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GUAL4COL

B. Chemical Name:

Guajacol,Guakwol,Guaicoo, Guajakol(CZECH),0-Hydroxyanisole,2-Hydroxyanisole,
l-Hydroxy-2-Methoxybenzene,O-Methoxyphenol,2-Methoxyphenol,Methylcatechol,
PyroguaiacAcid

c. Common Name:

Austral: Waterbury’sCompound,Belg: BaumeDalet, Canada:Cre-Rectal, etc. Various


names from differentcountries. Please see file.

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:
(S@ecij7cation@ @lesults)
-_ Assay: 99.5% min. 99.7%

E. Information about how the ingredient is supplied:

White or slightlyyellowcrystal mass or colorlessto yellowish,very refractiveliquid,


characteristicodor, darkensto exposureto air and light.

F. Information about recognition of the substance in foreign


pharmacopoeias:

Arg., Braz., Chil.,Fr., It., Mex., Port., Roum,., Span., and Swiss.

G. Bibliography of available safety and efficacy data including peer


reviewed medical literature:

H. Information about dosage forms used:

Expectorant

—-.
—-
1. Information about strength:

0.3-O.6ml

J. Information about route of administration:

Orally

K Stability data:
BoilingPoint: 205C
MeltingPoint: 27C to 29C

L. Formulations:

M. Miscellaneous Information:

__—_

Page -2-
. .

CERTIFICATE OF ANALYSIS ?C+w


------ ------ ------ -----
~. 577~3
PRODUCT: GUAIACOL LIQUID GRADE:PURIFIED
LOT # :X49993D28 CODE:R9128201
RELEASE #: N
SPECIFICATIONS RESULT
------ ------ -- ------

Colorless liquid , Conforms


1. Description
characteristic odor

27.5 deg C min. ,?8.0 deg C


2. Solidification point
99.5% min. 99.7% .P
3. Assay
~—————

.,.

ATTENTION: TONY HM’CHETT

Date :06/06/97 Prepared by .. A.M. SCU1

9257 Approved by

Our Order # 234202 Your PO # 52b09

.. . /
*---
QUALITY CONTROL REPORT

CHEHICAL NAME.:GUAIACOL PURIFIED (LIQUID)

MANUFACT’UPJZ
LOT No. :x49993D28

—------ —-- ----


PHYSICAL ‘1’KS’l’

SPECIFICATION TEST STANDARD. “usp——


. /BP /MERCK — /NF_/MART._/co.sPEcs._.

1 ASCRIPTION. :
WHITE OR SLIGHTLY YELLOW CRYSTAL MASS OR COLORLESS TO YELLOWISH,
L
/’

[
VERY REFRACTIVE LIQUID; CHARACTERISTIC ODOR; DARKENS ON EXPOSURE TO
AIR AND LIGHT.

2)SOLUBILITY.:
lgm DISSOLVES IN 60-70ml WATER, lml GLYCEROL; MISCIBLE WITH ALCOHOL,
CHLOROFORM, ETHER, OILS, GLACIAL ACETIC ACID; SOLUBLE IN NAoH soLuTIoN;
WITH MODERATELY CONC KOH, IT FORMS A SPARINGLY SOLUBLE COMPOUND.

–-.
3)MELTING POINT.:

4)SPECIFIC GRAVITY.:

5)IDE’NTIFICATION.
:
A)COMPLIES IR SPECTRUM AS PER COMPANY SPECS.

PASSES. : FAILS .:

COM4ENTS. :

ANALYST SIGNATURE. : DATE. :

PREPACK TEST.: DATE.: INITIAL.:

RETEST.: DATE. : INITIAL. :

.=.

.-
MATERIAI. ‘SAFETY DATA SIIFET Page 1 of’5

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MATERIAL SAFETY DATA SHEET

Guaiacol, 99+%
06742

MSDS Name: Guaiaed, 99+%

% 2-Methoxvphenol
.- Company Identification: Acres Organics N.V.
One Reagent Lane
Fairlawn, NJ 07410
For information in North America, call: 800-ACROS-01
For emergencies in,the US, call CHEMTREC: 800-424-9300
For emergencies in the US, call CHEMTREC: 800-424-9300

**++ sECTION 2 . COMpoSITION, INFORMATION ON INGREDIENTS ****

+----------------+--------------------------------------+----------+-----------+
I CAS# Chemical Name l% I EINECS# I
l----------------
1--------------------------------------
;---;;;----
1-----------1
90-05-1 IGUAIACOL [ 201-964-7I
+----------------+--------------------------------------+----------+-----------+
Hazard Symbols: XN
Risk Phrases: 22 36/38

**** SECTION 3 – HAZARDS lDE~IFICATION ****

EMERGENCYOVERVIEW
Appearance: clear slightly yellow. Flash Point: 82 deg c.
Light sensitive. Air sensitive.
Target O?cgans: Central nervous system, eyes, skin.

Potential Health Effects


Eye :
Causes eye irritation. Causes redness and pain.
Skin:
Causes severe skin irritation. May be absorbed through the skin.
Causes redness and pain.
Ingestion:
Harmful if swallowed. May cause gastrointestinal irritation with
.-. nausea, vomiting and diarrhea.
Inhalation:
May cause respiratory tract irritation.
Chronic:
Not available.
MATERIAI. SAFETY DATA SIIEET Pagc20f5

**** SECTION4 - FIRSTAID MEASURES ‘***

-%.= Eyes :
-—
Immediately flush eyes with plenty of water for at least 15 minutes,
occasionally lifting the upper and lower lids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of soap and water for at
least 15 minutes wh~le removing contaminated clothing and shoes.
Ingestion:
Get medical aid. Wash mouth out with water.
Inhalation:
Remove from exposure to fresh air m-mediately. If not breathing,
give artificial respiration. If breathing is difficult, give oxygen.
Notes to Physician:
Treat symptomatically and supportively.

**** SECTION 5 - FIRE FIGHTING MEASURES ****

General Information:
AS in any fire, wear a self-contained breathing apparatus in
pressure-demand, MSHA/NIOSH (approved or equivalent), and full
protective gear. Combustible Liquid.
Extinguishing Media:
In case of fire use water spray, dry chemical, carbon dioxide, or
chemical foam.
Autolgnitlon Temperature: 385 deg C ( 725.00 deg F)
Flash Point: 82 deg C ( 179.60 deg F)
NFPA Rating: Not published.
Explosion Limits, Lower: Not available.
Upper: Not available.

**** SECTION 6 _ ACCIDE~~ REL~E ~URES ****

General Information: Use proper personal protective equipment as indicated


-.4- in Section 8.
Spills/Leaks :
Absorb spill with inert material, (e.g., dry sand or earth), then
place into a chemical waste container. Remove all sources of
ignition. Use a spark-proof tool.

**** SECTION 7 _ HANDLING and STO~GE ****

Handling:
Avoid breathing dust, vapor, mist, or gas. Avoid contact with skin
and eyes. Use only in a chemical fume hood.
Storage:
Keep away from sources of ignition. Store in a cool, dry place. DO
not store in direct sunlight. Store in a tightly closed container.

**** SECTION 8 . EXpOSURE CONTROLS, PERSONAL PROTECTION ***+

Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.

Exposure Limits
+--------------------+-------------------+-------------------+-----------------+
I Chemical Name I ACGIH NIOSH IOSHA - Final PELsI
l-------------------- l------------------- -----------------------
1-----------------1
I GUAIACOL Inone listed none listed [none listed
+--------–-–-------–-+-------------------- ----––-––---–------+---------––-–----+

OSHA Vacated PELs:


GUAIACOL:
No OSHA Vacated PELs are listed for th~s chemical.

Personal Protective Equipment


.——.
Eyes :
Wear appropriate protective eyeglasses or chemical
safety goggles as described by OSHA’S eye and face
protection regulations in 29 CFR 1910.133.
MATERIAL SAFETY DATA SHEET Page 3 of 5

Skin:
Wear appropriate protective gloves to prevent skin
-—m
exposure.
Clothing:
Wear appropriate protective clothing to prevent skin
exposure.
Respirators :
Follow the OSHA respirator regulations found in 29CFR
1910.134. Always use a NIOSH-approved respirator when
necessary.

**+* SECTION 9 . pHySICAL AND CHEMICAL PROPERTIES ****

Physical State: Liquid


Appearance: clear slightly yellow
Odor: Aromatic odor
pH : Not available.
Vapor Pressure: 7 hPa @ 79 deg c
Vapor Density: 4.3
Evaporation Rate: Not available.
Viscositv: Not available.
Boilin g ;oint: 205 deu C @ 760.OQIQLLJQ
‘(--
Freezing/Melting Point:
Decomposition Temperature:
27 - 29 deg C
Not available.
Volubility: 1.7 G/100ML WATER (15aC)
Specific Gravity/Density: 1.1290g/cm3
Molecular Formula: C7H802
Molecular Weight: 124.14

**** SECTION 10 - ST~ILITy AND R~CTIVITy ****

Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
_.–- Incompatible materials, light, exposure to air.
Incompatibilities with Other Materials:
Strong oxidizing agents - strong bases - acid chlorides - acid
anhydrides.
Hazardous Decomposition Products:
Carbon monoxide, carbon dioxide.
Hazardous Polymerization: Will not occur.

**** SECTION 11 _ TcJXICOLOGIC~ INFORMATION ● ***

RTECS # :
CAS# 90-05-1: SL7525000
LD50/Lc50:
cAs# 90-05-1: Inhalation, mouse: Lc50 =7570 mg/m3; Oral, mouse: LD50
= 621 mg/kg; Oral, rat: LD50 = 520 mg/kg; Skin, rabbit: LD50 = 4600
mg/kg.
Carcinogenicity:
GUAIACOL -
Not listed by ACGIH, IARC, NIOSH, NTp, or OS~-

**** SECTION 12 . ECOLOGI~ INFOWTION ****

Ecotoxicity:
EC 50 (24 hr) Daphnia magna: 63 mg/1
Environmental Fate:
Guaiacol is biodegradable.
Physical/Chemical:
Not available.
Other:
Not available.

.-. **** SECTION 13 - DISpOS~ CONSIDERATIONS ****

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.
RCFA F-Series: Not listed.
RCRA P-Series: Not listed.
MATERIAL SAFETY DATA S[ {EET Page40f5

RCRA U-Series: Not listed.


Not listed as a material banned from land d~sposal according to RCRA.

*+** SECTION 14 . T~SpORT INFO~TIc)N ****

US DOT
No information available
IMO
Not regulated as a hazardous material.
IATA
Not regulated as a hazardous material.
RID/ADR
Not regulated as a hazardous material.
Canadian TDG
No information available.

++*+ f.JEcTIoN 15 _ REGULATORY INFc)~TIoN +***

US FEDERAL
TSCA
CAS# 90-05-1 is listed on the TSCA inventory.
Health & Safety Reporting List
None of the chemicals are on the Health & 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 # 90-05-1: acute, flammable.
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
Not present on state lists from CA, PA, MN, MA, FL, 01 NJ.
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 22 Harmful if swallowed.
R 36/38 Irritating to eyes and skin.
Safety Phrases:
S 26 In case of contact with eyes, rinse immediately
with plenty of water and seek medical advice.
WGK (Water Danger/Protection)
cAs# 90-05-1:1
..—. Canada
CM# 90-05-1 is listed on Canada’s DSL/NDSL List.
WI-MIS: Not available.
CAS# 90-05-1 is listed on Canada’s Ingredient Disclosure List.
Exposure Limits
MATERIA1. SAFETY DATA SHEET Page 50f5

**+* SECTION 16 . ~DITIoN~ INF(3~TIoN ● ***

MSDS Creation Date: 11/03/1991 Revision #2 Date: 9/02/1997

The information above is believed to be accurate and represents the best


information currently available to us. However, we make no warranty of
merchantability or any other warranty, express or implied, with respect to
such information, and we assume no liability resulting from its use. Users
should make their own investigations to determine the suitability of the
information for their particular purposes. In no way shall Fisher be liable
for any claims, losses, or damages of any third party or for lost profits
or any special, indirect, incidental, consequential or exemplary
damages, howsoever arising, even if Fisher has been advised of
the possibility of such damages.
----------------------------------------------------------------------------

\ JJ ;L to product information.
Appendix 1 A A27

A colorless, corrosiveliquidwitha pungentodour;


GlycoUic Acid Hydroxyacetic acid; HOCH,.CO,H =
weightper ml, about 1.22g.
_#””% 76.05
Formic Acid Solution, Non-aqueous A 5% VIV solution General reagent grade of commerce.
of anhydrous formic acid in chloroform. Slightly hydroscopic crystals; melting point, about 80”.
Non-aqueous Formic Acid Solution should be freshly
Glycyrrhetic Acid Glycyrrhetitt,ic acid; a rnkture of a-
prepared;itisan extremelycorrosive material.
sand ~-isomers with the ~-isomer predominating;
D-Fructose Laevtdose; ~H,lOt = 180.2 CWI-1460,
= 470.7
General reagent grade of commerce. General reagent grade of commerce.
A white, crystalline powder; melting point, about 103° A white to brownish-yellow powder; melting point, about
with decomposition; [a]~, about – 92° ( 10°/0w/v in water 292°, with decomposition; [a]~, about + 160° (I?40 w/v in
COnt~fing 0.05 d Of 5M iUStStIOt@. chloroform).
L-Fucose 6-Deoxy-L.-galactose; ~H120s = 164.2 &Glycymhetinic Acid 3&Hydroxy-1 l-oxo-18j3,20&olean-
General reagem grade of commerce. 12-enoic acid; CdMO, = 470.7
A white powder; melting point, about 140°; [a]~, about General reagent grade of commerce.
–76° (9% w/v in water measured titer 24 hours). Melting point, about 293°; [a]~, about + 170° (1?’. w/v in
Furfuraldehyde Furfural; furan-2-aldehyde; chloroform).
C,H,O, = 96.09 Glyoxal Bis(2-hydroxyanil) Bis(2-hydroxyphenytino)-
Generai reagent grade of commerce. ethane; C,,H,INZ07 = 240.3
A colorless or pale brownish-yellow, oily liquid; boiling General reagent grade of commerce.
point, about 162°; weight per ml, about 1.16 g. Melting point, about 200°.
D-Gaiactose CJI,ZO, = 180.2 Glyoxal Sodium Bistdphite
General reagent grade of commerce. (HOCH”SO$Ja),,HzO = 284.2
A white, crystalline powder; melting point, about 164°; General reagent grade of commerce.
[a]~, about +80° (10% w/v in water). A white or cream powder.
Gallic Acid 3,4,5 -Trihydroxybenzoic acid; C, H, O,,HZO = Gonadotrophin, Chorionic
188.1 General reagent grade of commerce.
General reagent grade of commerce. A white or almost white, amorphous powder.
Melting point, about 260°. Gonadotrophin, Serum
Gelatin Of the British Pharmacopoeia. Generalreagent grade of commerce.
A white or pale grey, amorphous powder.
;elatin, Pancreatic Digest of
,ticrobiological reagentgradeof commerce. Green S CI 44090; E 142; lissarnine green; acid brilliant
green BS
Gitoxin C,, HtiO,, = 781.0
Indicator grade of commerce.
General reagem grade of commerce.
A white, crystalline powder; melting point, about 283°, Guaiacol o-Methoxyphenol; CH,O.C,H,.OH = 124.1
with decomposition; [a]~, about +22° (0.5°/0 wiv in a General reagent grade of commerce.
mixture of equal volumes of chloroform and methanol). Colourless or pale yellow or pink crystals with an aromatic
odour; melting point, about 28°.
Complies with the following test,
HOMOGENEITY Carryout testA forIdentification described Guaiacol Solution A 5% wfv solution of guiziacol in
under Digitalis Leaf applyingtothechromatoplate a ethanol (96?40).
solution containing only the reagent being examined. The Guaiacol Solution should be protected from light.
chromatogram shows only one spot. Guaiacum Resin Resin obtained from the heartwood of
D-Glucose Dextrose; ~H,jOb = 180.2 Guaiacum oficinale L. and Guaiacum sancmm L.
Analytical reagent grade of commerce. Reddish-brown or greenish-brown, glassy fragments.
A white, crystalline or granular powder; [a]~, about Guaiacum Tincture Macerate in a stoppered flask 20 g of
+52.5” (IOVOw/v in water containing 0.2 ml of 5M guaiacum resin with 100 g of ethanol (’8W.) for 24 hours,
ammonia). shaking occasionally, and filter.
D-Giucose Monohydrate C,H,ZO,,HZO = 198.2 Guaiazulene 1,4-Dimethyl-7-isopropylmulene; >H,s =
General reagent grade of commerce. 198.3
Colouriess crystals or a white to cream, crystalline General reagem grade of commerce.
powder; [a]:, about + 52.5° ( 10VOw/v in water containing Dark blue crystals or a blue liquid; melting point, about
0.2 ml of 5M ammonia). 29°.
Guaiazulene should be protected from light and air.
Glycerol Propane- 1,2,3-wiol; HOCH,.CHOH .CH,OH =
92.10 Guanine 2-Aminopurin-6-one; C,H$N,O = 151.1
Analytical reagent grade of commerce. General reagent grade of commerce.
A colorless viscous Iiquid; weight per ml, about 1.26 g. Heavy Metals Masking Solution To 2.0 ml of 2M
Glycerol (85%) Glycerol containing 12.0 to 16.0°/0 w/w of ammonia add, in the following order, 1.5 ml of a 5°A w/v
‘--ater; weight per ml, 1.22to 1.24-g. sohstion of ammonium oxa~ale, 15ml of a So/Ow/v solution
of potassium cyanide, 45 ml of a 10OAw/v solution of
Aycerol Tnacetate Triacetin; C,H,,O, = 218.2
sodium acetale, 120 ml of a 500/0WIVsolution of sodium
General reagent grade of commerce.
Ihiosulphale, 75 ml of a 100/0WIVsolution of sodium acerare
A colorless liquid; weight per ml, about 1.16 g.
and 35 ml of lM hydrochloric acid.
Glycine Aminoacetic acid; H, NCH,.CO,H = 75.1 Heavy Metals Masking Solution should be prepared
Analytical reagent grade of commerce. immediately before use.
600 Expectorants
PREPARATIOtUS The main constituent is o-methoxyphenol. CHJ0.COH4.0H=124.~]
Euphorlsh
Liquid Extract (B.P. C. 1949). Ext. Euphorb. Liq. I in I: WI per ml (]iqutd) tibout 1.12 g: m.p. (cryslals) about 28°. It tends t
prepared by percolation with tlcobol (45”(,). Dose. 0.12 to 0.3 ml. become yellowish on exposure to light. @
Mist. Ersphorb.Co. (N. F. 1939). Euphorbialiquid extract 0.6 ml. potassium Soluble I in 80 of water; miscible,wlth alcohol. chloroform, ether, gtaci~
iodide 450 mg, sodium bromide 450 mg, glyceryl trinitrute solution zcehc ocld. urd fixed ~nd volatile ods: soluble 1,In I of glycerol but
0.06 ml, ethereal lobelia tincture 0.4 ml. water to 15 ml. Dose 15 ml. separates out on the tsddmon of water. Jrscompatlble wllh ferric saf~.
.-
Protect from light.
AMENDED
FORMULA. Evphorbiis liquid extract 0.5 ml, potassium iodide
Gcmiaccd has disinfectmt properties similar 10 [hose of creosote. It h&
450 mg. sodium bromide 450 mg. giyceryl triniIrate solution 0.05 ml. I J I___ ,..A ,.. .- .__,,...-, T“”;. w-,.,.. . . c-. Uh_A . S?O L,,.

Guaiacol Carbonate (B.P.C. 1949). DUOIal (CH30.C.H..0),.CO~


NOTE. Euphorbfum (B. P.C. 1934. Ne(h. P., Nerd, P., Por[. P., Sparr. P.. 274.3.
Swim P.) is the dried latex from the stem of Euphorbia @rr~t-ra. It is -d
emetic and oowerfcdlv oureative but it is not used internally on Foreign Phurrrmcoporias In Chil., Port., and Span. 4
account of its violent &t~on-&rd its tendency to cause acute nephritis. Gu~iacol carbontite is the carbonic =ter Ofgusia$ol. it is a white, almo]
The powder is violently sternutatory. Exterrmily, it acts as a vesicwrt and odourless. Iastelcss. crystalline powder. M.p. 83 to 88”. .+ .
was used for this purpose inveterinary medicine. Insoluble in water; soluble I in 70 of alcohol and I in 20 of ethe#’
readily soluble in chloroform; slightly soluble in glycerol and fixed OiIS
[I is decomposed by alcoholic potassium hydroxide solullon and guaiac6f’
Garlic (B. P.C. 1949. Span. P.). Allium: Ail scpamtes from the solution on the addition of excess acid. ‘ .&
The fresh bulb of ..fIliurn mficwrn (Liliaceae). Ithasa verystrong Guaiacol carbonate has the actions of guai,acol but is less kritant:fe<
liberates gsc~iacol slowly and incompletely !ss the mtestums, the Iarg?
wrd disagreeable adour and a strongly pungent and persistent taste. It
yields 0.1 to 0.3% of a volatile oil containing allyl propyl disulph]de part passing through the alimentary tract unchtirrged. Do~e: 0.3 to Igj
and diailyl disulphide. Stored in a cool dry place with free access of air
it may be kept for about 6 months after harvesting.
a
Guaiphessesin[B.P.C.).
Guaiacyl Glyceryl Ether; Guaiaci
Garlic hasexpectomnt. diaphoretic. disinfectant. and diuretic properties.
and !be juice was formerly used alone or ina syrup in the tre~tment
Glycerol Ether; Guaifenesin ( fJ.S.N.F.): Glyceryl GuaiacoIa@
of pulmonary conditions Precautions: administration of preparations of
Glyceryigwsyacolum. 3-(o-Methoxyphenoxy )propane-I,2dioj
garlic to children is dangerous and fatalities have been recorded. Dow: 2 C,0H1404= 198.2. “!’??
to 8 g. Foreign Pharmacopoeias In C:. ond Roum. Also in L’.S.,V.F. .zq

TheIarvicidal
principles
of garlic octive against the Cule.v mosquito
Dose: 100 to 200 mg every2 to4 hours.
were found to be diallyl di- and trisulphides. Na[ural and synthetic “q
samples proved fatal at 5 ppm. —S. V. Amcmkar md A. Banerji. White odourless or almost odourless crystals or crystaflj
Science. WczJs., 197 I. 174, 1343. aggregates with a bitter taste. M p. SW to 82°.
A report of allergic contact dermatitis to garlic.—E. Bleumink ef u1.. Er. Soluble I in 33 of water at 20°, 1 in 11 of alcohol &d~
f. Derm., 197L 87,6. chloroform. and I in 200 of ether; soluble 1 in 15 of gfyeet
Gadic juice and the extracted essential oil prevented the hyperlipaemia with warming, I in 15 of propylene glycol, and 1 in 80,7
and blood coagulation changes following fat ingestion in 5 healthy sorbitol syrup. A 2?4 solution in water has a pH of 5 to 7<is
subjecis.—A. Bordia and H. C. Bansal (letter). Lmscer, ii/1973, 1491.
is clear and coiourless. Aqueous solutions are stable and ,rn
I HYPERTENSION. In 5 consecutive
the blood pressure to satisfactory
cases of hypertension.
levels.—V. Srinivasan
garlic
(letter),
reduced
Lwrcer.
be sterffked by autoc[aving. Store in airtight containera.,~~
ii/1 969, 800. Toxic Effects and Precautions. Side-effects are rare with g;1
phenesin. Gastro-intestinal discomfort and drowsine~~ha
PREPARATIONS
been reported.
Gartic Juice (B.P.C. 1949). Succus AlIii. Bruise garlic 80 g and express the “a
juice; mix the mare with water 20 ml and again express tbe liquid: A metabolize of guaiphenesin was found to produce an apparJ
increase in urinary 5-hydroxyindo[eacetic acid. and guaiphenesin &l
repeat the operation until the volume of the mixed juice and washings
~mounts to 80 ml, and add alcohol (907.) 20 ml; allow to stand for i4days.
thus interfere with the diagnosis of the carcinoid syndrome. As*
patients being evaluated for the carcinoid syndrome should t
and decant or filter. Dcme: 2 to 4 ml.
discorstinuemsy preparation containing guaiphenesin for 24 hears be
Garfic Symp (B.P.C. 1949). Syr. AlIii. Garlic juice 20 ml, sucrose 80 g, the collrxtion of urine specimens for the determination of 5.hy&&
dilute acetic acid 20 ml. water 20 ml. Dose: 2 to 8 ml. indoleacetic acid. Acetanilide. mephenesin. and methocarbamol had~
reported to cause similar false positive reactions, and hexamine.~
delate and some phenothiazine derivatives to cause false tre@
Grindetia (B. P.C. 1949). Grindelia Robusta; Gum Plant; Gumweed; reactions. —A. T. Pederscn et af.. J. Am. med. .4ss., I
-Tar Weed. See also P.D. Reeme, Hosp. Formrd. Mgm(, 1970, S. 15. per M. P@
Foreign Pfranrracopoeios: 1ss Span. InBefg. and Brar. which allow also .4bsrr.. 1973.10.26.
the dried leaves and flowering tops of the marsh gumweed, G. humdis. Hyporcricaemia (serum-urate concentrations of less than 20 pg &,,~
and of thecurly-cup grsmweed, G. $quarrosa. In Fr. and Porr. which 6 patients could have been due to guaiphenesin. Therapeutic da
allow also G. squarrosa. 3 days reduced serum urate by up to 30 #g per ml in 4 patients.
Ramsdell and W. N. Kelley, Ann. irrfern. Med.. 1973.78, 239. ‘::
The dried leaves and flowering tops of thefield gumweed. Grinde/ics
camponcm (Composite) containing not less than ‘20°~ of alcohol Absorption and Fate. Guaiphenesin is readily absorbed”, 3 ~
(90~)-soluble extractive. Store in a cool dry place. the gastro-intestinal tract. It is rapidly met~bolised and excRf
G rindelia has expectorant properties and bas been stated to exert a :.,
in the urine. ,. *:-
spasmolytic effect. It has been used as a liquid extract in the treatment
Guaiphencsin was rapidly absorbed from the gastro-intestin~,
of aatbma and bronchitis. Large doses sometimes cause renal irritation.
blood concentrations of 1.4 jcg per ml occurring 15 minutes
Its nauseous taste may be masked with chloroform or glycerol.
dose of 600 mg in 3 heakhy fasting men. It was rapid]y e]iminatd-, 4
PREPARATIONS the circulation. having n holf-life of 1 hour, and was not detectab
Grfndelia Liquid Exts-act(B.P.C. 1949). Ext. Grindel. Liq. Grindeiia lfKl g blood after 8 hours.—W. R. Maynard and
,.
is exhausted by percolation with alcohol (90°~), the alcohol is removed 1970, S9, 1346.
by distillation, and the residue is dissolved in water 50 ml to which IO g of The major urinary metabolize of guaiphenesin was identified
‘3 &
sodium bicarbonate has oreviouslv been added: after effervescence metboxyphenoxy)lactic acid.—W, J, A. Vanrfen Heuvei et al.. .f. 1
bas ceased, tbe solution is’ &djusted” to 100 ml with alcohol (90~;) urd Sci.. 1972.61.1997.
filtered. Dose: 0.6 to 1.2 ml.
Uses. Guaiphenesin is reported to reduce the viscosity of~
cious sputum and is used as an expectorant in cough lin~
lF-
Guaiaeol (U1949).
For&grUfrar~>eiczs:
Rmcm.. Srwr,. and Swiss.
Gaiacol;
In Arg.,
Methyl Catechol.
Bra:., Chil., Fr., It., A4e.s.. Porr.
.— ._
and tablets.
When givenby mouth or by injection in large doses,‘r+
phenesin has a relaxant eflect on skeletal muscle si~
A co~ourlessoralmost colorless oilyliquid orcrystals with a penetrating that of mephenesin which it closely resembles structura~~
aromatic odour and a caustic taste, obtained as a liquid by fractional this effect is not produced by the doses normally employed 4
distillation of wocd-tar creosote or, usually as crystals. by synthesis. treatment of cough. J*.:
~
tics

teine
: {r/NN).
.rah~+
l,=-
),S*
46/).23-4.
*:OXO-]
(29+8Y)

).3.
-thlenyl)cabamoy l]mechyi)thlo)-
Fominoben
Fommoben Hydrochloride

+)ammomethyl]benmnllide
C21HZ,CIN101,HCI
CAS — )8053-3
hydrochloride).
I-~
Hydrochloride

PB-89. 3’-Chlom-~-[N-methyl-N-(mofPhohn~
(rfNNM).

hydrochloride.
= 438.4.
(fomlnobe~):24600-36-0(f.mi~ ,..
#

Y
- w ‘“
.,-;!

;+q!

%
~<..
.
+$;

~+
. .
.-,,.,,.
1
~acOI has disinfectant properties and has been genersJly considered t,
~ ss an expectorant (see p.1059).

~.ll~l.
~ ~ ~,idemnge ofsalts and derivatives
~ye beenusedStmdorly
e.ethylglycola[e,
including
more effective nrmam
p.1567.
~ ~dve~e effects are similar to those of Phenol, 1. Jogcr EGH Double+
(Ion ot’ gu.vmeml In m
ofguaiacol Preparations
theCmbona!e, Nwva of prepomriom w
calcium and sodium #y- Proprietary Preparac

ne is being studied for use as a mucoiytic ..:m$, “y.. &iates.pheflylJcetate,~d phenylbutyrate, See ZJISO id.: Bromril.
Fominoben hydrochloride is ~ centralIy. : Cuaiphenesm.p. 1069 and Polwsium Guaiacolsu]-
%
cough suppressant (see P. 1059) which is afao~,;~ 1074.
ed to have respirator’ystimuiant ProPe~s. It S;j@J.. Guaiphenesi
preparations
en in doses of 160 mg two or three ~mes ,tij~ J ~=s OfpmpamdOns u lisicd below; dcmils arc giten in pm 3 Gualphenesm (fJAN).
jictyon (2012-e) mouth: it has also been given by slow intrav&&..:
~prie~. p~PamtiOns Glyceryi Gualacofatq
I Balm; Yerba %nra.
injection. Ethen Guaiacyl Glycc
80( 3-08-9. References. “’”‘!? ‘ Guarfenesina: Guaifenc
I Sasak! T, cl ~~. E~fWIS Of {he ~noluWe ‘OminO~n fpB8$~ 3-(2 -Merhoxypheno~
:d leaves of Eriodicvon ca~ifi)~ic{tm (Hydrophyl- hypoxta m chrome obstructwe lung dwuc: cornparisoIs& C,0H(40, = 198.2.
dcxlromcthowhm u$mg J double-blind mcthnd J hit MCd
[985; 13:96-101 ,“0t CAS— 93-/4-/
.t. Ji$
3 Pharmocopoefos. In Au
:tyon has been used M an expectorant. It has Preparations
‘%- port.. Swiss, and US.
:en used tomsssk [hetaste
ofbitter drugs. Names of pmparauons m-etis!cd below: detaits are given in ~~’”:
-.
-,.
.A@ne AspiCIne QI
The standards of Ph, E
.-.* hniine: EUCalVQ
Proprietary mepanclOnS -.*.;( ~:&ii Simp Bo;ri: lmucalyt; 1
iratiofls oes [O the Convenrror
Ger: Nolcptan? [ml.: Teriont: Spufn: Broncomenalf; T‘”
t.- -uih Co&d~: Dolt? -BaIsam; WUX macopoela, see pxfi.
JC’
preparations ace tisled below; 6WIIIS are given m Pan 3. Tosifw :’ 2} Bti @edo-Kt. w
:tary Preparations Multi-ingmdfent pmp=itions. Gw Broncho-No+n . FncsJiOtina: FOSQ A while or siighdy gr,
%.
j&s& BatS~ICOT: a slight characwisuc
ngredient preparations. Ger: Miswl an:: /fa/.: Bronc& .?. ~ F(Femmmile) +:.
.,.~ ;“ %kamlcot; Bima
BP solubilities are: s,
cohol u-id in chkmjf~,
Glaucine (19251SI Lj;lex Fuene: Br~nc~ ASCPIIICXTen:: Bmncdk:. Bronqul- bilities are: soluble I
W. Bron,qyrm
NW B%U1mwMIA:Edus~n Fte Rccfal: Eu-
Boldine Dimechyl Ethec DL832 (dl-glaucine phos ~jpmspmne: &JC3h’fNOY@ii in chloroform, and ir
YI Cysteine Hydrochloride Glaucme: MDL.832 (dl-glauane phosphate). m- I Bafmm; Pul,mo Hidram l*: Tos Ma
. .. .
glycerol. A 1% soluo
Rtnnchorectum: Cwm S)TUP has a pH of 2,:
W rmmechosyaporphme.
C21Hl>N04 = 355.4. .. .
-2-ammo-3 -merCaptopmpionate hydrochloride. Adverse Effect
CAS I- 563fJ. I I.5 (dl-glaucine); 73239-87-9
NOIS,HCI = 185.7.
phosphate); 475-8 I-O (d.glo.tine); 5996-O Castro-intestinal t
— 34 I 1-58-3 (ethyl cyste{ne); 868-59-7 (ethyl
cme hydrobromlde). reported with gua
ne hydrochloride). .,. Guaiapate ~12soI.1) nausea and vomit
Glaucine is a centrally acting cough Guaiapate (US4N, dNN).
Icysteine hydrochloride is I mucolytic agent
Pharmacokine
(see p. 1059) which ISUSbeen studied MG-S4S4. I -{2-[2-(2-o-Mechoxyphenoxyethoxy)echosy]e-
1059) used in the treatment of disordem of the
p.
Guaiphenesin is o
phdte. dt+)pipendine.
r’m — act associated with excessive or vis- C,$H2SNO+ = 323.4. tract. h is membo
ms daily dose of 600 [o 900 mg has been d-Glmrcine has been used as the hydro
W-851-42-6.
n by ,..-~~hin2 or3 divided doses. the hydrochloride as a cough suppressmt.ti
Uses and Adn-
Europe. Ithasbeen obtained from Gla Guaiapate has been used as a cough suppressant. It
(Popaveraceae). ‘“”li~ Guaiphenesin is
isreportedto have cen[ral actions. tenacious sputum
References.
wietary Preparations
1. Rcdpath JfJS. Plcuvry BJ. Double-blind comptiann OfJba
p. 1059). It has bc
qudixant.
pmmy .md wdawc effects of cndeme pho to 400 mg every -
glwme phosphm in human vOlunteem. Br ~ may be given 10(
!982: 1* 555-8. .,,,, Guaietolin (127V5.V)
X Ruhk KH, #lal. O@cove evaluation of dcxlrnMetiOTbaa, dren ~ged 2 to 6
Guaietoiin (rINN).
hyl Orthoformate (5618t) gi.rucme aa mmmvc agents. Br J @ pfu It has beenused
5~14 %e~lguethol; Glyguecol. 3-(2 -Ethoxyphenoxy) propane-
ir de I@ Trierhoxy methane. Trle~hyl Oflhoformate. 3. Gaatpat H. cr ai.. Effic~y .md tolerability of glauti~,~ Ild,ol. Infertility. Gutiph,
momssg.e ~gcnt. C.rr Med Rts Optn 1984:9: 21-7 -I,lX ‘
i,bO1 = 148.2. LIH,604 = 211.2. tiliry in women WI(,
i—
rmcopoeios.
/22-5/-0.
In FK
.::J’ OS – 63834.83-3. cervical mucus. 1 Tf
mmion of cbis use
1. Check JH. et u(. [n
Guacetisal (12EOI-W) Guaietolinis art andogue of gtmiphenesin which is men. Ferrti SrcrIi i
<m
Iyl orthoformate is a cough suppressant (see :,%V ~ rJSan expectorant (see p. 1059). h has been giv- Respiratory disor
Guaceusal (rINN).
059). It is reported to be a respiratory antispas- Acerylsalicyhc Ac!d Guamcol Ester. o-MethosYphen~ ,~lj
coby mouth in doses of 300 to 600 mg two to three [ions m.hb[e ‘ove
)dic and is administered by mouth or rectally. acetate.
dfnesdaily. in was so dfecrive
discussed on p. I 05
“reparations C[6H,,05 = 286.3. :%K!
,., ~$ 1. Thomas J. Gu.uph
mes of prcparatmns are listed below; demils are g]ven m Pan 3 c4S — 55482-89-8.
.!%% IIVC ,~fl.1 J Phant,
oprietary Preparations
Wricosuric actio{
1~,: Aedmne; Fr: Aedmne. GuacetisaJ has been used in respiratory dis!,~ mm-umte concecm
,Iti.ingmdient pmparatimw. .Yww.. Recmquimyl: Recto- an expectorant (see p. 1059). It has afso been W effect in these pack
tnryl-Pmnr&ha2ine.
an Mrtipyreticto reduce fever, the more USU, ered to be clinictdl:
ment of which is discussed on p.2. Doses of 5WJ Guaimesal ((719.,) 1. R~msdcll C\!. er
J Rhcumdoi 197J
hove been administered by mouth two to *e.~- G~mes2J (dNN). 2. ,U.uhcmn CE, er C,
‘edrilate (s619 -x) daily. It has also been administered rectally.j~{ u).2-(c-Metio~pheno~) -2-methyl- 1,3-benzodioxan-4- rim on serum um
J d 4.
Wle.
?dnlate (df’$$ Preparations 36
zdrdatum: UCB-3928, I -Methyl- 3-morphohnopropyl pe*y - !tmws of prepwittions ore Iis(ed below: detads arc gi~n~ C16H1405
= 286.3. Preparations
Proprieta~ Preparations “I?M ~$ -81674.79.5, Namesof prepmm
ro-4-phenylpymn -4-caAoxy late.
M.: Batsacetik Brmtcaapm; GuaitaPm Guajobrow; f’co~ ,.. Officiat Pmpat-ati
:ZOHZ9N0, = 347.S.
.. Guaimesa[ is re~fied anti-inflammatory,
to have U.SP 23; Dyphylli!
:/4s — 23271-74-1. Gwufenesm T;]bleh
/Lf-- ,;.#!
~tipyretic, ~naicesic, and mucoiytic propefiies and Guaifenesin mrd P
‘ed~“’— ISa cough suppressant (see p. 1059) which @@CQl (201L ‘ :M4r k ken given (y mouth in a usual dose of 500 mg Guiufcncsm CLpwJl
@’O to three times dally as an adjunct in the(re~t-ride, znd Ocxmome
las-- “ivenby mouth as the mdeate in doses of Gualacok Methyl Catechol.
X6* In S) rup: GuwfenL
50 me .~eeto six times dail~. ~N of acute and chronic infections of the resPira- Cap.uie.: Theophi
CAS — 90-05- I (gucvacol); 553-/ 7.3 (guoiacol@
@V tract. [t h= &O been administered rectally in Proprietary Prep
Preparations ate); 60296 -02-8 (calclum guolocolglycolote); 4 l.[~~
‘PFOSi[ories, Amt.: Guaien, MY
(g.mocof phenylocetote). o ,“cl”$~ cc Auwra[.: RobIv.
Yames of reparations are listed below; details are given in Part 3.
proprietary Pwparacions _PharrrmcnPmias. Ins Fr., and Swo.S,-.&& ‘mesal has kc. repofied to improve fe,er, cough fre- Expec !oram: Cam.
( acol Carbonate. ~flcy and i“te”slry, ~d sputum viscosity m pa~entS with Expectomnc Resyl
S.Afr: Corbar S; Dykatus~ “’s”t. ,;%
@Itc m chro”lc bmm~,~s, I However, m xated in tie di~us- posyrup expeclor.
Wdei-ingrdent p~paratiOns Gez : Duohlt The main constituent of guaiacol is 2-methO;~ Nephulon G, Rob![
*WI the manage~nt of cough (ace p. 1059) MUCOIYtics we
CH30.C6H,.0H = 124.1. Robimwn; S. Afr.:
d
Cocillana/Guaipltenesin 689

tines, the larger part passing through the alimentary not significantly better that a placebo in aiding ckar-
k-
-W (B.P. C. 1?4,9). SUCCUS AlIii. Bruise garlic
tract unchanged. ance of secretion from the lungs.— D. B. Yeates
Am. Rev. resp. Dis., i977, 115, Suppl. 4, 182.
et al.,

