeeay-Mi.. thoroughly about 250 rng. of Th
“ F1~ mth
‘“*de’about
‘mtidy
‘Ver ‘furicacid for 4 hours and accurately welg
3 Gm. ‘dof anhydrous
potawium carbonate.
Place the mixture in a platinum crucible, cover with about
1 Grn. of anhydroua potassium carbonate, and heat moderately, gradually increasing the heat but not exa dull redness, rmtif the mass is completely
carbonized.
Extract the residue with boiling water until the last wsahing, after
acidification with diluted nitric acid, produces no opalescence with silver nitrate
T.S. Heat the combined waehinm which measure about 150 ml., on a water
bath, and add a solution of potassium permanganate (1 in 20) in small portions,
until the hot liquid remains pink. Add just enough alcohol to remove the ink
tin$ COOIto room temperature, dilute to exactly 200 ml., mix well, and llter
through a dry tilter, rejecting the first 50 ml. of fiftrate. To-exactly 100 ml. of tbe
subsequent
clear [email protected],
add about 1 Gm. of potassium idde
(free from iodate)
and an excess of dduted sulfuric acid, and titrate the liberated iodine with 0.1 N
Each ml.
sodium tbiormlfate, adding starch T.S. near tie end of the titration.
of 0.1 N sodium tbioedfate is uivalent to 2.115 mg. of 1.
Packaging and storag_Presem?hymol
Iodide in tight, light-reaista.ot containers.
remaine liquid
CATEGORY—&ltifllIlgd
;
a~ti-infective.
MSDS
Material Safety Data Sheet
Professional
Compounding
~enters of America
1-800-331-2498
9901 South Wilcrest, Houston Texas
77099
----
PRODUCT
CAS #:
24 Hour
Chemtrec
----
----
----
--
#: 30-1240
552-22-7
Phone
1-800-424-9300
IDENTIFICATION
------------------NAME: THYMOL IODIDE
---- ---- ---- ---- -- TOXICITY
DATA NOT AVAILABLE
HAZARDS
-------------------
---— —-—— ———— —--- -. HEALTH HAZARD DATA ----------------ACUTE EFFECTS
MAY BE HARMFUL BY INHALATION,
INGESTION, OR SKIN ABSORPTION.
MAY CAUSE IRRITATION.
THE TOXICOLOGICAL
PROPERTIES
HAVE NOT BEEN THOROUGHLY
INVESTIGATED .
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 INIjALED, 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 FLUSHING BY SEPA~TING
THE EYELIDS WITH FINGERS. CALL A PHYSICIAN.
.~
---- ---- ---- ---- ---- PHYSICAL DATA -------------------POWDER
APPEARANCE
AND ODOR:
---- ---- ---- 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
PREVENT CONTACT WITH SKIN AND EYES.
UNUSUAL FIRE AND EXPLOSIONS
EMITS TOXIC FUMES UNDER
AND
PROTECTIVE
CLOTHING
TO
HAZARDS
FIRE CONDITIONS.
—--— ———— ———— ---- --- REACTIVITY
DATA
-------------------
STABILITY
STABLE . K
HAZARDOUS
COMBUSTION
CARBON MONOXIDE,
HAZARDOUS
OR DECOMPOSITION
CARBON DIOXIDE
POLYMERIZATION
WILL
PRODUCTS
NOT OCCUR.
---- --—— ———— ——- SPILL
OR LEAK
30-1240
PROCEDURES
Page
1
-------------Cus
00999
STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
WEAR PROTECTIVE
EQUIPMENT.
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
CHEMICAL INCINERATOR
EQUIPPED WITH AN AFTERBURNER
AND SCRUBBER.
OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS.
IN A
--PRECAUTIONS
TO BE TAKEN IN HANDLING AND STORAGE --WEAR APPROPRIATE
NIOSH/MSHA-APPROVED
RESPIRATOR,
CHEMICAL-RESISTANT
GLOVES, SAFETY GOGGLES, OTHER PROTECTIVE
CLOTHING.
MECHANICAL
EXHAUST REQUIRED.
CAUTION:
AVOID CONTACT AND INHALATION.
THE ABOVE INFORMATION
ON THIS MSDS WAS OBTAINED FROM
HOWEVER THE DATA IS
CURRENT AND REPUTABLE SOURCES.
PROVIDED WITHOUT WARFUJ.NTY, EXPRESSED OR IMPLIED,
IT IS THE USER’S
REGARDLESS
OF ITS CORRECTNESS
OR ACCURACY.
RESPONSIBILITY
BOTH TO DETERMINE
SAFE CONDITIONS
FOR USE
OF THIS PRODUCT AND TO ASSUME LIABILITY FOR LOSS, INJURY,
DAMAGE OR EXPENSE RESULTING
FROM IMPROPER USE OF THIS
PRODUCT.
30-1240
-
—.
Page
2
(LAST
PAGE)
Cus
00999
—
TINIDAZOLE
B. Chemical Name:
1-(2-ethylsuphonylethyl)-2-methyl-5-nitroimidazole
C. Common Name:
Fasigin
D. Chemical grade or description of the strength, quality, and purity of
the ingredient:
Assay:
99.36% dry basis
E. Information about how the ingredient is supplied:
———_
An almost white or pale yellow, crystalline powder, odorless.
F. Information about recognition of the substance in foreign
pharmacopoeias:
British Pharmacopoeia1993
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:
Ripq T. The plasma half-life was about 13 hours. Chemotherapy,
1084.
Jokipii, A. M. M Concentrations in the CSF. Jantimicrob.
Bade, 1977; 14:
Chemother., 1977; 3:239.
Sawyer, P.R. A review of tinidazole in the treatment of trichomoniasis,
giardiasis. Drugs, 1976; 11:423.
—
—
amoebiasis, and
Wust, J. Figures achieved with metronidazole and ornidazole. Antirnicrob, Ag
Chemother. 1977; 11:631.
Wise, R. The median minimum inhibito~ concentration of tinidazole against Bacteroides,
Chemotherapy, Bade, 1977; 23:19.
Klastersky, J. The activities of [email protected] tinidazole, 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.
Welt\ J. S. A single doe of tinidazole was as effective as the longer regimen. A4edJ
Awl., 1978; 1:469.
Levi, G. C. A cure-rate in patients with giardiasis treated with tinidazole. Am J trop Med
Hyg. 1977; 26:564.
Anjaneyulu, R. Trichomoniasis. Jint. 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
K
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-
~
A N
A LY S I S
C E R T I F I CAT
E
N0..,.,,..3? O,........,.........,..
..... . ...... ;.
.
#
8th
October
Your Oral, No. .. ........
.................
.. . . ..... 1997
. ... .
MATERIAL”
.TIN ID AZOL~
..
...... .. ..
Our
12
Batch
._Kg..
,,lO.
. ...... 7.5179..............
I
.
,.,
Empirical
formula
Molecular
weight
Aspect
.
.
.
l-/~- (ethylsulfonyl) -ethyl j-2-methyl-5
. .. -nitroimidazole
. .... ........ ....‘.
.,
.)
5%+3<
Ref.No.........2..9
.0.5
..........,........ .
Quantity
,,Jp
w./jq/
.c8H13N204s
..
.
Specific
rotation,,..,
........ ....
247.28
.crystall+ne
,...,
powder
Color
creamish
Odor
characterlsti-cOdour..
..
.
Losson
drying
.,....... ..o..?565%
.4
Jr,,.
Residueon
Taste
.
Melting
point
Boiling
range
.!.26,:.!.oc
ignition
Chloride ...............................................
......................
..
Sulfate ................... .............................
conforms
Volubility
Heavy metak..
...’9?X”
Identification:::
. ......... .. .
....
1°
ITIm
positive.
..
.
..
.
... .
.
..---
0.046%
.
pH
-==
Titer
(Assay)
. ..-.
Other
requirements,
.. . ... .
i:..
d-”r-.
d
bi~ .... .
~.
.
.,-----rL .“
. ..
-...:”-
. ..
. .
99.36%
.
notes”
dry
__o basis
. . . .... . ..
..
.
Related substances
by TLC
............=
.
:
passes.
. ... .
:
Bulk density
...
. .
.
..
0.6502
..
CJrrl/U
&g::::--.’;:l;g””}~””””””
“:.:::’.:.:_”:;::
.
...”.::.:::..-:”.:
4y’
EXPIRY=DATE-~1”
Fe
.. ..
~.,
“.””:-
-
.-JUNE-20Q2
.
—-..
~~
~
fist
~k~
.-?
QUALITY CONTROL REPORT
cHEMIcAL
NAME.
:TINIDAZOLE
MANUFACTURE LOT NO. :77405
PHYSICAL
SPECIFICATION TEST STANDARD .:USP
~
l)DESCRIPTION
.:
pALE
YELLOW
FINE
CRYSTALLINE
—. /BP
TEST
/~RcX
POWDER;
/NF
——
— /CO.
/WT.
SPECS
ODORLESS.
\
F“
2)SOLUBILITY
.:
SPARINGLY SOLUBLE IN WATER AND IN ALCOHOL; SOLUBLE IN DILUTE ACIDS.
_—-.
POINT.:
3)MELTING
MELTS AT ABOUT 126-127
4)SPECIFIC
GRAVITY.
5)IDENTIFICATION
A)COMPLIES
PASSES
-.
:
.:
(A) AS PER IR SPECTRUM COCSPECS”
FAILS
.:
COMMENTS.
SIGNATURE.
PREPACK
TEST.:
.:
.:
:
ANALYST
~TEST
degree.
DATE.
:
DATE.
DATE.
:
:
INITIAL.
INITIAL.
:
:
:
._.
.-=
------------------ IDENTIFICATION ------------------PRODUCT #: T302 I
NAME: TINIDAZOLE
CAS #: 19387-91-8
MF: C8H13N304S1
SYNONYMS
BIOSHIK * CP 12574 * I-(2 -(ETHYLSULFONYL) -ETHYL)-2-METHYL-5NITROIMIDAZOLE * FASIGIN * FASIGYN * 1H-IMIDAZOLE, 1-(2(ETHYLSULFONYL)ETHYL)-2-METHYL-5-NITRO- * PLETIL * SIMPLOTAN *
SORQUETAN * TIFUDAZOL * TINIDAZOLE * TRICOLAM * TIUMONASE *
------------------ TOXICITY HAZARDS ------------------RTECS NO: N16255000
IMIDAZOLE, 1-(2-(ETHYLSULFONYL)ETHYL)-2-METHYL-5-NITROTOXICITY DATA
IYKEDH 11,811,80
ORL-RAT LD5O:271OMG/KG
IPR-RAT LD50:2720 MG/KG
IYKEDH 11,811,80
IYKEDH 11,811,80
SCU-RAT LD50:3000 MG/KG
IVN-RAT LD50:>250 MG/KG
YKYUA6 32,204,81
ORL-MUS LD50:3200 MG/KG
JMCMAR 21,781,78
IPR-MUS LD50:2730 MG/KG
IYKEDH 11,811,80
IYKEDH 11,811,80
SCU-MUS LD50:3940 MG/KG
IVN-MUS LD50:>250 MG/KG
YKYUA6 32,204,81
TARGET ORGAN DATA
BEHAVIORAL (SOMNOLENCE)
BEHAVIORAL (CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD)
LUNGS, THORAX 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,
DIZZTNESS, VERTIGO, AND VERY RARELY, INCOORDTNATION AND ATAXIA>
A METALLIC, SHARP, UNPLEASANT TASTE, FURRY TONGUE, GLOSSITIS,
R?
AND STOMATITIS
EXPOSURE TO AND/OR CONSUMPTION OF ALCOHOL
MAY INCREASE TOXIC EFFECTS.
CHRONIC EFFECTS
POSSIBLE CARCINOGEN,
_-
_r
-.
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, 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 EYELTDS WTTH FINGERS. CALL A PHYSICIAN
-n.
-------------------- 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 MTROGEN 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 RAISTNG DUST.
.-
6=,
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 --NIOSWMSHA-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
[email protected]===-+ PURPORT TO BE
ALL TNCLUSIVE 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
,
Sohtrion (5) Dilute 4 ml of solution (4) to 10 ml widl
me~hanol.
Solutwn (6) Dissolve 10 mg of 2-methyL5-nin-oimtizofe
(tinidazole impuriry A) in methanol and dilute to 100 ml
with
the same
solvent.
Solution (7) Dissolve 10 mg of r:mikzzole impurity B
EPCRS in methanol and dilute to 100 ml with the same
_-—.