~ ~Ipr,ess the Julc&. mix the mare with water


~ again exprms the liquid: repeat the opera! ion Ef~ccts orr blood. A dose of 200 mg of guaiphenesin was
found to prolon8 the activated-plaama clotting time in
volume of the m!x~ JUICeand Wa$hws
22 healthy volunteers. The same dose, given to 12
~,0 go ml, and add alcohol (90%) 20 ml; allow 2018-k healthy volunteers, was found to reduce platelet adhe-
~ for 14 days, and decant or titter. Dose. 2 to
siveness significantly.— R. D. Eastnam and E. P. Grif-
~: Guaiphenesin (B.P.).Guaiacyf Glyceryl Ether tiths, .Qmcet, 1966, 1, 795.
-s~p (B.F.C. 1949). Syr. AlIii. Garlic juice Guaiacol Glycerol EtheC Guaifenesin (.U.S.P.);
~ maw 80 g, acetic acid (6 per cent) 20 ml, Guaiphencsin 200 mg given as a single dose to 5 healthy
Glyceryl Guaiacolate; Glycet-ylguayacohsm; Guaj- subjects was associated with transient abnormality in
~a ~1, Dose. 2 to 8 ml.
acolum Glycerolatum. 3-(2- platelet aggregation patterns determined I hour after
*“ Methoxyphenoxy) propane- l,2-diol. ingestion, showing some inhibition of secondary aggrega-
CIOH1404= 198.2. tion but Icaa marked than that observed in other sub
jects given chlorpromazine or aspirin. Mean bleeding
CAS — 93-14-1. [imea as determined by a mdlticd Ivy technique were
Pharmacopoeias. [n Aus:.. Br.. Cz.. Roum., and U.S. prolonged by single doscx of aapirin but were no!
~ {B.P.C. /949). Gum Plant: G.mwed Tar affected by guaipheneain: thrice-daily doacs of indome-
White or slightly grey crystals or crystalline thacin given for 3 days caused some prolongation.— G.
L aggregates, odotsrl= or with a slight characteris- R, Buchanan et al., Am. J. clirt. Path.. 1977, 68, 355.
+-oparJas. In Be/g. and Fr. which also allow G.
tic odour and with a bitter taste. M.p. 78” to
+, G. robusfa. and G. squorrosa. Span. and POrI. Preparations
82° with a range of not more than 3“.
~ G. robusla; Port. also allowa G. $quarroscr. Coaifeneairr Capsules (f/.S.P.). Capsules containing guai-
soluble I in 33 of water at 20°, 1 in 11 of phenesin. Store in airtight containers.
k,i kavca and flowering tops of Grindelia carrspo- alcohol and of chloroform, and 1 in [00 of ethe~
i~iitae) contal,nmgnot 1:ss than 20% 0( aico- soluble 1 in 15 of glycerol with warming, 1 in 15 Gusifeneain Syrup (LLS.P.). A syrup containing guai-
~. )-soluble cxtractwe. Store m a COOI dry place. phencain and alcohol 3 to 4%. pH 2.3 to 3. Store in
of propylene glycol, and 1 in 80 of aorbitol syrup. airtight containers.
~ haa expectorant properties and has been stated A 27. solution in water has a pH of S to 7.
,_SS a spasmolytic effect. It has been used aa a Crmifeeesin Tablets (U3.P.). Tablets containing guai-
Aqueous solutions are stable and may be sten- phencain. Store in airtight containers.
~ ezwact or a tincture m the, treatment of asthma
~hitis. Large doses sometimes cause renal dis-
Iised by autoclaving. Store in airtight containers. Guaipbenesin Linctuses. (1) hmon+wowed. Guai-
.-+$. Its nauseoua taatc may be maskedwith chl- Adverse Effects and precautions. Gastrcr-intestinal phcneain 2 g, glycerol 10 ml, chloroform spirit 10 ml,
m orglycerol. discomfort and drowsineaa have been reported. menthol 10 mg, compound tartrazine solution 0.2 ml,
w , Very large doses cauae nausea and vomiting. water 10 ml, modified lemon syrup to 100 ml.
Rrstralss (2) Tolu-ffavoured. Guaipheneain 2 g, glycerol 10 ml.
# Liquid Extinct (B.P.C. /949). Ext. Grindel. A metabolize of guaiphencsin waa found to produce an cbioroform spirit 10 ml, menthol 10 mg, amaranth solu-
. c.,,.,id,a IO(3 g ia exhausted by percolation with apparent mcrca= in urinary S-hydroxyindoieacetic acid, tion 1 ml. tolu solution 10 ml, invsrt symp 20 ml, syrup
,.. .,, the alcohol ia renr@ed by distillation, and gualphencsm could thus interfere with the diagnosis to 100 ml.
w residue is dissolved in waler 50 ml to which of the carcinoid syndrome. Patients &!ng evaluated for bfodi/ied lemon syrup contains lemon spirit 0.5 ml.
sodium bicarbonate haa previously been added; the carcinoid syndrome should therefore diwxrtinue any citric acid monohydrate 2.5 g. invert syrup 20 ml, syrup
‘&eNcacence has ceased, the solution ia adjus[ed to preparation containing guaipbencain for 24 hours Lmfore to [00 ml.
.IS with nlcnhol (90%) .---,
and filtered. Dose. 0.6 to the collection of urine spscimens for tbe determination
Both Iemon-flavoured and tolu-flavoured guaipheneain
of S-hydroxy indokacetic acid. Acetanilide, mepheneain,
linctuses remained stable for 6 months when stored at
and methocarbamol had been reported to cause similar
temperatures from - 5“ to 37”.— Pharm. SOC. Lab.
false positive reactions, and hexamine mandelate and
Rep. No. P/6S/21, 1965. See also G. Smith, Pharm. J..
some phenothiazine derivatives 10 cause fatac negative
1966, /, 165.
reactions.— A. T. Pederaen et al.. J. Am. med. Ass.,
197o, 211, I I84. See also P. D. Reeme, Hosp. Formrd. Proprietary Preparation
Mgmt, 1970, 5. 15, per [m. pharm. Abstr.. 1973, IO. DiscsotarreExpectorant /Robires, UK). Contains in each
sfacol (RP.C. 1949). Gaiacol; Methyl Catechol. 26. 5 ml guaipheneain 100 mg, brompheniramine maleate
~– &OS-I (2-meIhoxyphenol). Hypouricaemia (serum-urate concentrations of leas than 2 mg, phenylephrine hydrwhloride 5 mg. and phenyl-
F 20 ug per ml) in 6 patients could have been due to propanolamine hydrochloride 5 mg (suggcated diluent,
sasoropoeias. In Arg., Fr., (f,, Mex., Port., Roum.,
guaipheneain. Tberapcutic doses for 3 days reduad syrup). Diosatme Expectorant DC contains in addition
m, and Swiss. ~
serum urate by up to 30 w per ml in 4 patients.— C. hydrocodone tartrate 1.8 mg in each 5 ml. Do$e. 5 to
!dourkas or almost colourlesa oily liquid or crystals M. RamadeO and W. N. Kelley, Ann. inrens. Med.. 10 ml four times dailfi children, 1 to 3 Years. 1 to
i s penetrating aromatic odour and a caustic taste, 1973, 78, 239. 2.5 ml; 3 to 6 years, 2.5 to 5 ml: 6 to 12 years, 5 ml.
&d as a liquid by fractional distillation of wood-tar
Absorption and Fate. Guaipheneain is readily DimatasM with Codeirre (Robins, UK). Cmrtaina in each
MS or, usually as crystals, by synthesis.
absorbed from the gastro-intestinal tract. It is 5 ml gmiphenesin 100 mg, ccdeine phce.phate 10 mg,
main constituent is 2-methoxyphenol, brompheniramine makate 2 mg, phenylephrine hydro-
).C$H4.0H = 124.1. Wt per ml (liquid) about rapidly metabolised and excreted in the urine. chloride 5 mg, and phenyipropanolamine hydrwhloricfe
)& m.p. (crystals) about 28°. [t tends to become Guaiphencsin waa rapidly absorbed from the gastro- 5 mg (auggestsd diluent, syrup). For cough. Dose. 5 to
@h on exposure to light, intestinal tract, blood concentrations of 1.4 LIg per ml 10 ml four times daily.
) of watev miscible with alcohol. chloro- occurring 15 minutes after a dose of w mg in 3
Dinrorme with Codeint Paedistric (Robins. UK). Con-
S. ether, glacial acetic acid, and fixed and volatile healthy fasting men. It was rapidly eliminated from the
tains in each 5 ml guaiphenesin 50 mg, ccdeine phoap
~ ~uble 1 in I of glycerol but separates out on the circulation, having a half-life of I hour, and was not
hate 3 mg, brompheniramine makate 1 mg, phenyl-
on of water. Incompatible with ferric salts, detectable in the blood after 8 hours.— W. R. Maynard
ephrine bydrochloridc 2.5 mg, and phenylpropanolamine
~ menthol, and ch}oral hydrate. Protect from and R. B. Bruce, J. pharm. Sci.. 1970, 59. 1346.
hydrochloride 2.5 mg (auggeatcd diluent, syrup). Dose. 3
The major urinary metaboiite of guaipheneain was to 6 years, 5 ml four times daily; 6 to 12 yezra, 5 to
I&d has dislnfecta”t proprtim similar to thoac of indcntified as &(2-methoxyphcnoxy )lactic acid.— W. J. 10 ml.
~e. [t has been mcd as an expectorant in doses of A. VandenHeuvel ef al., J. pharm. Sci.. 1972, 6/, 1997.
Exypfsea (Nomon, UK: Vestric, UK). An elixir contain-
~ to 0.6 ml. Adverse effects are similar to thoxe Of
Uses. Guaiphenesin is reported to reduce the ing in each 5 ml guaiphenesin 80 mg. brompheniramine
*. p.571
# viscosity of tenacious sputum and is used as an malcate 2 mg. phenylephrine hydrochloride 4.75 mg, and
... expectorant. It has been given in doses of !00 to phenylpropanolaminc hydrochloride 5 mg. For cmgh.
Dose. 5 to 10 ml four times daily, cbildrcn, 2.5 to 5 ml
—. 200 mg every 2 to 4 hours.
thre or four times daily.
When given by mouth or by injection in large
‘< Nosadrm Bronchial Syrup (Norma, UK: Fari[[on. UK}.
doses, guaiphenesin has a relaxant effect on Containa in each 5 ml guaiphencain 25 mg, diphenhyd-
aCol carbonate /B. P, C. 1949). Duotal. Bis( 2-mct-
skeletal muscle similar to thal of mephenesin ramine hydrochloride 5 mg, diprophylline 50 mg. and
, , .- .--,.- .. .
which it closely resembles structurally, but this ephedrine hydrochloride 7.5 mg. Dose. 10 ml every 4
~@. C, H+ O)l.CO=274.3. effect ia not produced by the doses normally hours chiIdren over 5 years, 5 ml. 1
!,

employed in the treatment of cough. Pbokoored Expectorant (formerly known as Pulmodrine


Guaiphcnesin was no better than water in lowering the Expectorant) (Medo Chemicals, UK). Contains in each
~ ~Wopoeia$. 1“ PorI, and Sp.n. viscosity of 27 sputum specimens ob[airred from chronic 5 ml guaiphenesin 62.5 mg and methyiephedrine hydro-
tiscol Wrknale ia the arbonic cater Of gUaiacOi. ‘t bronchitis, Deaca of 0.8 to 1.68 daily had no effect on chloride 625 Pg. Dose. 10 to 20 ml thrice daily; children, ,,

● ~ while, sputum or respiratory function when compared with 2.5 to 5 ml.


almost odourless, lamekss, crystalline
~ M.p. 83” to 88”. Practically insoluble in water: placebo in 1 I patients with chronic bronchitis.— S. R. Ro6itussin (Robins. UK). An expectorant mixture con-
le 1 in 70 Of ~lcohol and I in 20 of ether readily Hirsch et al., Chest, 1973, 63, 9. taining in each 5 ml guaipheneain 100 mg (auggestcd
IC in chloroform; siightly soluble in glycerol and From a study in 239 patients it was reported that, guai- diluent. syrup). (Also available aa Robituaain in
~ Oils. [t is decomw~ed bv ~lcOhOii~ @a~~ium phenesin reduced cough frequency and ]ntenstty in AusIraf.. Carmd., Ital.).
IXlde sOl”tlo” ~“d g&iawl &paratcs from” the SOlu- pa!icnts with dry or productive cou8h, and helped to Robitusairr AC (Robins, UK). Contains in each 5 ml
-
P
m the :lddit ion of excess acid. thin sputum, when compared to
placebo.— R. E. Robitr- guaiphenesin 100 mg, codeine phosphate 10 mg. and
%JI car~”ate has the actions of guaiacOl but ‘s son et al., Robins. Curr. ther. Res., 1977. 22, 284. pheniramine makate 7.5 mg (auggextcd diluent. syrup).
1 irr;ta”t, [t has ~c” “~cd in doses Of 0.3 tO ] g. ‘t A report of a double-blind croxaovm study in 19 patients For coughs. Dose. 5 to 10 ml rour times dady; children,
*tCS g“alaco{ ~IowIy and incompletely in the intes- with chronic bronchitis showed that guaiphenesin was 6 m 12 years, 5 ml.
.=>—
..
● GREDIENT NAME;

YDRAZINE SUL F ATE

B. Chemical Name:

HydraziniumSulfate,HydrazoniumSulfate

C. Common Name:

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:
(S’cijkations) (Results)
Assay: 99.0% min. 99.3%

—_
E. Information about how the ingredient is supplied:

White C@alline Powder

F. Information about recognition of the substance in foreign


pharmacopoeias:

USP 23, IndianPharmacopoeia3ti Ed.

G. Bibliography of available safety and efficacy data including peer


reviewed medical literature:

Gold, J. Use of HydrazineSulfatein terminaland PreterminalCancer patients: results of


investigationalnew drug (lND) study in 84 valuablepatients. Oncology. 1975;32(l): 1-
10

Chlebowski,R. T., Bulcavage,L., and Grosvenor,M. HydrazineSulfatein Cancer


patients with weight loss. A placebo-controlledclinicalexperience. Cancer. 1987; 59(3):
406-410.

_—_
Bair~ A. Theophyllineversus caffeine:comparativeeffects in treatment of idiopathic
apnea in the preterm infant.J Pediatr. 1987; 110:636.
Eisenberg M. G. and Kang,N. Stabilityof titrated ca&einesolutionsfor injectableand
externaluse. Am. J Hosp. Pharm. 1984;41:2405.

H. Information about dosage forms used:

1. Information about strength:

60m& 3 times/d

J. Information about route of administration:

Orally

IL Stability data:

Melts at about 254°


OxidizingAgents
.-. Bases

L. Formulations:

M. Miscellaneous Information:

-.——=

Page -2-
1..,
.

CERTIFICATE OF ANALYSIS
--------------------- --

GUDE: ‘A.C.S.
PRODUCT : HYDRAZINE SULFATE REAGENT CODE: G61O24
RELEASE #: N m+ :L609141

SPECIIWCM’IONS RESULT
----------—-- ------
{
CONFORMS
1. DESCRIPTION WHITE CRY--E mDER ~
-. * \_
To pass ~e%t$ Pass-es test
2* Identification
o.05~ max. 0.01%
3. Red due on Ignftf on
0.005% ma%. 0.0025*
4. Insoluble matter
99.0% min. 99.3* )0
5. ,~ c-

0.002% max. < 0.001%


6. Heuvy Metals

7, chloride 0.005%”max. 0.002%


.
0.001% max. < 0.0003%
a. Iron

./

ATTENTION : TONY HATCHETT

Date :04/09/97 Prepared by : A. iiAZ~

10690 Approved by :
.—— . ... ——-—.
_____ ._ ___ . _ _ .—.—c ____-—— /
.
---- .-

/
n=

.,.
—-. . . .. .-- —.’
QUALITY CONTROL REPORT

CHEMICAL NAME.:HYDRAZINE SULFATE A.C.S.REAGENT

MANUFACTURE LOT NO. :609141

PHYSICAL TEST

SPECIFICATION TEST !3TANDARD. :USp ——/Bp t~RCK_fNF_J~T”_iCO. ‘pEcs.—-

l)DESCRIPTION .:
WHITE TO ORTHORHOMBIC CRYSTALS.GLASS-LIKE PLATES OR PRISMS.

VOLUBILITY. :
SOLUBLE IN ABOUT
33 PARTS OF COLD WATER;FREELY SOLUBLE IN HOT
WATER.INSOLUBLE IN ALCOHOL.

MELTING POINT.:
MELTS AT ABOUT 254 degree. k

4)SPECIFIC GRAVITY. :

5)IDENTIFICATION .:
A)A SOLUTION RESPONDS TO THE TESTS FOR SULFATE.

PASSES.: FAILS.:

COMMENTS.:

ANALYST SIGNA-. : DATE. :

PREPACK TEST.: DATE. : INITIAL. :

RJZTEST .: DATE. : INITIAL. :


H~drazine Sulfate Page 1 of 6

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Hydrazine Sulfate

Hydrazine Suifate
11070

**** SECTION 1 _ cH~Ic~ PRODUCT ~ coMp~ Il)E~IFIcATIoN ****

MSDS Name: Hydrazine Sulfate


Catalog Numbers:
H320 500, H320-500, H320500
Synonyms:
-, -
-r— Diamine Sulfate: Hydrazine Monosulfate; Hydrazinium Sulfate.
Company Identification: Fisher Scientific
1 Reagent Lane
Fairlawn, NJ O741O
For information, call: 201-796-7100
Emergency Number: 201-796-7100
For CHEMTREC assistance, call: 800-424-9300
For International CHEMTREC assistance, call: 703-527-3887

**** SECTION 2 - c_J+fposITIoNr INFo~TIoN ON ING~DIE~s ****

+----------------+--------------------------------------+----------+-----------+
I CAS# \ Chemical Name
1% I EINECS# I
l---------------- l-------------------------------------- l---;--;----l-----------l
10034-93-2 IHYDRAZINE SULFATE \ 233-110-4 I
+----------------+--------------------------------------+----------+-----------+
Hazard Symbols: T
Risk Phrases: 23/24/25 43 45

+*** SECTION 3 _ ~Z~DS lDENTIF1~T1c)N ● ***

EMERGENCY OVERVIEW
Appearance: white.
Danger ! Corrosive. Carcinogen. May be harmful if swallowed.
Sensitizer. May cause lung damage. May cause severe eye irritation
and possible injury. May cause liver and kidney damage. May cause
severe skin irritation and possible burns. May cause severe
respiratory and digestive tract irritation with possible burns. May
cause cancer based on animal studies. Material is shock sensitive and
potentially explosive.
Target Organs: Blood, kidneys, central nervous system, liver.

--6=. Potential Health Effects


Eye:
Contact with eyes may cause severe irritation, and possible eye
burns . May cause eye injury.
Skin:
May cause skin sensitization, an allergic reaction, which becomes
I@lrazine Sulfate Page 2 of 6

evident upon re-exposure to this material. May cause severe skin


irritation with possible burns, especially if skin is wet or moist.
Ingestion:
May cause liver and kidney damage. May cause severe digestive tract
irritation with abdominal pain, nausea, vomiting and diarrhea. May
cause corrosion and permanent tissue destruction of the esophagus and
digestive tract. Exposure may cause anemia and other blood
abnormalities . May be harmful if swallowed.
Inhalation:
Irritation may lead to chemical pneumonitis and pulmonary edema. May
cause liver and kidney damage. May cause severe irritation of the
upper respiratory tract with pain, burns, and inflammation. May cause
effects similar to those described for ingestion.
Chronic:
Prolonged or repeated skin contact may cause sensitization
dermatitis and possible destruction and/or ulceration. May cause
liver and kidney damage. May cause cancer according to animal
studies. May cause digestive tract disturbances.

**** SECTION 4 _ FIRST AID ~URES **++

Eyes:
Immediately flush eyes with plenty of water for at least 15 minutes,
occasionally lifting the upper and lower lids. Get medical aid
immediately.
Skin:
Get medical aid immediately. Immediately flush skin with plenty of
soap and water for at least 15 minutes while removing contaminated
clothing and shoes.
Ingestion:
Do NOT induce vomiting. If victim is conscious and alert, give 2-4
cupfuls of milk or water. Get medical aid immediately.
Inhalation:
Get medical aid immediately. Remove from exposure to fresh air
immediately. If not breathing, give artificial respiration. If
breathing is difficult, give oxygen.
Notes to Physician:
Treat symptomatically and supportively.
Antidote:
No specific antidote exists.

**** SECTION 5 _ FIRE FIGHTING mums ****

General Information:
AS in any fire, wear a self-contained breathing apparatus in
pressure-demand, MSHA/NIOSH (approved or equivalent), and full
protective gear. Dusts at sufficient concentrations can form
explosive mixtures with air. Combustion generates toxic fumes.
Material is shock sensitive and potentially explosive. Greatly
increases the burning rate of combustible materials. Violently
decomposes when heated under confinement.
Extinguishing Media:
For small fires, use water spray, dry chemical, carbon dioxide or
chemical foam.
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
NFPA Rating: Not published.
Explosion Limits, Lower: Not available.
Upper: Not available.

**** SECTION 6 _ AccIDE~~ REL~E MEASURES ****

General Information: Use proper personal protective equipment as indicated


in Section 8.
Spills/Leaks:
Sweep up, then place into a suitable container for disposal. Avoid
generating dusty conditions.

**+* SECTION 7 _ ~LING and sTOp.AGE ****

Handling:
Wash thoroughly after handling. Remove contaminated clothing and
Hj&4zine Sulfate Page 3 of 6

wash before reuse. Use with adequate ventilation. Minimize dust


generation and accumulation. May form flammable dust-air mixtures.
..-. Loosen closure cautiously before opening. Do not get on skin and
clothing. Empty containers retain product residue, (liquid and/or
vapor) , and can be dangerous. Do not ingest or inhale. Avoid
mechanical shock and friction. Do not pressurize, cut, weld, braze,
solder, drill, grind, or expose empty containers to heat, sparks or
open flames.
Storage:
Keep away from heat, sparks, and flame. Do not store near
combustible materials. Store in a tightly closed container. Store in
a cool, dry, well-ventilated area away from incompatible substances.

● *** SECTION 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION ****

Engineering Controls:
use process enclosure, local exhaust ventilation, or other
engineering controls to control airborne levels.

Exposure Limits
+--------------------+-------------------+-------------------+-----------------+
I Chemical Name I ACGIH I NIOSH IOSHA - Final PELsI
l-------------------- l ------------------- l------------------- l ----------------- I
I HYDRAZINE SULFATE Inone listed Inone listed Inone listed
+--------------------+-------------------+-------------------+-----------------+

OSHA Vacated PELs:


HYDRAZINE SULFATE:
No OSHA Vacated PELs are listed for this chemical.

Personal Protective Equipment

Eyes :
Wear appropriate protective eyeglasses or chemical
--- safety goggles as described by OSHA’S eye and face
protection regulations in 29 CFR 1910.133.
Skin:
Wear appropriate protective gloves to prevent skin
exposure.
Clothing:
Wear appropriate protective clothing to prevent skin
exposure.
Respirators:
Follow the OSHA respirator regulations found in 29CFR
1910.134. Always use a NIOSH-approved respirator when
necessary.

**** SECTION 9 _ pHySIC~ ~ CH~IC~ pRc)pERTIES ****

Physical State: Solid


Appearance; white
Odor: None reported.
pH : 1.3 (0.2M solution)
Vapor Pressure: Negligible.
Vapor Density: Not applicable.
Evaporation Rate: Negligible.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 489 deg F
Decomposition Temperature: Not available.
Volubility: Soluble in water.
Specific Gravity/Dens~ty: 1.4 (water=l)
Molecular Formula: H4N2.H2S04
Molecular Weight: 130.12

+**+ SECTION 10 _ sT~ILITy AND REACTIVITY ****


----
Chemical Stability:
Stable under normal temperatures and pressures. Substance is shock
sensitive and thermally unstable.
Conditions to Avoid:
Mechanical shock, incompatible materials, temperatures above 160’C.
I{ydrazine Sulfate Page40f6

Incompatibilities with Other Materials:


xidizinq aqents, combustible materials, sodium amide.
.——__
F“azardous Decomposition Products:
Nitroqen oxides, carbon monoxide, oxides of sulfur, carbon dioxide.
Hazardous Polymerization: Has not been reported.

**** sECTION 11 _ TOXIC”LOGIC~ INFO~TION ****

RTECS # :
CAS # 10034-93-2: MV9625000
LD50/Lc50:
CAS # 10034-93-2: Oral, mouse: LD50 = 740 mg/kg; Oral, rat: LD50 =
601 mg/kg.
Carcinogenicity:
HYDRAZINE SULFATE -
California: carcinogen
NTP: Suspect carcinogen
OSHA: Possible Select carcinogen
Epidemiology:
Oral and intraperitoneal administration of hydrazine salts t
o animals have produced lung and liver carcinomas.
Teratogenicity:
No information available.
Reproductive Effects:
No information available.
Neurotoxicity:
No information available.
Mutagenicity:
Please refer to RTECS# MV9625000 for specific information.
Other Studies:
Skin irritation, guinea pig: slight. Eye irritation, rabbit:
severe.

**** SECTION 12 _ ECOLOGIC~ INFO~TION ****

Ecotoxicity:
No information available.
Enviromnental Fate:
No information reported.
Physical/Chemical:
No information available.
Other:
None.

**** SECTION 13 - DISpOS~ 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 F-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 INFO~TION ****

US DOT
Shipping Name: CORROSIVE SOLID,ACIDIC, INORGANIC, N.O.S.
(HYDRAZINE SULFATE)
Hazard Class: 8
UN Number: UN3260
Packing Group: II
IMO
No information available.
IATA
No information available.
RID/ADR
No information available.
Canadian TDG
Shipping Name: CORROSIVE SOLIDS NOS (HYDP.AZINE SULFATE)
Hazard Class: 8(9.2)
UN Number: UN1759
H@azine Sulfate Page 5 of 6

***+ SECTION 15 _ Regulatory INFO~TION ***+


_-—._
US FEDERAL
TSCA
CAS# 10034 -93-2 is listed on the TSCA inventory.
Health & Safety Reporting List
None of the chemicals are on the Health & Safety Reporting List.
Chemical Test Rules
None of the chemicals in this product axe 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 # 10034-93-2: acute, chronic, reactive.
Section 313
This material contains HYDRAZINE SULFATE (CAS# 10034–93-2,
>99%),which is subject to the reporting requirements of Section 313
of SARA Title III and 40 CFR Part 373.
Clean Air Act:
This material does not contain any hazardous air pollutants.
This material does not contain any Class 1 Ozone depletors.
This material does not contain any Class 2 Ozone depletors.
Clean Water Act:
None of the chemicals in this product are listed as Hazardous
Substances under the CWA.
None of the chemicals in this product are listed as Priority
Pollutants under the CWA.
---- None of the chemicals in this product are listed as Toxic Pollutants
under the CWA.
OSHA:
None of the chemicals in this product are considered highly hazardous
by OSHA.
STATE
HYDRAZINE SULFATE can be found on the following state right to know
lists: New Jersey, Florida, Pennsylvania, Minnesota, Massachusetts.
The following statement(s) is(are) made in order to comply with
the California Safe Drinking Water Act:
WARNING: This product contains HYDRAZINE SULFATE, a chemical known to
the state of California to cause cancer.
California No Significant Risk Level:
CAS# 10034-93-2: no significant risk level = 0.2 ug/day
European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 23/24/25 Toxic by inhalation, in contact with skin
and if swallowed.
R 43 May cause sensitization by skin contact.
R 45 May cause cancer.
Safety Phrases:
s 44 If you feel unwell, seek medical advice (show
the label where possible) .
S 53 Avoid exposure - obtain special instructions
before use.
WGK (Water Danger/Protection)
CAS# 10034-93-2:
Canada
CAS# 10034-93-2 is listed on Canada’s DSL/NDSL List.
This product has a WHMIS classification of D2A, E.
CAS# 10034-93-2 is not listed on Canada’s Ingredient Disclosure List.
Exposure Limits

**** SECTION 16 _ ADDITIONAL lN’f70~TIoN ****

MSDS Creation Date: 9/22/1995 Revision #3 Date: 9/02/1997


Hydraziw Sulfate Page 6 of6

The information above is believed to be accurate and represents the best


information currently available to us. However, we make no warranty of
__—. merchantability or any other warranty, express or implied, with respect to
such information, and we assume no liability resulting from its use. Users
should make their own investigations to determine the suitability of the
information for their particular purposes. In no way shall Fisher be liable
for any claims, losses, or damages of any third party or for lost profits
or any special, indirect, incidental, consequential or exemplary
damages, howsoever axising, even if Fisher has been advised of
the possibility of such damages.
--------------------------------------------------------------------------------

.-==

___
F -.
2016 ReagentSpecifications / Reagetzfs

Spec[rai purity—Measure in a I-cm cell at 300 nm, with a rous sulfide with diluted sulfuric or diluted hydrochloric add
suitable spectrophotometer, against air as the blank: its absorb- Other sulfides yielding hydrogen sulfide with d!luted. acids ~J
ance is not more than 0.08. be used. Is also available in compressed form m cyhnders. LT .,,
Hexanes (suitable for use in ultraviolet spectrophotometry); Hydrogen Sulfide Detector Tube-A fuse-sealedglass,hsb~
_~ usually a mixture of several isomers of hexane (C6H ,,J, predom- designed that gas may be passed through It and contammg s~l.
inantly n-hexane, and methylcyclopentane (CbH1*)—Use ACS able absorbing falters and support media for the mdlcator, t~
reagent grade. latter consisting of a suitable lead salt. -..
Hexanitrodipheny lamine (Dipicrylarnine), C12H5N7012— NOTE—A suitable detector tube that conforms to the mow
439.21—Yellow-gold powder or prisms. Explosive. Usuallycon- graph specification is available from National Draeger, Inc., p:o,
tainsabout 15% of water as a safety precaution. Insoluble in Box 120, Pittsburgh, PA 15230-0120 as Reference Number ij?
water, in alcohol, in acetone, and in ether; soluble in glacial acetic 19001, Measuring Range 1 to 20 ppm. Tubes having conditio~
acid and in alkalies. other than those specified in the monograph may be used,~
Wafer, Method 1 (921): not more than 16%. accordance with the section entitled Tests and Assays in &
General Notices. ,.:
Hexanophenone, C12H,bO—176.26-Yellow liquid.
Assay—Inject an appropriate specimen into a suitable gas Hydroquinone, C6H4(OH)Z—1 10.1 l+te, coloqless or whitt
chromatography (see Chroma~ography (621 )) equipped with a needle crystals. Darkens on exposure to au and hght. SoI$k
flame-ionization detector, helium being used as the carrier gas. in water, in alcohol, and in ether.
The following conditions have been found suitable: a 30-m X Assay—Weigh accurately about 250 mg, and dissoi~e b“l
0.25-mm capillary column coated with a I-pm layer of phase G3; mixture of 100 mL of water and 10 mL of 0.1 N sulfurlc acid
the injection port temperature is maintained at 280°; the detector in a 250-mL conical flask. Add 3 drops of a 1 in 100 sohtti~
temperature is maintained at 300°; the column temperature is of diphenylamine in sulfuric acid, and titrate with 0.1 N eerie
maintained at 180° and programmed to rise 10° per minute to sulfate VS until the solution is red-violet in color. Each mL’of
280°. The area of the C 12H[@ peak is not less than 98% of the 0.1 N eerie stdfate is equivalent to 5.506 mg of C6H4(OH)2. NIX
1 total peak area. less than 99% is found. ,,.
Refractive index (83 1): 1.511 f 0.002 at 20°. Melting range {74 1): between 172° and 174°.
Hexokinase and Glucose-6-phosphate Dehydrogenase Suspen- 3’-Hydroxyacetophenone, CsH802—136.15—Light br~m
/ sion—Use a suitable grade. 1 powder chips and chunks. Melts at about 96°. Sparingly soluble
.$uitabilify-When used in the assay of Iacttdose, determine in chloroform, yielding a clear, light yellow solution. +,,
that a suitable absorbance-versus+oncentration slope is obtained, Assay—Inject an appropriate specimen into a suitable ‘gst
using USP Lactulose RS, the reagent blank absorbance being chromatography (see Chromatography (62 1)) equipped with a
not more than 0.020. flame-ionization detector, helium being used as the carrier gas,
Histamine Dihydroehloride, CjH9N3 ~2HCI—184.07—Use LJSP The following conditions have been found suitable: a 0.25-nm
Histamine Dihydrochloride RS. X M-m capillary column coated with G 1; the detector and the
injection port temperature are maintained at 300°; the column
Hydrazine Hydrate, 85 ?L in Water, (NH2)Z. H20—50.06-- temperature is maintained at 180° and programmed to rise 10°
Colorless Ii uid. per minute to 280° and held at that temperature for 10 minutes
Asay- # ransfer 600 mg, accurately weighed, to a 100-mL The area of the main peak is not less than 97% of the total peak
..-. volumetric flask. Dilute with water to volume, and mix. Pipet area. :F
10 mL into a suitable beaker, add 1.0 g of sodium bicarbonate
and 50.0 mL of 0.1 N iodine VS. Titrate the excess iodine with 4’-Hydroxyacetophenone, HOCbHdCOCH3—136.15-Gray
0.1 N sodium thiosulfate VS, using starch TS as the indicator. powder, melting at about 109°. {i!
Perform a blank deterrmnation, and make any necessary correc- p-Hydroxyhenzoic Aci& C?H603—138.12—White crystals.:
tion. Each mL of 0.1 N iodine is equivalent to 12.52 mg of A$say—Transfer about 700 mg, accurately weighed, to a suit.
(NH2)2. H20. Not less than 83% is found. able container, and dissolve in 50 mL of acetone. Add 100 @
. Hydrazine Dlhydrochloride, (NH2)t 2HCI—104.97—White of water, mix, and titrate with 0.5 N sodium hydroxide VS, ds
powder. termining the endpoint potentiometrically. Perform a blank d$
Assay—Dissolve about 34 mg, accurately weighed, in 50 mL termination, and make any necessary correction. Each mL of O.\
of water. Add carefully while stirring, 1 g of sodium bicarbonate. N sodium hydroxide is equivalent to 69.06 mg of C,H60J: “’id
[Caution–There may be a rapi~ evolution of carbon dioxide.] less than 97% is found. :.::
Titrate with 0.1 N iodine solution, determ~ning the endpoint po- Melting range (741 ): over a range of 2° that includes 216°.
tentiometrically. Perform a blank determmatlon, and make any 4-Hydroxybenzoic Acid Isopropyl Ester, HOC6H4COOCh.
necessary corrections. Each mL of 0.1 N iodine solution is equiv- (CH2)2—180.20-Use a suitable grade.32 , $7$
alent to 2.63 mg of (NH2)z -2HC1. Not less than 98% is found. .!>’
!
Me{ting range {741): between 84” and 87°.
H drazine Sulfate, (NHJ2 ~HzSOt—130.1-Use ACS re- l-Hydroxybenzotriazole Hydrate, C6H~N30. xHzO—135~~~
l+- age t grade. (anhydrous)—White crystalline powder. Sparingly soluble igd
Hydriodic Acid, HI—127.91—Use ACS reagent grade (con- cohol yielding a clear, pale yellow solution. .wd
taining not less than 47.0% of HI). 2-Hydroxyhenzyl Alcohol, C7HsOr124.14—Off-white flakes
NoTE—For Methoxy Determination (see (431)), use hy- Very soluble in alcohol, in chloroform, and in ether; soluble M
driodic acid that is labeled “for alkoxyl determination,” or that 15parts water and in benzene. .!(
is purified as directed under Me[hoxy Determination (431). Use Asray—Inject an appropriate specimen into a gas chromatO
this grade also for alkoxyl determinations in assays in the indi- graph (see Chromatography (62 1)), equipped with a flame-iot
vidual monographs.
ization detector, helium being used as the carrier gas. The fo~
Hydrochloric Acid, HC1—36.46-Use ACS reagent grade. lowing conditions have been found suitable: a 0.25-mm X 30-Ic
Hydrochloric Acid, Diluted (10 percent)—Prepare by mixing capillary column coated with a l-~m layer of phase G2; the ~
226 mL of hydrochloric acid with sufficient water to make 1000 jection port temperature is maintained at 250°; the detector teo
mL. perature is maintained at 300°; and the column temperature ~
Hydrofluoric Acid, HF—20.01—Use ACS reagent grade. maintained at 150” and programmed to rise 10” per minute tt
280°. The area of the CTH@z peak is not less than 99% of th~
Hydrogen Peroxide, 30 Percent, H202—34.01—Use ACS re- total peak area.
..—-= agent grade. Melting range (74 1): between 83° and 85°. ,.
Hydrogen Peroxide Solution—Use Hydrogen Peroxide Topi- 4-Hydroxyisophthaiic Acid, CsH604—182.13—Colorlcs!
cal Solu lion. branched needles. Freely soluble in alcohol and in ether.
Hydrogen Sulfide, H2S—34.08—Colorless, poisonous gas, Mefring range (741): between 314° and 315°, with decoti
heavier than air. Soluble in water. Is generated by treating fer- position.

..4
r ,. $, ..

‘1
.?,
‘(c
&
-.

REAGENTSAND SOLUTIONS
-.
..
A fraction from petroleum containing about 90 per cent SOLUaILITY- Miscible with water.
of n.hexane.
WT. PER ML-1.03 g, Appendix 5.19.
DESCRImON - Colourless, mobile, highly flammable
liquid. ydma!ine
Sulphate: NHJWIZ,H*S04 = 130.12
P
DISTILLATION RANGE - Not less than 95 per cent, distils C~S—ti& 99.0 per cent of N2H.$Oq.
between 67° and 7W, Appendix 5,3.
l=ESCRItTION White. >crvsta.lline
- -—,--—----- -powder.
——
WY.PER ML - At 2tY, 0.670 to 0.677 g, Appendix 5.19. k
SOLUBIUTY- Freely soluble in water; practically insoluble
NON-VOLATtLE MATTER - When evaporated on a water-bath in alcohol.
and dried to constant weight at 105°, leaves not more than
0.01 per cent w/v of res;due.
MELYING POINT - About 254°, Appendix 5.11,
CHLORIDt!- 1 g complies with the Iimit test for chlorides,
Histamine .4ad Phosphate Appendix 3.2.2.
Of [he Indian Pharmacopoeia. IRON -1 g complies with the limit test foritvn, Appendix
3.2.5.
Histamine Dihydroehlori& :C5H&Jj,2HC1
= 184.07 .
SULPHATED ASH - Not more than 0.05 per cent, Appendix
DESCRIPTION - White crystalline powder. 3.2.7.
SOLUBILtTY - Freely soluble in water and in metbyi alco- ASSAY - Weigh accurately about 0.1 g and dissolve in 20
hol; soluble in alcohol. ml of water. Add 3 g of sodium bicarbonate and titrate
with 0.1 A’ iodine, using starch so[ution as indicator.
WLTXNG POINT - About 25(Y, Appendix 5.11.
Each ml of O.ZN iodine is equivalent to 0.00325s g of
tX-Histidine Monohydroddoride N2Hbso4.
~: CH.NH.CHjC, CH&H(NHJ COOH,HCI = ]91.62

. Contaills not less than 99.0 per cxmtof CJ-i9NjO:,HCl, cal- iiydriodic Add : HI= 127.91
ctdated with reference to the substance dried to constant Constant-boiling hydriodic acid contains 5s.0 per cent
weight at 105”. w/w of HI (limits, 54.0 to 56.0).
DESCRHION - White, crystalline powder. DESCRWRON - Almost colorless liquid when fleshly
made, but rapidly becoming yellow to brown owing to
SOLULULITY - Soluble in water.
the liberation of iodine.
Loss ON DRYtNG - Loses not more than 9.0 per cent of its
SOLLIBItrtY- Miscible in all proportions wit6 wafer and
weight, when dried to constant weight at 105”, Appendix
with aicobo[.
5.8.
BOUSNG POINT - About 127°, Appendix 5.3.
ASH - Not more than 0.1 per cent, Appendix
SLII.PHATED
3.2.7.
wr. PER ML - At 20°,
about 1.7 g, Appendix 5.19.
ASSAY - Carry out the method for the defe??runationof
CHLORXDE AND BROMIDE- To 0.2 ml add 15 ml of wafer, 50
nitrogen, Method A, Appendix 3.3.5, using 0.15 g and 7
mg of sodium sulpbate, 5 ml of dilute ammonia solution
ml of nttrwgen-fwe sulpbun”c acid. Each ml of 0.1 N sul-
artd 20 ml of 0.1 N sifvernitrate, shake and filter; to the fil-
pbutic acid is equivalent to 0.00639 g of C&~30,,HC1.
trate add 10 ml of dilute rzitn’c acid. The opalescence pro-
duced is not greater than the standard opalescence ob-
I_Iokhun Oxide : Ho20j = 377.86 tained in the limit test for cblon’aks, Appendix 3.2.2.
DESCRtFtYON - A yellow solid. SULIWAYE - Dilute 1 ml with 50 ml of water and add I ml
SOLURILITY - Practically insoluble in water. of barium cblon”de solution. The turbidity produced
should not be greater than the standard opalescence ob-
Holmium Pereh.lorate Solution tained in the iimit test for sulpbates, App?ndix 3.2.8.
A 5 per cent W[V stiktion of bolmium o.ride in 1.4 M NON.VOLATIIE MArmR - When evaporated on a water-
percblonc acid. bath, and dried to constant weight at 105°, leavq not
more than 0.5 per cent w/w of residue.
v~e Hydrate : NH2.NHZ,H20= 50.06
ASSAY - Weigh accurately about 0.6 g into a stoppered
DESCRtPTtON - Clear, colorless liquid with an ammonia- flask containing about 10ml of water, dilute with 25 ml of
water and titrate the free iodine with 0.1 N sodium tbio-

A-189
PHYSICAL TESTS AND DETERMINATIO~S

TABLE2

Size Kinematic Volume Bulb C Inside Diameter Inside Diameter


No. Viscosity Range (ml) of Tube N of Tube R
(Centistokes) (* 5%) (mm) (mm) (* 2’Yo)

1 3.5”to 10 o.(j4 5.6 2.8 to 3.2


1A 5 to 30 0.84 5.6 2.8 [0 3.2
~ 20 to 100 1.15 5.6 2.8 [0 3.2
2A 60 to 300 1.51 5.6 2.8 to 3.2 I

3 200 [0 1100 2.06 5.6 3,7 to 4.3

3A 600 to 3000 ~.74 5.6 4,6 to 5.4

4 2000to 10,000 3.70 5.6 4.6 to 5.4


4A 6000 to 30,000 4.97 5.6 5.6 (0 6.4
5 20,000to 100,000 6.76 5.6 6.8 to 7.5

350mlnImurn 200minimumflowumc for alt other sizes


flowtime;

any time while the flow time is being measured, the term- I ml of a liquid when weighed in air at 27,unless
ination must be repeated. otherwise specified.
Calculate the kinematic viscosity in centistokes (V)
Method : Select a thoroughly clean and dry pycnometer.
horn the equation:
Calibrate the pycnometer by filling it with recently boiled
v= ct. and cooled water at 25° and weighing the contents.
where
.%suming that the weight of 1 ml of water at 25” when
t = time in seconds for the meniscus to fall from weighed in air of density 0.0012 g per ml. is 0.’xK5o2g,
Eto F calculate the capacity of the pycnometer. (Ordinary devia-
C = the constant of the viscometer, determined tions in the density of air from the value given do not affect
by observations on a liquid of kr.own the result of a determination significantly). Adjust the
viscosity. temperature of the substance to be examined, to about XY
and fill the pycnometer with it. Adjust the temperature of
Method C : (Using the Rotating Viicometer) the filled pycnometer to 25°, remove any excess of the
The rotating viscometer measures the shearing forces in a substance and weigh. Subtract the tare weight of the
liquid medium placed between rwo coaxial cylinders one pycnometer from the filled weight of the pycnometer.
of which is driven by a motor and the other is caused to Determine the weight per millilitre by dividing the weight
revolve by the rotation of the ftrst. Under these conditions, in air, expressed in g, of the quantity of liquid which fills
the viscosity becomes a measurement of the angle of def- the pycnometer at the specified temperature, by the capa-
lection of the cylinder caused to revolve, expressed in city expressed in ml, of the pvcnometer at the same tempe-
newton metres. rature.
Method– Operate the Rotating Viicometer in accor-
dance with the manufacturer’s instructions and c-arty
out the determination of viscosity of the liquid being Specific Gravity
examined, at the temperature and angular velocity or The specific gravity of a liquid is the weight of a given
shear rate specified in the individual monograph. volume of the liquid at 25” (unless otherwise specified)
compared with the weight of an equal volume of r.uaterat
Calculate the dynamic viscosity (n) in centipoises.
the same temperature, all weighings being taken in air.

5.19WEIGHT PER ~ AND SPECIFIC Method : Proceed as described under Wt. per ml. Obtain
GRAVITY the specific gravity of the liquid by dividing the weight of
the liquid contained in the pycnomecer by the weight of
Weight per Mllilitre
water contained, both determined at 25” unless othemvise
The weight per millilitre of a liquid is the weight ~ g of directed’in the individual monograph.
A-137
.- --rr. -... -.,..., ; u.-~a i.s, u “L,, ti, ““”. .,4,!----

12831-c 5 mmutes. and then sodium nitrttc NM mg mtravcnousl! ~,::, aoses of 200 mg and above and lnchtded dda~t)m
for 3 minutes Treatment was a!med at rmducing mct- of :ne pupil, hyperreflcma. ataxla. and dysarthria ~
Hydrazine Sulphate. / [ haemoglobmaemia 10 !nactn,a[e lhc sulphidc. [n addillon szs some mmiiarity 10 the effects of a cohol — M T&
. he recewed sodium Ihmsu!phate 12.5 g b> Intravenous mo:t r~ al, (letter). Larcef, 1975. /. 5E3 See al~ M
m]ect)on — R J Surrc tr al.. Ann. Inrern Med., I gT6. H Greenwocd er al.. Br. J cl{n. Pharmac., ]97s, ~’
C’4S — 30:-0 :-: hvdraztnel, 10034-93-~
IstIl-
85.756. 165
pirafe]. Smerc insomnia in a 33-year-old woman fOllowlng ~
Further references R. P Smtth and R, E Goasclln, J
-~~_ys[ais. Soluble I in about 33 of water. freely OCCUp Med.. 1979. 11, 93. MSC accident responded to 4 COnsecuuve mgh:ly ~~
of ~-5-hydroxytryplophan tolall]ng 3 g — M. W ebb ad
ubie in hol u aLer: practically insoluble in aico- Uses. Hydrogen sulphidc is widely employed in J G Lirker (letter), hsrwer, 1981.1. 1365
J1. A 0.2M soiuiion in water has a pH of 1.3. many industrial processes
,Jfaaganere poisoning. 4 bencfi:ial respmse, m ~L.L
H,ydrazine suipnalc is empioyed in various indus- h}droxytryptophan. up 10 3 E dady, was achtevti ,n ~
trial processes. It is used in the preparation of 12833-a ~ttent m whom the symptoms of mangan- pOISO”,n8
h,ydrazine hvdrate which is applied afmr a sohs- faiisd to respond !O Iwxlopa.— 1. Mena ● r td.. .\m
tlon of plati~ic chloride for corneal tattooing (SCC H ydroxyestrone Diacetate. l& Hydroxy- Engl J Med.. 1970, 282, 5.
Chloroplatinic %cid. p.1693). ocstrone Diacetate. 3,16cr-Dihydroxyestra- ,Meara/, ii~ders. Of 107 patients with, cndagc~
An account OF the sumesaful treatment of industrial
1,3.5( 10)-wicn-17-one diacctate. depression given L-5-hydroxytryptophan dally m d,vld~
hydrazine Pmaon]ng with pyridoxine.— J. K. Kirklin er C22H160$= 370.4. doses by mouth for at least 5 weeks, the majwt!
al,. New Engl. J. Med., 1976, 294.938 CAS — 566-76-7 (hydroxyestrone); 1247-71-8 ra~dly obtained a beneticxal response.— 1. Sam
A reoor! of fasa] choroidal melanoma in a worker who (diacetale). Munch. med. Wschr., 1912. 114. 17,13. ,pm J. Am ~d
AS,., 1972. 222. 10S5. Further studies m depression S.
Hydroxycstrone diacctatc is a derivative of S Wine er al., Am. J. Psychiat., 1964, 121, 379, ~
ocstrone. II is claimed to have minimal systemic Ins phorm. Abstr., 1965, 2, 918; T. Pcrason and B .L
ocstrogenic effects when given by mouth but to RSOS (letter), LJWWCI. 1967. 2, 987: G. d’EIia cl IS/-
The use of hydrazine ssslphaw by a laboratory worker
was associated with the development of a syndrome retain effects on the vaginal mucosa. It is used in Acra pqvhiaf. scmxd.. 1978, 57. 239; L. J. van H,dL
similar 10 systemic lupus erythematosus.— P. J, Duram Neurops.vchobio/o~. 1980, 6.230.
the treatment of vaginitis and associated disord-
and R. A. Hams (letter), New, Eng/ J. Med.. 1980, After oral administration of ,L-~hydrOxY!ryptophan wo
ers.
303, 584. ? Peripheral d=r~xylaae. mhlblIOr, mild. to modemtt
A discussion of hydrazinc sulphate as an amineoplastic Proprietary Nmszes lmprswcment w= obtmned m 6 of 7 chro?lc undiffcr~
agent.— W. Regclaon. J Am. med Ass., 198C. 243. Col~ginOn (Z?oizo{, Spairr); Colpogynon (Laborarotic~ tiamd schizophrenic ps~icnta who were rcwstan~ to ph~
337. de [’Hepatrol. Swifz.): Colpormon (Millet. Arg.: othtatinea. Of 4 chrome parano!d ~hlzophrenlc paILmu
Arrphar-Rollarsd, Fr./. who were resistant 10 phenothlaz mea 2 beta me w-
afwr trealmem wiih 5-hydroxywyptophan and I
12832-k
12834-I improved. Some schizophrenic patients might have m
abnormality in acrotonin metabolism. — R. J. Wyau SI
Hydrogen Sulphide. Sulphurettcd Hydrogen.
H$=34.08, Hydroxyethylpromethazine Chloride. al.. 5cimce, 1972, 177. 1 I 24.