N+
solvent.
Me
C3H13N30tS
Q
Definition
247.3
Heat the plate at 110° for 1 hour and allow to cool.
Apply separately to the plate 10 id of each solution.
Develop over a path of 15 cm using a mixture of 25
volumes of bums-f-d and 75 volumes of tthyi acetate.
Allow tie plate to dry in air and examine in ukraznbfer
19387-91-8
Tinidazole contains not less -8.0
0/0 .&xi
ngt_m_ore
than101.O”kof
I-(2-ethyl
sulphonYlerhYl)-2- light {254 nm).
methhl-5-nitroimidazole,
CBH1/JzO+S,calculated
wti
Anv spots corresponding co tinidazole impurity A and
=rence cothedried substance.
to tinidazole impurity B in the chromatogram obtained
@
/
b
Characteristics
A_almost
white
or pale
with solution (1) are not more intense than the corresponding spots in the chromatogram obtained with
solutions (6) and (7), respectively (O.So/o).
Any other ~econdary spot in the chromatogram
obtained
with solution ( 1) is not more intense than the spot in tie
chromatogram obtained with solution (4) (O. So/O) and at
most one such spot is more intense than the spot in the
chromatogram obtained with solution (5) (0.20/.).
yellow,
crystalline p.o_wdeqpractically insoluble in warefi soluble
inZ;e&se and in dichloromerharse;sparingly soluble in
methanol.
Identification
[dennfic~rwn test C may bt omitted if
kiennj?caribn rests A,B,D and E are camid out. I&nnji~arion rests B, D and E ma> be omitred If idennj$can’on resfi A
and C are cawied oul.
V A,Method1.
A. MAingpoint,
125’ to 128°, Appendix
B.Dissolve
10mg inmirhunol and dilute to 100 ml with
the same solvent. Dilute 1 ml of the solution to 10 ml
with methanol. Examined between 220 nm and 350 nm,
Heavy metals 1.0 g complies with limit car D for heaz~
meraLs, Appendix VII (20 ppm). Prepare the standard
using 2 ml of lead standard sohuwn (10 ppm Pb).
by
SuIphated ash Not more than O. 1°/0 determined
Appendix IX A, Method II.
is 340 CO360.
C. Examine by infrared ~bsorprwn sp<crrophotomer~,
on 1 g,
Assay Dissolve 0.15 g in 25 ml of anhydrous aceric acid.
Titrate with 0.1 iu perchlonc acid VS, determining the end
point potenriometrically, Appendix VIII B. Each ml of
O.1.Mperchiotic acsd VS is equivalent to 24.73 mg of
C8H1,N10&.
Appendix IIA. The absorption
maxima inthespecrrum
obtainedwiththe substance being examined correspond
in position and relative intensity to chose in the spectrum
obtained with rinidazok EIWRS. Examine the substances
txe~ared as discs.
b. Examine the chromatograms obtained in the test for
Related substances. The principal spot in che chromamgram obtained with solurion (2) is similar in position and
size to the principal spot in the chromatogram obtained
with solution (3).
E. To about 10 mg add about 10 mg of :inc powder,
0.3 ml of hydrochloni acid and 1 ml of ~ater. Heat in a
water bath for 5 minutes and cool. The solution yields
d-sereaction characteristic of ?n”ma~ arornaric amine~,
oa drying Not more than 0.50/.,determined
on 1 g
drying in an oven at 100° to 105°, Appendix IX D.
Loss
Appendix 11B, the solution shows an absorption masimum at 310 nrn. The sptnjk absorbance at tie maximum
Storage
k
Store in a well-closed container, protected from
m.
Action
and use Amiprotozoan;
antibacterial.
1/96
f
The irnpurtttes limited
by therequirementsofthis
monograph include:
N%
.\ppendixVf.
Appearance of solutionDissolve1.0g m acerone and
dilute to 20 ml with rhe same solvent. The solution is
IV.\,
andnotmorei.n[ensely
coloured
ckar, Appendi..
rhanreference solutin Y<, .\ppendix IV B. Method II.
Related
~~aphy,
substances
Examine by rhin-kyer chromaroAppendix III A, using nhca gel GF:5J as Ihe
coating substance.
Solusion (f) Dissolve 0.20 g of the substance
being
examined in mdusnof wirh the aid of ultrasound and
dilute to 10 ml wirh rhe same solvent.
Solursbn (2) Dilute 1 TI of solution (1) co 10 ml with
merhanol.
EPCRS in
Solurwn (3) Dissolve 20 mg of rvndazok
methanol and dilute to 10 ml with the same solvent.
SoluIwn (4) Dilu~e 1 ml of solution ?) co 20 ml ‘.+~ti
mefhano[.
2-methyl5-nitro1Ff-knidazole
[tirliffcszole @lsrity
4
l-{2-ethylsdphony
lethyl)-
2 -met_hyl-4-nitroimidazole
(tinidzzok
-g
B)
,.“Y NH
N<
WJ .,/
N,
.N~V
Me
Me
o, 0
%/- f3+3
954
Metronlclazole
and
some
other
AntIprotozOal
su~mln had dificrmg toxiti}. Storage in the ts-opia
probably
also affected
the poccacy.— E. Nsracb:ri,
Trans. R. Sac. mop, Med. Hyg.. 1964.58, 413.
Agents
Br, J, Oph:hal., 1978.62, 427: B. Thylcfors. Bull
W/d
Hlth &g.. 1978, 56, 63.
Further ceferencea: B 0. L. Duke a al.. Tropcnmcd.
Pararil.. 1976, 27, 133; J. Andccson et al.. Troperrnred.
Pararii.. 1976, 27. 263; J Anderson cl al.. Tropenmed
Parasit., 1976, 27.279
Adverse Effecu Sucamin
may cause nausea,
vomiting,
abdominal
pain, diarrhoca,
urticaria,
collapse.
paracsthcsia,
hypcraesthcsia
of
the
Trypaaoaorwiasis. see Rcpxr
of a Joint WHO Experl
__ hands and soics of the feet. peripheral neuritis,
Committee and FAO Expcn Consultation, Tech Rep.
‘ever, skin ras n. dermatitis,
pho~ophobia, lachSer. Wfd Hlth Org. No 635. 1979.
/malion, ambi>opia. and uveitis. A serious effea
Preparations
M albuminuria.
with the passage
of easrs and
Sarada Iajcctka (B.P. C. /973/. A sterile soiutton O(
blocd cells, A~nulwymais
and hacmolytic
anacsuramin in Wata
ftvc Injections.
prcpaccd by dissolving,
mia are rare.
immediately
before use, the skrile
contents of a scaled
When used in onchocerciasis some of the effects
of Water for tnjcccontainer
in the requisite
amount
may represent an allergic reaction to the killed
scaled
wmainer
in a cool place. Protect
dorsa. Store the
filariac.
from light,
Rcfcrcnccs: Second Report of a WHO Expert Comrcsit.
proprietary
Namea
tec on OrsChoccrmams,Tech. Rep. Ser. Wfd Hlth &g.
Gccrrsanin(Bayer, Gcr.); Moranyl (Spscia. Fr.).
No. 33S, 1966.
Prrgnucy
●d S& acoum
Sucamtn bad ceratagenic
Crfcets in mitt.—
H. Tucbmann-Dupleacia
and
L.
Mercicr-Parot, Cf. Sianc. S&, Biof,. 1973,]67, 1717$
pcr Trap. Dis. Bull., 1974. 71, 1I07. A wmasan with 4798-p
advarreed trypasswsmmais
was sueceasfully tmarad with
suramin and mcizmprol.
in additims to supportive tbcvWin 13,146. NA”-p-PhcnylreckaPY. frOm t~ 2W week of pccgrsa~, she gaw birth tO cncdimcthylenebis[2,2 -dichloro-N.(2-cthoxy ethyl)acct.
amide].
an apparently nsrmsal child,— M. N, Lawemhal, Med.
J&mbia.
1971.5, 175, per Trap. Dis. Bull.. 1972, 69.
[email protected]
= 502.3.
CAS — [email protected]
Pmcawtkwva.
It
should not be used in the
preacnce of renai disease or adrenal insuffkkmcy.
[email protected] ●nd Fate. Following
intravenous
injection, suramin
becomes
bound to plasma
proteins
and a low cmsccntration
in plasmais nlaintaincd
for up to 3 months,
Uses. Suramin is
used in the treatment of the
early stages of African
trypanosomiasis,
eapccially Trypanosmsa
rhodesiotsc infcctiona, but as
it does not reach the cerebmspinal
fluid it is
ineffective in the advanced disease when the central nervous sys!em is affected.
Suramin is administered by intravenous injation.
To test the pat lent’s tolerance, it is advisable to
begin treatment u ith an injection of 200 mg folIowsd, if well tolerated after 24 to 48 hours by a
e~~ac
of 20 mg pcr kg body-weight (up to 1 g) on
‘ys 1, 3, 8, 15. and 22. The urine should be
steal before each doss, and if protein is present
the dose should be reduced or administmtion
delayed.
Combined
therapy with tryparsamide
has bscn
used. particular}
for late T. gambiense infection;
I 2 injections can be given intravenously at intervals of 5 days. each comaining suramin up to
10 mg per kg body-weight (max. of 500 mg) and
tryparsamide up to 30 mg per kg (max. of 1.5 g),
as a 20% solution prepared immediately
before
use. Two or 3 such courses have been given at
inlecvals of I month, Suramin is more commonly
used in conjunction with mclarsopro[.
Suramin has also been used in the prophylaxis of
trypanosomiasis.
in a dose of I g 10 provide
protection for up to 3 months: but it may mask
latent
infections.
As with pentamidine,
it is
importact to detcet more advanced infections and
to treat these ulth melarsoprol.
Suramin
is also effective in clearing the adult
I_ilariae of onchcccrciaais but has only a limited
action on microftlariae.
The usual dose is I g
(after an initial test dose) weekly for 5 or 6
weeks,
Diethyiarbamazine
is active
on the
microfilariae
anc the 2 drugs are sometimes used
in conjunction.
ccyatata. M.p. about
White
0ss.
142”.
Slightly
sokrbk in
watcc.
Headache. nauacs, vomiting, diarrhcca,
have been reported, bu! tcdozan
is
welt toicrated.
A6vame Effecth
●nd constipation
generally
Uaacs.Teclozan is used in the treatment
of intestinal
amocbiasis. About 20% of a doac is stated
to be
draorbcd and S0 be rapidly excreted. The usual dose is
100 m thcim daily for S days, or 500 mg daily. in
divid~ doses,for 3 days,
Of 5I patients with chronic intatinal amocbiasis given
tcdozasr 750 mg daily in divided doses after meals for 2
days. 43 wecc reported to bc cured; a further 5 patiensa
~~dd
to a -nd
eosrcsc of trcstmcnt with tccloran.
The dru$ was wetl tokrawd .— D, Huggins, ArraM ESC.
nac. Saudc p;bl, Med. Irop.. 1971, S. 29, per Trop. Dif.
Bra[[..
1972.69.399.
Of 30 patients with mild amocbiaais, 25 were rcpoctcd
cured after receiving tcclomn 100 mg thrice dail} for 5
days; 2 patients ccquired a second coucsc of treatment
snd 3 remainedccaiuantto teclozan. Two patients devciopcd diarrhoea during !reatmcnt
which was otherwise
well tolerated.—
A. Arcilla-Latonio
ej al., J Phi//pp.
reed, .4.ss., 1972, 48, 137, per Trop. Dis. Bull., 1973,
70.345.
A cure-rate of 92.8% (at 4 weeks) was achieved in 26
boys with chronic amocbiasis
given tcclozan
[email protected]
thrice daily for 5 days.— A. Z. E1-Abdin el al.. J.
EOPI. med. Ass., 1973, 56, 174, per Trop. DJS, Bull.,
1974, 71. 1028.
Cure in 56 of 60 patients wnh intestinal
amoeblasis
with mclozan 1.5 g in 3 dwided doses in
after treatment
24 hours.— P. Fcrnandcs tl al., Folha med., 1974.69,
293.
Cure in 26 of 27 children, aged 1 to 5 years, with
amocbiasis (usually chronic) after treatment with Icclo.
zan 750 mg in 3 divided dines in 24 hours.— H F.