(2-Hydroxyettsy l)dimethyl[ 1-methyL2-(phcn- Furdzer studies in schizophrenia: V. Zarmne CJ af.


CAS — 7783-06-4, othiazm- 10-yl)cthyl]ammonium chloride. Archs gers. Psychiat.. 1973, 28. 843; R. J wyau C!a!.
ibid 29, 597.
A colourlcss inflammable gas with a charac[cris- ClyH25ClN20s== 364.9.
tic odour the intensity of the smell gives no M.maclonars. Commeru on the use of the investigauonal
CAS — 7647-63-4 (hydroxysvhylpromethazine); drug L-5.hydroxytryptophan in the trcatmem of m}oclm
indication of concentration. 2090-54-2 (chIoride). nus and the view that in general its use should be dw
Adverse Effects. Hydrogen sulphide poisoning is a Hydroxycthylpromethazine chloride is an anti- couragcd. L-5-Hydroxywyptophan is usually cffectwc m
common industrial hazard and is cncoumered in histamine, posihj poxic intention myoclonus, a rare condition, b!
such places as chemical works. mines, sewage ma} exacerbate some other myoclonic syndromss SX~.
works, and stores of decomposing protein; con- Proprietary !Names nifican! adverse effects, espteialiy gastr~ intestinal dw
Aprobil (Recip, Swrd ). turhanccs. arc almost universal, even when given with s
centrations of 0.1 10 0.2% in the atmosphere may pcntrhcral decarboxylase inhibitor such as carbido~ -
-A. fatal in a few minulca. Pulmonary irritation, R. R. Young, J Am. med. Ass.. 1980, 243. 1569.
cma. and respiratory failure usually occur 12835-x
L. f. H~droxvtryptophan with carbidopa was administered
:r acute poisoning. prolonged exposure to low Hydroxymethylnicotinamide, Nicotinylmc- to 13” pati&ts with myoclonus and 16 patients MIIJ
concentrations may give rise 10 severe conjuncti- thylamide; fv’-Hydroxymethylnicotinamide. h’- other neurological disorders. FoilOwing administration ~
vitis with photophobia and cornea] opacity, irrita- Hydroxymethylpy ridine-3-carboxamidc. mou:h of maximum doses of 0,4 to 2 g daily with carb
tion of the respiratory tract, rhinitis, bronchitis, C7H8N102= 152.2. Idopa 100 10 300 mg daily more than 50% improvcmcrd
slomatitis. pharyrgitis. digestive disturbances, was obtained in I I of 18 patients with intention myccl~

headache, Iass]lude, and skin rashes, There are CAS — 3569-99-1. nus due 10 anoxia or other brain damage; only I pattotl
obramed no Improvement and in 3 it was 90% or mom
some similarities [o poisoning with cyanides. Crystals. M .p. 14 I” to 142°. Sparingly soluble in some patients derived sustainsd benefit for more than ?
A discussion of pxmsomng by hydrogen sulphide — Lrn- water and alcohol; free]} soluble in hot water years ?40 bsnefit was obtained by 2 patients with a!hc
crI, 1978, /, 28 Comments.— A Downie (Ietmr), [bId.. and alcohol. totIc urebral palsy, 2 with multiple sclerosis. 2 *IIJ
219. C. H B Blnns (letter). ibid., 501, A Downie (let- asenual tremor. 4 with cerebella intention tremor. I
ter). itd Hydroxyme[hylnicotinamide is a cholcretic and w~th Infanlilc spasms, 2 with dystonia musculoru~
Concentrations of abut 200 ppm caused Irritation of has been used in the treatment of various disord. de fo;mans, 2 with central pain svndromcs. or 3 *I~t
Lhe respirator) tract and. on prolonged exposure, pulm~ ers of the gall-bladder. Idiopathic epilepsy; some bcncfii” was obtained m I
nar~ oedema ToIIctty to the CXS could occur suddenly pallcnt with myodonus epilepsy and In I of 2 pallcnLJ
ai concentrations In exccas of 500 ppm and immediate
death mighl follow concentratmns in excess of
:i%’$!?:;;~cr., Br.ccLJ, M.,:l;g-cj;gsc With familial essential myoclonus Side-effects includd
Swirz); anorexia, nausea, dtarrhcea, and occasional vomiting ad
lCiIag-Chemtc, .
1000 ppm Irritauon 10 the eyes occurred at concentra- were rcducd by prochlorperazine or trimc[hobenzamtd~
(hbu(ec-Pharma, SwII:./.
Ilons of less than 50 ppm.— ,4ft-rhod$ for the Drltclmn and dtphcnoxylate; prior admlnis!ration of carb}dOP im
of Toxtc Substances ISI Air, H,vdrogen Sulphidc, Lon- I or 2 days b-e(ore therapy also reduced the gastro-lnl~
don. HM Stauoncr} Office, 1969. 12836-r Iinal side-effects.During the first week of thcrap! ~
Furthef references W W. Burnett CI al . Can med. PSIZcnls develo~ dyspnoca followed by hypen’cnl\lal@
.4ss J., 1977, 1/7, 1277: R. P. Smtth (letter), ihf.,
5-Hydroxytry tophan. 5-HTP; Ro-0783/B. and Ilghlheadedncss, with fainting in 1, pulmonar} fu~
1978, 1/8, 775: W W Burnett and E G. King (letter), 2-Amino-3-(5-hy ! roxy-l H-indol-3-yl)propionic lion ICSIS remained normal. Varying degrees of mcm-al
{bid., 776. J Am mcd Ass.. 1978, 239, 1374. acid. sumulamxn occurred in 10 patients: these were revcrslbk

Treatment of +dversc Effects. Afler exposure to CI, H,1N20, =220,2 on casage reduci ion and frequently disapWa red Or dlm~
mshed afler 4 to 6 weeks wllhout reduction, but -
hydrogen sulph]de place the pat!cnt in fresh air, CAS — S6-69-9. patlenu rquired concurrent administration of ~~h~
g]ve inhala~lons of oxygen and. if necessary, NOTE. The form of S-hydroxyxryptophan used clinica}l> naz; ne to maintain their antimwclonic dosage. OIhU
assist the respiration. Antibiotics may Lw neces- is generally the L-form side.effects included mydrlasis, blurring of visiOn. aM&
sar} if pulmorrar! infection occurs The conjunc- mlnzl pare, and bradvcardia — M. H Van Woert t( ‘~
5-Hydroxytryptophan is a precursor of serotonin .Yca Engl J Med.. 1977, 296, 70. Conlmcnt.— T
tival sacs should be carefully washed out if eye
(see p,1753) and has been used clinically in Munsal. ibid., 101.
IrrltaIiOn is se~ ere
attempts to treat disorders believed to be asso- SIUCIeS suggesting that the lrca:m. nt of Intcmmn M>e
In severe pmson!ng. amyl nnrite inhalation and
ciated with serotonin deficiency, clon~s with L.5-hydroxyt ryptophan and carbidO; ~
sodium nitrite b~ !n~ravenous injection have been
Changes in mood. mostly elevalion, were observed in 7 ?@s-dr-old man unmasked an abnormality In his abtl!l~
suggested neurological pat]ents wlthou! affcclive disorders and 1 to ‘mcIaboIIsc kynurcnine and resulwd In the dc$’e]~
A brmf review of the managemcm of sulphide poison- hcal!hy subJecl given L-5- hydroxylrypmphan 100 10 mer: of a sclcroderma -like illness — E M Stcrnbcr? 4
Ink! — R P Sm:th and R. E GosselIn. A ReY, Phar- 300 mg by intravenous infusion In scdlum chloride Injec. al.. \ C-K .Engl J Med 1980. 303, 782
t71iC & TOXIC 1976. )6, 189 tmn Carbidopa was also gwcn 10 reduce the severity of Fur. ncr references: D. Chadwick er al,, f.ancrr. 19’5. ‘“
_—-hg succes~ful ~realm~nr of a 47. }e~r.01d man ~l,h vomiting which always occurred 30 10 90 mlnutcs after ~~j J DcLean a“d J C. Richardson (Ietmr), ibfd ‘~~
rc hydrogen sulph~dc pxsoning using oxygen, amyl infusion and m increase Lhc amount 01’ L-5-h jdrox~- J H Growdon PI al.. Neurolog~, Mlnneap.. 1976 j6:
Ite lnhal~llon~ for 30 seconds out of each minu[c (or tryptophan entering the brain. !4curotoxtc!ty ~curred ;\?! W M Carroll and p. J Walsh, & m~d

,,
.,
ii
.-.

Hydrastinine Hydrobenzoin
ads canadcnsis L.. I$rry vol. 1. G. Brauer. Ed. (Academic Press, Ncw York. Atsdrierh. Nickles. Irrorg. SyrL 1, 90 (1939). Industria ity study: Grahan
md canadme. Syn - 1963) pp 469-472. Toxictty data: Witkin, Arch Irrd- Jieahh prcpcs by the action of sd}um hypochloritc on urea in tht Review of toxicol<
vdrx.stints: H opc er 13, 34 ( 1956). Toxicology study: Back, Thomas, ,4rrrs Rev, PCCSCOCC
Of NaOH: B 1.O.X Final Rep~ 36% Moocrieff Patty’s Indusrria{
et oL. ibid 1934. Phormoco[ 10. 395 ( 1970). Review of carcinogenictty ,Uarru~ Chem. 18, 177 (1 947). Revised lab procccfurcs Clayton, F. E. C
-rrz Bull. 27, 1947 studies 1.4RC MonogmpAs 4, 127-136 ( 1974k of toxicology: pfaffer, .%mons. Ber. 80. 127 (1947): Adams. Brown, Org. York, 1981) pp 2
, mm hmem 22, 619 R. von Burg. T. Stout, J App[. TOXJCOI.11, 447450 ( 1991). SySS @fl. vol. 1. 2nd cd. (1 941). p 309. Crystaf structure: Comprehensive Tre
“<aworth, Pinder. J Books: L. F. Audneth, B, A. Ogg, The Chemistry oj Hy. Nltm et uL, Acra Cryst 4, 269 (195 1); Jonsson, Hamilton, Wry 701. VIII, Su
., ~OIUrC 165, 529 druzmr (Wiley, New York, 1951); C. C. Clark. Hydrazme @ 26B, 536 (1970). Review of activity and cfinical stud- Jones in Compreh
m 293, 121 (1960) (Mathmson Chcm., Bal!imore. 1953). Reviews Troyan, ica in cancer cachexia: J. Gold, IVutr. Concer 9, 59-66 Bailar Jr. er oL, E
LAters 1963, 859. Irrd. Eng. Chem. 4S, 2608-2612 ( 1953); Ztmmcr. Cherrs Ztg. (f9g7). 276-293.
n. 29, 2328 (1964) 79, 599-605 ( 1955); Hudson et m!. “Hydrazine” ICIMellor’s *hOrhombic crystafs. Glass-like plates or prisms. d Mobile liquid, 1
>69). Binsynthcsls vol. VI1l. suppl. II, N/frogen (Part 2), 69-114 (1%7): Jones 1.37g: Curtis. Jay, J. prok~ Chem 39, 39 (1889), d’ 2.016. p/Osi ve?mp —8C
963). !n Comprehenswe {norgarric Chemisr~ vol. 2, J. C. Bailar, Jr mp 2!34”. .%] m about 33 parts watec freely sol in hot (mz/kg): 21.5 I.p
L-fa/.. Eds (Pergamon Press, Oxford, 1973) p 250-265. H WS=. Insol in afcohol. pH of 0.2 molar xq sobs 1.3. Courion: Acure t
W. Sch!cssl tn 3Cirk.Othmer Encyclopedto of Chemical Tech. No/e.’ This substance may reasonably be antici~atcd to be fall m blood prcssu
rro/ogy vol. 13 (John Wile> & Sons, New York, 4th cd., s carcinogen: Shenth Annual Report ok Grmirr@errs (pB95. hypotension, weak!
1995) pp 560-606. 10978I. 1994) p 231. USE: Industrial!
Colorlfi$ ml} Iiq, fuming il] air. Penetrating odor rcscm. USE: 1sS the gra ilmet ric cst imation of nickel, cOball and detonators.
bllng that of ammoma Burns wiih violet flame. Explodes cadmium: in the rcfinmg of rare metals; as asrtioxidanr in
during dlstn if traces of alr are present. also affcxmcl b} uv soldering flux for hght metals: as reducing agent in the msal- 4816. Hydrim
and me[al Ion catalysts. Can be stored for years if scaJcd in yab of minerals and slags: in separating polonium from tel - enej.1,1’,3.3’- (2H.2’
glass and Lept in a cool. dark place. t7iash and fire PI 126°F hstium: in tests for blood: for dcxtroying fungi and molds; in 1,1’,3,3’-tetr0 ne: r,
(5YC). Con!racls
on freexrng.di$ 1.146;d: 1.0253. d? the prcpn of hydrtinc hydrate. 322.27. C 67.09%.
1.024.
d~$1011:d: 1.0036.
d: 0.9955. one gallon of corn. tion of potassium c
mcrc!al product wcrghs 8.3t3 Ibs. rnp 2.0’. b~~::;;bb~ 4912. Hydrasine Tartrate. Hydrazine acid [anratc; J. OV. Chem. 23, ~
SG: bpj ~ 17r; bp10 ~ 2M bpn~ 236’ n bydrazine hydrogen sartra(c: hydrasirsc bisarcrate, C4H10- tion of nmhydrin w
NIOC; mol wt 1 S2. 13. C 26.38%, H 5.537., h’ 15.38%, () Chem. 211, 907 (I9
146444 DIpolc moment 1 83- 1.%). Didectnc cons’t~~t
[a]~ – 5t7 (c = (~~), 5 I : htent heat of fuston (rep) 3.025 ficd !molc, 52.7 wk. H2NNHj.C,Ht06.
~l!l, 238, 298, 316 latent heal of vaponzat!on (bp): 9760 kcal/mole (talc) Crystals. mp 182-183’. [u]~ +22.5’. SoIy m water at C?
1 7.8. Freely sol ln about 6 g/100 ml. pH of a said aq sohr 3,6.
Crit temp .78~. crsI pressure 14 atm. Dlacidlc base PI(I

c
x salts hydrolyze USE. In chcrrncal deposition of metafs (silvering mirrors,
[2s): -tJ 05 Forms WIIS w’l(h morgamc actds. Hlghlj
Powerful rcduclng agent. Dissolves many etc.): Owen, U.S. pat. 2.801,93S (1957 to Merck & Co.),
polar sollent
R. Patch, M. V
vol. IV (Springer.
Incrrgan!c substances Mist with waler, methyl. c!hyl. prop 4813. 4-HydrasirsobenserteauUonic Acid. p-Sulfophen - 1’.
yl, Isobut }I alcohols. Forms an azcmroptc mixlurc with yfhydrszsne: phcnylhydrtinc-p-sulfonic acid. CCHCN103S;
116”. [a]~ - 12T water, bp7@ 120.3”, whtch contains 55 mole-% (68.5 wergh!-
,ccrh@&slighlly sol
SOOIwc 188.21. C 38.2WC. H 4.28’%, N 14.88%, O 25.50%, S
‘.) N, H.. LDW m mice (mg:kg) S7 i.!.; 59 orall} (Wltkln). 17.04%. Prcpn by sulfonatian of phcrsylhydr’azine: L, Clai.
57,- “01ss): 4.2
D!hydrochlondc. HCNZ.2HCI. white crystalhnc PO* dcr. SSSS,P. Roosen, Ann. 278.296 ( 1894); by the reduction of p.
mp 198-. d 1 42 Frccl) sol In water, dlfsh!ly m alcohol diaaobcrszermsulfomc acid: Th Zmcke, A. Kuchcnbcckcr,
as . .mre hcmo- Caumrrr Potcntlal symproms of overexposure to h}dra. Dihydratc. prism
Arm. 330, 1 (1 903): L V. L.azccva ● f al., USSR pat. 1,057, -
zinc are lrntatlon of eyes, nose and throat, tcmporar) bl!nd - 493 (1983 to Tambo\ Plgrrsent). C.A. 100, 138755q (1984). reddish-brown at 2C
vdro-6 -methyl- [,3- ncss. d!rancss. nausea. dcrma(!t!s: burns $kln and eyes .% Used in rcaoln of 2-pyrazoline cmpds: M, Mukai er al.. hot waler: sol In M
-6,7 -methy)enecfg - ,%’IOSH Pocket Gutdo m Chcmtcal Hazords (DHHS XIOSH GJrL J. Chem. 57. 3M ( 1979): In isoln of volatile ketones: aq Na:CO solns (de
!,ne. C1tH1, NO). 90- I I 7, 1@%3)p 124 S&- crko Patty-s JmfusIno/ H.~gumeand W. Treibs. H. R6hncrt. Ber. 84, 433 (1951); in analysis of blue color ~ Can b
6.7670, 0 23. 16P< Toxwo/ogl, +01. 2E. G D Clayton. F E. ClaYmn, ~S ~CC amounts of sclcn!um: T. Kawashima er af., Anu/. the addn of acid.
J/ill, Ber. 20, 86 (John W’I)c\ & Sons. Inc., \cw }’ork, 41h cd,, I’?q.$1 pp Chin Acro 49, 443 ( 1970). e(dem, ifnd. 89, 65 (1977). blue color with amlr
![. 2.41,136 (1910). 3435.344] Hvdraunc mav rtison.abli be anliclpa[ed 10 “h L, SE. R@gcnt for I
yman, Rcmfry, J. a carctnopcn Seventh Annual Rqsort in Carctrro&ns (P BQ5- — acids and similar co:

J, App[. Chem. IIYM8). 1QQ4) p 231 4S17. Hydriodii


:oplperonylamlne LSE Chcmlcal ln[ermcdlate in manu{ of agncullura) che- ““-: \ / ‘0”” water. Marketed ]r
e
)13); Roacnmund, micals, spandc~ flbcrs and antlrsxidan!s Reducing agcnl:
47%, d 1.5, 10% d
}m safrole: Kmd - orgamc h}dranne dcnvs. rocket fuel Dthydrochlondt as
Needles from wa[cr. mp 286’. Sllghtly SOI in water, Iodide gas ln water [
S!ructure s[udy chlorine was cngcr for HCI ga! s!rcams sulfide according 10
dmhol.
Frykholm, Inorg. .SL
4810. Hydrazine Hydrate. H6N20. mol WI 5006 H 4814. 2-Hydrazinoethastol. 2-Hydroxycthylhy drazinc; Iodide.
12.08”;. !i 55. q6T. O 31 Q6”, H2NNH: HIO. Prcpd {ram 19-hydroxycthylh ydraz!ne.Omaflora. CIHSNIO; mol w! Colorless when fre
hydraimnc \ulfa!c b) the actlcm or NaOH, followed b! d)<:n 76.1o. C 31.57mo, H 10,60%. N 36.81% O 21.02’70. HO- or brown on cxposu
under nl[rof!cn CHICH, NHNH1. Prepn from hydraz]rrc monoh}dra:e and can be prevented bj
Fuming refracclve Ilquid, fa]n! charactenshc odor 1Jo.
2-ehlor&thanol: Gansscr, Rumf, HeIv. C/rim. Acla 36, 1423 phorous acid (H3P0,
lrnr pcxson’ Causes delayed eve Irrira!ton. dll 1.03. mP (1953): from hydranne monohydrate and ethylene oxide for some tlmc are us
– 51 T or below – 6Y (Iwo eutec!!cs). bp,~ 118-1 lT. bp~ Gvcr, O’Kcefe, U.S. pat, 2,660.607 (1953 to Eaton Labs.); be regenerated with 1
47”. n~ 1 42842 Strong base. very corroslvc. a!tacks glass. from hydrazrnc and ethylene ox!dc: Brit. pat. 776,113 ( 1957 Jr., Inorg. Syn. 2, 21(
1) SOIin alcohol. rubber. cork. bu[ no! stamlcss VIA stcci or Alleghen! StaIO- 10 OI1n Ma:hicson). air, preferably not U6C
I ID cold. moder- Iess 304 and 347 Molybdenum SICCISsuch as Allq!hcn! ~lorkxs, slightly ,Iscous I!quid. d 1.11. One gallon DISSOIVCS iodine. 1
- alcohol are yel - s~a!nless 316 should not be used Very powerful rcduclrlg weighs 9.26 tbs. mp –7rY bpl,J I 10-13&, bpn 145-153”, bp7m 12T> d 1.70. C
organic sol vents agcn! M!sable wl[h water and alcohol Insol ln chl@rO- &h pt 22&F (l O&C). MISC w!th water. Sol In the lower acid, at:acks natural
Debbie, Tinkl. fm-m and ether Slcohols Slightly sol In ether Cau[IOrr: Strong Ir
Mtxrurc ul[h methanol. C-Sw~j USE: Plan! growlh regulant. USE. Reducing agi
djotonic; uterine USE: Rcduclng af??nl, soi~ent for Inorgantc malcnal$ maceu!icals. disinfect
Manuf “Helmarr”’ ca[:,l:, st, consisting of 8WC hydr:,.lnr h}. 4815. Hydrazoic Acid. Hydrogen azide; hydronttric analytical purposes, s
drale. 19.5~< ethanol. 0.5 [o O 05T. copper, used to dec h>’ lcjd; ~rla~ojc ac, d: srlcks[offw assers[offsti”rc (Germs”).
lge root; yellow THERAPCAT: Expec
drogcn peroxide ]n V-2 IYIX rockets Mlxturc with mel~. HN,; mol WI 43.03 H 2,34 T., N 97.66’%, Produced b) the
led rhizome and SCtio” of sulfuric amd on sodium tide: L. F. A“d”elh, C, 4818. Hydrotreni
Qceaet conte not anol as propel}anr ~@6ct~.-.
F. G!bbs, fnmg. Syn. 1, 77 ( 1939): using stcaric acid Giin - phenyle!hyleneglycol
tber, Meyer, Z Elekrrmht.m. 41.54 I ( 1935). Prepn of water H 6.59’_c,O 14.93%
Sod ether scrl”s of hydrazolc acid W. S. Frost er aL, J Am. Forst, Z)ncke, Ann. 1
Chem. Sot. 55, 3516 ( 1933). L F. Audncth, C. F Gtbbs, Chem. soc 91, 1390
k P. W Schenk in Handbook of Preparative Inorganic
cit.; WC 51, 2163 (1920);
Chcm,srry vol. 1, G Brauer, Ed. (Acadermc press. New C. Heath. Boston, 11
& >OC. ;6, 3914 as collolds. and SOdIUrn hypochlonw ma> be used lnsltid ~t york, 2nd cd , 1963) pp 472-474 GC dctermn: J M Zeh - Improved method for
fnorgarric Chcm. bleachlng poudcr Adams, Brown, Org .S,WI 2, 37 ( l“~~) iler, R A Slmonajt}s, J Chrom ScI. 14,493 (1976),Toxic- mer: COllet, Synrhesu

,. .tirme Index beJow uxing dris section. Consult the .Vome Indtw bejore using this section.

.&
SCRI - Hydrazine Sulfate Page 1 of 2

.-.
HYDRAZINE
SULFATE
“...Since h.vdrazine su~fateyovided
relief of a wide s~ectrum of cancer
svmDtoms, it mav be recommended for
patients with end-sta~e cancer. ”

side effect.y...‘t
GENERAL INFORMATION
Hydrazine sulfate is an anti-cachexia drug which acts to
reverse the metabolic processes of debilitation and weight loss
in cancer and secondarily acts to stabilize or regress tumors.
Hydrazine sulfate is a monoamine oxidase (MAO) inhibitor
and is incompatible with tranquilizers, barbiturates, alcohol
and other central nervous system depressants. Foods high in
-
tyramine, such as aged cheeses and fermented products, are
also incompatible with MAO inhibitors. The use of
tranquilizers, barbiturates and/or alcoholic beverages with
hydrazine sulfate destroys the efficacy of this drug and
increases patient morbidity.

The U.S. National Cancer Institute (NCI)-published studies of


hydrazine sulfate (Journal of Clinical Oncology, June 1994),
reported as negative, denied the use of tranquilizers, with the
exception of the short-term use of prochlorperazine
(Compazine). However, under pressure of an investigation of
the NC1 studies by the U.S. General Accounting Office
ordered by Congress, the NCI in a subsequently published
paper (Journal of Clinical Oncology, June 1995) admitted to
the widespread use of both benzodiazepine and phenothiazine
tranquilizers, which are incompatible with MAO inhibitors, in
94% of all study patients. Moreover, approximately half of
these patients were given these tranquilizers on a long-term
—_ basis, and some on a continual basis. It was further admitted
by the NCI that concomitant drug use (such as tranquilizers,
alcohol, barbiturates, etc.) was not computerized and patient

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SCRI - Hydrazine Sulfate Page 2 of 2

records of such drug use were “incomplete.”


.--=
There is an abundance of published, positive, peer-reviewed
studies on hydrazine sulfate in the medical literature.
(Abstracts of some of these published studies are given on the
following pages.) These data emanate fi-om major cancer
centers both from the United States (randomized,
double-blind, placebo-controlled studies and single-arm
studies) and Russia (large-scale, multicentric Phase
II-equivalent studies). These data indicate the therapeutic
action of hydrazine sulfate to extend to all types of tumors.

Hydrazine sulfate has been demonstrated to produce only few


and transient side effects. There have been no instances of
bone-mamow, heart, lung, kidney or immune system toxicity,
or death, reported. Hydrazine sulfate has never been
demonstrated to be carcinogenic in humans.

For further information please have your HEALTH CARE


PROFESSIONAL (no patients or individuals, please) call the
institute.

COLLECTION OF ARTICLES IHOW T(3 CONTACT SCRI

A collection of articles on Hydrazine Sulfate has been


available on this site since 23 October 1996.

This page is designed and hosted by ~NextGenerofion ~ompt(tm .YY.Ytem.>and is the


property of the Svracuse Cancer Research Institute, 01996, Syracuse Cancer
Research Institute, All rights reserved.
Last modifted on 21 Janua~ 1997.

http: //www.ngen.com/hs-cancer/ 4/29198


SCRI - Article List Page 1 of 1

.-
n!
ARTICLES
The following is a collection of articles based on published
studies on Hvdrazine Sulfate. You may view the abstract by
clicking on the icon to the left. If the title of an article has no A
hyperlink, then that article is not present on this system (you &
may still view the abstract).

n “1-Iydrazine sulfhte
Non-Slnall-Cell
19901
Influence
Lunz Cancer”
on Nutritional
[Journal
Status
of Clinical
and survival
Oncology 8:9-15.
in

“Results of Clinical Evaluation of Hydrazine Sulfate” [VOPROSY


n ONKOLOGII 36:721-726, 1990]
“Altered Metabolism and Mortalitv in Patients With Colon Cancer
m RcccivinK Chemotherapy “ [American Journal of the Medical
Sciences 310:48-55. 1995]
“Influence of Hydrazine Sulfate on Abnormal Carbohydrate
m Metabolism in Cancer Patients with Weight Loss” [Cancer Research
44:857-861. 1984]
“Treatment of Primary Brain Tumors With Sehvdi-in rHvcirazine
D -“ [VOPROSY O~OLOG1l XO:SSZ-SS6. 19941
__—_ “Hvdrazine Sulfate in Cancer Patients
With Wciqht Loss: A
r!! Placebo-Controlled C’linical Experience” [Cancer 59:406-410, 1987] ~
“Anabolic Profiles in Late-Stage (’ancer Patients Res~onsive to
D Hydrazine Sulfl~te” [Nutrition and Cancer 3:13-19. 1981]
“ErfeCt of Hydrazine Sulflire on YVhole-bodv Protein Brealcdown
D Measurecl by ! 4C-Lysine Metabolisnl in Lung Cancer Patients”
[Lancet 2:241-244. 1987]
“Hvdrazinc Sulfate: A Current Pa-s-” [Nutrition and Cancer
m- 9:59-66. 1987]
“Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS)
m in the advanced cancer patients” [Investigative New Drum 13:89-97.
1995]
“Use of Hydrazine Sulfate in Terminal and Pretermina] Cancer
Patients: Results of Inlestizational New Drwz (lND) Studv in 84 &
m
Evaluable Patients” [Oncologv 32:1-10, 1975]

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National Library of Medicine: IGM Full Record Screen


_-

..-
.. . . . . .. ..-.—. . . . /
ix-’ ‘-””- ‘-”-” ‘-”-
‘“”’’
”--- “’””v
TITLE: Use of hydrazine sulfate in terminal and preterminal cancer
patients: results of investigational new drug (IND) study in 84
k evaluable patients.
AUTHOR: Gold J
SOURCE: Oncology 1975; 32(1) :1-10
NLM CIT. ID: 76101548
ABSTRACT: In a series of 84 various evaluable disseminated cancer patients
treated with hydrazine sulfate as a result of a
pharmaceutical-sponsored investigational new drug (IND)
study, it was found that 59/84 or 70°/0 of the cases improved
subjectively and 14/84 or 17°/0 improved objectively. Subjective
responses included increased appetite with either weight gain or
cessation of weight loss, increase in strength and improved
.—=
performance status and decrease in pain. Objective responses
included measurable tumor regression, disappearance of or
decrease in neoplastic-associated disorders and long-term (over
1 year) ‘stabilized condition’. Of the overall 59 subjective
improvements 25 (42°/0) had no concurrent or prior (within 3
months) anticancer therapy of any type. Of the 14 objective
improvements 7 (50°/0) had no concurrent or prior anticancer
therapy. Of the remaining cases in which there was either
concurrent or prior anticancer therapy, improvements occurred
only after the addition of hydrazine sulfate to the treatment
regimen. Duration of improvement was variable, from
temporary to long-term and continuing. Side effects were mild,
comprising for the most part low incidence of extremity
paresthesias, nausea, pruritis and drowsiness; there was no
indication of bone marrow depression.
MAIN MESH Hydrazines/ADVERSE
SUBJECTS: EFFECTS/PHARMACOLOGY/* THERAPEUTIC USE
Neoplasms/*DRUG THERAPY/METABOLISM
_—_- ADDITIONAL Drug Evaluation
MESH Gluconeogenesis/DRUG EFFECTS
SUBJECTS: Human

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Paresthesia/CHEMICALLY INDUCED
Remission, Spontaneous
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng

-
_. -

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hltp:l/130.14,32,43 /cgi...M-elient?28084 +detail+l http: //l3O. 14.32.43/cgi-biwlGM-client?28084*detail+ 1

National Library of Medicine: IGM Full Record Screen

k? v
TITLE: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled
clinical experience.
AUTHOR: Chlebowski RT; Bulcavage L; Grosvenor M; Tsunokai R; Block JB; Heber
D; Scrooc M; Chlebowski JS; Chi J; Oktay E; et al
SOURCE: Cancer 1987 Feb 1;59(3):406-10
NLM CIT. ID: 87077829
ABSTRACT: Hydrazine sulfate was evaluated using 24-hour dietary recalls and body
weight determinations before and after 30 days of either placebo or
hydrazine (60 mgu3 times/d) oral administration in 101 heavily pretreated
___ $“ > cancer patients with weight lo~After 1 month, 83°/0 of hydrazine and only
53?40of placebo patients completing repeat evaluation maintained or
increased their weight (P less than 0.05). In addition, appetite improvement
was more frequent in the hydrazine group (63°/0 versus 25°/0, P less than
0.05). Although caloric intake was only slightly greater in hydrazine-treated
patients, an increased caloric intake was more commonly associated with
weight gain in patients receiving hydrazine compared with those receiving
placebo (81% versus 53%, respectively). Hydrazine toxicity was mild, with
71 ‘Mo of patients reporting no toxic effects. Hydrazine sulfate circulatory
levels were obtained from a subset of 14 patients who completed 30 days of
treatment, with a single sample obtained in the morning at least 9 hours
after the last dose. Mean maintenance hydrazine sulfate levels, determined
using a spectrofluorometric assay, ranged from Oto 89 nglml (mean 45 +/-
16 rig/ml). These data, which demonstrate an association between 1 month
of hydrazine sulfate administration and body weight maintenance in
patients with cancer, suggest future clinical trials of hydrazine sulfate are
indicated to definitively assess its long-term impact on important clinical
outcome parameters in defined cancer populations.
MAIN MESH Cachexia/*DRUG THERAPY/ETIOLOGY
SUBJECTS: Hydrazines/*THERAPEUTIC USE
Neoplasms/*COMPLICATIONS~RUG THERAPY

lof2 4/29/98 3:13 PM



.-. Chapter 5

HYDRAZINE SULFATE

.. . . .- . ..
Hydrazme sultate, a simple, off-the-shelf chemical, ctramatlca[!y re-
verses cachexia (ka-KEK-si-a), the wasting-away process that kills
two-thirds of all cancer patients. This inexpensive drug, with little or
no side effects, also has a clinically documented antitumor action. It
causes malignant tumors to stop growing, to reduce in size, anti, in
some cases, to disappear. A growing number of cancer patients
diagnosed as terminal have experienced tumor stabilization and
remission through hydrazine sulfate therapy.
About half of all patients who take hydrazine sulfate experience
weight gain, restored appetite, extended survival time, and a signifi-
cant reduction in pain and suffering. Many patients report an in-
crease in vigor and su-ength and the disappearance of symptoms of
-. the disease, along with feelings of weI1-being and optimism.
While hydrazine sulfate may not be a sure-fire cancer cure, large-
scale clinical trials suggest that it affects every type of tumor at every
stage. It can be administered either alone or in combination with
cytotoxic chemotherapy or radiation to make the cancer more vul-
nerable to these standard forms of treatment,
Hydrazine sulfate is now undergoi-se 111 trials sponsored b~
the National Cancer lns[itute. lt is available to patients as a “comp.as-
—-.
slonate 1N’DIIWvestlgatlonal New ~rug], ” a designation con{erred by
fhe Food and Drug Administration on a case-by-case basis, so it is no
longer, strictly sp-caking, an “unconventional therapy, ” Yet even
though hundreds of patients across the country are using the drug,
it is not widely discussed or disseminated among practicing physi-
cians and its promise remains largely untapped twenty-four years
after it was first proposed as an anticancer treatment by Dr. Joseph
Gold. Meanwhile, hydrazine sulfate is widely available in the Com-

47
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OM1 JJEd
II

56 optlb , ‘) Immune “1P



ies
,,‘
57

ers, are your body’s first line of defense. If the cancer cells evade the and renal cancer, but its drawbacks are major and became evident early
natural killer cells, they proliferate and manufacture arrtjgerrs, which are on. Charles Moertei, M. D., of the Mayo Clinic, ctrarged that IL-2 is highly
telltale substances detected by the T-cc//s, your immune system’s sec- toxic, hugely expensive, and not particularly effective.2 Its side effects
ond line of defense against tumor growth. Specialized T-cells (or T-/ym- include fever, chills, malaise, swelling of the spleen, anemia requiring
phocytes) destroy cancerous and virus-infected cells. (The “~ in T-cell multiple transfusions, severe bleeding, SI ~ck, and confusion. Treatment
stands for ‘Ihymus-derived’< because these white blood cells, created in with IL-2, according to Dr. Moertel, may require weeks of hospitalization
the bone marrow, are carried to the thymus gland, which transforms them in an intensive care unit “to survive the devastating toxic reactions.”3
into T-cells. ) Other white blood cells, rnacrophages (Greek for “big After a few patients died because of interleukin-2, the National Cancer
eaters”), ingest the cancer cells. A wide range of other cells and sub- Institute, which had eagerly presented it to the public as a miracle drug,
stances that make up the immune system help to orchestrate a coordi- withdrew such claims.4

nated attack against almost any invader. Tumor necrosis factor (77VF),produced in the body in minute quantities,
Altogether, there are five major types of orthodox immunotherapy. The seems to kill cancer cells by destroying their cell membranes, although why
first is BCG, a tuberculin vaccine used in the treatment of cancer that this happens is not clear. Side effects occur :agularly; most patients develop
stimulates macrophages to kill cancer cells. Consisting of a weakened strain fever and chills as well as some nausea and vomiting. 5 Injected into
of the tuberculosis bacillus, b~G (which stands for bacillus Ca/mefte- cancerous mice, TNF causes their tumors to melt away. It is currently being
Gudrirr) apparently works best when combined with chemotherapy; yet as tested to determine its potential efficacy in treating human cancer patients.
a solo treatment, it has brought about some complete remissions and many Some observers believe that TNF, upon which the cancer establishment
cases of temporav or prolonged remission. Used by conventional as well has spent millions, is simply ?urrrorantibody, one of the four blood fractions
as alternative doctors, BCG has been particularly successful in treating used by Lawrence Burton, pioneer of a nontoxic immune therapy used i
malignant melanoma. It appears to work well when injected directly into the diagnosis and treatment of cancer (see Chapter 6).
tumors visible on the skin, though it has also been used to treat lung cancer Monoclonalantibodies are synthetic antibodies created through gene-

and other forms of the diseas~ One of the researchers who discovered splicing, fusing a cancer patient’s white blood cells with his or her cancer

BCG’S anticancer potential was Dr. Lloyd Old, who later became director of cells. When these bizarre hybridornas are reintroduced into the patient’s

the Sloan-Kettering Institute for Cancer Research. body, they manufacture specific antibodies said to attack only the cancer
Interferon is a family of proteins produced by the white blood cells in cells. Attached to anticancer drugs or natural toxins, monoclonals serve
response to viral infection. It stimulates the production of macrophages and as “guided missiles” by directing the antibodies they manufacture toward
/lymphocytes (white cells), blocks the growth of tumor cells, and transforms their malignant prey. Still in the investigative stage, monoclonals—like
some lymphocytes into natural killer cells. Hyped as a wonder therapy and interferon, interleukin-2, and TN F—promise to be tremendously expen-
miracle cure when it was first synthesized in 1980, synthetic interferon sive, a boon to the pharmaceutical-medical monopoly if they are ever
turned out to be very expensive and have toxic side effects. It produces used in cancer treatment. They are frequently touted by the media as the
fever, chills, and muscle contractions so severe that they may require next cancer breakthrough.

morph ine,’ Today, interferon ih Lpproved for use in the treatment of two rare The American Cancer Society freely admits that it will take “many

forms of cancer, hairy-cell leukemia and juvenile laryngeal papillomatosis. years to find the proper role of these [orthodox immunotherapy] agents

It may have limited value in a number of other rare conditions. The FDA in cancer treatment.” 6 Observers say this means twenty years or more
approved its use for AIDS patients in 1988, but it has largely been a failure Meanwhile, the ACS continues to use its enormous power and influence

in ARC-AIDS trials. Infected people who received it had flu-like symptoms, to restrict or suppress safe, nontoxic cancer therapies that have pro

fatigue, swelling, headaches, and even hallucinations. duced remarkable clinical results in human beings, such as the immune
/nfer/eukirb2, a protein produced by the T-cells, was also hyped by therapies of Lawrence Burton, Ph.D. (Chapter 6) and Virginia Livingston,

the cancer industry and the major news media as a cancer breakthrough. M.D. (Chapter 7), or the biologically based therapy of Stanislaw Burzyn-
The results to date, however, have been disappointing. IL-2, as it is ski, M.0. (Chapter 2).
called, has reportedly been effective in some patients with melanoma Ironically, Co/ey’s mixed bacteria/ vaccine, which has perhaps shown
58 Options

a greater cure rate than any other cancer treatment, is totally unavailable.
Dr. William Coley (1862-1 936), an eminent New York City surgeon and
Sloan-Kettering researcher, in the 1890s developed a vaccine made of
bacterial toxins that activated immune-resisknce mechanisms in cal cer
patients and cured hundreds. His daughter, Helen Coley Nauts, D.SC.,
has preserved and carried forward his important work. Yet, despite the
successful use of bacterial vaccines amply reported in the medical
literature since the turn of the century, today’s big drug companies have
no interest in what they view as merely an unprofitable item.
Staphage Lysate, a nonspecific bacterial vaccine made from sfaphy/o-
cocci, is legally sold today as a specific therapy for acute and chronic
staphylococcal infections. Unofficially, it has been widely used by pragmatic
doctors who have had encouraging results in treating multiple sclerosis,
cancer, herpes, allergies, arthritis, asthma, and many other conditions.’
Relatively inexpensive and almost totally nontoxic, Staphage Lysate can be
inhaled, injected, or taken orally. It is known to increase the production of
T-lymphocytes and to induce the natural formation of interferon and hter-
/eukin- 1, the predecessor of interleukin-2.
Immune therapies, whether orthodox or alternative, are generally used
as a treatment of last resort after patients have received toxic chemotherapy
or radiation. Many doctors believe that the prior use of immune-destroying,
often carcinogenic conventional treatments lowers a patient’s chances for
recovery through immune therapy. Chemotherapy often accomplishes the
destruction of the immune system, and radiation can cause severe, pro-
longed immune deficiency. At any one time, there are thousands of cancer
patients in the United States undergoing aggressive chemotherapy who
would benefit from any immune-enhancing measures whatsoever, even
supportive nutrition or vitamin supplementation.
96-34 Pediatric TheraPY

.-. G ~iram A et al. Theophylline~ersus


caffane: commrative effec[s in trcal-
176 Painter
zures.
MJ.
Cleve
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41b ed. Philadelphia
1992:S93
WB .$aund,wu;

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NOTICE Reprinted with permissbn
~HIS &!.T~~~AL MAY BE PROTECTEDBY through the Copyright
COPW?!GHTLAW (TITLE 17’,U.S.MWE) Clearance Center
.

Hydrazine Sulfate in Cancer Patients With Weight Loss

A P/acebo-Controlled Clinicai Experience

ROWAN T. CHLEBOWSKI, MD, PHD,* LINDA BULCAVAGE, MN, RN,’ MARY GROSVENOR, RD. MS,t
RAYNELLE TSUNOKAI, BS,” JEROME B. BLOCK, MD,” DAVID HEBER, MD, PHD,*
MICHELLE SCROOC, RD,t JOAN S. CHLEBOWSKI, MD,S JOCELYN CHI, MD,”
ENGIN OKTAY, MD,$ STEVE AKMAN, MD,” AND ISHRAT ALI, MD$

Hydrazine sulfate was evaluated using 24-hour dietary recalls and body weight determinations before and
after 30 days of either placebo or hydrazine (60 ma 3 times/d) oral administration in 101 heavily pretreatd
cancer patients with weight loss. After 1 month 83% of hydrazine and only 53% of placebo patients
completing repeat evaluation maintained or increased their weight (P < 0.05). In additio~ appetite im-
provement was more frequeri: in the hydrazine group (63% versus 25%, P < 0.05). Although caloric intake
was only slightly greater in hydrazirre-treated patients, an increased caloric intake was more commonly
associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81%
versus 53%, respectively). Hydrazine toxicity was mild, with 71% of patients reporting ❑ o toxic effects.
Hydrazine sulfate circulatory levels were obtained from a subset of 14 patients who completed 30 days
of treatmen~ with a single sample obtained in the morning at least 9 hours after the last dose. Mean
maintenance hydrazitre sulfate level% determined using a spectrofluorometric assay, ranged from O to 89 -.,-
ng/ml (mean 45 f 16 rig/ml). These dat% which demonstrate an association between 1 month of hydrazhte
sulfate administration and body weight maintenance in patients with cancer, suggest future clinical trials
of hydrazine sutfate are indicated to definitively assess its long-term impact on important clinical outcome
.- parameters in defined cancer populations.
Cancer 59:4WW1O, 1987.

W EIGHT LOSS commonly accompanies cancer de-


velopment and is associated with an adverse
prognosis.‘ ‘-3Although intensive caloric support now can
opment in this population.’4 If this hypothesis is correct,
amelioration of the abnormal carbohydrate metabolism
could provide a therapeutic approach to the adverse out-
be provided such patients, clinical trials evaluating caloric come associated with cachexia development in the cancer-
provision alone have not reported improved outcome for bearing host.
chemotherapy-treated populations with advanced can- We previously demonstrated that hydrazine sulfate is
cer M As a result, consideration of potential mechanisms metabolically active, improving the abnormal glucose
underlying the development of weight loss in the cancer tolerance and reducing the increased glucose production
population has led to development of alternative strategies rates seen in cancer patients with weight loss.’3 We now
for clinical intervention in these patients. Altered glucose report clinical observations on short-term hydrazine sul-
metabolism is a common metabolic abnormality in cancer fate use in a cancer population with weight loss using a
patients with weight 10SS,7-’3and it has been suggested prospective placebo-controlled study design.
that the inappropriate activation of pathways of glucose
metabolism leads to futile cycling and cachexia devel- Materials and Methods

The criteria for inclusion in this trial were: a diagnosis


From the UCLA School of Medicine, Department of Medicine, ●Di- of advanced cancer weight loss greater than 10’ZO from
vision of Medical Oncology and tctinical Research Center, Harbor-
~TCLA ~edi~ center, romance. and the $LJCLA ~h~l OfMedi~i”e,usual body weight; absence of severe hepatic or renal dys-
Department of Medicine, Division of Clinical Nutrition. and the function (bilirubin greater than 3 mgjdl and/or creatinine
$Southem California Perrnanente Medicat Group, Los Angeles, Cali- greater than 2 mg/dl); and normal mental status. Patients
fornia.
with a known history of diabetes mellitus or those receiv-
Supported in part by Grant CA373X) from the National Cancer In-
stitute, NIH: Grant RD- 163 from the American Cancer Society, and ing corticosteroid therapy were ineligible. Patients with
Grant RR-00425 (General Clinical Research Center) from the NIH. ascites or clinically significant edema were not entered to
__— Address for reprints Rowan T. Chlebowski, MD, PhD. Division of
-. avoid confounding weight determinations. Patients were
Medical Oncoloa. Harbor-UCLA Medical Center, 1000 West Carwn
Street, TorranceUCA 90509. entered either prior to receiving systemic chemotherapy
Accepted for publication September 9, 1986. or when a new systemic therapy program was initiated

406
:-—--”.. 3 HYDRAZINE SULFATEINCANCER CACHEXIA o Chlebowski
e(al 407

for disease progression. Measurable disease parameters TABLE 1. Pretreatment Characteristics of Cancer Patients Receiving
Hydrazine Sulfate or Placebo
were not required, and concurrent chemotherapy was
permitted. Both initial and reWat assessment of all study Treatment received

parameters, however, were conducted at least 2 days be-


H ydrazine Placebo
fore and 4 weeks after chemotherapy administration.
After informed consent was obtained, patients under- Number entered 71 30
went an initial assessment of nutritional parameters, in- Age in years
cluding caloric intake as described below. Patients sub- Median 56 59
sequently were treated with capsules containing hydrazine Range 32-77 36-77
sulfate (60 mg) or placebo which were prepared by Ana- Sex (% Male) 61% 65%
bolic, Inc. (Irvine, California). Hydrazine sulfate was given Dkeaw type
under IND 17, 67 I from the Food and Drug Adminis- Lung 46 [5
tration (FDA) (obtained by Dr. Chlebowski). All insti- Colon 13 4
Other breast 4 3
tutional requirements for human subjects review were Esophagus 2 3
met. The treatment program consisted of an escalating Nasopharyngeal 3 I
schedule of capsules containing either hydrazine sulfate Hepakxelluhr 2
Ovanan ; I
or placebo until the full dosage of 60 mg, 3 times/d given Prostate o I
before meals, was reached beginning on the 8th day. This
Performance score
program was based on the extensive Russian experience.’5 (Oorl) 14% 23%
Patients were contacted weekly to assess compliance and (2 or 3) 86% 77%
kept daily compliance diaries. The validity of daily com- Nutritional status
pliance diaries was checked against intake based on re- % Weight low (mean) 17% 14%
turned prescription bottles. Following 30 days of either CdOric intake
_- agent, the assessment of body weight, caloric intake, and >90% of RDA 39% 41%
~~herparameters was repeated. <90% of RDA 61% 5%
During the initial and repeat evaluation, all patients Albumin grddl (Mean) 3.4 3.3
received determination of body weight measured on the Concurrent chemotherapy 78% 74%
same printing scale; anthropometrics, including tricep
skinfold thickness, mid-arm muscle circumference, and RDA: recommended daily allowance.
serum albumin; caloric intake using a 24-hour dietary
recall history obtained by nutritionists and computer an- clinical management. Enteral tube feedings or parenteral
alyzed to give protein, carbohydrate, fat, and energy con- nutritional support was not given any patient while on
tents of the diet. Expected caloric intake was nomlalized study.
for each patient by weight based on a calculated recom- A totalof101 patients with advanced cancer underwent
mended daily allowance (RDA). Toxic effects of treatment initial evaluation. Sixty-one consecutive patients (includ-
and influence on appetite were determined by question- ing all 30 patients given placebo and 31 given hydrazine)
naire. were randomly assigned treatment in a double-blind fash-
In a subset of 14 patients, blood samples for hydrazine ion with treatment assignment based on published ran-
sulfate circulatory levels were obtained as a morning sam- dom-number tables. An additional 40 patients received
ple taken at least 9 hours from the last oral dose following hydrazine sulfate and represented a consecutive series of
30 days of treatment. Hydrazine sulfate levels were mea- patients seen in the Clinical Research Center meeting en-
sured using a defined’s” 7 spectrotluoromettic assay in try criteria for the trial. Statistically significant differences
which reaction of hydrazine sulfate with dimethylami- between hydrazine and placebo groups relative to pre-
nobenzaldehyde produces a colored derivative. Fluores- treatment clinical factors were sought using chi wuare
cence was subsequently determined in an Aminco Bow- contingency table analyses and Student’s t test. The sta-
man (Silver Spring, MD) spectrophotofluorometer with tistical differences between hydrazine and placebo treat-
an excitation wavelength of 466 nm and emission wave- ment were determined using the two-group 1 test.
length of 546 nm.
All patients were given defined, uniform dietary coun- Results
—-
selingbased on nutritional status at entry to insure com- A total of 10I patients with a variety of advanced can-
parability of dietary information available to patients on cers underwent initial evaluation. Patients receiving hy-
hydrazine or placebo treatment. The nutritional guidelines drazine sulfate or placebo were comparable with respect
all patients were provided with were designed to duplicate to tumor type, age, sex, performance score, nutritional
a routine clinical dietary assessment that would be ex- parameters and chemotherapy experience (Tables 1 and
‘$ wed to be a component of a cancer patient’s standard 2). The compromised nutritional status of the study POP
..,,-
y,”;
%
408 CANCER February 1 1987 vol.
59

TABLE 2. Corrcurrent chemotherapy of caner PatientsReceiving observation. Anthropometrics were unchanged over the
Hydmzine Sulfate or Ptaabo Accorchng to Disease Type
30-day study period. Caloric intake was only slightly
_—_
-— .
Study arm higher in the hydrazine treated population. When all pa.
tients experiencing an increase in caloric intake were con-
Chemotherapy given Hydrazine Placdm
sidered, however, weight gain was seen in a significantly
Lung cancer (n) 46 Is higher proportion of patients receiving hydwine sulfate
PACCO 15 4 while increasing caloric intake compared with those who
PVB 12
;
increased caloric intake while receiving placebo. The re-
ACCQ 9
ACO 2 o sults using hydrazine sulfate were closely comparable in
No chemotherapy 8 2 the 31 patients entered as part of the randomized trial
Colon cancer (n) 13 4 when compared with the 40patients added as a consec-
s-m 2 1 utive series. The results for the patients receiving hydmzine
5-FLJ+ vitamin K 7 1
4 2
or placebo who were entered as part of the randomized
No chemotherapy
trial were: weight maintained or increased, 71% versus
Other disease sites (n)* 12 II
53%; improvement in appetite, 63% versus 25%; caloric
No chemotherapy 4 3
intake increased, 69% ver.su.s37%; and increased caloric
P cisplatin (Platinol} A: doxorubicirr, (Adriamycin); C: cyclophos- intake associated with weight gain, 77% versus 53% for
phamide c CCNLJ; O vincristine (Oncovin~ 5-FU 5-fluorouracil; V: the hydrazine versus placebo patients respectively. In ad-
vinblastine; B: bleomycin; 5-FU + tit K 5-tluorouracil plus vitamin Kj
(Synkavite). dition, results in groups receiving or not receiving con-
● The patients with other disease sites received a variety of regimens current chemotherapy reflected those obtained in the en-
which included cisplatin in 62% and 50% of instances for the hydrazine tire group.
and placebo woup, respectively.
Thirty-five patients with cancer other than small cell
lung cancer (the predominant tumor type studied) com-
ulation is demonstrated by the 16% average weight loss pleted serial evaluation, with 26 receiving hydrazine sul-
experienced by the overall population. Of this advanced fate and nine receiving a placebo. In the lung cancer pa-
disease population with weight loss, 58 patients were able tients, weight maintenance or increase was achieved in
to complete repeat evaluations afier 30 days of treatment 83% of those receiving hydrazine sulfate compared with
—s.-
-——
(41 were given hydrazine; 17, placebo). Early disease pro- 33% of those receiving the placebo.
gression and/or death accounted for almost all cases not The short term hydrazine sulfate regimen used in this
having repeat study. Only two patients refiwd repeat trial was well tolerated by study participants. Compliance
evaluation. forms were returned by 90% of patients who completed
The influence of 30 days of hydrazine sulfate or placebo repeat evaluations, and indicated that 95% of the sched-
therapy on study parameters for all entered patients who uled dose was taken by the study population completing
undetwent repeat evaluation is outlined in Table 3. Weight 30 days of therapy. The mean maintenance plasma hy-
was maintained or increased in a higher proportion of drazine sulfate levels obtained from a subset of 14 patients
patients receiving hydrazine sulfate compared to placebo ranged from O to 89 rig/ml with a mean value of 45 f 16
thetapy (83% versus 53%, respectively P < 0.05). The use ngJml. Clinical toxicity of patients receiving hydrazine
of weight loss as a study parameter was not compromised sulfate was limited largely to mild to moderate nausea
by the development ofascites or significant edema, as this and lightheadedness with 71% of patients reporting no
did not occur in any patient over the 30 day period of toxic effects from hydrazine use (Table 4). Treatment was
discontinued for toxic effects in 10’%of patients receiving
TABLE 3, Influence of 30 Days of Hydrazine Sulfate or Placebo on hydrazine; while 6’% of patients receiving placebo had
Nutritional Status of Cancer Patients With Weight Loss
treatment stopped for “toxic effects.” Significantly, par-
Hydrazine Placebo asthesias or hypoglycemic symptoms were not repotted
❑=41* n=17 by any patient receiving hydrazine in this trial.
Weight maintained or
increasd (>2.5 kg) 83%t 53qo Discussion
Improvement in appetite 63%t 25%
Caloric intake increased Short-term administration of hydrazine sulfate was
(> 10% over baseline) 51% 37%
Increased caloric intake
better than a placebo in maintaining body weight and
associated with weight improving appetite in patients with advanced cancer in
gain (>2.5 kg) 81%t 53% the current clinical experience. The weight effect appar-
● Number completing initial and repeat study.
ently resulted from an increase in the effectiveness of the
t P< 0.05 hydrazine compared to placebo group. ingested calories, since a higher proportion of patients
-- 409
7 I-IYDRAZINESULFATEIN CANCERCACHEXIA o Chlebowski et al.

who increased their caloric intake on hydrazine were able TABLE 4. Patient Tolerance of Hydrazine
Sulfate or Placebo Treatment
to maintain or improve their body weight. The association
that we have reported]a between weight maintenance and % of Patients Treated
improved glucose metabolism in hydrazine-treated cancer
Hydrazine Placebo
patients suggests that interruption of abnormal metabolic
pathway function may underlie the improved nutritional No toxic efeets 71% 84%
status seen with hydrazine sulfate in the current trial. If Nausea and vomiting
Mild I2% I~%
this hypothesis can be confirmed, hydrazine sulfate could Moderate 5% O%
represent one of a new class of metabolic/hormonal Light-headedness 17% 6%
agents’9-21 directed at influencing the abnormal metab Treatment discontinued for toxic etkcts 10% 6%
olism seen frequently in patients with cancer.
No prior clinical experience with hydrazine sulfate in
cancer patients has prospectively evaluated caloric intake The relative lack of toxicity of short-term hydrazine
or included a placebo controI population. Single-arm sulfate administration in a 60 mg 3 times/d schedule to
studies involving 348 Russian and 84 American patients a large cancer population receiving other concurrent che-
with cancer have emphasized subjective parametem. 15“22 motherapy treatment was noteworthy. In the previous
In the American experience, Gold22 reported that 70% of limited clinical experience,15’2*’23only one report h= em-
the treatment group demonstrated subjective improve- phasized significant toxicity; Ochoa and coworkers24 re-
ment, including increased appetite with either weight gain ported a 50% incidence of polyneuritis associated with
or cessation of weight loss, increased strength and im- hydrazine sulfate use in a 29-patient experience. In three
proved performance status, or decreasd pain, as measured tnalS15.22,25
and the present report, polyneuritis was seen
by need for analgesics, In the Russian experienc% in less than 1% of the more than 500-patient cumulative
Gershonovich’5’23 reported that 50% of patients receiving experience. The lack of toxicity in the current experience
_=Avdrazine Sulfate m their sole thempeutic intervention
can be documented further by the good compliance re-
~ieved moderate or marked improvement in cachexia
ported by the patients in their diaries. The latter result is
wtth associated favorable symptomatic effects on appetite
interesting considering the somewhat wide range of hy-
and pain. Not all clinical studies of hydrazine sulfate have drazine sulfate maintenance circulatory levels observed
shown benefit. ln three small trials of hydrazine sulfate in the pharrnacotinetic component of thk trial. However,
(all entering less than 30 patients) where reduction in tu- these results are consistent with developing pharmac-
mor size was used as a major therapeutic endpoint, little kinetic information regarding the half-time of oral hy-
benefit was reported. 2*26The clinical effkcts ofhydrazine drazine sulfate administration. 17These data suggest that
sulfate on body weight observed in the current study in future clinical trials involving hydrazine sulfate shouid
conjunction with the metabolic effects of hydrazine that include determination of chronic circulatory levels to as-
we reported in 198412now provides a strong rationale for sess hydrazine sulfate bioavailability and permit correla-
further studies designed to assess the impact of hydrazine tion with metabolic, nutritional and clinical endpoints.
sulfate on clinical outcome in defined cancer populations.
Surprisingly, thirty-seven percent of weight-losing can- Conclusion
cer patients given placebo in this trial increased their ca-
loric intake by more than 10%, and 53% of the placebo This experience with hydrazine sulfate in an advanced
group maintained or increased their body weight over the cancer population points to a potential role for this agent
I-month observation period. This result in the placebo in maintaining weight in patients with cancer cachexia.
population may have been related to the nutritional Whether maintenance of body weight under these con-
counseling that was given in identical fimhion to patients ditions will be associated with improvement in important
on both treatment arms in this study. Placebo controls clinical outcome variables and overall survival will require
clearly are important in trials designed to alter and assess future prospective, long-tetm, placebo-controlled evahs-
nutritional parameters in cancer populations. ation in cancer populations with less advanced disease
The study protocol employed in our trial was not de- given defined systemic therapy. Such studies in the non-
signed to assess the influence of hydrazine sulfate on tumor small cell lung cancer population are currently in progress.
~owth characteristics. The short 30day period of treat-
— REFERENCES
‘lent and entry criteria preclude assessment of hydrazine
.ulfate influence on this parameter. Almost all of our pa- I. DeWysWD, Begg C,Latin PT et al Rognostic effeets of weight
loss prior to chemotherapy in cancer patients. Am J Med 198069:491-
tients with advanced solid tumors refractory to initial 497.
therapy, however, demonstrated no change in tumor di- 2. Costa G, Iane WW, Vincent RG er al Weight loss and eachexia
mensions during the 1-month period of observation. in lung cancer. Ncur Cancer 1981; 2:98-103.
410 CANCER Februmy 1 1987 vol. 59

3. Chlebowlci RT, Heber D, Bleck JB. Lung cancer cachexia. In Gmcrz ML, eds. Me&al Thetapy of Tumors. Leningrad USSR Ministryof
..#._ FA, ed. Lung Cancer 11.The Hague: Martinus Nijhoff PublisheE 1983; Heatth, 1983;91-183.
125-142. 16. Vickers S, Stuart EK. Simple, sensitive speetrophotothsorometric
4. Clamon G, Feld R, Evans WE, er a[. Effkct of hypcralimentation methed for hydrazine in plasma. Aria/ Chern 1974; 46:138-140.
on the suMval and respon= to treatment of patients with small cell lung 17. Chlebowski RT, Dietrich M, TsunokaiRet a/. Hydrazine sulfate
cancm a randomized trial. Cancer Treaf Rep 1985;69 i67– 177. clinical pharrnacokinetics. Proc .4m Assm Can Res 1985; 26:254.
5. Nixon DW. Hyperalimentation in the undernourished cancer pa- 18. Chfebovski RT, Heber D, Richardson B et al Asswiationbenwetz
tient. Cancer Res 1982; (Suppl) 42:727s-728s. improved Carbolzydratemetabolism and tight maintenance in hydrazine
6. Chlebowski RT. Critical evaluation of the role of nutritional SUPPOCI sulfate treated patients with cancer cachexia. Proc ,4m Soc Clirs Onco(
with chemotherapy. Cancer 1985; 55:268-272. 1983; 2:C372.
7. Rohdenberg GL, Bernhard A, Drehbiel O. Sugar tolerance in cancer. 19. Schein PS, Kisner D, Hailer D er a/. Cachexia of malignancy
JA.W.4[9 19; 72:1528-1529. Potential role of insulin in nutritional management. Cancer 1979:43:
8. Holroyde CP, Gabuzda TG, Putnam RC ef al. .Altered glucose 2070-2076.
metabolism in metastatic carcinoma. Cancer Res 1975; 35:37IO-37 14. 20. Burr ME,LowTY SF, Gorschboth C er al. Metabolic alterations
9. Waterhouse C, .feanpretre N, Keilson J. Gluconeogenesis from af- in a noncachetic animal tumor system. Cancer Res 1982:42:774-781.
anine in patients w“th progressive malignant disease. Cancer Res 1979; 21. Lelli G, Angelelli B, Giarnbiasi ME er al. The anabolic effect of
39:1968-1972. high dose medroxyprogesterone acetate in oncology. Pharmacol Res
10. Lundholm ~ Edstrom S, Karlberg I et al. Glucose [rzmover, @I- Commun 1983;15:561-568.
coneogenesis from glycerol, and estimation of net glucow cycling in 22. Gold J. Use ofhydrazine sulfate in terminal and preterrninal cancer
cancer patients. Cancer 1982; 50:1142-1150. patients: results of investigational new drug (lND) study in 84 evaiuable
II. Chlebowski RT, Heber D, Block JB, Serial assessment of glucose patients. Oncology 1975; 32:I-10.
metabolism in pa[ients with cancer cachexia. C/in Rev 1982; W69A. 23. Gershanovich ML,DanovaLA,[tin BA et aJ. Results of clinical
12. Chlebowski RT, Heber D, Richardson B, Block JB. [nfluence of study of antitumor action of hydrazine sulfate. Nufr Cancer 198I; 3:4-
hydrazine sulfate on abnormal carbohydrate metabolism in cancer pa- 12,
tients with weight loss. Cancer Res 1984;44:857-861. 24. Ochoa M, Wittes R, Krakoff L Trial of hydrazine sulfate (NSC-
13. Chletmwski RT, Heber D. Metabolic abnormalities in cancer pa- 15(XI14) in patients with cancer. CancerC/zemofherRep 1975; 59:1 t 5 I-
tienw Carbohydrate metabolism. In: Meguid M, Rudnck S, eds. Surg I 153.
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15. Gershanovich ML. Clinical effectsof hydrazine sulfate in patients 26. Lemer I-U,Regelwn W. Clinical trial of hydrazine sulfate in solid
with advanced malignant disease. Jn Filov VA, Evin BA, Gershanovich tumom Cancer Treat Rep t976; 60:959-960.