Bczcrra ●r al., Rcwa bros Med.. 1977. 34, Suppl
(Aug.), 50.
proprieta~ Nmsses
Falmonox IWtrsrhrop, Arg.; Wjnthrop,
USA)
Thridazole
which is a nitroimidazolc
Iikc
mctronidazole
has antiprotozoal
activity and i>
effective against Trichomonas
vagirwdi~, En~amand Giardia Iamblia. 1t is also
cxba hislolytica,
active against anaerobic bacteria.
In trichomoniasis
it is iven
v mouth in a dmc
of 150 m
twice daily
or 7 days or as a single
-to
both me~and
women. [t has been
given =ilar
doses in the treatment of giar-
diasis.
In amocbiasis
doses of 2 g once daily for 3 da>,
arc commonly uacd.
A review of tinidazole
in the treatment
or [r .
chomoniasis. amoclakis,
and 8iardiasis,— P. R Saw! y
●t al., Drugs, 1976, 11, 423.
Procdings
of a sympmium on the use of tinidazolc ::,
the treatment
of amoebiasis,
giardiasis,
and
[n.
cbomoniasis.—
~
1978, 15, Supp/. I. 1-60
The follosving anacmbic bacteria were inhibited 5:
3.I pg per ml of tinidazolcand killed by 6.3 @ per m:
Bomraides
Jrogilis and me[oninogtnicsas. Closrridl u Y
per~rirsgens and other spcciea of clostridia, .Eubacfer;um
Fusobacwn’um,
Peptacoccus,
PepIosIrepIcaccus,
arc
Veillorrclla spp. Propiorribacterium
arnc$ was relative,.
with me.
reaistars[. The
aamc figures
were achieved
ronidazolc and omidazolc. - J.WUst. Anrimicrob -1;
Chemother,, } 977, 11, 631.
—
The median minimum inhibitory concentration
of t!r
dazoie against
Bocteroidt$
spp was 0.12 ~g pcr ncomcarcd wth 0.25 sm ocr ml for mctrmsidazole onimorazole — R. WI~ >r al,. Chemorh trap),
BUSI,1977, 23, 19.
—
The activities of clindamycin,
tinidazoic.
and dox}c!.
clinc in vitro were compared against 376 anaerobic ha:.
tcria. Clirrdamycin and tinidazole had MICS of 0.5 arc
3 xg pcr ml respectively against 90% of 200 strains ~:
Bacreroides Jragihs. Tinidazole had an MIC of 12 .S
72 strains of the Closrridlum
spp bu:
pcr ml against
bcnzylpenicillin and ampicillin were more actwc Tin, dazolc was generally leas active than benzylpeclcilllr
ampicillin,
ccpha lot bin,
erythrom YCI;
rarbcnicill in,
chioramphenlcol,
tetracycline,
and doxycyclirre again,:
20 strains of Bacteroidcs
melamnogcrricus,
54 of [n:
Fusobacterium
spp., and
30 strains
of anacro’c, c
?~?i!?ltr?~iyfi?k’
4799-s
Tinidazols+~3?~.
The bioiogod half-life of tinidazoie was 12.7 berm
after admimstration
of 150 mg as a single dose anc
when admmislcrcd
!wicc daily for 7 days to 7 voiun.
tcecs Tbe maximum serum conccntcation
was 8.9 I “~
per ml.— P. G. Welling and A. M. Monro. Armrc#mr~z.
rei-Forsch., 1972, 22. 212E, see also B. A. wood am
A. M. Monro, Br. J. verrcr. Di$., 1975, 51. 51. pe:
Abstr. Hvg..
1975.50.382.
.e
Ttrc peak serum corr&rtrations
of tinidazoie in 4 volufi.
leers 6 to I 1 houm after a single dmc of 2 g wcr:
bc~wccn 20 and 40 Kg per ml, and 48 hours after irrgm.
tion the serum corrccntration was still above the minima
trichOmOSSati6ai Concentration for moat of the 8 stratns
of Tm”chomonas uafl”rtalis examined.— A. Forsgrcn and
J. Wallin. i7r. J. verrcr. Dis,, 1974, 50, 146 and 148, per
Abstr. Hyg.. 1974, 49.593.
In 6 gynaccological patients given a single doac of [ml.
darokc 2 g peak acrum axsccntrations
were 3210 52 ME
per ml 3 to 6 houra after the dose, and 18 to 35 Pg per
mI g.5 to 15 hours after the dose. Concentrations
in
saliva, vaginal secretions, pccitoncal fluid. and various
tissue homogenates
wecc broadly comparable with those
in serum. The trlasma half-life was aboui 13 houcs.— T
Ri
●t al., Chemotherapy,
Bask, 1917. 23, 227, per
srr., 1977, 14, 1084.
In 4 hvnlthy subjects given tinidazolc 2 g conccntra [ion;
in the CSF 90 minutes later (17 to 39 pg pcr ml) were
88% of those in acmm.— A. M. M. Joki ii e! al,, J
Chemorhcr., i97~
amirrsicrab.
I-[2-
Onchoccrciasis.
Lcs ocular dctcnorauon
was obsc -~~~~j~~~l]-2-me;hyl-5-nitroimidazoie.
In a group of paucnrs with onchcccrciasis who had been
trcawd 14 to 15 i cars earlier with a slnrslc full mucsc of
CAS — 19387-91-8
suramin 4.2 g, than was seen in a symilar untreated
Colorless
crystals. M,p. about
127°.
group.—
F. H. Budden, Tram. R. Soc rrop, Med.
Hyg., 1976. 70, $44 The !ncidcncc of optic atrophy
Adverse Effects and Precautions. As for Met.
increased from I m 25 to 5 In 25 three years after
ronidazole, p,968.
patlcnls had been treated with suramm 5.2 g (total
dose) for ocular Orschocerctasis. There was no change I< Absorrstissn
and Fate. Tinldamk is ~bsorbedfrom
the Incidence ( 1 in 23) in 23 Patwm not given&[email protected]
tra~
~uram]n — B. ~n}lcfors and A Rolland, flu//, W/d
pharmam fn~l~ of ~,n,dazolc ~nd ~cLrO”idaZo\C ,“
.-—–’r!h Org., 1979, ?:, 479.
man and in mice.— J. A Taylor e! al,, An flrmcrob .4g
ef dwcuss tons of the treatment of onchwerclasis.—
Chemofher., 1969, 267.