.—-.=

‘#% !
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I
with permission
the Copyright
illCe Center

~~~j~E PROTECTEOBy
I?IM MATERIALMAYBE “-”----+
QQPY61QHTLAW(TITLE17, U.S.CoBE)

Oncology321-10 (1975)

Use of Hydrazine Sulfate in Terminal and Preterminal Cancer


Patients: Results of Investigational New Drug (IND) Study in
84 Evaluable Patients

Joseph Gold
Syracuse Cancer Research Institue. Syracuse, N.Y.

Key Words. Hydrazine sulfate therapy in advanced cancer patients . Treatment of ad-
vanced human cancer with anti-gluconeogenic drugs . Interruption of cancer cachexia
as a means of cancer chemotherapy . Interruption of ghsconeogenesis as a means of
cancer chemotherapy
-.-—-
Abstract. in a series of 84 various evaluable disseminated cancer patients treated with
hydrazine sulfate as a result of a pharmaceutical-sponsored investigational new drug (IND)
study, it was found that 59/84 or 70 % of the cases improved subjectively and 14/84 or
17 % improved objectively. Subjective responses included increased appetite with either
weight gain or cessation of weight loss, increase in strength and improved performance
status and decrease in pain. Objective responses included measurable tumor regression,
disappearance of or decr~se in neoplastic-associated disorders and long-term (over 1 year)
‘stabilized condition’. Of the overall S9 subjective improvements 25 (42 $%)had no concur-
rent or prior (within 3 months) anticancer therapy of any type. Of the 14 objective im-
provements 7 (50 %) had no concurrent or prior anticancer therapy. Of the remaining cases
in which there was either concurrent or prior anticancer therapy, improvements occurred
ordy after the addition of hydrazine sulfate to the treatment regimen. Duration of improve
ment was variable, from temporary 10 long-term and continuing. Side effects were mild,
comprising for the most part low incidence of extremity paresthesia, nausea, pruritis and
drowsiness; there was no indication of bone marrow depression.

Hydrazine sulfate has been used as an investigational new drug (lND) for
over 1 year in the treatment of advanced cancer. Its proposed mechanism of
action is as a gluconeogenic blocking agent at the phosphoenolpyruvate carboxy-
kinase (PEP CK) reaction, attenuating host energy loss as a result of increased
giuconeogenesis in cancer and therefore interrupting the systemic cycle of tu-
mor-energy gain–host-energy loss (tumor growth-host cachexia) (1, 2). EarIy
reports indicated that hydrazine sulfate, administered orally to advanced cancer
patients, resulted in marked subjective and objective improvements (3), subjec-
tive improvements including increase in appetite, cessation of weight loss and/or
Gold 2

weight gain, improved performance status, and decrease in pain; objective imp-
rovements included measurable reduction in tumor size and reduction in or
disappearance of neoplastic-associated disorders (effusions, jaundice, etc.). Dura-
tion of improvements was reported as variable and side effects, minimal. In
further reports (4), in which hydrazine sulfate was used in conjunction with
conventional chemotherapy in patients with disseminated neoplasia, it was un-
clear as to which type of therapy resulted in the reported subjective and objec-
tive improvements. The present report, undertaken as a pharmaceutical-spon-
sored ND study and representing a series of 84 evrduable cam of various
terminal and preterrninal cancer patients, indicates a high degree of anticancer
activity in patients treated with hydrazine sulfate alone.

Procedures and Protocols

Physician selection, Thisstudy was the result of separate inputs of many clinicians -
oncologists as we[l as others - whose participation was under pharmaceutical lND sponsor-
ship. As such, this study is designated as ‘uncontrolled’.
Patient selection. Patients with any type of disseminated neopfasia, who no longer
responded to chemotherapy and/or radiation, were considered eligible for hydrazine suffate
therapy. A minimum prognosis of 2 months was recommended.
Drug and protocol. The drug consisted of 100 % purity hydrazine sulfate mixed with
an inert starch in capsular form (pharmaceutical [ND preparation) for oral administration.
Protocol of drug administration was as follows: 60 mg q.d. X 4; 60 mg b.i.d. X 4; then
60 mg t. l.d. as maintenance. In patients weighing less than SOkg, dosages were halved (i.e.,
30 mg q,d.X 4; 30 mg b.i.d. X 4; then30 mg t.i.d. ).[n theeventthata b.i.d. schedule
producedsatisfactoryresults,this dosageschedule was maintained at the clinician’s discre-
tion. In no event was a single dosage ever to exceed 60 mg.
Ccvrcwrerr/ anticancer medication. The continuing use of concurrent antieanee.r medi-
cation was acceptable if it was no longer producing a demonstrable anticancer effect by
itself.
Data presentation. A 4-sheet data page (’Patient Report Form’) was required to be
completed by the chnician during the course oftreatment ofeachpatient. These data sheets
included the following information: detailed history, site of tumor and metastasis, prior
treatments (defined in this study as any type of anticancer therapy given within 3 months of
the initiation of hydrazine sulfate therapy; prior treatment data included dates of therapy,
types and quantitation), concurrent medications, performance status evaluation, objective
tumor size and site evaluations, subjective observation ratings and check list, laboratory
data, clinician’s statement of patient evaluation prior to hydrazine sutfate therapy, cfini-
cian’s statement of evaluation of results of hydrazine sulfate therapy, clinician’s evaluation
ofsideeffects ofhydrazine sulfate
therapy, and cfinician’s
signature.
Criteria for designation as “improvement; Designation of subjective improvements was
made on the basis of improvements indicated in the subjective observations rating check list
and~or affirmation of Improvement in the clinic]an’s statement under ‘ctinician evaluation’
section. In general a subjective improvement was based on a quantitatively measurable or
estimable parameter such as strength (number of hoursambulatory, quafity ofambulation,
e{c.), appetite (food intake), weight (scale measurement) and pain (quantitative need for
analgesics). Objective improvements were designated on the basis of measurable reduction is’s

,,.
. .. . ,,. .
Hydrazine Sulfate Therapy in Advanced Cancer Patients 3

tumor size, long-term (1 year or more) ‘stabilued condition’ in a previously rapidly growing
neoplasm, and disappearance of or reduction in neoplastic-associa ted disorders. EachcaseM
., thiscategorywasto be supportedby relatedlaboratory’measurements,where possible.
.!Men”a @ desigrrakwsaa ‘nonevaluable ~ Cases were deleted from evaluation for any
of the following reasons: (a) inadequate prognosis: patient survival of less than 3 weeks;
(b) inadequate drug trial: dmg trial of 1%s than 3 weeks; (c) insuftlcient data submitted on
Patient Report Form: no evaluation possible, and (d) concurrent treatment with newly
initiated cytotoxic chemotherapy: patient response nonevaluable.

Results

( Of a total number of 158 cases submitted in the study, 84 were evahrable


and 74 nonevaluable. Of the evaluable cases 14 (17 %) were categorized as
,>* ‘objective (and subjective) improvement’, 45 (54 Yo)as ‘subjective improvement
<,
.!:, ..
only’, and 25 (30 ‘%0) as ‘no improvement’. The indicated overall improvement
.7.
‘,4
;.
,.
Table 1. Categorization of evaluable cases in Investigational New Drug study of hydra-
zine sulfate

Site and/or type Objective Subjective No Total


of primary tumor and improvement improvement cases
i
,- subjective Onfy
,r ..-. improvements
. ~f
.:,
,,, ,
[ ,. Brain (astro,glio) 2 0 0 2
Breast (afl) 2 6 2 10
& Colorectal-gastric 2 12 8 22
z.” GaUbladder 1 0 0 1
Hodgkins, stage IV o 0 2 2
Liver (primary) o 0 1 1
<5 Lung (all) 2 11 2 15
Melanoma o 1 2 3
Neurosarcoma (neck) o 1 0 1
t ~., ovary (all) 1 3 1 5
,,* 4 8
t.: Pancreas 1 3
~“ Primary unknown o 2 0 2
i: ● Prostate o 1 2 3
1
1 0 1
~$ ~;~ous cell (n~k) ~ 1 0 1
Tonsif (palatine) 1 0 0 1

. ..
.,. —..-. ----- -----

Gold 4

Table11 Nonevaluable cases: reasons for exclusion from evaluation

Inadequate prognosis Inadequate drug trial, Insufficient New concurrent Total


suMval time, weeks weeks on drug data cytotoxic cases
chemotherapy

O-1 1-2 2-3 0-1 1-2 2-3

11 11 9 8 6 11
I I I J

31 25 15 3 74

rate was 59/84 cases, or 70 Yo.Of the nonevaluable cases, 31 (42 %) were in-
cluded under ‘inadequate prognosis’, 25 (34%) under ‘inadequate drug trial’, 15
(20 %) under ‘insufficient data’, and 3 (4%) under ‘newly initiated cytotoxic
chemotherapy’. Categorization of evaluable and nonevahsable cases is given in
tables I and H, respectively.

improvements’
Improvements were noted in tumors from almost all of the 19 reported sites
of origin. No particular siteof origin or tumor type was ‘most susceptible’ to
hydrazine sulfate therapy, although the largest number of cases came from colo-
rectal and lung carcinoma, which reflects the general incidence of these diseases
irr the population. The duration of improvement was variable, being reported
from very temporary (1 week) to in excess of 1 year and continuing. It was
possible to obtain follow-up reports in only less than half of the improved cases.
Objech”veresponses. Of the 14 reported objective responses, 7 (50%)
showed measurable tumor regression; 2 of these were accompanied by a disap-
pearance of or reduction in neoplastic-associated disorders (effusions, jaundice,
etc.). An additional 2 (14 %) of the 14 cases were classified as longterm ‘stabi-
lized condition’, both of which represented preterminal lung cancers whose dis-
ease had been rapidly progressive prior to hydrazine sulfate therapy. They are
currently both alive and well 17 and 18 months after initiation of hydrazine
sulfate therapy, respectively; neither are on any kind of concurrent anticancer
therapy. The remainder of the 5 (36%) cases were classified as objective re-
sponses on the basis of amelioration of neoplastic-associated disorders, accom-
panied by marked subjective improvements. (In this regard all 14 cases showed
subjective improvements.) AN objective responses were also accompanied by
tumor-related laboratory improvements, where measured.
Subjective responses. A total of 45 cases displayed subjective improvements
only; this number, added to the foregoing 14 cases, gave a combined total of 59
subjectively improved CWS. 48 (81 ~C) of these showed an increase in appetite
Hydrazine Sulfate Therapy in Advanced Cancer Patients 5

Table [If. Response analysis in improved cases

No con- Concur- Concur- Concur- Concur- Prior Prior Prior Total


current rent rent rent rent cyto- steroid radia- cases
or prior ant i- steroid steroid steroid toxic therapy tion
anti- cancer therapy and and therapy therapy
cancer (incl. only prior prior
therapy cyto- cyro- radiation
toxic) toxic therapy
therapy therapy

Objective 7 3 1- 1 1 1 14 ,,
responses (50%) (21%) (7%) (7%) - (7 %) (7 %)

Subjective 18 17 5 1- 3 1 45
responses (40%) (38%) (11%) (2%) (7%) - (2%)

with either weight gain or a cessation of weight loss. 48 (81 %) showed an


improvement in performance status as measured by art increase in strength,
=-— hlation or both. And 21 (36 %) showed a decrease in pain as measured by a
.iinuted need for analgesics.
Ongoing concurrent (or prior) anticancer rhffap.v. Various of the improved
cases were treated with either steroids and/or cytotoxic chemotherapy and/or
radiation, prior to initiation of hydrazine sulfate therapy, as indicated in
table III. In all these cases the noted improvements occurred a~rer the addition
of hydrazine sulfate to the therapy. In regard to the objective responses 7 (5O %)
of the 14 cases were treated with hydrazine sulfate alone, without concurrent or
prior anticancer therapy of any type, while 7 (50%) of the cases did receive
concurrent or prior anticancer therapy. In the subjective-only responses, 18/45
or 40 YO of the cases were treated only with hydrazine sulfate, without concur-
rent or prior anticancer therapy, while 27 of the cases (60 Yo) did receive concur-
rent or prior anticancer therapy.

‘No Improvements’
Of the 25 ‘no improvement’ cases 2 (8 %) expired within 3–4 weeks after
hdtia}ion of hydrazine sulfate therapy; 2 (8 %) had very little information in
their Patient Report For-r-n so that actual categorization became difficult; 9
(36 %) had a d~g tri~ of only 3–4 weeks, and 14 (56%) had concurrent anti-
~cer therapy which consisted of cytotoxic drugs, radiation, steroids or combi-
nations thereof. In only .5 cases were these foregoing considerations not a factor,
i.e., the patient had ~ adequate prognosis and drug trial, had no concurrent or
prior arttic~cer therapy, and had sufficient information submitted on his Pa-
tient ReportFormto support a Categotiation of ‘no improvement’.
.$
..n&_-
.+
:=-
Gold 6

Nonevaiuable Cases
The general breakdown of categories of the 74 nonevaluable cases is given
above and in table II. Of a total of 31 of these cases excluded from evaluation
because of inadequate prognosis (survival time), 11 died within 1 week of initia-
tion of hydrazine sulfate therapy, 22 died within 2 weeks, and the full 31 died
within 3 weeks. Of a total of 25 additional cases excluded from evaluation for
reasons of inadequate drug trial, 8 were on drug for only 1 week or less, 14 were
on drug for 2 weeks or less, and the full 25 were on drug for 3 weeks or less.
Thus, of the 56 cases excluded from consideration for the foregoing two rea-
sons, 19 had a survival time or drug trial of 1 week or less, 36 had a survival time
or drug trial of 2 weeks or less, and the full number – 56 – had a survival time
or drug trial of 3 weeks or less.

Side Effects
Side effects were determined on the basis of evahrable cases only and were
in general mild. They comprised: extremiry paresthesia (5 %); this condition
was diminished or eliminated by a reduction of dosage and/or administration of
pyndoxine hydrochloride (vitamin B6) in excess of 25 mg daily; ?urus@ (4 %), in
most cases transient; nontransient nausea was eliminated by a reduction of dos-
age or withdrawal of medication for a period of several days, then reinstitution
of treatment at lower dosage levels; dry skin or trirnsienrpruri?is (3 %); ‘dizzi-
ness’ ( 1 %); ‘drowsiness’ ( 1 %); possible rhrorrrbophlebiris ( 1 %) (it was not
known whether this condition was drug-related). The total ewduable cases show-
ing side effects numbered 13/84 or an overall 15 %. There were no deaths
attributable to hydrazine sulfate therapy, either in the evaluable or in the non-
evaluable cases.

Discussion

It is important that a detailed analysis of a study of this nature include not


only the obviously improved cases as a result of hydrazine sulfate administra-
tion, but also the nonimproved and nonevaluable cases. Such factors as poor
patient and clinician selection as well as inadequate protocol planning, must be
assessed as to their quantitative contribution to the latter two categories.

Nonimproved and Nonevahurble Cuses


Lack of proper patient selection, via inadequate patient prognosis and inade-
quate drug trial, contributed heavily to the large number of nonevaluable and
nonimproved cases. Minimum protocol-recommended prognosis was 2 months,
yet as many as 3 1/74 or 42 % of the nonevaluable cases were so designated
because of a suMv~ time of 3 weeks or less, while in the nonimproved category
Hydrazine Sulfate Therapy in Advanwd Cancer Patients 7

2/25 or 8 % of the cases had a survival time of only 3–4 weeks. [n addition, as
many as 25/74 or 34 % of the nonevahsable cases were so designated because of
an inadequate drug trial (3 weeks or less), while 9/25 or 36 ‘ZOof the nonirn-
proved cases had a drug trial of only 3-4 weeks. Thus, in the nonevahsable
categoty the number of combined inadequate prognosis and inadequate drug
trial cases totaled 56/74 or 76 %, while in the nonimproved category the number
of combined cases of ‘borderline-acceptable’ survival time and drug trial
(3–4 weeks) totaled 11/25 or 44 ‘%. Such large percentages, representing inade-
quate prognosis and inadequate drug trial, must be attributed chiefly to improp-
er patient selection and not to the occasional misevahsations which arise in any
study.
Lack of proper clinician selection was also an apparent factor in this study,
manifest chiefly in those cases in which too little information was submitted. In
Gold 8

and 40 % (18/45) of the subjective-only responses were also the result of hydra-
zine sulfate therapy alone. This constitutes strong pn”r.nafac%e evidence indica-
ting hydrazine sulfate to be a clinically active anticancer agent in itself. It is
important to remember that even in those cases which received concurrent or
prior anticancer therapy, the noted improvements occurred only afrer the addi-
tion of hydrazine sulfate to the treatment regimen. Thus, whether as a sole agent
or in combination with other agents, administration of hydrazirre sulfate to
advanced cancer patients is linked to marked anticancer responses.
Moreover, hydrazirre sulfate is apparently not a ‘tumor-specific’ agent, as
can be seen from table I. Virtually all types of cancer – especially those which
ultimately promote a degree of host cachexia – are apparently susceptible to its
actions. Reports, in addition to those of this study, which have reached this
laboratory, indicate that the spectrum of disease beneficially affected by hydra-
zine sulfate extends to cancers arising from all organ systems and/or tissues in
the body. The most dramatic responses reported to date have been those with
primary lung neoplasms, although this observation may prove to be premature as
more and earlier cases are reported.
T%e duration of improvement has been unpredictable, but has generally
been longer in those cases responding objectively (as well as subjectively). Some
of the responses have been of very short duration. But others have been quite
lengthy. To date three cases in this study – two primary lung and one ovarian –
are alive 17, 18 and 21 months after institution of hydrazine sulfate therapy
alone, respectively; all three were previously considered terminal or preterminal.
Preliminary indications suggest that the improvements brought about hy hydra-
zine sulfate therapy – whether objective or subjective – have been accompanied
by extension in survival time and that the quality of this survival time was high:
patients who had obtained objective response and/or increased appetite, strength
and decreased pain as a result of hydrazine sulfate therapy, were reported to
have been restored to a more positive orientation toward living.
The duration of improvement may also be related to the degree of advance-
ment of the disease. The patients in this study were in general in the very latest
stages of disease, yet there were many improvements, some of which were
marked. However, it is generally regarded that any modality of anticancer thera-
py has its best chances of success when used early in the course of disease.And
this is probably true of hydrazine sulfate. There would seemingly be no disad-
vantage in instituting hydrazine sulfate therapy early in the course of disease,
especially in those cases where the ultimate clinical course is virtually unaffected
by any known therapeutic modality. Moreover, since the toxicity of hydrazine
sulfate is apparently of a low order of magnitude, unlike many of the cytotoxic
drugs whose ‘side effects’ can produce extreme patient discomfort and death, it
would seem prudent to investigate the effect of this drug on early patients,
rather than use it at the very last stages as a ‘resurrective’ type of therapy. If

,;+~
!
.’,

Hydrazine Sulfate Therapy in Advanced Cancer Patients 9

positive responses can be obtained in terminal patients – as indicated in this


study – it seems only reasonable that a greater degree of positive response could
6e expected in early patients, as is the case with many other anticancer modali-
ties.

Side Effects
The side effects of hydrazine sulfate are indeed of a very minor nature as
reported in this study, with the possible exception of ‘torpidity’ or ‘drowsiness’
which had less than a 1 % incidence and occurred only in very advanced bedrid-
den csse(s). The most frequent side effect, occurring usually after the 6th week
of therapy, appears to be the development of mild extremity paresthesias, partic-
ularly of the fingers and toes. This condition reportedly can be diminished or
eliminated by dosage reduction and/or addition of vitamin Bd (in excess of
References
#y
.
I
h
“, 0ncology32: 11–20 (19751
1 Gold, J..’ Cancer cachexia and gluconeogenesis. Ann. N.Y. Acad. Sci. 230: 103-110 %
(1974). ,$j;
2 Go[d, J.: Inhibition
ofgluconeogenesis at the phosphoenolpymvate carboxykinase and ‘;y
$
pyruvate carboxylase reactions, as a means of cancer chemotherapy. Oncology 29: “,
74-89 (1974).
$.-:
3 Gold, J.: Use of hydrazine in advanced cancer patients: preliminary results.
sulfate “r: Primary C<ell Hyper
Proc. Am. Ass. Cancer Res.15:83 (1974). ,
4 Strum, S.B.; Bierrnan, H.R., and Thompson, R.: Hydrazine sulfate in patients with &.
neoplasia. Proc. Am. ASS Cancer Res 16:243 (1975).

Joseph Gold, Syracuse Cancer Research Institute Inc., Presidential Plaza, 600 East Genesee
Street, Syrocuse, NY 13202 (USA)
A. INGREDIENT NAME:

METRONIDAZOLE BENZOAT E

B. Chemical Name:

5-nitro- lH-imidazol-l-ylethyl benzoate

c. Common Name:

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:

Assay: 99.54% calculatedas dried basis

E. Information about how the ingredient is supplied:



White or slightlyyellowish,crystallinepowder

F. Information about recognition of the substance in foreign


pharmacopoeias:

The IndianPharmacopoeiaVolumeI (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
Periodontal, 1995; 22(3): 185-187.

H. Information about dosage forms used:

Suspension

I. Information about strength:

400mg- 3 times daily, for 5-10 days


.—.

J. Information about route of administration:

Topically

K Stability data:

Melts at about 99-102°


Keep container tightly closed

L. Formulations:

M. Miscellaneous Information:

Page -2-
.——. ——— —-. ___ ... _-_—b-_.: — —
-— .. ..... . . .. .,._ ..-. -- —- :.. .= .- . -.. .-. .—— .. .—-
. ..._.— _. .._,
.-. ---
.. ..-.... .E,~& ~.- -=-=-=.-. —— --
-——.
. ._ L.-. Q _-_z _______
A- —–.a —. , ——
-.Z :______ —- +==..=- .——-.e_-_—
—- r
. ..-

. . _ .- .._. ,,.. -- —-- --- ___ _ ...——

Milan, llth December 1997


_.——=
2 x 25-kg drums

.
J

Manuf. date : July 1997

ANALYSIS CERTIFICATE ..... ......N.O.............3.2.4.3...............................................

Your Oral. No. .........of .....t.h.e ....l..O.t..h .....D.e.c.........l..g.9.?............ Our Ref. No . ............?..?.. ?.....

.. Quantity Batch
MATERIAL M,ETRONIDAZ,OLE,,,
B,EN,ZOATE B.P.
.

. .....rn.icz.o n.. zed . .. ... ....... ..... . ... ....... ................ .... .... ............................... KG 50 ..........
. .... .............. - 0712 . ......

Empirical formula ... ........ ...... .... .

Molecular weight .

Aspect ,....... .... .. ......?owder..crg.n


i?.ed... ?owder

_— Color ..,.,, ,....slig. ...ye..llow..ish,..

Odor

Taste Residue on ignition ...0.03?8%


%

Melting point ,.,...,..,,..?.9.,..


- ....!02...C
\. ..O ................. Chloride . ........... ....... .... .. ..... .. .. .. .. . . .

Boiling range . Sulfate ................................................ ..................... ....... .


/’
Volubility.. practically insoluble ..inwater; Heavy metals, .......E.e.SS..Nan 20 PPm
freely.soluble in Dichloromethone; soluble
iII Acetone ............ “ Identification ......... A) Melti.ng............9.
%..-...
102°C
B) complies
... . . .. .. . ... .. . .. .. c)"``
"-"""
"""'"'"`""``""""""""""`
D) Related substances pa
pH .....(acty).ty). 0.09 .~ ... ........... ... .
E) te

0’ Titer (Assay) 99.54% calculated as dried basi.sc

Other requirements, notes Results ,.of test or ...analysis


. ... .. . as per . B.P.
.
L...
. . . ....
-. . ...
.. . . .. . .. ..

_——.= /
/’

,/
/’
QUALI~ CONTROL REPORT

CHEMICAL NAME.:METRONIDAZOLE BENZOATE POWDER

MANUFACTURE LOT NO. :0712

PHYSICAL TEST

SPECIFICATION TEST STANDARD. .. ugP_/BP_/MERCK_/NF_/MART . _/Co . SpECS . _“

l)DESCRIPTION .:
WHITE OR SLIGHTLY CREAM TO YELLOWISH, CRYSTALLINE POWDER OR FLAKES.

2)SOLUBILITY .:
VERY SOLUBLE IN CHLOROFORM,ALCOHOL;SOLUBLE IN ETHER,INSOLUBLE
IN WATER.

- —.
-— 3)MELTING POINT.:
MELTS AT ABOUT 99-102 degree. K

4)SPECIFIC GRAyITY. :

5)IDENTIFICATION .:
A)COMPLIES BY IR SPECTRUM AS PER COMPANYSPECS.
B)A SOLUTION PH IS 5.8.

PASSES. : FAILS .:

COMMENTS .:

ANALYST SIGNATURE.: DATE .:

PREPACK TEST.: DATE. : INITIAL. :

RETEST .: DATE .: INITIAL. :

_-—-..

.
30/04 ’98 15:58 FAX 0039 2 6693128 TC @lo2

1/4

——__

MATEItLIU SAFETY DATA SHEET


J ● cHEMraL l?Ranuc!T mENTn?IcAz!mN

Product name : MRITK)NIDAZC)LK13 ENZOATE-


Chendcdztune : MMtluoylmytdgdM=Inethy-1-h.mru hmazolc
Emp. Formula ‘ CIJ-wP, “ 2753

2. COHIWWZKW i ~Z’!Kllf ax nv~

Chmniul name us w EINEcs XV Symbol %


l-Q~Yl==@w- 69196-W3 Xn 99%
imhkole

a mizARv mEmm!cAl%Qlv \

Effect(s) of iove.thmpsum May cause Miaiion m mapkatxaf’y appamtua.

Symptoms of (ovar)exposure
Inhalation : not availnble
skin : notavailable
Eyes s not avdlable

4. lmusz’Am&EA8t?RE8
Inhaiaiioxu Kffecta A4kyh irritating.
Fimt aid Remove victim to fresh h. ~p victim at rest consult a doctor.

skim Efhcb May ba irrkidng.


F- aid Remove ctmadned c.bthing, WMh off witi plenty pf water and
noap, Consult a doctor.

EyelE Effect$ May be initating.


Fir$t aid Wash out with plenty of water, Cmsult a doctor.

Inge8tiozi: Effecti LDm 1,050 mg/Kg


Fket aid Wushout mouth with water. CcInault a doctor-

30/04 ’98 15:47 NR. TX/Rx 4143 Po 1

fIPR 313 ’98 D9:23 EIE1392 6693128 PFIGE. EU2


30/04 ’98 15:58 FAX 0039 2 6693128 TC @lo3

Product ruun= METROhlIDAZC)LE BENZOAT’E Fa$e 2 of 4

—_
a. nRE PYGHTUVG MEASUWES
f
7
Extiqpishing measures

..
II Suitable Water spray, COW Wun, &v chemical
II

Not be uswd :

Hazardous thermal : CO, CO,, NOX


decomposition and
combustion products

I?wWfive ●quipfuat : Self=contaimd breathing apparatus. FuJIprotective clothing.

6, AC!CmENZXL RELEAaE MEASURES

Personal precautions : Wear suitable protective cloth.hg. When wing do not eat,
drink OY srmkit.

II Environmental precautions : Not available, II

- I
Ck4ng proc.dum

See section8 and 13


: COUsctspilled materM. a~= up affeckd area* water.

1]
I
7, IUNDLLNG ANV &2131UQE

Hadting : Ventibtion recommended. When iuh-ig do mot eat, &ii or smoke.

StO&e : Keep mnlai.mas tightly closed -K

8. EXPOSURE C!4)NTROLSI / PXW3NAL PRC)T~ION

Reepiratoxy protection : Airlrned respirator or dust mask, type El

Rubber
II l-kid protectirm : $bWS.

II Eye protection

skin protection
:

:
Safety goggles or face shield.

Working clothing.
\

30/’04 ’98 15:47 NR. Tx/ru 4143 Po2

RPR 3L3‘98 09:24 0039 2 6693128 PRGE. EIE13


30!04 ’98 15:58 FAX 0039 2 6693128 TC !i?Jo4

Prodmct name: METRONIDAZOLEBM4TZC3ATE Page 3 of &

—–.

Appearance ; ay6talline pow&r Vapour premsre : Not available


COIOU.T : White tc) yellowish-white Vapmr deneity : Not avaiIable
Odour $ Odourlew Fhh point : Not available
hlo~~~ poht : 99°- 1113°~ Autoignition : Not available
)3dUIl$ point : Not available Flammability : Not flammabhi ,
Relative dansity : Not avadabla 13xploaive properties: Not avdabIe
Bulk (kr@ty : Not available Upper limit : - I
Soh.biZify in water ; 0.5% at ZO°C Lowsr limit : -
pH x Not avajkbfe Viscosity : Not available
Partition coeffkient I Not avadable Conductivity : Not available

10. ST4XlmzlmY4m RmmTmmY


Conditions to avoid : -
Materials to ●void : CM&zing agents
Hazardrm.a decomposition : NOx
pmwhwta

–-
1 I , eCOZOtWCAL JIWWWAmOIV
Acute tOXiCity
oral .. Not available
JMt’m.d : Not available
Xllllalatioxl : May be irritating
Eye irritation : May be imtating
Skin hitatiOn x My be untatlng
CM&z Mformation : Not available
1

1
12. ECOLOGICAL IIWW?XATION

Mobility : Not available

Persistixtce and : Not available


degradability
Bioaccumulative : Not available
pot’emtlal
I%otoxicity : Not avaflabIe
b-

30/04 “98 15:47 m, TX/Rx 4143 P03

9PR 312 ’98 09:24 0039 2 6693128 PmE . EW14


30/04 ’98 15:58 FAX 0039 2 6693128 TC k?Jo5

Product name: METROIVIDAZO1.E IIENZOATE page 4 Of 4

,
—.-
13. DISPCMALCCXVamERAT19JVS
[

-IL
Methods of dispodl : Combustion in an i.rdxwrator for chemical wa6te.

Danger(s) : Not available

II 14. 17tAJVSl%lRT llVFORdOITWIV 1

Speciai precautions :

Classification
UN Coda : Packaging group :
ADIUILH) : ICAO/I.ATA :
IMO :
)

15. REGULATORY INFORMATION

liC Classification

Contaitla: l-(2&mzoylogefiyl~2-chyl-5-fitio imidazole

.—=. Syrr’tklol: %

IWlk phrases: 20/22

Safety phra6es: 2


16. OTHER lNFORMM70N

The information contained in this 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 of we are beyond cur control.

Furthermore, nothing contained herein shall be construed as a recommendation to use


any product in conflict with existing patents covering any materia[ or its use.
, 4

Issued on January 1995

. . .. .
_@==

30/04 “98 15:47 N-R. TX/Rx 4143 P04

RPR 3~ ‘ 98 Ei9:24 0039 2 6693128 PwiE. m5


Storage Store in a well-closed container, protected from 100 ml with lM hydnxhlkc ad. Examined benveen
light. 220 nm and 350 nm, Appendix II B, the solution shows
Preparation. nvo absorption maxima, at 232 nm and 275 nm. The
specijic aluorbunce at the maximum at 232 nm is 525 to
Methylprednisolone Acetate Injection
575.
Action and uae Corticosteroid. C. Examine by infiand absmpnbn spectmphawmeny,
.-
1/95 Appendix ~ A. The absorption maxima in the spectrum
obtained with the substance being ex.amined correspond
in position and relative intensity to those in the specnum
obtained with metmndz ok benzoate EIW?.S.
MetoprololTartrate D. Examine the chromatograms obtained in the test for
Related substances under ukoiokt light (254 rim). The
IdentMcation Test A. Iine 4. For’ 18°’ read ‘-180’. principal spot in the chromatogram obtained with solution
(2) is similar in posiaon and size to the principal spot in
Line 6. Afkr ‘residue’ insert ‘, Appendix II A’.
the chromatogram obtained with solution (3).
12/93 E. To about 10 mg add about 10 mg of n“nc powder, 1 ml
of water and 0.3 ml of hydnxti ad. Heat on a water
Heavy meta.b Line 2. For’1 ml’ read ’10 ml’. batb for 5 minutes and COOLThe solution yields the
7/94 reaction characteristic of pninay ammaric amikes,
Appendix VI.
Add the following statement.
Appearance of solution Dissolve 1 g in &nerhyvown-
Frepasationa ml with the same solvent. The
annde and dilute to 10
Metoprolol Injection solution is not more opalescent than rz&wtce qwnstbn 11,
Metoprolol Tarrrate Tablets Appendix IV A, and not more intensely coloured than
refervna soktion G~, Appendix IV B, Method II.
Acidity Dissolve 2 gin a mixture of 20 ml of &nethyl-
“ and 20 ml of water, previously neutralised with
Metronidazole f~
0.02Ai hydrvchicnic ad VS or 0.02M socbn hydmde VS
using 0.2 ml of methyl mdsoiunbn. Not more than 0.25 ml
Add a five-poimed star (*) to the title.
of 0.02M sodium ~dmxde ~ is required to change the
7/94 colour of the indicator.
Preparadona Add the followin~ Related substances Examine by thin-layer chmmaro-
Metroniclazole Intravenous Infusion graphy, Appendix III& using silica gel HFZH as the
_=—_. J?t coating substance. Heat the plate at 110° for1 hour and
allowto coolbeforeuse.
~ (1) Dissolve 0.20 g of the substance being
examined in aczwn.e and dilute to 10 ml with the same
solvent.
Solution (2) Dilute 1 ml of soluuon (1) to 10 nd wirh
acewnt.
Soti (3) Dissolve 20 mg of metronidazoie benzoare
EZ%XS in acewne and dilute [o 10 ml with the same
solvent.
Sohuion (4)Dilute 5 ml of solution (2) to 100 ml with
acew?le.
Sohuim (5) Dilute 2 ml of solution (2) to 100 ml with
acewne.
Sokrion (6) Dissolve 10 mg of metrvmdazok EK7RS in
C13H13N30q 275.3 13182-89-3 acetoneand dilute to 100 ml with the same solvenr.
De~tion Memonidazole Benmare contains not less Solution (7) Dissolve 10 mg of 2-methyI-5-ninwimiiazok in
than 98.5°A and not more than 101.0?/. of 2-(2-uLgt&+_ aczwne and dilute to 100 ml with the same solvent.
.5-nitxw MKmidazol- I-ylethyl benzoate, C13H13N~Oq, Soktim (8) Dissolve 10 mg of metroniah.zole EFCRS and
calculated with reference to tie dried substance. 10 mg of 2-tmx.hyl-5-nitrvirmdazok in acetone and dilute to
50 ml with the same solvent.
Charactdatics~:_or slitirJyyellowiahLq~ine
.— Apply separately to the plate 10 pl of each solution.
powder or flakes; practxally insoluble in w-, k~~” Develop over a path of 15 cm using ethyl acerae. Allow the
6 -e in aichbmmdmw , soluble in aceron.q slightly plate to dry in air and exaxnine under uitrawioktlighr
soluble in erhnol (96%); very slightly soluble in ether. Q54 nm). In the chromatogratn obtained with solution
Identification Idennj@nim test C may be omitted if (1) any spot corresponding to metronidazoie or 2-methyl-
dennj5carim tzsts A, B, Dand Earecanied~ I&nnj%z- 5-nitroimidazole is nor more intense than the correspond-
riontesu B, Dand Emaybeomitrd tf@n@ca&n r.esrsA ing spot in the chromatograms obtained with solutions <6)
and Carecamkiour. and (7) respectively (O.5°/0). Any other secondy spa is
.-. A. Making ~“~ 99° to 102”, Appendix V & Method 1. not more intensethan thesporinthechromarogram
B. Dissolve 0.1 g in lM hy&octi acid and dilute to obtainedwithsolution(4)(0.50/o) andat most one such
100 ml with the same acid. Dilute 1 ml of the solution to spotismore intensethanthesporinthe chromatogram
...
Loss on drying : Not more than 0.5 percent, determined zole, transfer to a sintered-glass crucible and extract with
on 1.0 g by drying in an oven at 105°, Appendix 5.8. six quantities, each of 10 ml, of hot acetone. Cool, add m
the combined extraets 50 ml of acetic arzbydn”de,0.1 ml
Assay : Weigh accurately about 0.45 g and dissolve in 10
ml of glacial acetic add, add a few drops of l-naphtbol- of a 1 per cent w/v solution of bn’iliantgreenin glacial .’
ben~ein solution and titrate wim 0.1 N percbloric qcid acetic acid and titrate with 0.1 Npercblotic acid to a yel-
until a pale-green colour is produced. Perform a blank de- lowish-green end-point. Perform a blank determination
termination and make any necessary correction. Each ml and make any necessary correction. Each ml of 0.1 N
of 0.1 N pemblonc acid is equivalent to 0.01712 g of percblotic acid isequivalent to 0.0 1712g of Q-IN$C)3.
c&&Joy Storage: Store in well-closed, light-resistant con-
.:.,’
Storage : Store in well-cksed light-resistant con- tainers. .
tainers.
.

1- .;
{.
.~,,
Metronidazole Benzoate ;;
-.
.,.
Metronid.azole Tablets Benzoyl Metronidazole
‘“i
Category: Anti-amoebic; antitrichomonal; anti- ~
CH2CH200CC#5
giardial. ~.,,
,

Dose : Metronidazole. For trichomoniasis, 200 mg .“{


three times daily, for 7 days.
For amoebiasis, 400 mg three times daily, for 8to .,
‘$
..&

10 days.
For giardiasis, 2 g daily for three successive days
C,3H,3N30+
Category : Am.i-amoebic.
~01. Wt. 27.5.27
1
>
.
.
.’,’
for adults, 1 g daily for children and 400 mgdailyfor 1
infants. Dose: For amoebic dyse~tty, the equiwdent of 400 ~$
mg of rnetronidazde three times, daily, for 5 to 10 G .$
Usual strengths: 200 mg; 400 mg, ‘.%
um. , >$
‘-
Standa.rcls: Metrotddazole Tablets contain nQt less NOTE –200 rng . b“
than 95.0 per cent and not more than 105.0 per cent mately equivalent to 125m metmnidazoie. -.;
t .,.,4
of the stated amount of Metronidazole, CJ-1~505. ~i ,,.
Description: White or cream-coloured crystalline “:~
The tablets may be coated. -,.
.#
powder, ociourles; almost tasteless.
I~.
kkntifkation : (A) Shake a quantity of the powdered
Solubillty: Sparingly soluble in wazer; soluble in
tablets equivalent of Metronidazole with 4
to about 0.2 g
ml of N stdpbtinc acid and filter. To the filtrate add 10 ml Chir)@~, in acetone, and @ ~CObO[ @Oper cent).

ofpicn’c acidsolufion and alow to stand for one hour, the Standards : Metrohidazole Benzoate is 2-(2-me-
precipitate after washing with cold water under suction thyl-5-nitro-imidazol- l:yl) ethyl benzoate. It con-
and drying at 10Y melts at about 15(Y, Appendix S. 11. tains not less than 98.0 per cent of C13H,3N304, cal-
(B) Comply with Xdentifbtion test(B) describeci a- culated with reference to the dried substance.
der Metronidazole, using a quantity of the powdered tab.
Identification : (A) The light absorption, in the range ~

I
lets equivalent to 10 mg of Merzonidazole.
230 to 530 nm ofa l-cm laverofa 0.001 percent w/vsOlu- $
2-Methyl-5-nitroimidaznle : &mply with the test des- tion in etlyl alcoboiexhibi~ a maximum only at 30$1 nm; ~
cribed under Metronidazole, using as solution (1), a solu- extinction at 309 nm, about 0.3, Appendix 5.15A.
tion prepared in the foUowing manner: Shake a quantity “:i
of the powdered tablets equivalent to 0.2 g of Metronida- (B) It gives the reactions of benzoutes, Appendix 3.1. ;
zole with 5 ml of mixture of equal volumes of cbiomfonn Melting range : Between 100” and 102°, Appendix 5.11. ~,
and metby[ aicobol for five minutes and filter. The chro- pH : Between 5.0 and 7.0, determined in a 2.o per cent ‘+
marogram obtained with solution (1) may also show w/v suspension, Appendix 5.10. 7
1“.
spots due to excipients. .
Free benzoic add : Not more than 0.2 per cent, deter- ,,J.
Other requirements : Comply with the requirements mined by the following method: Dissolve 0.50 g in 2.5 ml ;
stated under Tablets, 1
of aicoboi and titrate with O.I N sodium hydroxide. using G
Assay : Weigh and powder 20 tablets. Weigh accurately a pbenoi redsoiution as indicator. Perform a blank determi- .j
quantity of the powder equivalent to 0.2 g of ?4ecronida- nation and make any necessary correction. Ezch ml of ‘~
$
320 $
MORPHINE HYDROCHLORIDE

0.1 N sodfwn bydmxide is equivalent to 0,01221 g of Stan&i&: Morphine Hydrochloride is the trihyd-
C7H502. rate of the hydrochloride of 7,8-didehydro-4,5a -
Related substances : Carryout the method for tbin- epoxy- 17-methylmorphinan-3 ,6a-diol, which may
kyer cbromutogrrzpby, Appendix s,4.3, using siliGa gel be obtained from opium. It contains not Iess than
HF 254 as the coating substance and a mixture of 8 98.0 per cent and not more than the equivalent of
volumes of chloroform and 2 volumes of acetorwasthe 100.5 per cent of C,71-I,JJ05,HC1,calculated with re-
mobile phase. Apply separately to the plate 10 pi of each of ference to the dried substance.
three solutions in a mixntre of equal volumes of methyl
alcohol and cbkm~onn containing (1) 6,0 per. cent Wiv Idendtkation : (A) Sprinkle a small quantity in powder
of the substance being examined; (2) 0.02 ~r cent w/v of form on the surface of a drop of nitric acid; an orange. red
2-rrtetbyL5-nitrvimialzzdle R.S. and; (3) 0.02 per cent colour is produced.
w/v of metn?niahzdeR.S. Afterremoval ot’ the plxe, (B) To a 2 per cent w/v solution add pofawiwn~eti-
allow the solvent to evaporate and examine under an qwnide solution containing I drop per ml offenic cb[o-
ultra-vioiet lamp having a maximum output at about 254 n“a%tes~-sofurion: m immcdixe bluish.grccri colour k
nm, The spots in the chromatogram obtained with produced (distinction horn codeine).
solutions (2) and (3) are more intense than any
(C) Add 5 ml of .w@urfc acid to 5 mg in a test tube,
corresponding spots in the chromatogramobtained with
and add 1 drop of fem”c cbl(jn”de tesi .YIJ(ItfL’fJH. and hrJt
solution (1),
in boiling water for two minutes; a deep blue colour is pro-
Sulphated ash: FJOC more than 0.1 per cent, Appendix duced. Add a drop of nitric acid; the colour changes to
3.2.7. dark red-brown (codeine and ethylmorphine give the
Loss on drying: Not morethan 0.5 percent, determined same colour reacrions, but dihydromorphinc and
on 1.0 g by chying “in vaeuo at 60”,” Appendix5.8. papaverine do not produce this colour change).
Assay : Weigh accurately about 0.5 g and dissolve in 50 (D) Add to about 1 mg of the powdered substance in a
ml of acetone. Add 10 ml of acetic anbydn’ak arid titrate porcelain dish 0.5 ml of sulpbutic acid containing 1drop
with 0.1 Npercblo?ic acidu.sing brilliant green solution of fonnalukbyde solution. A purple colour is formed
as indicator. Perform a blank determination and make any which turns to violet.
necessary correction. Each ml of 0.1 N percblon”c acid is (E) D~solve about 5 mg in 5 ml of water, and add 1 ml
equivalent to 0.02753 g of C,.}H,5Nj04. of hydrogen peroxide solution, 1 ml of dilute ammonia
Storage : Store in well-closed, light-resistant con- solution ‘and 1 drop of a 4 per cent W:Vsolution of copper
tainers. sulpbate.A transient red colour develops.
(F) Asolution (1 in 20) gives the reactions of chlorides,
Appendm 3.1.

Addityor AlkAnity : Dissolve 0.2 g in 10 ml of fleshly


boiled and cooled water add 1 drop of methyl red sofu-
Morphine Hydrochloride tion. Not more than either 0.2 ml of 0.02N sodium bydr-
oxr’a%or of 0.02N bydmcbio?ic acid is required to change
Ho the colour of the solution.

1; Sped.flc optical rotation: Between -112° and -115”,


calculated with reference to the dried substance and deter-
mined in a 2 per cent w/v solution, Appendix 5.12.
o\ H+
.\
-ordum wits : Heat 0.2 g with sodium bydmxide
NHCH3 Cl-, 3 H20 solution on a water-bath fcr one minute; no odour of
f ammonia is perceptible.
iii
HO’” Othefallcdoids : Not more than 1.5 percent, calculated
with reference to the dried substance, determined by the
C,7H,~O~, HCI,3H20 hfo~. Wt. 375.85 following method: Transfer 0.5 g co a separator, add 15 ml
Category: Narcotic, analgesic. of u’uter, 5 ml of ,Vsodium b~’dmxide, and 10 ml of
chlomfonn. shake. allow ro separate, and transfer rhc
Dose: 10 to 20 mg. chloroform solution to another separwor. Repeat the
Description: Colorless, glistening needles or extraction with WO further quantities, each. of 10 ml,
white crystalline powder; odourless; tzuxe,bitter. of cbforojomn. Wash the mixed chk.xoform solutions
with 10 ml of 0.1 N sodium hydroxide and then with two
Volubility: Soluble in water; sparingly soluble in successfie quantities, each of 5 ml, of water, evaporate to
alcohol; practically insoluble in sohent eth-and in dryness on a water-bath, and dry the residue to constant
cldomfm, soluble inglycen’n. weight at 105’.
321
la
TITLE: Elimination of Elyzol 25% Dentalgel matrix from periodontal pockets.
AUTHOR Stoltze K
AUTHOR Department of Periodontology, School of Dentistry, Faculty of Health
AFFILIATION: Sciences, University of Copenhagen, Denmark
SOURCE: J Clin Periodontal 1995 Mafi22(3):185-7
NLM CIT. ID: 95310528
u
ABSTRACT: Elyzo 25?40Dentalgel (E ) which is devel@ed for use in tk.lreat ment of
&fiodontitis ~ei a sus e sion of metronidazole benzoate ——...
(400A) in .—.
a mixture
of glyceryl mono-o eate (GMO) and triglyceride (sesame oil). Metron~iikole
~eriodon@lFockets
can be de ——24-36 h——-—
afte licsj$j.au. The
aim of the present study was to estirn-a~ethe period of t=hat 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.
MAIN MESH Glycerides/ADMINISTRATION &
SUBJECTS: DOSAGEIANALYSISI* PHARMACOKINETICS
Metronidazole/* ANALOGS & DERIVATIVEWADMINISTRATION &
DOSAGE/ ANALYSIS/* PHARMACOKINETICS
Periodontal Pocket/* METABOLISM
.~. Sesame Oil/ADMINISTRATION &
DOSAGE/ANALYSIS/* PHARMACOKINETICS

1 of2 5/5/98 12:48 PM


—_

PEN’T~E NE TET RAZOLE

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, Cardiotonicurq Cardosal, Cordosaq Cenalene-M, Cenazol, Centrazole, Cerebro-
Nlciq Coranormal, Coranorrnol, Corasol, Coratoline, Corazol, Corazole, Corazole
(Analeptic) Corisaq Corsedrol, Cortis, Corvasol, Corvis, Coryvet.

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:
(Minimum) (Resusltj
— Assay 98% 99.80%

E. Information about how the ingredient is supplied:

White crystals, slightly pungent and bitter, ve~ stable, not easily attacked by other
substances.

F. [formation 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:

Ju~ H. W. Absorption and Fate. J l%mn. Sci., 1975;64: 1843.

Khazi, I. A., Mahajanshetti, C. S,, and Gadad A. K. Pentylene tetrazole induced


_—_
convulsions. Arzneimitte~orschung, 1996;46(1 0):949-952.
--——..
Erol, D. D., Calis, U., and Demirdamar, R. Pentylene tetrazole-induced seizures in mice.
L Pharm. Sci. 1995; 84(4):462-465

H. Information about dosage forms used:

Orally
Injection

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:

Leptazol is a sterile solution of pentetrazol 10% and sodium phosphate 0.25’XO in water for
injections, adjusted to pH 7.8 with dilute hydrochloric acid or potassium hydroxide
solution.

M. Miscellaneous Information:

_——_

Page -2-
Page 1
PRODUCT: PENTYLENmH~OLE -
-. k
..
— . .-

CATALOG No: PEI 04 **
LOT NO: MJ0251

DESCRIPTION
.. . LIMIT -’
RE5ULT
MIN. MAX.

D“”....
ASSAY’
.. =. --+,—_— :-_
--- . ----- .. ..—_
;....._ .. ..— .. . .. .. . .- .. 99.80 %
“. .. MELTING RANGE .
59-61C 59- 61C

,
. .
.. -

-.

-.
.:-.
. ““1
_....__.
--’v.

.—----
.’ .,. . .. ,. .. . . . . .
. .

—.. - ---
. . —..
. ... . .- . .. .

... ------- ---


.. ..- -=i-
-+-%-. . .. ~

j +
9 &“ /
.6 ‘. APPROVED BY:
-., QUALITY CONTROL REPORT

CHEMICAL NAME.: PENTYLENETETRAZOLE

MANUFACTURELOT NO. :MJ0251

PHYSICAL TEST

SPECIFICATION TEST STANDARD. “. USP


——/BP /NiERCK— /NF_/MART._/co.sPEcs._.

l)DESCRIPTION .:
NOT EASILY
Fj WHITE CRYSTALS, SLIGHTLY PUNGENT AND BITTER; VERY STABLE,
ATTACKED BY OTHER SUBSTANCES.

2)SOLUBILITY .:
FREELY SOLUBLE IN WATER AND IN MOST ORGANIC SOLVENTS. SLIGHTLY SOLUBLE
IN ALCOHOL,

3)MELTING POINT.:
.~. MELTS AT ABOUT 57-60 DEGREES.
-k -

4)SPECIFIC GR+VITY. :

5)IDENTIFICATION .:

PASSES .: FAILS. :

COMMENTS.:

ANALYST SIGNATURE. : DATE .

PREPACK TEST.: DATE. : INITIAL. :

RETEST. : DATE. : INITIAL. :

_=—=

..
_—.
------------------ IDENTIFICATION ------------------
PRODUCT #: P720-7 NAME: 1,5-PENTAMETHYLENETETRAZOLE, 98?40
CAS #: 54-95-5
MF: C6H1ON4
SYNONYMS
. ... .—..... * ANGIOTON* ANGIOTONIN* CARDL4ZOL* CARDIAZOLE*
ANGIAZOL
CARDIFORTAN* CARDIOL* CARDIOTONICIJM* c~os~, * ~~os AN*
f

CORANORMOL* CORASOL* CORATOLINE* COR4ZOL * CORAZOLE*

(ANALEPTIC)* CORISAN* CORSEDROL* CORTIS * CORVASOL* CC!R.YIZI


CORYVET* ALP~BETA-CYCLOPENTAMETHYLENETETRAZOLE*
DEAMOCARD*
DELZOL-W* DIOVASCOLE* DEUMACARD* GEWAZOL* KARDIAZOL*
KORAZOL*
KOR4ZOLE * LEPAZOL* LEPTAZOL* LEPTAZOLE* METRAZOL* METMZOLE *

NAUR4NZOL * NAUR4ZOL * NEDCARDOL* NEOCARDOL * NEURAZOL* NOVO


coIL4-
- VINCO * OPTICOR* PEMETESAN* PENETRASOL* PENETRATSOL* PENETIAZOL
*
PENTACARD* PENTACOR* PENTAMETHAZOL* PENTAMETHAZOLUM*

PENTAMETHYLENETETRAZAL
* PENTAMETHYLENETETRAZOL *
PENTAMETHYLENETETRAZOLE* PENTAMETHYLENE-l,5-TETRAZOLE* 1,5-

PENTAMETHYLENETETRAZOLE * PENTAMETILENTETRAZOLO (ITALIAN) *


PENTAZOL *
PENTAZOLUM * PENTEMESAN * PENTETRAZOL * PENTETRAZOLE *
PENTIWZOL *
PENTROLONE * PENTROZOL * PENTYLENETETRAZOL * PENTYLENETETRAZOLE
*
PETAZOL * PETEZOL * PETR4ZOLE * PHRENAZOL * PHRENAZONE * PM’T * PTZ *

STELLACARDIOL* STILLCARDIOL* TETRACOR* 6,7,8,9-TETRAHYDRO-5-


AZEPOTETRAZOLE* 6,7,8,9-TETRAHYDRO-5H-TETRAZOLOAzEP~ * 7,8,9,10-

TETRAZAB1CYCLO(5 .3.O)-8,1O-DECADIENE * l,2,3,3A-TETRAZACYCLOHEPTA-8&

2-CYCLOPENTADIENE * TETRASOL * TETRAZOL * TETRAZOLE,


PENTAMETHYLENE- *
.- 5H-TETRAZOLO(l ,5-A)AZEPINE, 6,7,8,9-TETRAHYDRO- (8CI,9CI) * TT87 *
VASAZOL * VASOREX * VENTIUZOL * YETRAZOL *
- -.
~—
------------------ TOXICITY HAZARDS -------------------
RTECS NO XF8225000
5H-TETRAZOLOAZEPINE, 6,7,8,9 -TETRAHYDRO-
TOXICITY DATA
ORL-MAN LDLO 147 MG/KG 85DCAI 2,73,70
IVN-MAN LDLO:29 MG/KG 85DCAI 2,73,70
ORL-RAT LD50 140 MG/KG JPPMAB 13,244,61
IPR-RAT LD5062 MG/KG TXAPA9 18,185,71
SCU-RAT LD50:85 MG/KG TXAPA9 18,185,71
IVN-RAT LD50:45 MG/KG AIPTAK 135,9,62
REC-RAT LD50:8 MG/KG AACRAT 46,395,67
ORL-MUS LD50:88 MG/KG JPETAB 128,176,60
IPR-MUS LD50: 55 MG/KG AIPTAK 123,419,60
SCU-MUS LD50:70 MG/KG BCFAAI 111,293,72
IVN-MUS LD50:3 1400 UG/’KG AIPTAK 103,146,55
PAR-MUS LD50:72 MG/KG ARZNAD 6,583,56
SCU-RBT LD50:76 MG/’KG JAPMA8 29,2,40
IVN-RBT LD50:30 MG/KG PHTXA6 21,1,58
SCU-FRG LD50: 1600 MG/KG PLRCAT 1,7,69
REVIEWS, STANDARDS, AND REGULATIONS
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)
CENTRAL NERVOUS SYSTEM
=-.. FIRST AID
IN CASE OF CONTACT, 1MMEDIATEL% FLUSH EYES OR SKIN WITH COPIOUS
.-.
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 NIOSWMSHA-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
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 CLOTHTNG, GLOVES AND EYWFACE
-_
_-— 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 PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
IModafinil/Phendimetrazine Tar-wate 1555
function during the first few weeks of pemoline therapy was Pentetrazol is a central and respiratory stimulant
considered essential amd it waa recommended that semm err-
similar to doxapram hydrochloride (see p. 1550). It
zymes should be measured at no less than every 2 weeks for
the frrst 6 ~ecksandthen every other month
has been used in respiratory depression but when
1. Anonymous ‘Hypcrkinesi<’ can have many causm. cymploms. respiratory stimulants are indicated other agents are
JAMA 1975. 232; 1204-16, generally preferred. It has also been included in
2. Patterson JF. Hepauh, assockmedwuh pemohnc. SOurh6frd J
1984, 77:938
multi-ingredient preparations intended for the treat-
ment of respiratory-watt disorders including cough,
Effects on muscle. See under Effects on the Nemous Sys-
tem, p.1555.
cardiovascular disorders including hypotension, and
for the treatment of pruritus.
Effects on the nervous system. Choreoathemsis and
rhabdomyolysis developed in a patient following a marked Administration has been by mm and by injection. ti
increase in intake of pemoline. 1 Abnormal movements re- Porphyria. Pentetrazol has been associated with acme at-
sponded 10 dkz.epam tacks of porphyria and is considered unsafe in patients with
For a discussion on central stimulants provoking Touretfe’s ilCUtt porphyria. 1
syndrome, see Dexamphetamirre Sulphare. p. 1548. 7’
i ,kk’o~ MR. McCOII,KEL.Porphvria: drug lisp GImEOWper.
1. Brisccc JG, eI al. Pcmolmc-induced choreoathetosis and rhab- phyna Research tlmt, University of Glasgow. 1991.
domyolysis. Mcd Toximf 19S8; 3: 7?.-6
Preparations - -Q
Effects on the prostate. Experience in one patient suggest- Names of preparations are timed below derails are given m Parr 3.
ed that pemolme might adversely affect the prosfate gland or
Proprietaq Preparations
interfere with teats for prosratic acid phnsphatase used in the
Spain: Cardiompide.
diagnosis of prosraric csrcmoma.]
1 Lmdau W, de Girolaml E Pcmohne and the prostate Lmcer
Multi-ingredkmt preparations. Fc:CMsintex-Pencdzolt: Gee:
1986; i: 738 Cardanrinolt; J&siviIat; Poikilotont; Sympamcardt; Iral..’ Carcha-
zol-Paracr@na; Spain: Cardiorapide Efcd; Espemom Comrmsi-
mm; Ftuidin Infantilt.
Pharmacokinetics
Pemoline is readily absorbed from the gastro-intes-
tinal tract, About 50% is bound to plasma protein. It
is partially metabolised in the liver and excreted in Phenbutrazate Hydrochloride
the urine as unchanged pemoline and metabolizes. (1485-y)

It has been suggested that magnesium hydroxide Phenbumzate Hydrochloride (R4NM).


might increase the absorption of pcmoline. Pemo- Fenbm-azate Hydrochloride (rfNNM); R-381. 2-(3-Methyl-2-
line with magnesium hydroxide is known as magne- phenylmo~holmo) etfryl 2-phenylbutyrate hydrochloride.
sium pemoline. c~3H*9N03.Hcl = 403.9.
CAS — 4378-36-3 (phenbutrozate); 6474 -85-7 (phen-
References.
butrozote hydrochloride).
1. Vmmculm NPE, # a[, ?harmacokmclms of pcmolinc in plas-
ma, saliva and urmc follo*mg oral admm!smstnon.Br J Chn
Pharmaco[ 1979,8:459-63. Phenbutrazate hydrochloride was formerly used as
2. Sallcc F, r! al Oral pcmolmc kmcucs m hyfxractwe children.
Chn Pharmacol Ther 1985.37:606-9.
an arrorectic agent.
3. Colher CP. r: al Pcmohne pharmacokmetncs and long term
lhcrapy m chddrcn wl!h altenl!on defic,t dmorder and hypcrac.
liwry. Ch. Plwmrnamkmet 1985:10: 269-7S

Phendimetrazine Tartrate (1486-J)


Uses and Administration
Phendimerrazine Tam-ate (BANM, rlNNM).
Pemoline has similar actions to dexamphetamine
(see p. 1548) and is used as an alternative to dexam- Phendtmetrazine Aod Taruate; Phendimetrazne Brtmrate.
(+).3,4. Dlmethyl-2.phenylmorpholine hydrogen tartrate.
phetamine or methylphenidate in the management
C12H17N0, C4H606 = 341.4.
of hyperactivity disorders in children (see p. 1544).
CAS — 634-03-7 (phendimetrozine); 7b35-5 I-O
In the UK theinitial dose by mouth in such children (phendtmerraztne hydrochloride); 50-38-8 (phendlmetro-
is 20 mg each morning. increased by 20 mg at week- zme tortrote).
ly intervals to 60 mg. If no improvement occurs the PhOrrnocopoeras. In us.
dose can be gradually increased to a maximum of
A white adourless crystalline powder. Freely soluble in wa-
120 m: each morning. In the USA37.5 mg isgiven
fer sparingly soluble in warm alcohol; practicably insoluble
each morning initially. increased gradually at week- in acetone. in chlomfomr, and in ether. A 2.5% solution in

~$Dexarnphetamine Sulphate, p. 1547; howev-


ly intervals by 18.75 m:: the usual range is 56.25 to waler h~s a pH of 3 to 4. Store in ainight containers

k
#fects and sympathomi-
of over-stimulation
75 mg daily and the maximum recommended daily
$.:~ctivity are considered to be less with dose is 112.5 mg. Adverse Effects, Treatment, and Precau-
, ~, e: There have been reports of impaired liver Pemoline is also an ingredient of an oral prepara- tions
“@s.m patients taking pcmoiine; ils use is con- tion. also containing yohimbine hydrochloride and As for Dexamphetamine Srslphate,p. 1547.
‘-“.-d in uatients with liver disorders. There methyltestosterone. which is given with the inten-
~so been ~me or isoiated re~ chores, tion of managing failure of sexual desire and func- Pharmacokinetics
tioning in males and females. Phendimetrazine tartrate is readily absorbed from
~Z and neutropenia.
the gastro-intestinal tract and is excreted in the
.. Paranoid psychosis was $:::: PemoIine has been given with magnesium hydrox-
ide (magnesium pernrrline)in an atteItSpttO irICreNe urine, partly unchanged and partly as metaboiites,
*pmoline 75to 225 mg1 including phenmetrazine.
e of the drug, development ;pressive its absorption.
Msyndrome. andlnability t! ed de-
~-anditw~evideni :hat[hep :ted m Preparations Uses and Administration
me. % Namesof prepmtions are hwed klou. de{aih are gw’en m Pan 3. Phendimetrazine tartrate is a sympathomimetic
a, Proprietq Preparations agent with the actions of dexamphetamine (see
Conad. CyJert. GPr. Senmr: Tradon: S.Afr: Dymdcn: Swi[:.:
Sumul. UK Vohml: L’SA Cylcn.
p, 1548). It is used as an anorectic and is adminis-
_“’on gm~h. Results of a study in -
imgges~ed thar growth suppres$icm w’
7 >euc
Multi-ingredient preparations. Gee: Cephalo-Teknosalt;
tered by mouth as an adjunct to dietary measures in
~lid
k.ofprolonged ~reatmen! with clinical ital. Dcadyn: S.Afi. Lenruge\ic, Spare Neumcordm. UK Prow- the short-term treatment of moderate to severe obes-
fpcmoline a,nrfthat this effect might be dosl ess ity. The use of adjuncts in the management of obes-
!.Under Dexampheurnme Sulphme, p. 1548. ity is discussed on p. 1544 where the use of stimulant
+nLC, cr.i Impmrcdpmulh ,nhypcrk, ncnc anorectics such as phendimetrazine is questioned.
?gpenolinc JPed!mr 1979. 94:53%-$1 4
\On the liver. of ~hildrei] lak,”g pemolim fo
Pentetrazol I,437.,! The usual dose is 35 mg [WOor three times daily 1
x % had elevated Concemrations o{scrum a Pentem.zol (BAN, dNN).
hour before meals, but doses should be individual-
Sferase [SGOTI and serum alanme amln
Corazol; Lepmzrd: Pemamethazol; 1,5-Pentameth leneterm-
ised and in some cases 17.5 mg twice daily may be
‘1
b:~~); the effecr WM sra!ed to be transient a ~e, Pen~azol: Pemetrazoium: d
Pentylenetetrazol 6,7,89 Tet-
adequate: the dose should not exceed 70 mg three
I
— times daily. An alternative dose is 105 mg once dai-
rah~m-5H-tetrazoloazepme
~btis was asswia,ed with pcmollnc }“ o Ifhye /- u.,_ ly in the morning as a sustained-release preparation.
@renzyme v;i}”es feII m normal af[cr w>thdr.! !PIO,.4 - ,Jo.z

1~ with lower dose+ did not increase the em 8s — 54.95-5. Phendimetrazine hydrochloride is used similarly; it
esting a COXICthreshold. Close anenrmn 10 he ~hormocopowas In Aus(., Cz., Hung., and k. isgiven by mouth in doses of 15 to 40 mg daily.
~~tde”otesaprepmationno Io”gerac[ively

,
368 Central and Respiratory Stimulants

1437-V 1438-g 144?-n

pentetrazo~(B. P.. Eur. P.). Leptazol; Pentazol; Phertsttine. N-(a-Mcthyiphcnethy l)nicotinamide Cropropamide. AfN-Dimethyl.@
Pentamethazol; Penty[enetetrazol; Pentetrazohtm; diphosphate: N-(cr-Methylphenethy l)pyridine-3-carb- crotmtamido)but yramide, w
oxamide diphosphate.
Corazol; 1,5-Perttamethylenetetrazole. 6,7,8,9-
Cf$H,6N10,2H3P04 =436.3 CAS — 633-47-6.
Tetrah ydro-5H-tetrazoloazepine. ,-
C6HION4=138.2. CAS — 139-68-4 (base): 2964-234 (diphosphare). .’$.
1
1442-h .; j.%
CAS — 54-95-S, Pharmacopoeias. In ffus.
Odourless urlourleas crystals or white crystalline powder Crotethamide. 2-( N-Ethylcroto~.

L
Pharmacopoeias. In Arg., Aust., Be[g., Br., Cz., Eur.,
with a bitter saline tasie, soluble in water and alcohol; butyramide. \
Fr.. Ger., Hung., Ind., Int.. It., Jug,. Mex.. Neth., !e
practically insoluble in ether. A 5% solution in water C11H2ZNZO:=226.3.
oral., Pol., Port., Rus., Spars.. Swiss, arid Turk. i
has a pH of 1.8 to 2.4. CAS — 6168-76-9.
Colorless, almost odourleaacrystals or white W
crystallinepowder with a slightly pungent bitter Usas. Phenstirre is claimed to stimulate the central *\
nervous system in a similar way to dexamphctamitre
taste. M.p. 57” to 60°. soluble 1 in leas than 1 without causing vasoconstrictiors. It is also claimed that I443-m !;
of water, of alcohol, and of chloroform, and 1 in it reduces blood pressure. In the USSR it bas been Prethcamide. G 5668, A“l!!!
‘r”
less than 4 of ether; soluble in carbon tetra- employed similarly to dexamphe.tamisre as a centrat sti- parts by wt of cropropamide ati&
chloride. A 10% solution in water has a pH of mulant; i! has also been suggested in the treatment of
CAS — 8015-51-8. .,.:-
5.5 to 7. A 4.91% solution is iso-osmotic with hypertension.
serum. Sohstions are sterilised by au toclaving or Prethcamideis soluble in d-
by filtration, avoiding contact with metal. Protect ether. -’l
from light. Adverse Effects. Side-effects &.*
An aqueous solution of pentetrazol iao-osmotic with 1439-q paraesthesias, restlessness, m%
serum (4.9 1%) caused 100% hacmolysis of crythrocytea
Picrotoxin (B.P. 1963). Picrotox.; Picrotoxinum; Coccu-
tremors,dyspnoca, and ftualsio
cultured in it for 45 minutes.— E. R, Hammarlund and
K, Pederaen-f3jergaard, 1 pkrrm. Sci., [96 [, 50.24. lin.
Gastro-intestinal disturbart~,.~
CmH340,,
=602,6. have also been reported
Pentetrazol in a concentration of I to 3% inhiL ited the Prmaution, Prethcam;de s~g
growth Escherichia coli, Bacillus sub;ilis, Staphyl*
of CAS — 124-87-8.
coccus aureus. and Pseudomoms aeru~”nosa. This sub care to patients with epilepsy:.
in the E.P. i 958 that no bac-
Pharmacopoeias. In Arg., InI., It., Me%., Span.. Swiss,
stantia ted the statement
Uses. Prethcamide is a reapu .$
tericide needed to be added to solutions for inJection.— and Turk.
R. J. Gilbert and A. D. RwaeO, Pharm. J., 1963, 1, An active principle from the
seeds of Aranrirra ctsccufss$ which has been given in usr@’i
Ill. (-A. panicuhrta) (Menisp-ermaceae). three or four times daiIy in .,1
Odourlesa, colourleas, flexible. shining prismatic crystals respiratory insufficiency in chr~
Adverse Effects. High dosage produces epilepti-
or white or nearly white microcrystalline powder, with a Ithas also been given intram~
form convulsions, and overdosage may result in very bitter taste. M.p. about 199”. intravenous injection, and b~ 1!
respiratory depression. Soluble I in 350 of water, I in 35 of toiling water, I in sion.
Treatment of Adverse Effects. As forNiketham- 16 of alcohol, and 1 in 3 of boding alcohol; soluble in
Proprietary Preparations ‘~.,
ide, p.367. [f perttetrazol has beers ingested the glacial acetic acid and solutions of acids and alkali ~
hydroxid=, slightly soluble in chloroform and ether. A Mlcoren (Geigy, UK). Prethcamidqfaq
stomach should be emptied by aspiration and of 400 mg. (Also available as Mad
Iavage. saturatedsolution in water is neutral to litmus. Solu- ~ -.
tions are sterilisad by autoclaving or by filtration. Nerh., Switz. ).
.,
Precautions. Pentetrazol may provokeseizures in Protect from light. Other Proprietary Names “‘.
patients with epilepsy or other convulsive disord- The potency of picrotoxin solutions diminished as the Micorene (Befg.).
ers. pH increased above 7.— P. W. RamwelI and J. E. “k .,
Shaw, J. Pharm. Pharmac., 1962, 14, 321. -J

1
Absorption and Fate. Pentetrazol is readily .>
absorbed after administration by mouth and by Advene Eflscts ssrd Trestsnent. As for Nikethamide, A “?
! injection. It ia rapidly metabolised, chiefly in the p.367. As little as 20 mg may cause severe poisoning. 1444-b ‘::1).
liver. About 75% of a parenteral dose has been Uses. Plcrotoxin u a respiratory stimulant with actions
!: reported to be excreted in the urine. and uses similar to those of nikethamide (p.367). [ss Prolintane Hydrochloride
Peak plasma mncentrstiona of abut 2#g per ml were duration of effect is brief. Prouvlohenethvl) twrrolidine hir&

1
obtained about 2 hours after s dose of 100 mg of Wn- It was formerty given in usual doses of 3 to 6 mg c,5H2;N,Hcl~i5-3 .8. ,:~
intravenously.
tctrazol by mouth. The drug was excreted in the CAS -– 493-92-5 (prolintarre)~~!
urine.— W. R. Ebert er tr(., J. pharm. Sci., 1970, 59, chloride).
1409.
,:”$A
Plaama-pentetrazol concentrations in 3 patients, who
A white odourless powder ~th
were taking the drug regularly, ranged from 1.45 to M.p. about 133”. Solubleirr’~~
1440-d
3.1 UR oer ml when measured 1.25 to 5 hours after a chloroform; practically insolu~l%/
100%g” dose.— H. W. Jun et al., J. pharm. Sci.. 1975, Pipradrol Hydrochloride (lf.P.C. /963). a-(2- Pipsr- Adverse Effects and Precautti
64, 1843. — id yl)benzh ydrol hydrochloride; aa- Diphen yl-a-(2-piWr-
nausea, and tachycardia hay, ‘
Uses. Pentetrazoi is a respiratory stimulant with idyl)mcthanol hydrochloride.
patients receiving prolintarte.”’,~

1
C18H2, N0,HCI=303.8.
actions and uses similar to those of nikethamide with care in patients taking ,rnWo.
(see P.367). It has been given in usual doses of CAS — 467-60-7 (pipradrol); 71-78-3 (hydrochloride}. inhibitors, and should not k’
/’
administered subcutaneously, intra- with hyperthyroidism or epile ,
J’- #S;rly, or intravenously. Pentetrazol has
been employed in the elderly to alleviate the
Odourlesa,
almost white
decomposition.
tasteless,
crystalline
SoIubte. t in 30
small white
powder.
crystals
M.p,
of water,
about
I
or white
290”
in
with
35
or

of
Uses. Prolintane hydrochlorid~ a
stimulant of the central nertp
symptoms of senility. For this purpose it has alcohol, 1 in 1000 .of chloroform. and 1 in 8 of methyl
alcohol; practically insoluble in ether. A 1% solution in
been given, in fatigue and .to~.’
been given by mouth in a dose of 1 2 m usually with vitamin suppIemen
water has a pH of 5 to 7. protect from light.
usually in conjunction wit 10 mg twice daily, with thel~~~ ‘
ii’ , but tts value has not- been substan- Adverse Effects. Pipradrnl hydrochloride may muse given not later than mid-afterrt~
tiated in trials. nausea, anorexia, aggravation of anxiety, hyperexcitabil-
ity, and insomnia. Epigastric discomfort, skin rash, Proprietary Preparations t,
--%n~a~-h=~-~mdfia~o~y Villcscon(Bcwhringer Ingelheim,’ UK
3( as an aid to the diagnosis of epilepsy.
——-——-_.—...—————’
Preparations
dizziness, and hallucinations have been reported.
Prccatrtioara. Pipradroi hydrochloride is contra-indicated
in each 5 ml prolintanc hydrochlOri.
hydrochloride 1.67 mg, ribdtavine; -
in endogenous depression, in agitatsd prepsychotic
c ‘-.etrazo[
0.25% in Water
(Lf.P.C. 1963).
IO% and
Inj. Leptazol.
sodium
A sterile
phos@i.
for tnjec!ions, adjusted to pH 7.8 with
patients, chores, paranoia, obsessional dmorders, and
anxiety
cated.
states, and in patients for whom ECT is indi-
salt)

water)
1.36 mg, pyridoxinc hydrochlo. ~
namide 5 mg, and alcohol 12.2% w[Y:&4
and Tsbiets each containing ~
chloride 10 mg, thiamim monn-nitrate.5
dilute hydrochloric acid or potassium hydroxide solution. 3 mg. pyridoxinc hydrochloride }.
Usse. P1pradrol hydrochloride is a stimulant of the cen-
/ The addition of a bactericide is unnecessary. Dose. 0.5 tral nervous system which was formerly given in usual 15 mg, and ascorbic acid 50 mg. !?p~: %
_to I ml subcutaneously. doses of 2 to 6 mg daily in fatigue and some depressive of appetite and mood. Dose, 10 ml of W.
‘Proprietary Names states. twice daily; children 5 to 12 Years. 2.5,~0 .,
Cardiazol (Knoll, Ger.; hfedin.ra, Spuim Krro/1, .Swifz.); Proprietary Namss Other Proprietary Names . ~.;,7J
Cardiorapide (Rapide, Spairr); Metrazol(Knoll, USA). Detaril (/SOM, I/a/.); Stimolag Fort is (Lagczp, .Switz. ). Promotil (Fr.).
“,Jk.
!,
http://l3O. 14.32.46/cgi. ..M-client? 10900+detail*2 http: //l3O. 14.32.46/cgi-bim’IGM-client?10900+detail~-2

National Library of Medicine: IGM Full Record Screen


-

F?
TITLE: Facilitati& of pentylene tetrazole-kindled seizures by mild thyroid
hormone deficiencies.
AUTHOR: Pacheco-Rosado J; Angeles-Lopez L
AUTHOR Department of Physiology Mauricio Russek Escuela National de
AFFILIATION: Ciencias Biological, LP.N., Mexico, D.F.
SOURCE: Proc West Pharmacol Soc 1997; 40:75-7
NLM CIT. ID: 98098613
MAIN MESH Convulsants/* TOXICITY
SUBJECTS: Kindling (Neurology)/* PHYSIOLOGY
—-– Pentylenetetrazole/* TOXICITY
Triiodothyronine/BLOOD/* DEFICIENCY
ADDITIONAL MESH Animal
SUBJECTS: 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 (Pentyienetetrazole)
6893-02-3 (Triiodothyronine)

.—.=

lofl 5/5/98, 11:53


AM
l?
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 Department of Chemist~, Kamatak University, Dharwad (India).
AFFILIATION:
SOURCE: Arzneimittelforschung 1996 0ct;46(10):949-52
NLM CIT. ID: 97085798
ABSTRACT: A series of 6-substituted imidazo(2,1-b)-1,3,4-thiadiazol&2-sulfonamides
(V) were prepared by condensation of
2-amino-l,3,4-thiadiazole-5-sulfonamide (H) with an appropriate
2-bromo-ketone (HI). Bromination of V in glacial acetic acid gave the
corresponding 5-bromo derivatives (VI). Five selected compounds (15-18
and 28) were evaluated for their anticonvulsant and analgesic activities.
Compounds 15-17 showed maximum protection (83Yo) against ~entyIem
tetrazole induced convulsions and maximum electroshock induced seizures
while the standard phenobarbital sodium and phenytoin sodium showed
100°A protection, respectively. Compounds 15, 16 and 18 showed superior
analgesic activity to acetylsalicylic acid in rat caudal immersion test.
MAIN MESH Analgesics/* CHEMICAL SYNTHESIS/PHARMACOLOGY/TOXICITY
SUBJECTS: Anticonvulsants/* CHEMICAL
SYNTHESIS/PHARMACOLOGY/TOXICITY
Sulfonamides/* CHEMICAL SYNTHESI!VPHARMACOLOGY

_—___

1 of2 5/5/98 11:54 AM


http://I3O. 14.32.46/cgi.. .M-client?l 0900tietail+3 http://l3O. 14.32 .46/cgi-hin/IGM-client? 10900+detail+3

ADDITIONAL Animal
MESH Convulsants
.-= Dose-Response Relationship, Drug
SUBJECTS:
Electroshock
Female
Indicators and Reagents
Male
Mice
Pain Measurement/DRUG EFFECTS
Pentylenetetrazole/ANTAGONISTS & INHIB
Rats
Rats, Wistar
Spectrophotometry, Infrared
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY O(Analgesics)
NUMBERS: O(Anticonvulsants)
O(Convulsants)
O(Indicators and Reagents)
O(Sulfonamides)
54-95-5 (Pentylenetetrazole)

2 of2 5/5/98 11;54 AM


http//l3O. 14.32.46/cgi...clieot?t? 10900+detail+5 http://l3O. 14.32.46/cgi-bio/’1GM-client?lO9OOtdetail +5

m
.-: TITLE: Synthesis and biological activities of some 3,6-disubstituted
thiazo10[3,2-b] [l,2,4]triazoles.
AUTHOR Erol DD; Calis U; Demirdamar R Yulug N; Ertan M
AUTHOR Hacettepe University, Faculty of Pharmacy, Pharmaceutical Chemistry
AFFILIATION: Department, Ankara, Turkey.
SOURCE: J Pharm Sci 1995 Ap~84(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 lR 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]triazoks was evaluated for
anticonvulsant activity and observed as potential anticonvulsant
candidates. All compounds examined exhibited activity against both
maximal electroshock and pentyiene tetrazoleinduced seizures in mice.
MAIN MESH Anticonvulsants/*CHEMICAL SYNTHESIS/PHARMACOLOGY~”
.- SUBJECTS: Antifungal Agents/* CHEMICAL SYNTHESIWPHARMACOLOGY
Thiazoles/*CHEMICAL SYNTHESIWPHARMACOLOGY
Triazoles/*CHEMICAL SYNTHESIWPHARMACOLOGY
ADDITIONAL Animal
MESH Candida/DRUG EFFECTS
SUBJECTS: Convulsions/CHEMICALLY INDUCED/PREVENTION & CONTROL
Electroshock
Male
Mice
Microbial Sensitivity Tests
Pentylenetetrazole
Spectrophotometry, Infrared
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY O(Anticonvulsants)
NUMBERS: O(Antifungal Agents)
O(Thiazoles)
O (Triazoles)
54-95-5 (Pentylenetetrazole)
A
__-..

2of3 5~519811:55 AM
/4. INGREDIENT NAME:

PIRAC ETAM

B. Chemical Name:

l-Acetamido-2-Pyrrolidinone, Euvicor, Gabacet, Genogris, 2-Ketopyrrolidine-l-


Ylacetamide, NootroL Nootropil, Nootropyl, Normabra@ 2-Oxo-Pyrrolidine-Acetamide,
2-Oxo-Pyrrolidin-l-Ylacetamide, Piracetam, Pirazetrq Pirroxil, PyracetamjPyramq 2-
Pyrrolidininnoneacetamide, 2-Pyrrolidoneacetamide, UCB 6215

C. Common Name:

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:

AStiy: 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 Journalpf 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 Stand,
-
1976; 54(2): 150-160.
-.. Simeq J., Waters, B., and Resniclq M. Effects of Piracetam in children with learning
disorders. Psychopharmacol.Bull., 1980; 16:65-66.

Steginlq K. J., The cliical use of Piraceteq a new nootropic drug: the treatment of senile
involution. Arzneim-Forsch, 1972; 22:975-977.

Wllsher, 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.
d Leant Disabili& 1985; 18:19-25.

Mondadori, C., Petschke, F., and Hausler, A. The Effects of Nootropics on Memory: new
Aspects for Basic Research. Pharmacopsychiatry. 1989; 22:102-106.

YaI, V., Derzhiruk, L. P., and Mogilevstil, A. Piracetam-induced changes in the


functional 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. Psychopharmacolo#. 1988; 94(l): 74-
78.

De Deyq P, P., Reuclq J. D., and Deberdt, W. Treatment of acute ischemic stroke with
Piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Stroke.
1997; 28(12): 2347-2352.

DI Ianni, M., Wilsher, C. R., and Bl~ M. S. The effects of Piracetam in children with
dyslexia. L Clin P.sychopharmacol. 1985; 5(5): 272-278.

Wdsher, C. R., Bennett, D., and Chase, C. H. Piracetam and dyslexia: effects on reading
tests. J Clin Psychopharmacol 1987; 7(4): 230-237.

Reisberg, B., Ferris, S. H., and GershoL 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 Sherma~ K. A. Profound effects of combining choline and
Piracetam on memory enhancement and cholinergic fi.mctionin aged rats. Neurobiol
Aging. 1981; 2(2): 105-111.

Page -2-
Buresov~ 0, and Bures, J. Piracetam-induced facilitation of interhemispheric transfer of
visual tiormation in rats. Psychophannaco/o~”a. 1976; 46(l): 93-102.

Dimond, S. J., Scarnmell, R. E., and Pryce, I. G. Some effects of Piracetam (UCB 6215,
Nootropyl) on chronic schizophrenia. Psychophannacologv. 1979; 64(3): 341-348.

Dimond, S. J. and Brouwers, E. M. Increase in the power of human memory in normal


man through the use of drugs. Psychophannacolo~. 1976; 49(3): 307-309.

%r~ S. J., David-Remacle, M., and Weyers, M. Piracetam facilities retrieval but does not
impair extinction of bar-pressing in rats. P~chopharmacology. 1979; 61(1): 71-75.

Brandao, F., Paula-BarboW M. M., and Cadete-Leite, A. Piracetam impedes neuronal


loss withdrawal tier chronic alcohol intake. Alcohol. 1995; 12(3): 279-288.

Mindus, P., Cronhol~ B., and Levander, S, E. Does Piracetam counteract the ECT-
induced memory 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 Neuropharmacol. 1986; 9 Suppl 3
S27-38.

Song, C., Earley, B., and Leonard, B. E. Effect of chronic treatment with piracetam and
tacrine on some changes caused by thymectomy in the rat brain. Pharmacol Biochem.
Behav. 1997; 56(4): 697-704.

H. Information about dosage forms used:

Patients received either 3.3 g of Piracetam daily or matching placebo syrup. Each dose of
test medication was 5 ml. administered before breakfast and again before the evening
meai. 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. Infomnation about route of administration:

Orally

Page -3-
.
K Stability data:

L Formulations:

M. Miscellaneous Information:

See File

Page -4-
..—
. . ..
\
-.-— ._

CERTIFICATE OF ANALYSIS
.—_-

Coa No: 7777

:
& PIRACETAM b .
.

Batch No: 96120006


✍❞
Manufacturing Date: Dec”3 199
>

Testing Result

Appearance
[identification
Welting Point
___
152.5-153.5°C
hity of Solution Clear
leavy Metais
< 20ppm
ksidue on Ignitio&
0.02%
ass on Drying
0.12%
%
99.27% 0 /

~onclusion: to China Provincial Standard ‘


v’

:marks: The above testing result is per rnanul%c~er’s informan%&

/0 97
-. /

–—-. ~’/

~
--~ ,-~-. -
~.4L+..--—-_” _+_:_. “...-–<
.G- . . . ..
-~ — ,—. . . ------ .—— —
--.—-.!— — .-
- ----
— , ~m_-
—— .—. —
>--.———- -, . . -_+

~e —
.-. .—
.:. -.—-:.-.
--- ----

_—-—
_—— - ——.:-~— — ----- ——- -

---” ---- ,.-— -.,-------
~:.:-_— -...=.=- . . . .. . ----- .-. -- ~—
. ..~. -----

.—. —. ..- -— .. . . . ..
A.~-+-. -
—. .<~qk... --- . ._. a_ ...—
— ----- ...-
-.
-..+
QUALI~ CONTROL REPORT

cWICAL = .: PIRACETW

W4NUFAC= LOT NO. :97060036

PHYSICAL TEST

/cO. SPECS. .
SPECIFICATION TEST STm-.:USP_/BP_/~R~_/NF_/=T._

l)DESCRIPTION .:
WHITE TO OFF WHITE CRYSTALS FROM ISOPROP~OL OR WHITE TO OFF WHITE
CRYSTALLINE POWDER.

2)SOLUBILITY. :
VERY SOLUBLE IN WATER; SOLUBLE IN ALCOHOL, ESPECIALLY IN ISOPROP~OL.

3)MELTING POINT.:
.&%
MELTS AT ABOUT 151.5-152.5 degree.

4)SPECIFIC GRWITY.:

5)IDENTIFICATION .:
A) COMPLIES IR SPECTRUM AS PER COMPANY SPECS.

FAILS .:
PASSES .:

COMMENTS .:

DATE. :
ANALYST SIGNATURE. :

DATE. : INITIAL.:
PREPACK TEST.:

DATE. : INITIAL. :
RETEST .:
.-
------------------ IDENTIFICATION -------------------
PRODUCT #: P5295 NAME PIRACETAM
CAS #: 7491 -74-9
MF: C6H1ON2O2
SYNONYMS
1-ACETAMIDO-2-PYRROLIDINONE * EUVIFOR * GABACET * GENOGRIS * 2-
KETOPYRROLIDINE- 1-YLACETAMIDE * NOOTRON * NOOTROPIL * NOOTROPYL
% *
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-PYRROLIDINEACETAMIDE, 2-OXO-
TOXICITY DATA
IPR-MUS LD5O:>1O 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-MAM 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, INGESTION, 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 CLOTHING AND

.4.
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 EYELIDS WITH FINGERS, CALL A PHYSICIAN,


-------------------- PHYSICAL DATA --------------------
APPEARANCE AND ODOR
SOLID
------------ FIRE AND EXPLOSION HAZARD DATA -----------
EXTINGUISHING MEDIA
WATER SPRAY.
CARBON DIOXIDE, DRY CHEMICAL POWDER OR APPROPRIATE FOAM.
SPECIAL FIREFIGHTING PROCEDURES
WEAR SELF-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES,
UNUSUAL FLRE AND EXPLOSIONS HAZARDS
E?vfITS 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 MATERL4L 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-MUSHA-APPROVED RESPIRATO%
_-
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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q8noJq] Suyuea[ a]epu.il]spue ‘saouelsqns qxolomau leJaAas
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afksoa ‘uo!loe Jo sapow jo Jaqwnu e
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o] ]u!od si?u!pug maN ,,~qJoM uIela2eJ!d saop MOH,, ‘uoqsanb
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// s6rtJu l.JeUJS ZL1
Nootropics: Preclinical Results in the Light of *
Clinical Effects; Comparison with Tacrine
Cesare Mondadori
Hoechst Marion Roussel, CNS Research, P. O. Box 6800, Brrdgewater, NJ 08807+800

ABSTR4CT: This review is meant to serve several purposes. Firw it smcys the preclinical and clinical
profiles of piracemrn-like nootropics. Second. the conditions under which che nootropics are active in preclinical
studies are identified and anaIyzed with a view [o finding a common denominator that could explain the
observed effects. Third, the clinical profile is examined. on the one hand to assesswhetkr these drugs are in
fact active in humans, and on the other to determine how che clinical effects of the noorropics compare~ids
thoseof tacrirre. Lady, the clinical data are then further scrutinized to tisess whether the) fulfill the expecta-
tions based on the preclinical findings.

KEY WORDS: Noouopics. piracetam. oxiracerm. prarruncetarn. amracetam. racrine. preclinical. clinical.
res~rrders, norrresfwnders

INTRODUCTION mind, and .rropos. toward. and thus reflects not a


class of chemical structures. but the supposed

--—=- The discovery of piracetaml shook faith in effect of these compounds on cognitive processes.
. aracelsus’ famous axiom, “dosis fack venenum.” It is consequently inevitable that a certain ten-
This memory improving substance not only was dency exists to attach this Iabel to all memory-
devoid of other biological activity but also had no enhancing subsunces (for a comprehensive re-
toxic effects whatever at doses up to grams per view, see references 3.4).
kilogram of body weight. Even today, nearly 30 The present review is devoted entirely to the
years after the discovery, the “nootropic” class of piracetarn-like preparations and focused on their
substances newly created to accommodate pira- direct nootropic effects. i.e., the spectrum of ef-
cetarn still splits pharmacologists into two camps. fects on the memory of intact animals, rather than
For some, the absence of toxicity indicates a lack on their mechansm of action. The latter aspect
1
of any pharmacological action, while others see it was the subject of recent reviews.’~ Since it is
as pointing to a new therapeutic approach. De- impossible to assess the activity of a substance
pending on the observer’s standpoint, ehher the without recourse to reference compounds, both
nonresponders in clinical trials testify to the inef- the preclinical and the clinical results are dis-
ficacy of these agents, or the responders bear out cussed on hat basis. Tacrine, theonlycompound
their ac[iviry. This controversy has severely hin- registered for the treatment of AIzheirner’s dis-
dered genuine scientific progress and has pre- ease. is taken as the sole reference drug for com-
vented full advantage from being taken of the parisons of the c~inica.1resuhs.
therapeutic potentizd of the nootropics.
Piracetarn is long since not the sole represen-
tative ofthis class. h themeantimea great many Il. PRECLINICAL EFFECTS OF
suucrurally related active compounds have been THE NOOTROPICS
synthesized. confrming rhe need to assign the
~—nootropics to a category of their own. The lerm
noorr-op~c ckrives from the Greek words rroos. oF.

IW5&3!96/S5.ffi
C 1996 by Begell House, inc
357
tion of central nystagmus in the rabbit. [ further that piracetam and pramiracemm improved per-
tindings made during the past 25 years showed formance in an object recognition test.:’3
thin i[s main action consists in the improvement .\niracetarn: ! and oxiracetarn22were obsetwed to

_=——=. of cognitive functions. The earliest studies were have positi~e effects in a social-recognition test
concerned with pharmacological modulation of in rats.
the amnesiogenic effects of a cerebral elec- In sum. from the data so far available it can be
troshock. When Giurgea and Mouravieff Lesuisse4 concluded that the noomopics exert a distinct
demonswated that piracetarn reduced the disrupt- memo~-enhancing effect in various learning situ-
ing influence of ~ electrosh~k on the orients. ations and in different animal species. In most
[ion of rats in a water maze, this effect was taken experiments the acquisition or storage of the in-
as an indication that pirwetarn improved memory formation occurred under the intluence of the
consolidation. Over the years, this antiarnnestic drug and retention was assessed after an internal
action of the piracetam-like preparations has of- of at least one day. Effects on short-term retention
ten been confined. Studies with animceta.m.’ have been described (e.g., in a delayed-altema-
oxiracetarn,~pramiracetam, and a series of ana- tion or delayed matching-to-sample task, and so-
logues9 all showed a distinct protective action cial recognition after short intervals), but these
against the effect of electroshock on memory. observations have not yet been confined.
This rather indirect indication of a nootropic
action was supplemented and reinforced by t%d-
ings showing a direct memory-enhancing effect. A. Which Memo~ Processes Are
A great many results emerged from experiments Facilitated by Nootropics?
in avoidance learning. For example, aniracetam
and piracetam[o” and oxiracetami2 were found to The many experimental situations in which
exert direct effects on the acquisition and reten- nootropics have been asserted to exert a memory-
tion performance of rats and mice in both passive- enhancing action raise the question whether there
and active-avoidance paradigms. Of particular is a common denominator underlying ail these
value were the results of investigations in which effects: such as a similar target process, or whether
the preparations were administered immediately even the whole spectrum of activity of the
after the learning trial (’post-trial’). In Such con- nootropics is the same. The available evidence
ditions, the animal experiences the learning situ- would suggest that their activity spectra are nor
ation without being under the influence of the identical, but at least very similar. inasmuch as all
dmg ~d is I&ewise uninfluenced during tie re- these preparations improve passive avoidance:::’
tention test. Arty demonswable effect can then be and active avoidance, ‘2.3and all of them improve
ascribed to a direct action of the substance on retention pert-on-nance.even if administered posl-
memory processes that outlast the learning sirua- tnal.’3 The results of studies with post-trial ad-
tion for some time. Several experiments showed miniswation reveal a high degree of concordance:
that nootropics can improve the memory under it has been demonstrated that all four prototype
such conditions. ’314 nootropics—oxirac etam. piraceram, pramir3-
The Ieaming situations in which piracetam- cetam, and aniracetam-can enhance memo~
like nootropics were active were not limited to even if administered up to eight hours after the
experiments involving avoidance behavior. Pra- learning trial. After an interval of 16 hours, an
rnimcetarn had positive effects in a place naviga- effect was no longer evident. ”” It can be inferred
tion [ask;s and was also found co improve the that under these conditions all these drugs ~ffect
~cquisition rate in a 16-armradial maze.‘bwhereby a process that outlasts the learning si[uation by
the effect related exclusively to reference memory. more than 8. but less than 16. hours (a hypo[he~ls
not working memory. A slight. but ignificant. relative to the process affected IS advanced in
effect of pramiracetarn was dso demonstrable in reference IJ ~.The improvement in retention per-
a delayed dtemation r-rid.’- .\niracetam likewise formance in all these experiments Was 3s5eS5cd
displzyqi positive effects in 3 radial mazes md 2 w-ter 2-I or 72 hours. i.e.. at a time when [he
matching-to-sample [es[. 0 \[oreo\er. i[ ~as found memory content is generally supposed [o ‘re

358
present in a long-term form. It was further shown the ACE inhibitorcaptopril. the caIciumantagonist
:–- ? the retention perr-cmmanceof mice exposed to nimodipine. and the gamtna-arninobutyric acid B
. ●arning situation tier receivin~ a single dose (GABAB)-receptor antagonist CGP 36742 in a
of oxiracetam was distinctly better than that of passive-avoidanceparadigm (F@re 1).It was sub-
controls even after one. lwo. or four months.~c sequentlyobsetwedthat all these LTM effects were
This finding lent additional suppcIrI not only to equally steroid sensitive: i.e.. experimentdy el-
the assumption that the substances ultimately evated aldosterone or corticosterone le~els sup- 1

improve long-[enn memory (Llll ] storage, bu[ pressed the effects of all these memory enhance]s t
also to the supposition that after intends of 1 to to the same extent.U3[The pharrnacodynamics of
120 days memory is based on the same substrate. oxiracetarn. arecoline, CGP 36742, and captopril
Also in accord with the hypothesis that the were similar there was an 8-hour drug-sensitive
nootropics improve LTM storage are the responses window afterthe learning trial (F@re 2). Note that
evoked by pramiracetxn]b and aniracetam18in the thememory-enhancingeffecs inducedby captoptil.
radial maze, in which solely effec~ on reference CGP36742. and the muscarinic cholinergic ago
memory were obsened. Thus, the only effects nist arecoline followed almost exact.1 y the same
remaining to be explained me those noted in the pattern as that of oxiracetarn, in chatthey were not
delayed matching-m$arnple tesr:c and the im- immediately detectable, i.e., not in evidence as
provements seen in the social-nxo-tition test after soon as the animals showed sie~s of retention. At
a two-hour intenal.: If these efi-ects hold good leasta funher 16-20hours elapsedbeforeit emerged
for all nootropics, they can be taken as an indica- ~I=W 3). This surprising concordance in the find-
tion that the facilitation of LTM is just one aspect ings strongly suggests that all four of these drugs
of a whole range of activity; if not, they could affect the same process.
indicate differences in the activity spectra of the By analogy with the results obtained with
various nootropics. Many indicanons of differ- oxiracetarn. it seems reasonable to assume that
--–-es have been obsemed. Comparative studies the process in question is LTM storage. This con-
pramiracetam and etiracetam. for example. clusion is proposed purely as a possible common
showed that only etiracetam had effects on memory denominator and must not be construed as an
retrieval.~’ Moreover. a long list of experiments exhaustive description of the activity spectrum.
indicate quantitative and qualitative differences The totality of the cholinergic effects induced by
in the biochemical activity spectrum of piracetam- physostigrnine activates the brain quite differ-
like nootropics42&wso that there is hardly cause ently from blockade of the angiotensin-convert-
to expect such drugs to display an identical spec- in.genzyme or the effects of piracetam. It is con-
trum of activity. sequently logical that, despite the common effects,
Thus, the most obvious common feature of differences in the activity spectra are to be ex-
the nootropics is their capacity to facilitate LTM pected. Such differences have been observed in
storage. This conclusion isconsistent withthe experimental studies: only captoptil facilitated
majority of the available precliniczd results.
De- memory retrieval after a ?-month retention inter-
spite thehighde+gree ofsimilariq inthe observed val: piracetarn did not.jz Piracetam and pramira-
effects. some experimental findings do appear to cetam improved performance in an object recog-
indica[e differences in the acti~]? spectra. nition test.zowhereas physostigmine had no such
effect. ~j In contrast to pramiracetam.lb and
aniraceram.Igphvsostigrnine
. had no memory-en-
B. Effects of Nootropics Compared with hancing effect in radial-maze tests.’” .~us~.how-
Those of Other Memory Enhancers ever. be conceded that these results are not de-
rived from comparative studies.
In summary. all memo~-enhancing com-
pounds display similarities in their activities and
In [he intensi~iesand dynamics of their effects in
LT\fexperiments. The eh-e~!~ Me steroid sensi-
[]te and‘xComedetects’nie oni~af~er a laDseof

359
x+
.

3(-?$+
. *
K-E
——==
_- X-X*

NS C NIM
LO
IlilCAP .STR CC?
3.0 0.1 U
1 c ‘EM
3.0 03
ARE PHY
0.03
c PIRm
mo

FIGURE 1. The effects of various memory-enhancing substances on the retention performance of mice in a
lm
.

i
ANl Oxl
100 lM

passive-avoidance task. Mice were given footshock for leaving a “safe- small platform in the center of a grid floor.
.

mglcg p.o.

The spontaneous (%aseline”) Iatencies to step onto the grid were measured. Retention (i.e., the retest Iatencies)
was assessed 24 hours later. The histograms represent the step-down latencies in seconds. Solid columns: baseline
Iateneies; blank columns: retest Iatencies of drug-treated animals; hatched cofumns: retest Iatencies of the vehic!e-
treated controls. NIM: nimodipine; CAP: captopril; STR: strychnine; CGP: CGP 36742 (GABAB antagonist); THA:
tacrine; ARE: arecoline: P!iY: physostigmine; PIR: piracetam; PRA: pramiracetarn; ANI: aniracetam; OXI: oxiracetam.
Physostigmine was given orally 30 minutes, all other substances, two hours, before the learning trial. Optimal doses
for memory improvement were determined in independent pilot experiments. Prolongation cdtll{ I @S! !..iPIICIFS (m

ccmpanson with the no-shcck controls [NS] and baseline Iatencies) indicates learning. Prolongation of the retest
Iatencies in comparison with the retest Iatencies of the vehicle-treated controls indates drug-induced memofy
improvement. N = 25 mice/group. ● 2p<0.05, “*2P< 0.01, ***2P< 0.001 (Mann-Whitney U-test)

——–_.

several hours. There are, nevenheless, experimen- in victims of head trauma.:556 in patients with
tal findings indicating differences in activity spec- Korsakoff’s syndrome.j’ and even in patients with
wa. both within andbetween the various groups of atificiai pacemakers.~sThe numbers of patients
memory enhancers. above all in tests not related in each study ranged from 4%to 289.4’Durations
[o L~l. of treatment also varied .~eatly: for example, 9
days,sa4 weeks, a3’~3 months.3Q1*’;J1 and up to
1year.N The Smdydesign was variously open,sq@
111.THE CLINICAL EFFECTS OF single-blind,~3b1double-bhnd,~’g~ parallel with
THE NOOTROPICS placebo controls3s”39$i”J~ or active controls,bzh3
crossover,37J4 or enriched:~~ even comparisons
Any attempt to pinpoint common features in with historical controls were used.~
the available clinical data on these compounds NO less heterogeneous was the clinical and

quickly runs in[o certain problems. One major psychometric instrumentarium employed to as-
difficulty is due to the heterogeneity of the patient sess the effects. Besides neuropsychological tests
populations. Studies have been carried out in prob- and scales. psychophysiological tests were also
able cases of Alzheimer’s disease. y]s in a mixed used. The quality of reponing differed -greatly.In
population of Alzheimer and multiinfarct dementia some studies. the test used is not simply men-
patients. L in rnultiinfarct patients.’~ in patients tioned but described exactly (e.g., reference 40).
with psychoorganic syndrome, - in aged volun- whereas in others the sole indication of the namre
teers.’9 in studenu. so in epileptic patients.$’ in of the effect observed and the methodology ap-
d: slexic schoolchildren,:: in patients suffering plied was the single word memo~.b3In evaluating
from effects of cxpcsure to organic solvents.~~’~ the effects, the psychomemc tests were some-

360
times supplemented by staff-rated scalesg~;some-
times only staff-rated scales were used,b: or even
-—.
‘s[ the clinician’s global impression was given.ti
Ihe study design was entirely adapted to demon-
strating the existence of an effect of the prepara-
tion in patients.
Surprisingly. at first glance sc~tiny 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.,39for instance. showed that after KIMee
months
the 30 patients treated with oxiracetam in a double-
blind, parallel-design study displayed significant
FIGURE 3. The emergence of the memo~ facilitation
improvements in 9 of the 18 tests used compared
effect induced by the nootropic oxiracetam (100 mcj
with their baseline perfotmmncebefore the begin- kg), the ACE-inhibitor captopril (3 mg/kg), the musca-
ning of treatment. The 30 placebo-treated patients. rinic agonist arecoline (0.3 mg&g), and the GABA8-
on the other hand. showed no improvements. and receptor blocker CGP 36742 (1 O mg/kg). The animals
even performed sikmificandy worse in two of the were trained in a passive-avoidance situation and
treated immediately thereafter. Retention performance
tests. The positive effects wereparticularly clear-
was measured at various intervals (1, 2, 8. 16, or 24
cut in the Mini Mental State Examination hours) after training and treatment. The columns indi
(MMSE), the Auditory Continuous Performance cate the drug-induced prolongation of the retest laten-
Test (ACPT), Rey’s 15 words Test. the Block cies (in percent of the veh~le-treated controls). ● 2p4.05,
-2 fxo.ol, ‘“*2pc0.001. Prolonged Iatencies ind=te
better memory. All treatments were given intraperito-
nealfy immediately after the learning tral (from Mondadori
et al., %c. F/ad. Acad. Sci., 91, 2041, 1994).

Tapping Test (BTI’), the Mattis Word Fluency


Test, Luria’s Alternating Series, and the Instru-
mental ActivitiesofDailyLiving Test(IADL-E).
Seninetal.38 petfonneda studywithanira-
cetam,usinga testbattery different from that
applied by Villardita. At theendofthe6-month
treatment period the authors found significant
improvements of performance in all 18 param-
eters assessed. As in Villardita’s study, positive
effects were recorded in Rey ’s 15 Word Test.
?iote that besides effects on cognitive param-
<10s Ih M W 8h 16n
eters. these authors also observed distinct effects
on behavioral parameters. The 6-month study
FIGURE 2. The effects of various compounds on
with aniracetam performed by Pa.metti et al.b~
memory if administered at various intervals after the
learning experience. The animals were exposed to the
according to a similar design yielded practically
passive-avoidance situation, and afterthe Indicated m- identical results: in 17 of 18 tests, aniracetam
tervais (<10 seconds, 1, 2, 4, 8, 16 twws) treated”wth improved the patients’ performance. In this com-
optimal doses of the memory enhancers. Retest was p~ative study the activity spectrum of aniracetam
performd after 72 hours. The columns Indicate me in some tests was distinctly different from that
prolongation of the retest Iatmcles (ir 2ercent of :he
vehicle-treated matched controls). P~olonged Ialencws
of pirace:3m. Unlike aniracetam. for instance.
-.
— pu3cenrn displ~yed no effects in Rey”s 15 Words
~dicate better memo~. ARE. arecolme: CAP: caDIoo P!:
JXI’ C)Xl~CeWT7. “2xc.05 ““2x(I.L)l, “-2@.~1 Test. In [he Toulouse Pieron Test. and [n the

361
Raven Test. According to the Sandoz Clinical score in the SCAG was significantly better (the
Assessment Geriatric (SCAG) Scale, however. IPSC-E was not used). The duration of treatment
the effects were nearly iden[ical. Bottini et al.w in this study was only four weeks. .More modest
.——-—. observed distinct effects of oxiracetam in five of still were the clinical effects nom-l in the study
.—
eight cognitive tests. In particular. there were of piracetam performed by Abbuzahab et al.~~ in
significant positive effects on verbal fluency. OBS patients (geriatric memory): apa.n from a
similar to those described by Villardi[a et al., slight overall improvement. no relevant effects
and the retention of a shot-tstory (after a delay of were observed. Much more pronounced positive
10 minutes) was also improved. In the 12-mon[h effects emerged from the investigation by Moglia
study with pirxetam conducted by Croisile et et al.J~ In this parallel-design study in 21 + 22
al..]’ indications of a retardant effect of :he drug OBS patients, these authors showed that oxira-
on the progress of memal decline were noted: in cetam induced an overall improvement in cogni-
the placebo group a significant deterioration was tive and behavioral parameters. Panicuhrly no-
evident at [he end of the year in 8 of 14 tests. table were the significant improvements seen in
whereas in the piracetam group negative results the Benton Visual Motor Retention test (as also
were recorded in only one test. In contrast to the used by Itil et al.) and in the arithmetical part of
findings of Senin et al. and Parneni e[ al., direct the Wechsler AduIt intelligence Scale (WAIS).
comparisons of the performance of placebo- The conclusion that the general well-being of
treated and piracetam-treated patients yielded the patients vested with oxiracetarn had improved
scarcely any statistically significant results. The is consistent with the many global clinical as-
study carried out by ,Maina et al.’[ in the largest sessments, as exemplified by a 3-month pla-
population samples of all (?J = 144 + 145), posi- cebo-controlled study in 60 patients with two
tive (good to very good) effects of oxiracetam doses of piraceut.m carried our by flouinard et
were recorded in 90 of 145 patients ~global evalu- al.~’ In this study, the results of the monthly
ation), whereas, according to the same criteria. evaluations by the nursing staff (Nurses Global
only 27 of 144 placebo-treated parienrs were Improvement Rating Scale) clearly indicated an
rated as showing good or very good responses. improvement in the patients’ sense of well-be-
Only 51 of lW patients taking oximcetam as ing, whereby particular emphasis was placed on
against 107 of }44 receiving placebo were rated alertness. socialization. and orientation. Another
as showing no effect or a poor effect. Note that study by Foltyn et aL,65showing aniracetam to
the patients in this study, in contrmt to those in have been effective over a duration of four weeks
the study by Villardita er al.. showed positive in N = 30 +30 patients. was based exclusively on
effects in the IPSC-E (Inventory of Psychic and staff ratings.
Somatic Complaints, Elderly). Statistically sig- Nootropics were also tested for efficacy in
nificant increases in the IPSC-E scores were also completely different clinical indications. McLean
recorded in the 6-month study performed by et al.,fi for example, examined prami.racetam in
.M~goni et ~.,3f3 while no Chan,ges were Seen in four patients withheadinjuriesor anoxiaand showed
the placebo-treated controls. that the drug exertedclear-cut effect5on immediate
Itil et al.ti also reported significant effec[s of and delayed recall. In patients with pacemakers, in
oxirace[am in the IPSC-E, not in Alzheimer pa- whom the fued heart rate often leads to diminished
tients, but in diagnostically less precisely defined cerebral circulation and consequent disturbances of
cases of organic brain syndrome (OBS), These perfommnce during exertion, piracetam was found
effects were more pronounced tian the corre- to induce a slight improvement in psychomotor
sponding effects of piracetam. Such changes in testsj? no cognitive tests were performed, how-
the [PSC-E suggest that oxiracemrn exerts effects ever. In a study in epileptic patients with memory
that can be manifest as an mprovement in the disordem. Aldenkamp e: a.l.s’ observed no effects
quality of life of the patients. The results obtained after 12 weeks. but all parameters measured re-
by Salem et d.’s in their study of a similar patien~ vealed a rend favoring oxiraceram.
population were far less dis[inct: JDan from an In some investigations. comparative evalua-
improverhent in verbal memo~. or.iy the overall uons were made of the effects of nootropics. In
.—===

362
the above-mentioned study by Itil et al,,ti oxira- patients in the Alzheimer’s Disease Assessment
___ cetam was found to have a slightly better effect on Scale (ADAS). In patients witi alcoholic organic
cognitive parameters than piracetarn, whereas mentai disorders also, a srudy conducted by I
piracetam displayed a slightly better antipsychotic Fleischhacker er al.s’ demonstrated no relevant
effect than oxiracetarn. Although the .meater effi-
cacy of oxiracetam in regard to cognitive aspects
improvement after treatment with piracetarn.
Given the existence of studies with positive
I
was confiied in the studies by Ga.Ilai et al.*l and and others u-ith negative results or overall ra[-
Ferrero.a~ these studies were not ctied out under ings, one question that arises is what “positivr’
double-blind conditions and are consequently not or “negative’ means to the individual patients.
admissible as valid scientific evidence. The same As regards the positive studies. tha[ question has
applies to the smdy conducted by Falsaperla,b~in already been answered, insofar as it was often
which the effects of oxiracetam were compared mentioned that only a limited number of patients
with those of deprenyl in Alzheimer patients. Here. responded to the treatment (e.g., reference 41).
both drugs improved the patients” performance Unfortunate). in the clinical studies with nootro-
above baseline levels in a whole series of tests, pics, only scant information is given about the
deprenyl emerging as the more effective treat- frequency of significant therapeutic effects and
ment. Aniracetam was also shown to be slightly the quality of such effects in individual patients,
more active than piracetam in the study by Parnetti The fact that. despite many nonresponders. posi-
et al.b- tive overall ratings were still reported would at
In contrast to the many posi[ive results re- least seem to justify the reverse question of hour
ported. a 3-month srudy in Alzheirner patients often individual responders were present evrn iJ]
performed by Green et a.l.~ and using a broad the negative studies. For want of adequate infor-
battery of neuropsychological tests revealed no mation on responders and nonre-spenders in most
signs of efficacy of oxiracetam, either onthebasis double-blind studies, illustrative data must also
__ of group analyses or in individual patients. Simi- be drawn from the results of open trials. [n the
‘arly, a 3-month trial by Hjorther et al.sj with a study performed by Claus et al..~: [he conclusion
very extensive test battery gave no indication of that piracetam was ineffective was based on [he
arty effects of oxiracetam: neither behavioral nor lack of significant effects in the ADAS in 10
memory parameters showed any signs of improvem- patients. In fact, however, there was at least one
ent. Note that this trial was done in a special responder with a reduction of more than four
group of OBS patients, suffering from toxic points in the ADAS and significant. drug-related
encephalopathy following exposure to organic improvemerm in both the Visual Selective Re-
solvents. In full concordance with these results. minding Task (total and delay) and Logical
Somnier et al.fi detected no signs of efficacy of Memory Immediate Recall. l%ese effects were
aniracetam in such patients. A notable feature of inevitably submerged in the calculations of the
this study was that Sornnier employed a crossover means values and statistical ana.lys]s.In the study
design. Other crossover trials have also revealed by Baumel et al.’s also, where the drug effects
no positive effects. Lloyd-Evans et al.” were were rated as ve~ modest, 4 of the 12 patients
unable to detect any effects of piracetam in a 6- showed responses. In that the case repcms were
month double-blind trial in OBS patients. The 2 x described as ~pical. thiswm a substantial effect
4-week crossover study with oxiracetam per- from the viewpoint of the auaIiq of life. This
formed by klo[loy et al.3Tin Alzheimer patients outcome is closely similar [0 the results of the
likewise showed no effects. In none of these cross- open study in six patients b} Dager et al.,59in
over ,-ials was the fwst druyplacebo phase evalu- which there was one definite responder. Irrespec-
ated separately as a parallel study. Negative re- tive of the ex[ent to which ~?e cited data were
sults fmher emerged from an enriched-design attributable to drug effects. thy demonstrate the
study by Claus et al.. ?s wh~ concluded from their need for anal>ses of this nature.
.—-. results UIJt prxnimcetam IS ineffective as a symp- it can be concluded that he pmicetm~-like
toma[lc treatmen[ for .Nzheimer patients. This nootropics can ?Yoke si~nl~ican[ ~~fe~[j in

rating was based on the scores acmeved O} 10 .+!zheimer pat]en:j. becorrun: manifest on the

363
one hand in cognitive improvements and on the Nfost of the subsequent studies initially failed
other in behavioral aspects. The effect appears to to contl-m Summers’ results. A crossover study
become more marked during prolonged treatment. conducted by Davies et al., ~l for example. in
The variousnootropics differ in their activity spec- which 10 patients were treated for up to four
tra. In general, however, there were only a limited months. showed hardly any notable effects of
number of responders. The few efforts made to the combiiled treatment with THA and lecithin.
characterize this group of patients (e.g., reference Only in I of 10 tests were positive results re-
59) were unsuccessful. corded. The same results were obtained by Cha-
tellier et al.;~ In this crossover study with 67
patients. tacrine (combined with lecithin) was
IV, COMPARISON WITH THE CLINICAL administered orally for four weeks. Apart from a
EFFECTS OF TACRINE slight improvement in the Physician’s Score, THA
was ineffective, Neither in behavioral scales
Any attempt to characterize the clinical ef- (Stockton) nor in cognitive scales (MMSE) were
fects of the nootropics almost automatically ne- any effects demonstrable. Similarly, in a cross-
cessitates a comparison with cholinomimetics. ln over trial done by Gauthier et al.73over two 8-
contradistinction to the nootropics, cholinergic week treatment periods. the response to THA was
substances are used in Alzheimer patients, not limited to an improvement in the MN4SE.Despite
because of their memory-enhancing effects in this improvement, the authors rated tie effect of
animals, but because of the existence of a cholin- THA as clinically irrelevant. No effect whatever
ergic deficit in these patients.@In this respect, the was obsemed by .Molloy et al.74 in a multipie
patient population studied is homogeneous and, crossover study with treatment periods of three
unlike the very mixed populations treated with weeks. Neither’the overall evaluation nor a de-
ncxxropics, includes only (probable) Alzheimer tailed analysis of individual patients revealed any
patients. The group sizes are similar to those in indications of effects.
the nootropic studies. The methodology used is Positive results. on the other hand, were ob-
more nearly uniform but different from that tained in the trial conducted by Davis et al.~sThe
adopted for noowopics. The following section is 215 patients who had responded to tacrine in a
confined to tetrahydroaminoacridine (THA, preliminary crossover phase were subsequently
tacrine. Cognex”), a cholinesterase inhibitor and treated for six weeks in a parallel srudy. By com-
the only substance so far registered for the treat- parison with the placebo controls, the tacrine group
ment of Alzheimer”s disease. showed a slight. but si-gniilcant. decrease in men-
The fwst study by Summers et al.’0was con- [al decline (.DAS co-titive subscale). Two of
ducted in three phases. In the first phase, the the three quality-of-life assessment scales used
tolerability and efficacy of incremental doses of indicated changes in favor of tacrine: Progressive
THA were assessed in 23 patients. THA was Deterioration Scale (PDS) and Activities of Daily
always administered in combination with leci- Living (ADL ). The changes in the MMSE were
thin. In a second double-blind, crossover phase, slight and statistically not significant, and the
15ofthese patients weretreated withthebestor clinicians global assessment (CGIC) likewise
highest doseofTHA, orwithplacebo, forthree failed to detect any effects. In a similar, but more
weeks. after whichthetreatments wereswitched. prolonged (12-week) parallel study by FarIow et
Onlythe12patients showingaclear-cut response al.,’s ven much the same results were obtained:
toTHA inthesecondphasewenton toreceive the .M3AS co-gnitivesubscale indicated some re-
long-[em treatment over periods ranging from 3 tardation of cogni[ive decline. but the MMSE
to 26 months (enriched design). The final assess- sho~d no changes. [n contrast to the study by
ment revealed distinct positive results (global Davis. however. the physicians” and caregivers”
assessment, orientation, .Mzheimer deticit scale. global ratings were sigtilcmtly better. In across-
names learningtest), whereby only patients classed over smd~ by Eagger e[ al..~~in which 468 pa-
M Stages 3-4, but not Stages 5-6, on the Reisberg tients were ueated for considerably longer ( 13
scale rc!sponded. ~eekj ~L?ancho~ein \IOUOy ’S j~d~.-~ rd-ie MMSE

364
- and the MITS (.~bbreviated Mental Test Score), biochemical, and endocrinoiogicaJ profile that
but not the .%DL. revealed an effect of tacrine. would serve to identify likely re.pmders.
--~e effects in t-he.MMSEwere consistent with the To sum up, although there are clear indica-
..ndings of Gaurhier e[ al..-: but not with those of tions that cholinesterase inhibitors do exefi clini-
Farlow et ai.-b and Davis et af.T5;the absence of cal effects, it is equally clear that only a cemin
effects in the .M2L were a[ variance with the number of patients respond to the treatment. “rhe
results obses-ed by Davis cv al.75 use of enriched-design studies oiten makes the
Recm-ttstudies disclosed the entire range of proportion of responders appear larger than it
possible effes. Distinctly positive effects emerged really is. As with nootropics, longer durations of
from a 30-w-eekparallel study by Knapp et al’s In therapy improve the chances of evoking demon-
this study witi an initial population of 663 patients, strable effects. The psychometric scales and tests
all three prirnq’ outcome measures (ADAS cogni- employed were in most cases not comparable
tive subscale. Clinicians’ Interview-Based Impres- with those used in the nootropic rnals. In the few

sion. and Final Comprehensive Consensus Impress- studies in which comparable scales and tests
ion) showed significant effects of tacrine. In (MMSE, A.DL) were used, the effects obsermi
addition. positive effects. among others, were dem- were of roughly the same ma=a-tude as those
onsuated by the Pro.messive Deterioration Scale produced by the nootropics. Although the meth-
and the hfJfSE. but not the .ADL. The effects odology was much more nearly uniform than in
indicated b> the MMSE were in agreement with the nootropics studies, there was no test that
those noted by Gauthier et al..73Eagger et ai.,n and yielded consistent) positive results in all trials.
Davis et al..-: but contrary to those seen by Farlow
e[ al.7sand Nfol.loyet aL74Although consistent with
the fmdirgs of Eagger et al.,n the absence of ef- V. PRECLINICAL EFFECTS OF THE
fects in the .Q3L conflicted with those of Davis e[ NOOTROPICS IN THE LIGHT OF
aL75Exactly he opposite, i.e.. no indications of any CLINICAL FINDINGS
-*cect whatel-er, emerged from the study by Maltby
- al.79u-ith = initial population of 57 patients and Before considering the extent to which the
a 3&week duration of treatment. Neither the Care- clinical data meet the expectations based on
givers’ rating-based scales nor the cowtitive scales preclinical findings. I must stress once again that
showed sigm of changes. Halfway between posi- the clinical investigations were exclusively aimed
tive and ne-~ave results lie the findings reported at showing whether or not the preparations ex-
by Wilcock et al.w In a 2 x 3-month crossover erted any therapeutic effects. For that reason a
study in 41 patients these authors noted positive wide battery of tests was used, comprising both
trends in favor of tacrine, but statistically the dif- behavioral aspects and co~itive performance.The
ferences we= scarcely significant. In a study with somewhat unfortunate efforts of many authors to
154 patients. Weed et ai.s[ likewise merely ob make use of data from animal experiments in
setwedpxitive trends, but there was no significant explaining the rationale of their studies and dis-
effect of tatie in the overall group analysis. The cussing the clinical results should no[ be allowed
results nevefieless indicate that therewereindi- to obscure the fact tha[ neither were the studies
vidu~responders, The same applies toa 3 x 6- designed to validate the preclinical results, nor
weekcrosscver smdy ofAlzheimer patients con- were the clinical results in any way adjusted to
ductedby Gustafsona2 in which there was no seine that puqoose.
detectable ol-erall effect. but individual responders In the vast majority of the preclinical studies,
were noted. II is. above all. the enrichment studies a design was used in which the experimental ani-
that cob. r-heexistence of a subset of respond- mals were exposed to the learning situation while
ers. althou~~ men after the mrichment not d] under the influence of the drugs and then tested
patien~s respmd to the treatment. In the light of for retention 24 hours later, either still, or no
these tindin~s and in view if the need to optirruze longer. under the influence of tie drugs In the
=–——–
e theratm.
. . :1 :S surprising “ha[ sarcely an> efforu c!lmcal s[udies. howe~-er, retenuon perr”onmmce
dve been ~Jce :0 estabtish q oharrnacoiog]ca!. U2j tested m-ter snort-[erm in[e~~als. I.e.. either

365
immediately after acquisition or after a lapse of by the fact that the combination of psychological
10 minutes. The se~eral hours’ delay preceding training and nootropic therapy proved particu-
[he dmergence of detectable memory-facilitating larly effective, not only in dyslexic children. but
effec[s that has been observed in the most recent also in other forms of coguitive underper-
animal experimen~ “:3 strongly emphasizes the forrnance.~3Moreover, it appears very likely that
crucial importance of allowing long enough re- the effects obsetved after long-term treatment of
ten[ion intervals, provided only, of course, that Alzheimer patients might. at least partially. be
the clinical effect and the memory facilitation based on such effects, too.
observed in animals come about by way of the However, the many reports on an improve-
same mechanism, Wlxit the long-term memory ment in noncognitive aspects inindividual studies
tests used in the clinical studies detected was not or patients make it seem improbable that
the influence of the substances on long-term stor- nootropics act exclusively on LTM storage. h is
age. but their influence on retrieval from LTM. conceivable that the effect comes about via a
i.e.. on the recaIl of information acquired while modification of general processes that play an
not under the intluence of the drugs. Often, learn- important role in the pefi-orrnanceof brain cells.
ing capacity was tested before and at the end of The improvement in long-term storage would then
the rreatment period: i.e., performance without be only one of the measurable consequences. The
the influence of the drugs was then compared reason for the usually modest extent of the clini-
with performance wbile under the acute influence caf effects could be that the action of the sub-
of the drugs. There is thus still no sound scientific stances is confined to cells that are still function-
evidence of the predictive validity of the animal ally competent. But since the individual patient’s
procedures. This aspect should be examined in specific pattern of functional deficits reflects the
specifically designed clinical investigations. impairment of the neurcmal circuits essential ro
The various reports nevertheless do contain this function, it may be that the aspect most im-
at least a few ailusive remarks consistent with paired through degeneration afso affords the least
the expectations based on animal experiments. room for improvement. This applies equally to
In the study with oxkacetam by Dager et al.,~9 cognitive and noncognitive performances. It is
—— for exarnpIe, there is a sentence reading: “al- therefore perfectly conceivable that while mea-
though long term recall improved only negligi- surable effects in one aspect or another may be
bly. his long term memory storage (learning detectable in a wide-ranging psychometric inves-
capacity) and reco-tition memory were moder- tigation. these aspects may be of little therapeutic
ately enhanced. ” Similarly McLean et aLsdstate relevance to the symptoms that are particularly
that: The most drwnatic demonstration of im- disabling for the patient.
provement with pramiracetam . .. recurred in the
selective reminding test-delayed recall, long term
memory retrieval and long term storage.” Last. V!. SYNTHESIS AND OUTLOOK
but no[ least, there are a number of reports con-
cerning the effects of piracetam in dyslexic chil- Given the observed overalI positive effects of
dren that possibly pint to effects on LTM stor- the nootropics and their occasionally quite dis-
age. In a double-bLirrd. placebo-controlled study tinct effects in individual patients. this category
by \Vilsher et al.s: r-hechildren showed greater of compounds would appear useful. The results
facility in reading and comprehension after a 36- available so far give no indication [hat tacrine is
week phase of treatment with piracetarn. It is very superior to the nootropics, or vice versa. The
probable that the improved performance at the effects of these drugs seem to be similar. although
end of the treatment period reflects. not an acute the complication that the double-blind nature in
,
effec[ on memory ren%xd. but rather an improved connection with cholinomimetics is very prob-
availability of the !=owledge acquired through- ablywishful thinking(dicrirninativestimdus prop-
out ‘he duration of ~eatment. i.e.. long-term re- erties.” side effects, e.g.. reference 74) has been
tention of infonna[icn acquired under the influ- completely left out of consideration. In [he ab-
ence of piracetam. TTJSview is strong!y supponed sence of comparative srudies. the tacit assump-
.——-.

366

tion that the cholinomimetics are more effective of a series of cyclic irnides, J. Med. Chern.,
sal activiry
most Iikeiy reflects the supertlcial plausibility of 30,498.1987.
.-. 10. Yamad~ K.. Inoue, T., Tanaluz M., and Furukav~
le underlying hypothesis rather than the existing
T., Prolongation of latencies for passive avoidance
clinical results. Together, the clinical results responses in rats treated with aniracetam or piracemrrr,
present a mirror image of the preclinical profile. PharrMcol. Biocherrt Behav., 22.645, 1985. -
In order to maximally exploit the a~ailable II,.Mondadori. C. and Petschke, F., Do piracerarn-like
therapeutic possibilities, i[ would be desirable [o compounds act cenrrally via peripheral mechanisms?
Brain Res.. 435, 310, 1987.
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12. Sansone, -V. and Oliverio, AwAvoidance facilitation
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The steroid dependence of the memory-facilitat- Pnchiar~, 13, 89, 1989.
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percentage of Alzheimer patients have elevated pounds can improve reten[ion preformance, even if
administered up to 24 hours afrer the learning experi-
plasma cortisol concentrations.gs This approach
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would, of course, be valid only if the memory- 14. .Mondadori, C., Hengerer, B., Ducre~ T., and
enhancing effects seen in preclinical studies and Borkowski, J., Delayed emergence of effects of
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91, 2041. [994.
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15.PoscheL B. P. H., Ho, P. M., Nmte~ F. W. and
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16.Murray, C. L. and Fibiger, H. C. The effea of
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Luna-Nebraskaneuropsychological bartery. Dug Dn. wgmgumilduals. ,4ctcPsyti. Scaruf,54, 150.1976.
Res.. [-i, 217, 1988. 50. Dimond. S. J. and Brouwem. E. Y. M.. Increzse [n
37 MoIIov. D. W.. Guyatt G., and Brown. G.. Effecrs the .wwcr or’human mcmc~ in normal man hrough
of J ,xeum on cogniuon, behavlour and ~cuvines tie usc cidrugs. f~c+optimoco(ogy. 49. 3@7. 1976
of daily Iivmg m demenua. Y. Chn. Exp. Geronrol., 51. Alden.karnp. .L P.. van Wieringen, A.. Alpberts,
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A.. }[arini. G.. k-i~mdita. C., md parnefi, f_.., conrroil~. ne”uropsychoicg. cd ~d neurophyslologl -

368
cd in~esti~ations
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_—-—x cMhoiop, 24.90. 1990. results of long-term therapy ~ Ith oxiraceram in pa-
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macol., 7. 230. 19s-. drugs as demonstrated by the example of tie rmu
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_—~

370
‘ALL’.4TIO\ OF THE EFFIC,$C}” OF PIR4CET,A\l IX TRE.4TING IN’FOR\l.ATION
?OCESSI\G. RE.\DI?iG .4XD W“RIT1,NG DISORDERS 1S D}”SLEXIC CHILDREN

Ptrace[am. a new c!as, of drug (n<%~::~pl!l[htwgh[ 10 enhance spec]f]c cogmute sLIIIs, was grven In a ;.WO mg d~ll} dose[o half of
ro”pof fi[I\.[1.c d\sIe\Ic bois aged !- 13 >ews. In a 12-wA. douhlc-h[ind placcb+ccm[rolied ,Iud} The other half O( [he subjecls
~i,<~ pI~C-~,l AI] Su.PJeC:S mcl [he ‘.dlwlng L’rlkna rwrm.si Intel ligmrct normal educml,mal ,.ppor~uni;ies. no severe cmouonal
bl<mj. no neur.~iog~~lhmdlcap~.:.x~ ph?slcal health. nm mkirsg other p~>chowoptc mcdlcgtion. and sconrq 31 least one md one
[ >eisrs below their mental age ecwalen[ on [he Gilmore Oral Reading Tes[. Xon-verbal t audim~ and visual) and verbal
ce=F- and memo~ Skills were examlncd. and redln~. spelling. language and Unung abditm Ueremcawredusing standardized
(n ,. Compared to [he piacel<’ conmol group. Inshviduais tre~ied w I[h Pwacetam dld mm shots swlsu call} slgnlfican[
>ro\ements abc+e th.ar basehne sc.vescm measures of percepmxs. memory. language. reading ~ccumc} or comprehension. or
[Ing accurac> ‘d.wettr. resdlng >~d and numbersof word<wntlen m a umcd period were ,Ignlf)cmttl> enhanced In $ubJeC1$
IICd WI[h Pmace[am, as compared @ plwebo Ef[wu\e refidin$ anj unung atrll!t>. takng both rate and accurx> Inm

is.lderauon. were also $Ignlflcantl> :rnpro. ed [n (he Pmace[am as compared [o [he placebo wea[men[ group. The medic~[lon was
l-tolerated and med]cal cxammauon: jh~wed no slgn!f]can[ adlerse reacuons.These resul[s encourage further stud> O( Pwacelam
ieterm]ne more prw=l> {he mechtirusm of act]on b: vduch$pecIfIccognl~l~e AsIIsarc af[ecwd

TRODUCTIO\ and Arnan. 1975). and impulsivi[y and social be-


havior fBarkley and Cunmngham. 1980: Conners
Recent re~lews of chemotherapeutic [reatment and M’ern. 1979). Hcwe\’er. s[udies of educational
learmng dlsabllittes have emphasized [ha[ [he abl I]ties using standardized reading. spelling and
rceptual and behavioral changes induced by anthmeuc tests hake failed [o demonstrate any
~~~ do no[ n<cesjarl]y lead [O improved academic slgnifican[ differences In the performance of
rformance (.%m~n. “1980: ~~err>. 19S1 ). This treated children (Quinn and Rapopor~. 1975: Weiss
nclu>ion has kn based pnmanl} on research e[ J1.. 1975 I or non-hyperactive ciuidren (Gi[t Ie-
th central nemous system s[lmulants such as m~n-Klein and Kleln. 19?6: Aman and W’erv.
?thvlpherudate I W[alin) and ciex[roamphetamlne lQS:).
~e\ednne). Such s[imulan{s hale hem shown 10 This discrepancy} betueen the drug-induced im-
pro~e attention span ( Barh;e>. 1~~~: Bar~leY provements in behavioral con[rol and [he absence
J J~ch~on, ;~--,. mem~>r> {S2rague. 19-2: ~ err> of chmge in sch~>ol-performance ma~ be clut In
p~r: ICI [he us\ <~ch child :S ~s.jlgned [he proper
dclsase, [n [he pa~:. clin]c:~n> ~nd !nie::!g~[or.
hI,J/< ~.:u~t~ IE, J[ ih< ~>~tlrn~l d,~\JQt [,1 i~pr~~it
. .