“ a’”’ ‘“’’m’”’”
Amocbiasis. In a series of controlled studies 436 palien!:
with intestinal amwbiasis
were treated with tinidazolc
600 mg twice daily for 5 days or 2 g once dail! for 3
days, or mctronidazole
400 mg thrice daily for 5 days o2 g onm daily for 3 days, Cure-rnms for tinidazole wcr<
97.2% and 88.3% respectively in p~tjents passing !rophc.
zoitea and .S1.2% and 93.4% in those passing cysts, COT.
pared with 87.5% and 73.3%, and 84.2% and 47.3% (omctronidazolc.
A cure-raw of 96% was achieved in ~:
patmnts w Ith hepauc ammbiasis
gwcn Iinidazolc 2 ;
once daily for 2 days, compared with 75.5% in 49 g}ic~
metron!dazolc
A cure-rate of 88.3% was achicvcd in QJ
patients with g!ardiasis given tinidazole in a mean dm:
of 61.8 mg ~r kg as a single dose, compared
UI[?.
46.7% in 92 given metronidazolc
56 mg pcr kg — J S
Bakshi ef al., ~1978,
/5, SUppl 1, 33
I
---1-—
[n a multiceatre study in 8 countries a cure-rate of 95%
was ~chlevcd in 502, pmmnts with amocbiasis given timdazole 2 g once dady (50 mg pcr kg body-weight
for
children) for 2 or 3 da>s. An excellent response was
achlevcd in 60. and a EC06 rcatzmssc in 17. of 82 with
-tpatic amocbiasia. A c~re-rate “of 88% was”achieved in
i children with giardiasis iven a single dmsc of about
.0 mg per kg. A cure-rate of 95 2% was achieved in 8S9
pawns
with Irichomonal vaginitis given a single dose of
. I g.— V. V. Apte and R. S. Packard. XI
978. !5,
Suppl. I, 43.
Of 88 aboriginal children mfcctcdwith Giardia Iamb/id
or Enummeba hi$lofyrltu
23 received a single dose of
~inldazole 1 10 1.S g. 23 tin!dasole I to 1.5 g daily for 3
da}s. 23 metronidazolc
200 mg fwics daily for 3 days,
and 19 were left untr=tcd. Both metronidamle and tini-
dazole SUUXWUIIYcleared the majority of G. Iumblia
infections but .& hisro/) Ims i cctioraawere more efYcctivcly ~r~tcd with tinidazoie. ?A single doseof tinidazolc
was as effective as the longer regimen. No adverse rcacuons wcurrcd with either drug.— J. S. Wdch cr al.,
.Med. J. AusI.. 1978.1.469.
Further referenti
N. Islam and M. Hasan, Curr. rher.
Res., 1975, 17. 161: J. N. Scragg et al., Archs Dis.
Ch,ldh.. 1976.51. 3fJ5.
Teclozan/Tryparsamide
Scc also under Amoebiasis, shove.
Further references L. Jokipii and A. M. M, Joki ii, J.
infect. Dis.. 1919, 140, 9E4; M. B. Tadroa, J. 1./?1.
Sot, Arrurif.. 1979, 9, 467, per Trap. Dit &dL, I960,
77, 125; A. Sabcharcon et a[., S.E, Asian J. wop. med.
publ, Hlth. 1980, 11, 280. per Trop. Dis. Bull.. 1981,
78, 161.
.$wifz.~ Faai yne (Pfizer, Fr.); Simplotan (Pfizer,
Tricbcgin (C f icst, ItaL); Tricolam (Pfi:cr, Spain).
Ger.);
PropAyfxsis in megery. In a prospective. rarrdswniaed,
Trypaaoside
(B.P. /968). Tryparaa,m.: Tryparsamidouble-blind swdy of 6 months’ duration involving 71
durrx Glyphanmainc. T
patients 2 g of tinidazoie given before surgery prevented
(carbmroyimethy lammo phenylarsortate hemlhydrate.
wound infection after elective colonic surgery in 37 of
[email protected],MH,0~~
“u’”
hydrogen ~
treated
40 patients in comparison with 28 of 31 patients
CAS — 554-72-3 larrhydroud; 6159-2%1 (hem,hydrafe).
with Iaccbo.— P. S. Hunt et a!., Med. J. Asst..
1979,
Pharmacopoeias. h [rd.. int., It., A4ex., and Turk.
1, 10!
postoperative infections occurred in 6 of 50 pmticnts who
A cdout’faa,
odourfcaa, crystalline
powder which is
reccivsd 2 g of tinidazole
12 to 18 horrrz bcfora slowly affcctcd by light.
undergoingelectiveatdonzinalhystarcctomy and 2
SOMk 1 in 1.5 of water, forming a neutral solution;
bum paatopcrativd~
infections occurred in 28 4%
sdubfe 1 in 3500 of alcohol; practically
insoluble in
similar control patients.—
P. C. Appcibaum
et at.,
chloroform aod ether. A 4.62% solution is iao-aamotic
Chemotherapy. Bade, 1980.26, 145.
with aerzsm. Aqueous SOkItiON deteriorate
on storage
and sbosdd be @
immdlaiely
after preparation; soluFurther referencax: J. Adno and R. Casscl, .S. A/?. med.
tJona for injcctlon are preparzd aseptically. Store in a
J., 1979, 56. 565 (gynaecologicai surgery); M. Karhunen
cd
pkarz in small airtight omttaincra.
Protect from
er al., Br. J. 06wer. Gynaec.. 1980, 87. 70 (byatcrcckigkzt.
tomy).
as a singie dose prorriekoni-i~
Tinidazok
2
f.iL<r abscess. ‘31ridazole 57 ma ocr ku bod~-wciaht
duced parasitological mm in 47 of SO patients with tri&Ily for 5 dafi or 50 mg fcs k; daily I%r 3 daya ;as
chomosziasis, camparcd
with 32 of 50 gi’rcrt meteffective in the treatment o amoebic liver abaccaa in 23
, ronidasole.—
R. Anjmseyulu •~ af., J. im. med. Rex.
of 25 children aged 3 months to 6 ears.— J. N. Scrs
y1977,
5,436
.and E. M. Proctor. Arch Dis. Chj/ dh., 1977. S2. 408.