J.

>hor[-[<rrn memor> ~blli[le> ( Rudel .md tlenckl~.


19-4: TJIIJI. 1980J: TJIIJI. 19SOb) ~nd p~~~~rLWd-
.s=%
ing ~nd n~mlng ~biii[ies (S\ mnms md R~poport.
1972. DencLIJ ~nd Rudd. i976J,
Three >tudies have tes[ed [he effw[s ~li Pir~ce-
[am ~>n le~rnlng-disabled popul~[ions The firs[
jtud} rep~~rted was by V“ilsh<r et JI. ( 19-9). who
uscci .dul[ dyslexics w subjects. In this s[t.i~~. 16
I
oduit J}slewcs were ma[chd on the basis of their
W +1S [Q jcorcs wi[h ]4 c~~n[ro( $ubj~~[~ f~~r J
?-week pi~cebo-controlled. double-blind. crosswer
trial of lN30 mg daily dose of Piracet~m. The
Jy>lexic subjects met the cri(eri~ ou[!ined bv
Thoms<m 11977). Since subjects in this stud> dem--
onstr~tet-f significant car~owr effects due [o the
crossover design. Wilsher e[ JI. only ex~nllned
resul[s from the first period of treatment to ~vold
the confounding effects from previous exposure [o
I
Pirxe[am. In comparison to placebo tre~tment.
results jh~~ed [hat in [he dyslexic group who
received Plrwxtam verb~l le~rning impro~ cd by
almos( tuice thal of the non-dyslexic control group
receiving Piracetam ( 152 compared [o S.6? ). The
test ujed w M a serial memory verbal learning [~jk
with 10 [hree-le:ter nonsense syllables. [n addition.
the number of instonces that a subject k~rned the
.—. nonsense ~}Ilable m-id then forgot it on [he very

next trial dropped by almost half ~mong the dys-
lexic group treated wi[h Pirwetam ( – 4-,1?). bu[
was not ch~nged in [he d> sle.tic plxebo tre~tment
group,
Simmn e: al. ( 19S0) w~re the first [cl [est [he
et’ficac} tli P!racetum on learning skills oi children.
They tr<~[ed 29 “Ieurning disordered’ boys be-
[wen [he Jges of 3 and 14 with J -WOti mg d~ii~
~Qjd of plrlce[~m in J double-blind. crossof~r
plxebo-controlled -t-week j[ud~. Al] children were
at Ieaj[ one year behind their Jge group In either
reading. spelling or arithmetic on [he V“ide RJnge
.Acn]e\emen[ Test (WR\T) ond Jll h~cf a Full
Scale ~“ISC-R IQ of Z[ leaj[ S5. Their findings on
measures of global Ixhavlor .md learning were
nc>n-jlgnificanl. although [he ~uthor points OU[
[hat [he ~hort duration oi [re~tment. corr]over
eifec[.; due [o [hc cromo~er des~~n. ~nd the sm~ll
number Ii pJIIents in \ ~ri~’u~ rre~lmen[ xubgr~~up~
nl~de >1.il:>[lcal .Mal}sds dlificul[ to in[erprel.
[n J :tcond jtud} b> W’ilsher e[ al, ( 19S5}. 16

__.—m
I

4? I

I
Pcrf~~rmance Scale IQ or a Verbal Scale IQ of 90
or m~lrt. ohtalried ulthin 9 months of [he ini[ial
\ 1>1[.{ ~ I Th<! had J Reading Quotient of less than
fL)IIOUI~~ crit&a: [h<} had J Full ScJle V: ISC-R or equ~i [O 0.S5. {4) English was their primar~
[Q ~rea[~r [hdn 90. ~ Readtng or Sptlllng .Ag< of langu~ge. {5 }Informed consen[ was ob[ained from
J[ least [uo vears behind their mcnt~l age b~>ed bo[h p~[ien[ and parent or legal guardian. (6) I
on the U“ISC-R. normal educa[lonal oppor!unllles. The} had normal audiological and ophthalmologi-
no severe <m~>tlonal problems, normal he.iring ~nd cal functioning (7) There was no significant rreu-
n(>rmJ] ~l;i(>n. and n~>gross neurol~>slcal de!’l~:[s. r~>loglcJl handtcap, I S) They had no severe emo-
The chlh-lrerr were [ej[ed on [heir re~ding ~~1111} [ional dI>[urbance as a priman symptom. (9) There I
I speed. accuracy. ond comprehension) and J 5-rein was no were educational deprivation. ( 10) The}
free-writing sample was ta~en [o measure [he [o(al had n,> clinically significant laboraton abnormali-
number of words uri[ten and [he percent~gc of ties. n~~r on} medmd conditions which might pur
>pelling mlstak<s. T- Ies[ c.~mptirls~ms be[ueen the [hc p~i)~n[ 3[ additional risk or interfere with the
meuns of [he (WO treat rncn[ groups at the b<<in- conduc: of [h< s[ud}. ( 11 ) They had no his[o~ of
nlng and [he end of [he ~ ueeks shined no sl~nifl~an[ adlcrsc reac[ion or hypersensi[i~i[> m
significant differences on anv of the dependent Plrace:~m. ( 12) The}-werenotinvolved
in an>
measures. However. further Jnalvsls comparing [he therap}e; u hich mi~J[ in[erfere with the evaluation
mean treatment of efficacy and safet). including: psychostimulant
different< between
changes from baseline. using the
[he p(~s[- md pretrea[men[ medic~ticm ui(h[n 6 months of the initial ~’isit.
I
>ccmes for each subjecl. rm m.led lmpr~~kenwn:s In conccrm[an[ dru~ therapy with psychostimulants
reading speed and accurac~ and mtal words writ- or an} drug for tmo[ional disturbance. concom-
[e-‘~- in~iildual~ [rested with Plracel~m. In J!] ? itant therapy with Tofranil for any indica~ion.
SIL .s. the Piracetam medicat]cm was exlremely lnresu~atlona] drug [herapy within one month of
well-tolerated. the In]tial Ylsi[. or concomitant chronic trea[men[
The present stud> was de,isyed to replic~[e ~nd with bronchodilators which have central s[imulant
extend [hc findings of LJ’ilsher e[ al, ( 1984). >fore ac[ivi[~.
rigorous patien[-selec[lon Inclusion and excluslon- Th~ Reading Quo[lent was calculated as equal
an cri[ena were used. Drug dosage and regimen to: ReJding Age x IO(Y2 by Chronological Age x
were equivalent. bu[ [he ciinlcal trial was extended Fuil Scale WISC-R IQ. The Reading Age was
[o 12 weeks and addi[lonal 5UbJeC[j. [est sl[es. and deriwcf from the Accuracy Score of the Gilmore
psychometric tests were included. Oral R.xtding Test — Form C. Grade Scores from
the G!lmore were converted [o Age Scores using
Tabie II provided in the Ga[es-:NtcKillop Oral
METHODS Reading TesI. .Abnormal audiological functioning
was defined as a loss of grea[er than 20 dB in
ci[her car for two frequencies in the normal range
f~oo, 1000. SOOO.3000. 4C00 Hz. using pure [ones).
,Ahnormai ophthalmological functioning ~aj de-
fined as less than Xl~’44J corrected ~lsion In both
ttcj as (eslecf b) [ht ,Amencan Op[Ical E Chart.
S“lgnlfic~n[ neurological handicaps u ere defined m
an> of [he following: acquired neuroiog]cai dis-
e~.e. :{~j~l~~i neurol~~gcoi signs u:th functional
lmp~l:men[ ~~rj<lzur<> ulthln [he l~j[ 5 yetir>. The
pJ[)er.:~
hJd no( recet~ed antlccm~vl>~n[ thcrap>
for J: ;<J>[ !U!3 itJ.r> prior [o [he lnlti~l \Is;!
Ej~~:::,}n.lj ~~j -~,l[l,)~~! <\Jiu~il,in> ,&<r< MJ.ic
I
u

l?~ [tt~ medical Staff followin: IJjua] clinicol praC- was t~ken during [he second visit and ~bbre~la[ed
[Ice. Four subjects were droppd from [he j[ud}: physic~l examinations were performed J( [he sec-
one moved. one suffered from ~n ~s[hm~ at[t~h ond and si~[h week visits. Observatmns for possJ-
and was treated with bronchodil.stcrs (In vmla[mn ble ad~erse effects and assessment oi general heolth
wilh the pro[ocoi) and [wo were removed from [h< were emphissized. Laboratory ev~luatlcms were ob-
s[udv due to medicaI complica(lo~s unrela[ed to tained at the induction ~isi[. [he 6-week. and [he
study medication (both were taking placebo). The 12-week visits. The laboratory tests included
f~c[ [h~[ ~ child was currently recei~ing academic hematology. urinalysis and biood chemistry [o [es[
rerncdial ~ssis[ance or had recel’:ed ~u~h [uloring for possible adverse side-effects.
in the pus[ did no( preclude entr> inw [he stud}.
T~J[S

Procedures AII 6 study centers followed the same protocoi


Placebo and Pirace[am [re~tmen[s were ran- and used a common battery of tests to measure
domly divided amor,g 6 groups of 10 subjects. drug efficacy. In addition. each site conducted
each on a double-blind basis with the restriction ddi[ional “special studies’. Only the results from
that there be equal numbers of each tre~[ment the common test batte~ and special s[udy con-
wi[hin Patients were then
each of [he 6 groups. ducted at the San Diego site are reported in this
assigned to one of the 6 groups on the basis oi paper. The common test battery was administered
their age: that is. 8-ye~r-olds were assigned [L> at the induction and final (week 12) visits. while
Group One, 9 years oids to Group Two. and ~~~ the speciai study (ests were given at the induction
forth. When all the [reatment medwation had been and week 6 visit. At the San Diego Center. ail
used up within a group. the pa[lent was assigned testing for an individual patien[ was administered
[o the group with the fewest members. Patients by the same tester and took approximately 1j h.
received either 3.3 g of Piracetam daiiv or~ These tests included: the Gilmore Orai Reading
i~g placebo syrup. Each dose of test medication Test — Form C at the ini[iid visit and Form D at
w’as j mi. admlnis[ered before bre~kfa~n [he final visit —. Information for Reading Accu-
before the ev~A—5~d~~~e racy. Comprehension and Rate were inciuded: the
t
medication
‘<
contained 1.65 ~ ..—
of Pirwetam. S0 Digit Span subtest of the W[SC-R. both digits
@sage adjustments were allowed. fowards and backwards adrninis[ered ~ia a tape
The study consisted of fisi[s. An ini[ial recording: the Gates- \lc Killop Syllabication sub-
screening visit usually occutmd one week prior to lest — Form 1 at the induction and Form 2 at the
(he start of meatment. The treatment period was 12-week visit: the Wide Range Achievement sub-
12 weeks long. wilh follow-up vis~[s a([er 2 weeks. [est for Spelling: a 5-rein free-writing sampie wJs
6 weeks. and 12 weeks of treo[mert[. .\t week 4 and taken to include [he total number of words. num-
week 9. [he patient’s pfents were ccm[ac[ed to ber of words misspelled ~nd the number of cxcur-
$> $ review dosage instructions ~nd IO determ;ne rences of the most frequently written word: [he
~-hh<[.. wy.a.dverse.e.f fe.cts had been obsemed. Rapid Automatized Naming Test (Denckla ~nd
At the initial screening, pati;n’~;-iv~re tes[ed to Rudel. 1976): a behavioral assessmen[ in [he [es[-
determine their eligibility. Hearing and visual in~ jitua[lon made at [he in~uction~nd Iz-week
acuity [es[s were given. a devclopmerrtal hlst~~ \ijltj on a rating SCaie of 1 [O -1 ( 1 being excel len[.
[aken. IQ tes[ing was done m needed. jnd [he 4 being poor). measuring distractibility from fol-
Gilmore Oral Reading TesI was also administered lowing instructions. socia[ appropriateness. coop-
[o provide a calculation of the Reading Quo[ien[. erativeness. ~[tention and general motor acIi~i[>:
Assessment of education experience m-mlemotion~l ~nd a parent’s global ~ssessment of the child’s
he~l[h was fiiso performed at this [ime. beh~wor ob[ained JI the 12-week \ISIL on J r~[lng
.4 compie[e physical e.xamlnat)on was per- w~le of 1–5. where 1 IS much irmproveci ~nd 5 I>
formed bv a physician ~t the second or Inductlcn much ~orje. considering their behavior J[ home.
~lsi[ and ~gain at the Ias: vlsi[ ~ medic.d h[smm in(erac[wt wi[h peers ~n~ school repws concern.
..
I
_—.
.=— -.

I
~ beha~’ior
and performance
in el’aluating the occurred. the final testing [ook place using the
ange from [he start of the s[udy. next Iowcs[ set: e.g.. failure cm set 6. final [es[irrg
In addition [o these common [ests. we con- on set 5. During the iearnmg portion. children
c~ed additional special studies. Subjects were were presen[ed wi[h pairs of pictures. one after the
en the Repetition Test. developed by Tallal other, until [he set was comple[ed. Each pair was
)80). with 3 sets of stimuli: (1) non-verbal audi- presented for 3 s with an in[eru-ial intenal of two
I
.y [ones (75 ms duration). differing in funda- seconds. After all of the pictures in a set had been
I
:ntal frequency: (2) non-verbal visual nonsense presented. the child’s recall abilities were tested in
lpes (75 ms dura[ion): and (3) auditory s[op- the following way: [he s<~~nd picture of <ach pair
nsonant vowel syllables ( ba\da) with 40 ms was grouped. mixed and then laid down on the
ration formant transitions. The Repetition Test table in fron[ of die child. Using the same order as
$ been shown to be a highly sensitive measure of presen[:d m the learning portion of the test. the
‘ceptual and memory functioning. In addition. first picture of each pa}r presented to the
s theoretically based on a model of perception
u dj
I
child. and h~ was asked [o find [he picture [hal
~ is comprised of a series of substests designed goes with i[ among the pictures laid dou n on the
assess levels of perception and memo~ in a table in front of him. Tnis procedure u as cc]n-
rarchical manner (see Tallai. 1980. for a detailed (inued until all pictur~s had been ma[ched.
,cription Four dependent
of these procedures). Children were scrored for [he total number of
I
asures were made on each of the 3 versions of correctly matched pictures. improvements on [his
Repetition Test. Subjects were scored for the tes[ suggest increases in ! isual learning and recall.
al number of correc[ trials. the number of cor-
[ @21s using interstimulus intervals (1S1’s) of
~< .,
le number of trials using 1S1”sless than RESULTS
) m> and the number of trials needed to reach
:erion. Imprcwemen[s in trials [o criterion scored From the initial sample of 61 children. 57 suc-
[icille an increased rate of learning stimulus–re- cessfully completed [hc stud}. From this group.
)nse associations. Increases in scores on trials two children had poor compliance during the last I
h shor[ 1S1’s sugges[ an improvement in rate of 6 weeks of the clincial trial period (below 70% as
Kessing and temporal sequencing abilities. measured from the remaining bottled medication ).
provements in the longer 1S1 scores su~es[ an ConsequentI>. they wer? removed from the data
rease in short-term and serial memory. analysis leaving 55 children. 2S from the piracetam
I
In addition to these experimental perceptual [reatment group and 27 in the placebo treatmen[
i memory tests. subjects were also given [he group.
ken Test (DeRenzi and Vignolo. 1962) [o assess Table 1 presents [he demographic and baseline
ep[ive language comprehension skills and a characteris[lcs of the Pirace[am and placebo trea[-
red associate visual memo~ lest designed for ment groups. T-[esI and x 2 comparisons betueen
i study. In the visual memo~ test the tester the two groups showed nc signlfican~ demographic
[rutted the child by saving. ‘ 1 would like to see differences, Sote [hat a ‘m~gh percentage of the
k we]] vou can remember differen[ pairs of chiidren were jctlve!> rccs:ilng remedla[ [U[orlnc
[ures. 1 will show you IWO pictures. one after for their reading probiems tea. W?),
o[her. Try to remember them as a pair tha[ go Table 11 shows Lhe base!ine scores for [he
ether’, Testing [Ook place in two parts. a learn- Piracetam- and piaceb+treatcd groups on the
and a recall sec[ion, During the learning sec- common [es[ ba[te~. >o[e th~[ the Gilmore Or~l
1. children were prcsen(ed with pairs of p]c[ures Reading [est ,\a~ scored ,n :u,l ua!s Fir>[. lnJl-
lnged M a sel. C1-uldwt were presen[ed ~llh t Iciual readln~ 3bIi Il\ ior JccIur3c\. comprenen>lon
) of 2. 4. 6 and then S pairs. If a~child success- and rate was scored. Se:>nd. because b\ reoding
I —
r~r~lled all n~lrs wl[hjn a se!.[he~ mo~ed [(~ m~>re <Iov.li, ~cJur3c\ JCJ ;.l~,~rehensltlc md~ ‘Te
r–- .l~he~s<!~nd uere [es[ed If~ni fallu~e Irnpro ied ~>: >I:: ‘.t::.l. :>m;,~>:le rt32Jifi: .(.~rt.
~)[her signific~n[ baseline Jifftrences bet~~em
groups on [he common test battery.
..—=
Table 111 gives the baseline scores for the
Pirxetam- ~nd plwnh-[rested groups on [he t\-
perimenlal test battery. T-test comparison> be-
tween groups at baseline again showed no sign] fi-
cant difference on all but one me~sure. The placebo
group performed significant! bet~er than [he
Pirmxtarn group on [he Paired .Associaw ~’isu~l
\femon Test x baseline ( t = 2.0. P < 0.05}. There
were no o[her baseline differences on the experi-
mental test battery.
To assess the effect of drug trtotment,the mean
change from baseiine was calculated for each $ub-
jwt on each measure and then a~eraged and com-
pared for each treatment group.
Table IV shows the mean change from baseline
fposttest-pretest scores) for each measure in the
common test battery for [he Piracetam and piacebo
groups. AS seen in Fig. 1 for individual re~ding
scores, the Piracetam group demonstrated a s[o[is-
tically significant improvement over the placebo
group (at the P <0.003 level O( .~ccuracy} on their
reading rate from the Giimore test. The Pirmxtarn
group increased [heir reading speed by almost 8
words per min ( - 10%) whereas ~he placebo group
decreased by 3 words per min ( – 4’%). lea~ mg J
difference of almost 11 words per min between Lhe

l..
0

s- 4c0J?Ac”
-19.

..-.
47

Imore oral reodlng

kcur~cy ( ~r~de rating] 3.1 ns.


Reading comprehension
{.grade ra[ing) 49 rr.s

-.
., 6 n.h.

Im.we composl[c reading


,1 correct x ra[e I
%xurac) 6774..3 n,s.
Comprehension 6646.? n.s.
-7.- n.s.

n.>.
n.s.

rcen[ of spelling trrors h P -= 0.01 ‘

n.s..

n.>.

n.s.

n.s.

,BLE 11[
GI. YORE3RAL READING
selrrre Jcores ~’or the Pfrm cram und piorebo Kroupx on [he
C3HPCK1TE SCORES
7erlmenfa/ iest bur{en
PCRCENT CORRfCT X UGWS PW ffINUTE

5( name Ptracelam Plocetw [-[es{

)n. \crbal —
ua I lest
Long 1S1”s
Shorl 1S1’s

pct]uon [es[ —
Iablcs
Long 1S1”s , I
s.
Shcrl 1S1’,

Petlllon lest —
n-, erbal audl[om
Long 1S1’s
Shorl 1S1’s

>red J,S,N-.t~k<
\f~~~~ ,~.,

ken [e, l
,Pdr,.
:-J
2 .--—-=

IWO groups, This incrcme in reading speed for the .A comparison of composite and individual
Pirxe[~m group was mxornpanied by improved reading scores reveals that although [he placebo
reding accurac> or.d comprehension. d{hou.gh group did increxe in their reading accuracy mti
similar g~ins were OIN found In the placebo group comprehension this was accomplished J{ the ex-
~nd. thus. canrm[ be ~scnbed [o drug effect. There pense of [heir reading speed which decreased. pro-
Were no significant dlffcrcnccs between groups on ducing very little
effective
change in thar o~erall
reading mxuracy or comprehension. re~ding performance. The Piracetam group. on [he
Composi[e reading test scores shown in Fig. 2 other hand. not only improved their reading accu-
demonstrate tha[ the Pirwx[am group significan[l~ racy and comprehension but also simul[ancousl>
Impro\ed their effective reading by 16% during the was able [o increase their re~ding rate. Th]s re -
courje of the StUCI\, on bo[h [heir effectlke reading sul[ed in significant gains in their o~erall reading
accuracy ~nd comprehension scores. whereas the performance.
pl~cebo group decreased on both composite reod- Fig. 3 shows tha[ on the Free-Writing Test.
ln~ jc~r~j, This jiff<r<n~e [n performance between both groups showed an increase in the Iota] num-
[he IWO [reatmen[ groups was highly significant ber of words written. The Pirxetam group Irc-
(~ff~Cil~C reoding ~c~urlc>. 1 = 3.J;. P < 0.0011 pro~ed 157 whereas [he pl~cebo grouD sh~we~
effw:i~e rt~din~ cdmprehen.sion. f = l.~~. P < only a 51 gain. although [his difference ~a~ n~’c
0.004). st~tistically significant. The Pir~~ ttam ~mup. how -
.

___ I
49

WRITING SAMPLE (5 MINUTES) sistent ui; h previous fincflngs. shoxing no siytifi-


PERCENT AGE OF WANGC FRW W.5ELX can[ medi:~l abnormalities among the Pirwxtam-
trea[ed subjec:s. The double-blind rating of drug
24 . tolerance b} Ihe ph>jlc:an [hat Pirace-
indicated

2et;
tam uas u ell-[ckra[ed b> the children t meon rat-
ing = 1.] I =O.] ). I exce[]en[. 4 poor). Except for
the one child who suffered from an asthma attack.
all the c!ul~ren uho uere trea[ed with Pimcetam
rem~tnwi heal[h~.

DISC L’SSIO\

‘OTAL !JOR05 uRIT7E\ PERCENTAGE W


Three ~<jul[~ confirm Some of the pre~ious find-
SPELL ING ERRC$5
ings O( N“l]sher et al. ( 1964} that Piracetam in-
~ PIRACHAt! :N = 28) crrases [t-,: ro[t of reoding and of writing accurac~.
n PLACU3G Chs 27)
The amount of changes found in this presen[ stu~y
3 Percentage of change from baseline (posttest mmus are comparable m the results obtained by Wilsher.
[es[ scores) made by Ihe P1racctam and placebo treaImenI
ups are shown for [he S-m!n free-witlng sample. The m(al
in R“ilsher”s S-ucek s[udy. subjects improved their
reading ra[e b> 57. The amount of change found
I
rrber of words wnt Ien m 5 nun i=! each [reatmcnt group. a>
In the prescn[ 12-week s[udy is proportional LO
I as the percentage of spelling errors are graphed.
W’ilsher”~ data with a 101 improi’emen[ in reading
ra[e. This finding. sern in the light of Wilsher”s I
:r. show significant impro~ement over the previous c!a[a. suggests that [he degree of Pirace-
~cebo group in the accuracy of their spelling tam-i nduc:d Improvement in reading and writing
cO.008). The Piracetam group decreased the ma~ bc rejaled [O [he duration of treo[ment. Hou -
-centage of spe!ling errors (number of errors,/ c~er. Impro\emcnt o~er time was mx assessed
a] words written) by 4% whereas [he placebo directl> In [he presen[ s[ud). ,Addi[ional studies
mp Increased in spelllng errors by over 7T. w i]] be n~esjan to es[ablish [he effects of dose-
ese figures change. however, ifoneplacebo ’out- cfurall~n.
r’ subject. who scored well above [he rest of the The presen~ study failed 10 confirm Wilsher’s
N.Jp (83%). is removed from the analysis. Then previous findings of drug-improved reading accu-
: placebo group shows only a 4.5% increase in racy. The Tack of improvement may be due In parl
41ingerrors (P <0.02). Nevertheless. the mends [o some \ en Iargc placebo responders: in fac[. [he
nain the same. Overall. the Plracetam group no[ largest Impro$?men[ in rexfing accurac! (797)
I! increased in their wnung speed. but also uw [’>un~ in 3 member Oi the placebo group.
proved in their spelling accuracy. The placebo Subsun~ial changes in reading accuracy ~nd
Iup’s Increase in writing speed. however. was comprehension a.bIIIIv occurred over the course of
‘se[ b} additional spelling errors. [he s[udi ;or man~ of Ine J~jie\lc children in both
Analysis of the mean change from baseiln< [he P;race:am- and pksc:bo-[rested groups. This
-etest–post[est scores) for each measure in the was somtu ha[ unexpected as [he reading skills t>f
penmen[al Lest bat[e~ for [he Pirace:am and d’ slexlc c!uitiren as 3 group 3re Known [0 be
~cebo groups showed that [here were no slgnifi - dlfficuli {J remeciiate. Tnese marked changes ]n
n[ differences found bc[ueen treatmen[ goup~ re~d]ng suggesI tha[ p?rhaps the ~[ttn[]on ~nd
an~ of the e.xpenmen[~l percep[u~l. memo~ d: po>i[l~e ~e:niorcemeni ~isn [LI [he children in [he
IgUa W megsures gwn. ;Iud>. [ogs:hc: ul[h the exprc>.<d goal of heiplng
Res~i[> from Iabora[,m e’,alu~[lon> ~f blood :he.m IrTI.;Tu\t :oe:r ~e~din~ sk:i[ fi~ uslr, g J untque
~t:,q,.,~, ~ ~<jiLJ::,>n ~~4t~ ~,1 Lhe ,mar,l\~~ =~~,
<w=. hema[olog~
-. .JPJ unn.i! .j]$ ‘Jere cC~n- !,
.
mJde. 1[ IS of consl~er~ble interest th~[ the Im- wrile ~j much w [hey could during a specified !
provements nokxi in [he plxebo-tre~ted grcup [Ime-period. The placebo-treated children did just ;
-. . mirror [he (nsIructions ~iten 10 tfl~rn on r~~di~g (hat. The} mcretiseci the number of words Mril[en
1
I
~nci wn[lng [esIs, ~ier [he:r Original baseline performance. However,
On the Gilmore reading [CSI children were [~’id as ~zs found In reding. they made this g~in J[ the ;
[o red [he passages as well as [hey could. .\l - e~pense of something else. in [his case an in-
though [he children on placebo did Improve the[r creased number of spelling errors. The dyslexics
remding ~ccuracy and cornprehenslon. M !n- on piroc:[am did no{ show this.lose-to-gain”pa[-
~[ruc:ed to do. thev did so bv slow[ng down th<:r tern. R~[her. they incre~sed both the number of
rdlc of re~~ing (wer their bas<iine rexfing ra[e) [d words uri[tcn as uell M decreasing [he number of
.whicve this improvement. Thus. they h~d (o [c~je $pelling errors they made. Even though (he only
ground in rate in order [0 gain it in accur~cy Jnd slgni ficant difference between groups noted at
comprehension, The dvslexics cm Piraoxim. Jn b~seline was the number of spelling errors made.
the other hand. did not need to resorl [o ;Fns w ith [he Pirxetam group making more errors than
s[ro[egy to ~ctueve improvement in reoding aucu - [he plxcbo group. by the end of [he study this
racy md comprehension. Rather. [hey were able to order was reversed. The Piracetam group made
significantly increase their reading rate as well m fewer spelling errors than the placebo group.
their accur~cv and comprehension over their ocgl - Some of the measures in the special perceptual.
nill baseline performance. That is. (hey did ac~[ memor} and receptive language studies suffered
have to lose ground in order 10 gain ground. r~ey from ceiling effects. as most of the subjects found
gained both speed w-d Impro\ed accuracy ~nd be relatively
these tests to easy.indicating mic-
comprehension over [he course of [he $[ud~. The quateperceptual.
memory and language abilities
percentages of subjects in [he Piracetam Jnd for [hc:r age. Most of the subjects performed aI
placebo [reatment groups showing g~ins and losses (he top of the scale on all subtests of the Repe-
In reding accuracy and rate ~re shown in Fig. 1. tition Ttst M well as on all 5 parts of the Token
On [he wrr[ing sample subjects were [old to Test. indicating normal perception and receptive
language abilities at the onset of the study. hence
.-= leaving Iiltle room for improvement. Only 4 sub-
jects s,c~red at least one standard deviation below
the mean cm the Token Test. suggesting that Mat-
[is et ~1.’s(1975j language disorder syndrome was
poorly represented h this dyslexic sample. Sub-
jec[s JISO >cored highly on perceptual sub(~sts ~i
JII 3 Rqm;i[ion Tests. indicating that they hd no
difficult: m discriminating be:ween che di!~eren[
audito~ or visual stimuli. A subgroup of 19 sub-
jects did have difficulty discriminating betw:een the
two computer-synthesized speech syllables /ha/
and , da; with M ms formant transitions. On [he
Rqx[]tlon Test however. perhaps due to the ~er:
small s~mple size. a x~-tes[ indicated no si:nifi -
can[ differences between Piracetam and plwxbu
groups on tlms test. Contrary to previous findings
(Dimond. 1975: Wilsher et al.. 1979). jubjec[~
[ak[ng Pir2cetam did not demonstrate s[a[islicdl>
Sl:nlficdn[ ImPro\-ements in [h~ir shor[-[erm ~nd
serl~l inemdry skills. althou:~ some differences
be[ween non-verbal and verbal stimuli were !ound.