Further reprta
of the successful usc of 2- doaa of
Of 16 patients with hepatic amocbiasis 15 were cured
tinidazole in women.— H. T. M. Rao and & R. Sheafter treatment with timdazoie 2 g aa a single dose daily
IIOY, J. in:. med. Res.. 1978, 6, ti, J. P, Ward. Med. J.
for 3 to 6 days, cumparcd with 12 of 15 given metArsst.. 1976, 2, 651; R. Jones and P. Enrfera, ibid., 1977,
for 4 to 10
romdazole in the same doss ~U;fi~n
.?. 67% M. Masax et al., Boln chif. Parassit.. 1976, 31,
rugs, 1978, IS.
da}s. — N. [slam and K.
46. pzr Trop. Dis. Bull., i 977, 74.291.
&IPp/.
~, 26.
Successful
usc in men of single l-g doses of tirridazFunhe.r refercnca.—
H. A. Meyer, E. A/ii. med. J..
ole.— N. KaWamura, Br. J. verrrr. D&
1978, 54. 81,
191+ S1. 923, ~
@p
Ois. Bull. 1975, 72.720
S.
pm Abstr. Hyg., 1978.53.463.
S, Mathur ●t 4,, J, In!. med. Res., i977, 3, 429 M. A.
Scc also under Amocbiaais. above.
Quaderi e; al., J. !rop. .Wed. Hyg., 1978, 81, 16.
t’egiwiris
Administration
of a single dose of tinidazok
with giar6iasis
2 g to 35 women with Gordnerella vagirralis (Hrremophafter a single dose of unidazolc;
2 others were cured
ilus
vaghzfis)
infection
led
to diaappamrtcc of tbc bacafter a second dose. 0c6a were: under I ycm, 500 m ;
teria in 33; of the other 2 women the count was reduced
7 years, 1 g. 12 years, l.: g.— S. Danzig and W. L. F
in one ansf a repzat mcstmem wcs auccuaful in the
Hatchud
(letter), S. A r. med. J.. 1977, 32, 708, pzr
second. Two women relapsed after 15 to 20 rfqm and
Trop. Dis. Bull.. 1976. { 5. 7E3.
repeat treatment was succssaful. All the patients’ partncure-rale of 96.7% in patientt with giardiaais trcamd
em were given the same dose of tinisk.olc.
and
h tinidazole 150 mg t~icc daily for 7 days.— G. C.
abatinencc from sexuai intercnursc was rccommcndcd for
m J trop. .Ued. Hy ., 1977, 26. 564, per
at least 24 houm.— M. Bardi ●r of. (letter). hrscer.
%+#”,;,
“,978, ?,. 648. !kc also S. Y. Salih
1960.1. 1029.
a~~pR. ~~ AMa\Ia,
J. mop. Med. Hyg., 1977, 80, 11,
Sec also under Trichomoniasis, atmve.
per Trop. Dis. Bull.. 197?. 74, 731.
Cure of 53 of 55 patiems with giardiasis given tinidazPrOpriGta
M=
OIC2 g as a single dose. — N. A, El Masry et al., Am.
Faai in (P7 izcr. /Ial.); Fasi8yn (Pfizer. Arg.; Pfizer.
J. rrop. Med. Hyg., 1978. 27, 201, per Trop. Dis. Buff., ~+ ustral.; Roen”g, Belg,; Pfi:er, Dam.;
Pfizer, Neth.;
1978. 7S. 544.
Pfizer. Now.;
Pfizer, S. Afr.; Pfizer, Sued.: Pfizer.
Giardiarir. Cure in 35 of 3E children
985
_
~~
Side-effects include dizziness, tinnitus,
IIcuac$ vosmtmg, bcadachc, fever, exfoliative dermatitis,
~~
[email protected]$
and bmdprdia
immediately after an
toxIc ‘~
c ccta~ M occur.
upon the optic nerve:
pkt~~~mgc
Traatrarcot should be discontinued immediately
if .iaual
dcfccta a~n
though, blindness may occur suddenly,
-y
If optic utju~
is already
present. visual
6cfecta may not bccomc apparent until a few weeks
after a course of treatment has been completed.
UTr-yprzamide
u trypanocidal,
Because it Wnetratas tbz Ce.rcbroapirrd fluid ii has been used in (he
treatment
of Afnan
trypanoaomiasis
with central
aemuus system involvement psr-titularly in Tryparsosoma
garrrbierrse infactiona. It bas beers given in doses of 30 to
60 azg per kg body-wci bt (up to maximum of 2 g)
intravactody
csch week ?or 12 to 14 weeks. The trypanaonrcs may become rcaiatant to lryparsamidc.
BectuMc
of tbz risk of blindness. melaraoprol is now preferred.
For the usc of ~rsamidc
in conjunction
with
auramirs, see p.984.
-~
TryInjactbm (BP. 1968). Tryparxam.
lnj. A
stcnlc aokution in water for Injections. prepared by dissdving, immediatelybeforeUSC,the sterilecontentsof a
scaledcontainer in the requisite amount of Water for
lnjcctiona.
r—=
.
Page Number
Database:
..
Medline
<1995
to
February
: 1
1998>
<1>
Unique
Identifier
96415043
Authors
__—=
Salo JP.
Salomies H.
Title
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
It was postulated
that tinidazole
decomposes
by
hydrolysis.
different mechanisms
under basic and neutral/acidic
conditions .
<2>
Unique Identifier
96415042
Authors
Salomies H.
Salo JP.
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
The mobile phase used was methanol-diethyl
validated.
ether-chloroform
(1:9:3, v/v/v) allowing small changes in
Detection was at 314 mm. Rf values being
its composition.
was achieved for tinidazole
0.1-0.4, baseline resolution
and the hydrolysis
products. The analytes were stable on
the sorbent and could be precisely and accurately
measured
Page Number
;$-%
n.
.?-.
in the range
20-170
ng per band.
: 2
TRANSAmIONS
OF THE ROYAL
Treatment
tinidazole
SOCIETY
OF TROPICAL
MEDICKE
AXD HS’GEXE,
VOL. 77, No.
6, 845-846 !1983)
of non-invasive
amoebiasis. A comparison
alone and in combination
with diloxanide
S45
between
furoate
PEHROLOV PEHRSOX A?iD ELIAS BEYGTSSOX
Depl. of Infectwus Diseases, Karolinska
Institute, Roslagstull HosMrL
BOX S6S1, S-11489
Stockholm,
Sweden
Summary
Tinidazole (40 mg/kg bocfy-weighr in one daily dose for five days) and tinidazole (same dose) plus
diloxanide furoate (20 [email protected] body-weigh: +vided imo three daily doses for 10 days) were compared
as treatments for arnoeb]asls. The para:mc cure rates were 44 and 91 Yoresps+tive!y. We cannot,
therefore, recommend tinidazole alone m this dosage as a treatment for non-mvaslve anmebiasis.
Tfidazole
Introduction
(Fasigyn) has recently been widely used
as an alternative to metronidazoie for the treatmen[ of
infections with Enramoeba hiscolytica. In a previous
study (PEHRSON, 1982), tinidazole was given to a
series of patients with chronic intestimd or asymp.#Ynatic amoebiaais. When checked by at least three
al specimens taken on different days, one month
~ter treatment, we found a parasitic cure rate (p. c.r. )
of O% (0/14). This should be compared with the
results obtairstxl in other studies, showing a cure rate
of 77 to %VO (MrsRA& LAIQ, 1974; PRAKASHe! al.,
1974; JOSHI & SHAH, 1975; BAKSHI er al., 1978),
using the same dosage schedule but mainly in cases of
acute intestinal arnoebiasis.
To investigate the reasons for the unsatisfactory
response we obtained, which could be due to too low a
dose or to a iow efficiency of tinidazole in the gut
lumen, we carried out a new trial with a higher daily
dose of tinidazole and compared the effect of this
with
higher dose with that following treatment
tirsidazole and diloxanide furoate (Furamide) in combination. This fatter was found to be an effective
intraluminal amoebicide (WOODRUFF & BELL, 1960,
1967; WOLFE, 1973), whose mode of action upon the
amoeba is unknown. We omitted Furatnide as a single
regimen, because it is considered to be ineffective
against invasive asnoebiasis and there is always a risk
of developing an invasive form of the disease if
zymocieme differentiation of strains of Enramoeba
histolyricu is not performed routinely $ARGEAUhT &
WILLLAMS, 1978; SARGEAUh’T el al., 1982).
Materials and Methods
During the period of the study, 41 patients were
diagnosed as suffering from ammbiasis, All of them were
supposed 10 have contracted their infecuons abroad, as
amoebiasis is not considered to be endemic in Sweden. No
cases of acute, d~senteric amoebiasis or diagnosd or
suspected cases of lwer abscess were included. The patients
_~had not received any anti-amoebic drug during the previous
.e- ‘ear. Nine of the patients had a concortsiram infection with
two with Canspy;iardia fambha, two with Shigclfa finwi,
~bacter jejm”,
one with Salmonella puratyphi A, one with
Hynunolepisnana, one with Ascati lumbticoide~andonewkb
Trichti trichiura
In a predetermined, random order, the patients were
18 being treated with rinidazole
abcated to twO ~UpS,
alone and 23 with the combination.
All were hospital
its-patients sad kept under supervision during treatment.
Dosage schedules
(1) tinidazole 40 mg%g body-weight in one daily dose for five
days;
(2) tinidazole as above plus difoxw”de furwate 20 mg&
bady-weight
divided
intothreedaily
dosesfor10 days.
Approximately
one month after the treatment was completed, checks were made, including the examination of at
least three stool specimens taken on different days. One of
these was examined by direet microscopy of freshly passed,
loose faeces induced by a SO%magnesium sulphate purgative
and the other normally passed speeitnens were examined
by the formol-ether-concentration technique describsd by
RtDLEY & HAWGOCSD(1956). Failure was defined as the
persistenceof amoebic rrophozoi[esor cysts in any of these
specimens.
Thoseinwhom the treatmem with dnidazole faifed were
later treated with the combination of tinidazole qd diloxanide furoate and those in whom the combination faded were
daily for
-ted
with metrotsidazole 40 mgkg body-weight
10 days.
Results
Data on the participants and the results of the
checks one month after treatrnenr are shown in Table
I. 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
10/’-level (two-tailed test) and in favour of the
combination. 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
paras]tes did not seem to affect the outcome of the
treatment.
Discussion
Our results with tinidazole alone (44°/0 p.c.r.), in
treating non-d ysemeric amoeblasis, are unsatisfactory
and differ vet-ymuch from those obtained in previously published studies by different authors, using the
same dosage schedules (77 to 96% p.c.r.) (ISLAM&
HASAX, 1975; AnE & P~CURD, 1978) or lower
(MtsRA& LAIQ, 1974; PRAKASHer al., 1974; JOSHI &
SHAH, 1975; BAKASHI e? al., 1978). The patients in
these studies were, however, mainly cases of acute
amoebic dysentery, a factor which may have in!lucncd the results.
A weak amoebicidal effect of the nitroirnidamles on
the cyst stage of E. histoiysia was observed by
COMPAIUTIVE
846
Tabk
44+’-s
I--Some characteristics ad
TREATMENTS OF NON-NASIWZ AMOEBIAS15
treatment results of 41 patients with non-invasive amoebiasis
Patients with
symptoms v.
asymptornatics
Swcdcs v.
other
nationalities
No.
Median age
(age range)
years
Tinidazok
4omgllcgxl+v
18
28 (9-68)
11:7
8:10
8
44%
Tioidazok 40 mg/lqj x 1
x V + diforcanide
furoate500mg
x3xX
23
26 (6-68)
15:8
11:12
21
920/.
Treatment
SPILLMAN et al. (1976), but this report was contradicted by BAKSHI et al. (1978). Our drug u-k+ was
carried out in a country in which amoeblasis N 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
tinidaurle alone are due to its ineffectiveness in
eradicating cysts in the lumen of the gut, either
because of too effective absorption (MONRO, 1974) or
inactivation by aerobic organisms as shown by R4LPH
& CURm
(1978).
tinidazole was combined with diloxanide
fitroate, we obtained a cure rate of 910A, which maybe
compared with studies by WCODRUFF
& BELL
(1%7), in which they reported a cure rate of 95’%0in
When
amoebic cyst-passers treated with diloxanide furoate
alone for 10 days and WOLE% (1973), who found a
cure rate of 83% 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 combination.
;+-%.
Acknowledgements
We wish to thank Mrs. Ingcr Pont&s, dsc head nurse its
the tropicafward and Birgit Lirrdkg, dse chief technician at
the laboratoW of tropical diseases, for their devoted work
with the patients.
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