——.
. 1

I
sing non-~ erba] stimuli. [rc2tmen[ groups showed This pat[ern of results calls for a much closer
1 significant differences on the mtol number of examination of the different stages of memory tha[
,rrect stimulus series recalled in [h< audito~ mav be affected by Piracetam. Fu[urc studies
odali[~ of the Repellt]\~n Test. In the VLSUJi ~h~uld examine possible materisl-spa’ific effects
odali[~. subjects on placebo found it easier [o of Piracetam on various memor} components. such /
call the proper sequence of the visual nonsense- as working capacity. rehearsal strategies. re[rieval.
aped stimuii. as demonstrated by their improted retention and recall. in addition. [h< questions of I
1,
ores for total correct [rlals with long [S1”s. In dosage-dependent memory effects should be in-
)n[rast. when test items could be terbally re- vestigated.
:orsed. as {n the Paired Associate Visual Memory Subject selection prwedures ma> OISOhave im-
tst. which used namable pictures as s[imuli. and portant implications for drug studies with dyslei]c
Ie Digi[ Span suboests. the Piracetam-trealed children. Several different subgroups of reading-
oup”s mean final performance and chunge from or language-impaired children. exhibiting differcm[
]seline was almost twice [hat of [he placebo profiles in [he areas of perceptual. memory and
“twp on bo[h tests [ Fig 5). The difference b+ language func[ions. have been cfescnlm?dI see Tallal I
~een groups. however. was not slausticall} jig- and StarL. 1982. for rmiew). Baseiinc tej~ scores
ficant in ei[her case, These [rends [ouard im- suggesl [h~[ the majoril~- of re~ding-impaired
:oved memory for verball) mediated material children par~icipa[ing in this stud! did no[ haw
Iggest thala significant improvement in verbal sisytific3nt perceptual. memory or receptive lan-
wmo~ scores migh [ be realized with a larger guage deficits associated with their reading disabil -
lmple size. a longer duration drug trial. or more i[v. Thus. it was difficult to assess [he pmential
:nsiti\e measures. In addition. Pirace[am’s effecl [Iwrapeultc rfficac) of Piracetam in trcturtg such I
n m~mor) could be mediated by drug-dosage. A deficits in the present stud). lrt order [o bet{er
.-— —..
Ir: :.g. 4800 mg/’day ) dosage might produce assess Pmsce[am”s ability to effect perceptual.
gn,. ..ant ‘results. since pre~ious findings used a memory or receptive language deficl[s. it will be
osage in this range. important to select a group of resoling- or lan-
I
guage-impaired children who show significant def- I
icits in [hese areas at baseline testing. Compari- I
sons between different subgroups of reading-t m-
paired children. selected on the basis of specified
behavioral profiles. may be m impor[ant factor in
50. assessing the effects of noo[ropils on k~rmng- and
~
language-impaired children.
I
4; In summary. Pirace[itm appears to improle
verbal fluencv.as demonstrated b~ Incremed ra[ts I
’32 of reading and writing accurac>. These trend>
encourage a potential role for P\race[~m in [he
, Is clinical remediatmn of dyslexia. although questions
abou[ drug-dosage. duration of tre.i~men[. possible I
e interaction wi[h o[her remedial procedures. di/-
ferent13i effects on various SUbgrOUpSoi learn] ng-
impmred children and selectlvit~ ~f drug -respond<
rematn unanswered Some of these i>jut~ ~re being ,
inves[lga[ed presen[ly,
One final no[e of c3utwn — gl~en [he number
of ~nalises pvrf~>rmed. some .~i :ne Tesult> ~>h-
tained cL~uld be In[erpre[ed .X ;!l.ln;e ~1<.wrrenit~

Seiecti\e rtplicat~~,n of [hew fini:n~ u :h J dI’fc~-

4
I

/&-
.
.
ent

v~lida[e
group of dyslexic children
these results.
is necessary (o
x’ ( 19-61 P~act[am-induced
m~nce: ~ con[roiled
4cr~ Pwchw .SCand.,
Mudy
Improwmen!

54 150-160
on normidiy
of mcn:ll
Jglng
pcrfor.
,ndI\lduJls.

Quinn. P.O. and Rapuport. J,L.t1975)One yew foIlow-up of


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.Aman. 31 G, and W’ecry. J,S. ( 1982) Me[hylphenldate and children with Ieamlng disabtll[les. ,Ywrupwcr.;/wyu 12

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Chdtf fr~chwyv. tn press, m,eon. J . Walers. B, md Resnlck. .W. ( 1980) Effects of
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; .4 bnorm. Chdd Psychol,. 5; 35 I -369. Sprague. R.L. ( 1972) Ps>chophjrmacology and Ieursmg dis-
B~rkle>. R.A. and Cunn]rtgham. C,E. ( 1980) The parenl-chdd orders. ~. Operaf. Psychiatry, 3: S6-67.
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by s[imulan[ drugs. In R.(M. Knights and D,J. Bakker hyperk]ne!lc chrldren: differences In dose effmtj cm leom-
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nomsc nervous sys[em actiwty and stimulant drug effec~s. acrd .Yaorropic Drugs Paper presemed at Third lntemation~l
1 Ch,ld PsychoI. P$vchmrp. 18: 347-357. College of Congress on Psychommattc Medlc:nc. Rome,
Calliauu. L. and Marchau. .W. ( i975) C!irtlcal mial of P1race- [taly.
[am in disorders of consciousness due 10 head Injury ,4cIa nk. K.J. ( 1972) The clinic~l use of Pirace[~m. J ncw
4 nwsrhemol. Belg.. 26: 51-60. noo[roptc drug: [he treatment oi jenlie :n~cslu[wn
*
Conrsers. C K. and Werry, J.S. ( 1979) Pharmacothempy. In f-f. .4rznelrn -Fwrch., 22:975-977.

Quay and J.S. Win-y ( Eds. I. Pswhopatholoycol Dmrrders of Symmes. J.S. and Rapopor[. J.L. ( 1972 I Unexptx:ed reading
Ch(/tfhoad Wile>, New York, failure. Am. J Orrhopmch/ur~, 42: 82-91.

Denckla. M.B. wsd Rudel. R.G. 119761 RJpId “Jutoma[tzed” Tall.11. P (19gOa) Perceptual requlsl(es for ktnguJgt. In R
naming ( R. A.X. ): dyslexia differen(la(ed from other leam- ScJuefeibusch ( Ed.). .Von-Speech Lsrrguage and C.>mmurric~-

mg disabtIiues. .Versroprycho/o,gfa, 471-479. non. University Park Press. Baltimore,


De Renzt. E. and L’ignolo. L.A. ( 1962) The Toktn TesI: a T.dldi. P ( 1960b I Auditory temporal perception. pimrucs ~nJ
>ensluse WS[ 10 detec[ receptive disturbances m .sphasla. reading disabilities in children. Brufn berg,. 9 IS:- 198,
Bruin. 85:665-678. Tallal, P and Smrk. R.E. ( 1982) Perceptual/mo[or profiles of
Dlmond. S.J, ( 1975) The effects of a rsootroplc sub>unce on [he reading-impaired duldren with or withou[ concormtant or~l
cripocl[y for verbal memory and Ieamtng in normal man. language deficits. ,Ana/. Dvsle.r[a. 32: 163-176.
Third Congress o~ lnrernwional Colleye of Psychosomanr Thomson, .M. E. ( 1977) [denufylrsg (he dyslexic chsl.-l. Dysle.rIa
.~ledicfne. 9: 16-20. Rec.. Is: 5-12,
Dtmond. S.J. and Brouwers. E.Y M. ( 1976) [mprovemert[ of L’CB ( 1980) ,Vwrropii, LCB. Pharmaceutical Dlsts;on. Brus.
human memory ~hrough [hc usc of drugs. Ps)c/rop/rarmaco/- SCIS.Belgium.
,)Q. 49: 307-309. Weiss. G,. Kmger. E,. Danielson, IJ ~nd Elman, .\~. ( 1975 I
Gt[tlcman-Kleln. R. md Kleln. D F ( 19+5 I Are beha~loral and Effec[ of long-term ~re~tment of hyperactive ch;dren ulth
psychome[nc changes relaled !rr methylphenidate-treated. me(hylphendale. Cwr. Med. ,.SSSW.J,. 11: 159- i65.
h~perlcuve chlldrenq In(. J .Wenr /feu/rh. 4. 182-198. W’trn, JS.(198]
)Drug+andIearrung.
J, Chi/d ff~chcl Ps\ch/-

Gl[[leman-Kleln. R. and Kleln. D F ( 1976) .Wcthylphcnldate U:fl, 22: 281-2%3.


t(fec[s In learning disabilities psvchometnc changes. Arch. W’erry, J.S. and <man. M.G. ( 1975) Me[hylphemdate Jnd
Gcn. fs~chturn, 33 655-669. Halopendol in chsidren. effects on ~[[en[ion. memo~ md
Jack>on. \l. D ( 1980) Furlher e,ldencc for a re!auonshtp be- JCII\; I> ,4rch Gen. fswh(m~, 32. 790-795.
[uecn memom access ~nd reading ablll[v. Journcd of ;’erh Wllsh.er. C.. ,A[k)ns. G, and v~ns(ield, P , 1979) Rrace!am ~s
Lwrn Vtrb Brhat.. 19:683-694, ~n md (o Ieamlrrg In d}sle~ia, preitm]nan repor~. PsI,Ao.
\fIIIIS. S.. French. J.H. and Rapln. 1. ( 1975) D)sle~la In + pharmacolo~, 65: 107-109.

*-
children and young
[ogtcd j: ndromes.
us. P.. Cronholm.
adults:

De[
three independent
Wed.

B.. Levander,
Chl/d Veuro/.

S E. and %h~lltng.
neuropsyche
17: 150-163.
D - p
*
r her, C.. ,A~klns. G.
P:rxet~m
18: 19-:5.
and Mansfield.
on dvslexIcs” read!ng abllll\
P (19S5i
J l-am.
Effecrs of
DIsdv/..

-#==%
.. 102

The Effects of Nootropics on Memory:


..—-!%

New Aspects for Basic Research
k’
C. Mondadon, F. Petschke, A. Hau.der
PharmaceuticalResearch Department, CIBA&EIGY Limited, Bade, Switzerland

f!oTICE ..-
T,wS M,fl.TERfALMAY BE PROTECTEDBy
COP’Y,3;G}P;T LAW (TITLE 17, U.S. CODE)

Summary Wirkungender Nootropika auf das Gediichtnis:


Neue Aspekte fur die Gmndlagenforschung
The mechanism through which nootropics of
the piracetam type (i.e., piracetarn itself and its analogues ox- Es besteht noch immer keine Gewillheit dariib-
iracetam, pramiracetam, and aniracetam) improvememory er, auf welche Weise die Nootropika des Piracetamtyps
is still uncertain. Its elucidation will, however, not only mark (Firacetam und dessen Analogverbindungen Oxiracetam,
an advance in the treatment of cognitive disorders, but also Ramiracetam und Aniracetam) das Ged5chtnis verbessem.
shed light on the basic processes of memory storage. Al- Die ICh%ung dieser Frage wiirde nicht nur einen Fortschritt
though the great majority of the findings available so far bei der Behandlung kognitiver Sttmmgen darstellen, son-
seem to suggest cholinergic mechanisms, divergent results dem such die der Gediichtrtisspeicherung zugrundeliegen-
are obtained whenever parallel experiments are performed den Vorgange erhellen. Obwohl die gro13e Mehrzahl der bis-
with two or more of these compounds. More recent observa- Iang verfiigbaren Befunde auf cholinergische Mechanismen
tions indicate that interactions with steroids take plaw. All hinweisen, werden widerspriichliche Ergebnisse enzielt, so-
four compounds are inacxive in adrenalectomized laboratory bald parallele Experiment mit zwei oder mehreren dieser
animals; chemical blockade of the adrenal cortex with Verbindungen durchgefi.thrt werden. Neuere Beobachtun-
aminoglutethimide and pretreatment with epoxymexrenon, gen scheinen auf Wechselwirkungen mit Steroiden hinzu-
a potent mineralocortieoid antagonist, eradicated the deuten: alle vier Verbindungen sind bei adrenalektomierten
.—-=
memory-enhancing effect of all four substances. Labortieren unwirksam; sowohl eine chemische Blockie-
rung der Nebennierenrinde durch Aminoglutethimid als
such eine Vorbehandlung mit Epoxytrrexrenon (einem po-
tenten Mineralokortikoidantagonisten) blockiette die ge-
dachtnisverbessemde W%kung aller tier Substanzen.

The elucidation of biochemical bases and the learning and-tnemory and speculation about the possible in-
regulation of memory is one of the greatest challenges in neu- volvement of this type of receptor in memory processing ( ,kfor-
robiology. [t is therefore hardly surprising that every year riset al., [986). In the meantime, it has become evident that the
hundreds of papers are published dealing with some paflicu- responses seen under NMDA blockade only apply in certain
Iar facet of memory. Our knowledge of the subject matter in- circumstances and to certain processes of memory ( ,klon-
creases almost daily, but more in width than in depth, We now dadoriet al., 1989). Thus, while the assortment of transmitters
know of many transmitters, receptors, and modulators that irw+ved in memory processing increases, that does nothing to
play some part in memory processing: but each new finding is alter the fact that almost every pharmacological manipulation
soon relativized by the realization that it is not generally valid, of the CNS has some influence on certain, though not all,
but simply sometimes true under certain limiting conditions. forms of learning and memory (Mondadori, 1987).
In this field, progress tends to follow the discovery of a new
pharmacological tool, e.g., a new specific receptor blocker or The opposite way of seekln~ insight into the
activator, or an enzyme inhibitor. Consequently, the prevalent processes of memory consists in charaaenzlng biochemically
method in efforts to identify the mechanisms and the neuronal the substances known to affect memory, and then attempting
networks operative in memory processing relies on the testing to correlate certain components of their biochemical profile
of mechanistically specific preparations for potential effects withtheireffect on memory. The memory-blocking effects of
on memory in animal models. For example, the ?JNIDA block- certain antibiotics such as puromycin, anisomycin, and Lvclo-
em (MK 801, AP5, and AP7) that recently became available heximide, for instance, inspired a very large number of studies
-- encouraged studies of the influenw of NMDA blockade on of the possible relations between inhibition of protein synthe-
sis - scientifically the most appealing aspect - and memory
(for a review see, for example, Davies and Squire, 1984). The
Phannacopsychiat. 22 (1989) 102-106 (Supplement) underlying mode of action has, however, always remained
0 Georgl%ieme Verlag Stuttgan New York conjectural, because these antibiotics exert many other known
7he E~ects OfNootropics on Memoty: NewAspectsfor Basic Research I%armacopschiat.22 (1989) 103

effects (see, for example, Flexner and Goodman, 1975; Rain- hemispherical transfer ( Buresova and Bures, 1976), on
bow et al., 1979) and quite probably just as many other un- augmentation of paradoxical sleep in rats ( Werzel, 1985), on
=-”mown effectsthat might equally well be responsible for the increased theta power in the hippocampal EEG, and on a re-
;sturbanm of memory, or at least contribute to it. The possi- duction in the power of cortical slow waves (Poschel et al.,
bility that the known biochemical effect under scrutiny may 1985).
not be responsible for the obsetved effect on memory, or that
that effect may be due to the intetplay of several discrete ef- htteresting and biochemically inexplicable ob-
fects, must always be taken into consideration, even in studies servations indicate that both piracetam and oxiracetam inten-
using the abovmentioned “specific tools”: failure to do so sify the anticonvulsive effects of anti-epileptics such as car-
makes false conclusions unavoidable. bamazepine ( Mondadori et al., 1984; Mondadon and
Schmurz, 1986; Hawkins and Meih.mby, 1986).
One practicable and valid approach to the ex-
perimental investigation of mechanisms underlying memory Btiemieal effects of piraeetam-
storage, or the regulation of memory storage, maybe afforded like nootrwiea
by the piracetam-like nootropies, These are interesting prep-
arations, above all because they exert distinct, positive effects There are relatively few data available on the
on various manifestations of memory, yet provoke few or no biochemical effects of the piracetam-like nootropics. For a
side+ffects. The fact that they have so far been found to dis- long time, the observation by Nickolron and Wohhuis ( 1976)
play scarcely any effects in most of the traditional assays used that piracetam stimulates adenylate kinase activity was the
in biochemistry laboratories may make them appear all the sole measured biochemical effect. Woe/k (1979) then showed
more or all the less attractive, depending on the viewpoint of that piracetam increased the incorporation of 32P in
the observer. lf, however, as has already been suggested ( Giur- phosphatidylinositol and phosphatidyl chloride in glia cells
gea, 1973, 1982), they do act specifically on cugnitive and neurons. Grauet al. ( 1987) reported an increase in glucose
pro~ses or on the structures and mechanisms responsible for utilization under hypoxic conditions and accelerated recovery
cognitive processes,then the elucidation of their mode of ac- of the EEG. Poschel et al. (1983) demonstrated that neither
tion might represent a very significant advance. The following piracetam nor pramiracetam bound to muscarinic cholinergic
remarks, illustrated by a selection of experimental observa- receptors; nor did binding occur in a dopamine assay with
tions, will be concerned with the progress made to date along haloperidol. The uptake of GABA and serotonin was not af-
this line of research and the possibilities emerging from it. fected by piracetam or by pramiracetam. I%gsley et al. ( 1983)
.-. found no evidence of activity in traditional pharmacological
Neuropharmaeologieal fiiings assays. No effects were detetible on the concentrations of
noradrenaline, dopamine, 5-HT, or 5-HIAA in the cortex or
The first experimentally demonstrable effect midbrain of the rat. At very high doses (200 mgikg i.p.),
of piracetam, the prototype substance, on the CNS was inhibi- piracetam increased striatal HV without affecting DA levels,
tion of central nystagrnusin the rabbit ( Giwgea et al., 1967). In indicating that it augments the turnover of DA. Pramiracetam,
retrospect, however, the vast majority of the experimental pre- however, did not increase DA turnover. Receptor assays re- I
clinical findings seem to be indicative of effecls on cognitive vealed no af?lnity of either piracetam or pramiracetam for DA
processes,in particular on learning and memory in a very wide muscarinic, alpha 1,2- and beta 1,2-adrenergic, 5-HTI -, 5-
variety of forms. Piracetam, for instance, diminishes the dis- HTz-, GAB& adenosine, and benzodiazepine re~ptom, On
ruptive effect of a cerebral electroshock on the orientation of the other hand, it was shown ( hgsley et al., 1983; Shih and
rats in a water maze ( Giurgea andMouravieflkukse, 1972). figsley, 1985) that pramiracetam increased high-affinity cho-
Many other authors have also observed anti-amnestic effects line uptake into hippoeampal synaptosomes. The effective t
of piracetam and related substances: distinct protective effects doses were 44 and 88 mg/kg i.p.: neither higher nor lower
against the disturbance of memory following cerebral electro- doses were active. Surprisingly enough, piracetam at 100 and
shocks in passive- and active-avoidanw tests on mice and rats 300 mg/kg and aniracetam between 10 and 200 mg\kg both
were noted by Cumin et al. (1982) after treatment with had no effect on high-affinity choline uptake. These results
aniracetam and piracetam, and by Mondadon et al. (1986) with piracetam are slightly at variance with the observations
after treatment with oxiracetam and piracetam. Sara (1980) reported by Pedala et al. (1984). These latter authors found
observed similar responses toetiracetam. Buder et al. (1987) that both oxiracetam and piracetam exerted positive effects on
described anti-amnestic effects of a whole series of piracetam high-affinity choline uptake in the rat conex and hippocam-
analogues, including pramiracetam. Numerous observations pus, The discrepancy may have been due to the timing of the
have also been made of direct positive effects on learning and determinations.
memory: aniracetam and piracetam ( Yamada et al., 1985;
Wohhuis, 197 I ), etiracetam (Sara, 1980) and oxiracetam The above cholinergic effects are supple-
( Mondadori et al., 1986) were found to exert direct effects on mented by findings made by ~pignoli andPepeu ( 1986) which
acquisition and retention performance in rats and mice in pas- demonstrated that oxiracetam prevented the decrease in the
sive- and active-avoidance paradigms; pramiracetam in- ace[ylcholine content of the cortex and hippocampus induced
_+reased the acquisition rate in a 16-armed radial maze ( Murray t,Y cerebral electroshock treatment (piracetam was inactive).
‘Id Fibiger, 1986) and in a place navigation test (Morris maze) Further observations show that piracetam reduces
, Poschelet al., 1985): positive effects of aniracetam were dem- scopolamine-inducedamnesia (Piercqy et al., 1987) and, ac-
onstrated in matching-to-sample tests(Pon[ecorvoet al., 1985). cording to one interesting report (Pilch and Miiller, 1988), ele-
AJl these findings are supplemented and indirectly supponed vates the muscarinic cholinergic receptor densit) in the frontal
by observations of a facilitating effect of piracetam on inter- cortex of aged rats.
104 Pharnracopsychiat.22 (1989) C. Mondadori, F. Petschke,A. Hiiu.der

Taken as a whole, this selection of findings nenolone), and 11-hydroxylation (i.e. glucocortieoid bio-
might at first glance give the impression that the piracetam-like synthesis) (for a review see Santen et al., 198I). Exactly as
nootropics act by way of cholinergic mechanisms. This con- adrenalectomy, this pretreatment rendered the four
clusion is all the more plausible because there is a very large piracetam-like nootropics inactive. Arninoglutethimide itself
.——.
body of literature on the significance of cholinergic mecha- had no effects on the retention performance of the mice. These
nisms in learning and memory (see, for example, Drachman, data provided the first indication of the involvement of prod-
1978; Barrus, 1980). On closer scrutiny of the available results, ucts of the adrenal cortex in the mediation of the effects of the
however, it becomes plainly evident that there is not one single piracetam-like nootropics. It must be cmtceded [hat amino-
report in which several piracetam-like nootropics tested con- glutethimide is not entirely devoid of effects on the adrenal
currently have actually been found to produm the same ef- medulla: increases in catecholamine levels have been ob-
fects. l%e observed effects, insofar as they have been studied, served (Duckworth and Kitabchi, 1971). To exclude this possi-
are not common to all nootropics (Shih and I%gsley, 1985; bility, mice were pretreated with epoxymexrenon. Pretreat-
Spignoli and Pepeu, 1986). Considering their similarity in ment with this specific mineralocorticoid antagonist (de Gas-
structure as well as in their pharmacological profiles of activity paroet al., 1987) gave similar results: the memory-enhancing
on learning and memory, it seems quite likely (or at least quite effects of the piracetam-like nootropica were completely
possible) that all representatives of this class modulate blocked; and again the drug itself had no effect on memory.
memory via the same mechanism. Failing any definite evi- lltese findings prove that steroids can play a role in the media-
dence to the contrary, this is certainly reason enough to con- tion of nootropic effects. Furthermore, these were the first
tinue the search for one common mechanism of action shared pharmacological experiments in which all four prototype sub-
by all the substances belonging to this class. stances behaved in exactly the same way. ( Mondadon”et al,
1989, in press)
Are steroids involved in the mediation
of nootropic effects? It is interesting to note that certain other sub-
stances also lose their memoty-modulating activities in the ab-
Even if allowance is made for indi”tidual varia- sence of the adrenals: e.g. amphetamine and hydroxyam-
tions dependent on their particular phamnacokinetica, it is still phetamine (A4arrz”nezet al., i 980) and vasopressin (130rellet al.,
true to say that whenever neuropharrnacdogkd agents are ad- 1983). However, the effects of these drugs appear to be de-
ministered systemically the brain is flooded with active sub- pendent on the function of the adrenal medulla,
stance. One may well wonder what chance there is of im-
proving the performance of such a complex and finely tuned Although autoradiographic studies of the rat
organ by so crude a method. On the other hand, there are in- brain give the impression that oxiraeetam does not readily
_____ dications pointing to the existence of endogenous physiologi- penetrate the blood-brain barrier (Mondadoriand PerscAkz,
cal mechanisms that can, under certain circumstances, 1987), the above-mentioned findings as a whole cannot be
heigthen the performance of the memory: flash-bulb memo- taken as evidence that the piracetam-like nootropics act pe-
ries (see e.g. Brown and Kulik, 1977), i.e. abnormally sharp rec- ripherally. Amongst various other possible mechanisms (see
ollections of certain events mostly associated with highly also Mondadoriand Perschke,1987), it is conceivable that acti-
emotional states, are a good example. lf such mechanisms do vation of steroid receptors in the brain may be a prerequisite
in fact exist, then they obviously deserve to be regarded as for the efilcacy of the piracetam-like nootropics; in other
potential targets for pharmacological interventions. In this words, steroids may mediate the action of nootropim on
cmrtex~ account must also be taken of the ~ssibility that the memory. The converse is equally plausible, i.e. that these prep-
selective physiological activation of certain neuronal mecha- arations directly or indirectly modulate the effects of certain
nisms in the brain proceeds via peripheral mediators. Nor can steroids on memory. There is ample evidence to show that
one simply dismiss the further possibility that the memory steroids can exert an influence on memory (see for example,
facilitation induced by nootropic drugs may come about Micheau et al., 1985; Bohus and de K/oet, 198 I ), A new facet
through modulation of such processes. Since the pituitary- emerging from the authors’ experiments is that aldosterone-re-
adrenal axis plays a significant part in emotional states, it ceptor-mediated activity may play a part in memory pro-
seemed impofiant to find out whether piracetam-like nootrop- cessing or its regulation.
ics retained their activities in adrenalectomized animals. They
did not: oxiracetam, piracetam, aniracetam, and pra- How these effects come about is unclear; but
rniracetam showed no memory-enhancing effeets in extrapolation from findings on the peripheral effects of
adrenalectomized mice ( Mondadori and Pe(schke, 1987). A steroids discloses a particularly fascinating aspect. It has been
series of funher studies proved that the blockade of their ac- demonstrated that in various organs steroids affect specific
tivities was not an effect of dosage: even s@nificantly higher gene expression by mod ., ii:g the rate of transcription of d
doses of the nootropies were ineffective after adrenalectomy specific set of genes ( l’amamoro, 1985; Schufz, 1988). It
( Mondadon, Ducret and Petschke, 1989, in press); Accord- would therefore be extremely interesting to know whether
ingly, the next question was whether the products of the piracetam-like nootropics can exert direct effects on gene tran-
adrenal medulla or of the cortex are the critical components in scription, or modulate the action of steroids on gene transcrip
the activity of nootropics. To answer that question the animals tion. There are already a number of publications on the effects
~.,erepretreated with aminoglutethimide, which is an inhibitor of steroids on protein synthesis (Arenarufer and Vallk, 1980:
— of several cytochrome-P450-mediated hydroxylation steps in Ergen et al., 1980; Nesder et al., 1981; Mikusnic et al., 1986).
steroid biosynthesis in the adrenal cortex: e.g. 18-hydroxyla- Since it is known that protein synthesis plays an important part
tion of corticosterone (i.e. aldosterone biosynthesis), side- in the formation of memory traces (for a review see Davies and
chain cleavage (i.e. conversion of cholesterol to preg-
-.

7he EjXectsof Nootropicson Memoty: New Aspects for Basic Research Pharrrwopschiat. 22 (1989) 10S
.-
.
..%wire,1984),it is conceivable that nootropics may improve Hawkins, C. A., J. H. Me/lanby: Piracetam potentiatm the antiepilep-
__memory via modulation of protein synthesis: tic action of carbamazepine in chronic experimental Iimbic
epilepsy. Acts Neurol. Stand. (Suppl. 109) 74(1986) 117-121
Martinez, Jr., J. L., B. J. Vasquez, H. Righter, R. B. Messing, R. A. Jm-
Ilte present observations, which suggest that sen, K. C. Liang, J. L. McGaugh: Attenuation of amphetamine-ind-
steroids may be involved in the mediation of the nootropic ac- uced ersharrccment of learning. Brain Res. 195 (1980)433443
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cannot simply be dismissed. Europ. J. Pharrnacol. 106(1985) 3946
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(1978)651-661 costerone Increases the Amount of Rotein I, Neuron-specific t
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Neurochem. 35 ( 1980) 598-602 macol. 25 (1976) 2241-2244
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Gm.Tea, C. E., F. Mouraviefl-Lemi.rse. EtTecr Facilitateur du Piercey. M. F., G. D. J“ogekang,S. R. Franklin,A. H. Tang:Reversal of
Piracaam sur un Apprentissage Re@*;tif chez Ie Rat. J Pharrrra- scopolamine-induced Amnesia and Alterations in Energy Meta-
Col.3 (1972) I7-30 bolism by the Nootropic Piracetam: Implications Regarding Iden-
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115 - Pilch, H., W. E. Midler: Piracetam Elevates Muscarinic Cholinergic
Giurgea, C. E.: The Nootropic Concept and Its Respective implica- Receptor Density in the Frontal Cortex of Aged but not of Young
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=--- pothesis on the Mechanism of Action of the Ant]motion Sickness Ma~~hing-lo-Sample Performan .e of Monkeys and Pigeons. Phar-
Drugs. Arch. int. Pharrnacodyn. 166 (1967) 379-387 macol. Biochem. Behav 22( 1985) 745-752
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Poschel, B P H., P M. Ho, F. W’. .Vmlemarr, M. J. Callahan: Pharmac-
ologic Therapeutic Whdow of Ramiracetam Demonstrated in
..-

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CH402 Basel
New Cognition Activator Agcn~ Praminmetam (C1-879). Psycho-
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Raikxrw, T. C., P. L. Hoflman, L. B. Flexner: Studiesof Memory: A
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Drugs on in Vitro Rat Hippocampal Synaptosomai Sodium De-
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2145-2152
Spignoli, G., G. C. Pepeu:Oxiracetanr Prevents E1ecuushock-Induced
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Sc/witz, G.: Control of Gene Expression by Steroid Hormones. Biol.
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Wefze/, W.: Effects of nootropic drugs on tJte sleep-waking pattern of
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Week, H.: Effects of Piracetam on the Incorporation of‘2Pintothe
Phospholipids of Neurons and G[ial Cells Isolated from Rabbit
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W’ohhuir, O. L.: Experiments with UCB 6215, A Drug Which En-
hancts Acquisition in Rats: 1SSEffecu Compared with Those of
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Yamada, K., T hue, hi. Tanaka, T. Funduwa: Rolongation of
Latencies for Passive Avoidarrcg Responses in Rats Treated with
Arriracetam or Piracztam. Pttarmacol. Biochem. Behav. 22 ( 1985)
.- 645-648
Yamanrofo, K. R.; Steroid receptor regulated transcription of specific
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–—-.
.
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 reallya vitamin-likecompound
consistingof a niacinanalog (n-nicotinoyl)uniquelybonded to GABA
(gammaarninobutyricacid). When niacinis bound to GAB~ it creates a
moleculethat readilypenetrates the blood-brainbarrier to enhancecerebral
and peripheralcirculation.What enables picamilon to work so well is the
synergism between the niacin and GABA molecules.

Suggested dose: One tablet, two to three times a day.


If cognitive enhancing results do not occur in 30 days, double the dose.
.:

Piracetam is a derivative of the amino acid GABA that increases the


sensitivity of receptors in the brain involved in 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.

Suggested dose: Piracetam should be used in doses ranging from 1600 to


: :-l,:; il .,,. .,.: .,
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may produce side effects such as minor irritation, People using Retin A
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National Library of Medicine: IGM Full Record Screen

•1
— 000

00000

m
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 Physical-Technical Low Temperature Institute, National Academy of
k AFFILIATION: 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
60-70% of the ❑ eurons 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 calciumchannel blockers, generally
reversed or weakened the effects of piracetam on the changes seen in test
cells. This indicates that the effects of piracetam twult from its action on
calcium channels; seiective changes in calcium channels may determine
which piracetam-inductiefkts appear at the cdhrlar Ievak It is
hypothesized that the piracetam-sensitive cellu[ar plasticity mechanisms
may make a significant contribution to its nootropic action at the
behavioral leveL
MAIN MESH Lymnaea/*PHYSIOLOGY
SUBJECTS: Neurons/*DRUG EFFECTS
Nootropic Agents/ANTAGONISTS & TNHIW*PHARMACOLOGY
Piracetam/ANTAGONISTS & INHIB/*PHARMACOLOGY

.-.

3/1 1’9812:06 PM
ADDITIONAL Animal
MESH Cadmium/PHARMACOLOGY
SUBJECTS: Calcium Channel B1ockers/PHARMACOLOGY
_—_ Electrophysiology
Ganglia, Invtwtebrate/CYTOLOGY~~SIO~GY
In Vitro
Membrane Potentials/DRUG EFFECTWPHYSIOLOGY
Nifedipine/PHARMACOLOGY
Parietal Lobe/CYTOLOGY/DRUG EFFECTS
Patch-Clamp Techniques
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY O(Calcium Channel Blockers)
NUMBERS: O(Nootropic Agents)
21829-25-4 (Niftiipine)
7440-43-9 (Cadmium)
7491 -74-9 (Piracetam)

•1 IDIOO
00000

—_

~*f2 3/1198 12:06PM


National Library of Medicine: IGM Full Record Screen

— -.
.-——

F?
TITLE: Nootropic drugs and brain cholinergic mechanisms.
AUTHOR: Pepeu G; Spignoli G

& AUTHOR Department of Preclinical and Clinical Pharmacology, University of


AFFILIATION: 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 evkknces
demonstrating an interaction between nootropic drugs and-brain
cholimwgie mechanisms; second, to define the rdationship between the
effects 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 these drugs pmwnt or revert scopolamin~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 dos~effect relationships
result for both actions. Phosphatidylserine restores acetylcholine synthesis
and conditioned responses in aging rats. 4. The medmiam through which
the action on cholinergic systems might take place, including stimulation of
the high affinity choline uptak% are discussed. The information available
are not yet sufficient to define at which steps of the cognitive process the
action on cholinergic system plays a role and which are the influences of
the changes in cholinergic function on other neurochemical mechanisms of
learning and memory.
MAIN MESH Acetylcholine/* METABOLISM
SUBJECTS: BraWDRUG EFFECTS/* METABOLISM
---- Psychotropic Drugs/* PHARMACOLOGY

1 of2 310I98 4:39 PM


-r . .. .

ADDITIONAL Animal
MESH Receptors, Cholinergic/DRUG EFFECT!YMETABOLISM
SUBJECTS: Scopolamine/PHARMACOLOGY
---. . Synapses/DRUG EFFECTWPHYSIOLOGY
PUBLICATION JOURNAL ARTICLE
TYPES: REVIEW
REVIEW, TUTORIAL
LANGUAGE: Eng
REGISTRY O(Receptors, Cholinergic)
NUMBERS: 51-34-3 (Scopolamine)
51-84-3 (Ace-@choline)

310/98 4:39 PM
El
TITLE: Piracetam elevates muscminic cholinergic receptor density in the frontal
/ cortex of aged but not of young mice.

b’ AUTHOR: Pilch H; Muller WE


AUTHOR Psychopharmacological Laboratory, Central Institute of Mental Health,
AFFILIATION: Mannheim, Federal Republic of Germany.
SOURCE: Psychopharmacology (Berl) 1988; 94(1):74-8
NLM CIT. ID: 88158509
ABSTRACT: Chronic treatment (2 weeks) with -am (56Q m eneedaiiy P@
eiwtted m-tholinoceptor density in the frontal cortex of aged (18 rmmths)
female mice by about ~ jmt had no cffkct on m-ehdinoceptnr
densityk thefrontal cork of young (4 weeks) mk The effect of
piracetam on m-cholinoceptor density as determined by the specific
binding of tritiated QNB was not affected by concomitant daily treatment
with either choline (200 mg/kg)or scopolamine(4 mgkg). It is concluded
that the effectof p’ uacctam w m-chdinoceptor dedty could explain the
po~e ef&t.s which have been reported for combinations of cholinergic
prwmor treatment with piracetam on memory and other cognitive
functions in aged experimental animals and patients and could also
represent part of the possible mechanism of action of piracetam alonm
MAIN MESH Aging/* METABOLISM
SUBJECTS: Cerebral Cortex/DRUG EFFECTS/* METABOLISM
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Receptors, Muscarinic/*DRUG EFFECTS
ADDITIONAL Animal
MESH Atropine/PHARMACOLOGY
SUBJECTS: Female
Male
Mice
Oxotremorine/PHARMACOLOGY
Quinuclidinyl Benzilate/PHARMACOLOGY
Scopolamine/PHARMACOLOGY
_—__

1 of2 3,1098 4,40PM


,,..~.,,.- ”.. ..-- ..,,- Iy . .. . . . . . . -..- . ...-”../ . ---- .

PUBLICATION JOURNAL ARTICLE


TYPES:
LANGUAGE: Eng
.——-
REGISTRY 0 (Pyrrolidinones)
NUMBERS: O(Receptors, Muscarinic)
51-34-3 (Scopolamine)
51-55-8 (Atropine)
6581 -06-2 (Quinuclidinyl Benziiate)
70-22-4 (Oxotremorine)
7491 -74-9 (Piracetam)

_—-_

3110/98 4.40PM
2of2
National Library of Medicine: lGM Full Record Screen

——-=.
la

m
TITLE: Treatment of acute ischemic stroke with piracetam. Members of the
f Piracetam in Acute Stroke Study (PASS) Group.
~ AUTHOR: De Deyn PP; Reuck JD; Deberdt W; Vlietinck R Orgogozo JM
u

AUTHOR Department of Neurology, Middelheim Hospital, Antwerp, Belgium.


AFFILIATION:
SOURCE: Stroke 1997 Dec;28(12):2347-52
NLM CIT. ID: 98074088

I et-3 311198 ll:59AM


ABSTRACT: BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with
neuroproteetive properties, has been~ti in pilat.fidim @ -e
compromised regional cerebral blood flow in patients with acute strdkc”
and, ~ seun after onset, to improve clinical outcome. We performed a
multicenter, randomized, double-blind trbd to test whether piracetam
conferred benefit when given within 12 hours of the onset of acute ischemic
stroke to a large group of patients. METHODS: Patients received placebo
or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks
and 4.8 g daily for 8 weeks. The primary end point was necrologic outcome
after 4 weeks as assessed by the Orgogozo scale. Functional status at 12
weeks as measured by the Barthel Index was the major secondary
outcome. CT scan was performed within 24 hours of the onset of stroke but
not necessarily before treatment. Analyses based on the intention to treat
were performed in all randomized patients (n = 927) and in an “early
treatment” population specified in the protocol as treatment within 6
hours of the onset of 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 Barthel 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, 95°/0 confidence intenal, 0.97 to 1.59; P = .15). Deaths were
fewer in the piracetam group in those patients in the intention-to-treat
population admitted with primary hemorrhagic stroke. Post hoc analyses
in the eariy treatment subgroup showed differences favoring piracetam
relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam
60.4, placebo 54.9; P = .07) and 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: Piiimn did not influence
outcome when giveII within 12 hours of the onset of acute ischemic stroke.
Post hoc anatyses suggest that piracetam may confer benetlt when given
within 7 hours of o- particularly in patients with stroke of moderate
and severe degree A randomized, placebo-controlled, multicenter study,
the Piracetam Acute Stroke Study II (PASS II) will soon begin.
MAIN MESH Cerebral Ischemia/*DRUG THERAPY/MORTALITY
SUBJECTS: Cerebrovascular Disorders/*DRUG THERAPY/MORTALITY
Neuroprotective Agents/ADVERSE EFFECTS/* THERAPEUTIC USE
Nootropic Agents/ADVERSE EFFECTS/* THERAPEUTIC USE
Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE

—_-
.-—

2of3 3?1198 11.59 AM


ADDITIONAL Acute Disease
MESH Aged
SUBJECTS: Aged, 80 and over
Double-Blind Method
Female
Human
Male
Middle Age
Support, Non-U.S. Gov’t
Survival Analysis
Treatment Outcome
PUBLICATION CLINICAL TRIAL
TYPES: JOURNAL ARTICLE
MULTICENTER STUDY
RANDOMIZED CONTROLLED TRIAL
LANGUAGE: Eng
REGISTRY O(Neuroprotective Agents)
NUMBERS: O(Nootropic Agents)
7491 -74-9 (Piracetam)

.-

311!98 11:S9AM
3of3

R
TITLE: The effects of piracetam in children witlm!dydeb
-- -./ AUTHOR: Di [anni M; Wilsher CR; Blank MS; Conners CK; Chase CH; Funkenstein
HH; Helfgott E; Holmes JM; Lougee L; Maletta GJ; et al
6
SOURCE: J Clin Psychopharmacol 1985 Oct;5(5):272-8
NLM CIT. ID: 86009005
ABSTRACT: Following previous research which suggests that piracetam improves
perform~n~e on tasks associated with the left hemisphere, a 12-week
double-blind, 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
perfo~ance. Children wire 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
,., ,
populatiom~~witlr~~ &
q,~~ other eflects on W?ding were obse~ed” ~ addition)
~~~s ,.. . obsem~ in
those piracetam-treated patients who showed relatively poor memory at
baseline. It is,mggested that Ion te~ treatment with piracetam may
%${$,:.,,,::, ..
result in ad
MAIN MESH Dyslexia/*DRUG THERAPY
_-— SUBJECTS: Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
Pyrrolidinones/* THERAPEUTIC USE
ADDITIONAL Adolescence
MESH Child
SUBJECTS: Clinical Trials
Depression/CHEMICALLY INDUCED
Human
Male
Memory Disorders/DRUG THERAPY
Memory, Short-Term
Support, Non-U.S. Gov’t
PUBLICATION CLINICAL TRIAL
TYPES: CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE: Eng
REGISTRY O (Pyrrolidinones)
NUMBERS: 7491 -74-9 (Piracetam)

_—__

2 of3 3/10:98 3:54 J’M


TITLE: Piracetam an~exia: effects on reading tests.
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 ~x.xm ●
have
shown improvements in reading skills, V4KM memwy and v*’
~g •b~, W -!ydm=d IWO-S@ of ktta
‘#&&Two hundred twenty-five dyslexic children between the ages of 7
years 6 months and 12 years 11 months whose reading skills were
significantly below their intellectual capacity were enrolled in a multicenter,
36-wee~ double-blind, placebo-controlled study. Children of below average
intelligence, with abnormal findings on audiologic, ophthalmologic,
necrologic, psychiatric, and physical examinations, who were emotionally
disturbed or educationally deprived and who had recently been treated
with psychoactive medication were excluded from the trial#&dam w-
wcii -ted, with no serious adveme clinical dabora!ory#f&ts
.s@@k?IIt improvements in
re4ng &w’@ay Oralxkadiing Ti%tyan(freadEig c4nnpm!Eb8io!9
(Gilinore Oral Reading Test). Treatment efftwts were evident after 12 weeks
and were sustained for the total period (36 weeks).
MAIN MESH Dyslexia/*DRUG THERAPY/PSYCHOLOGY

SUBJECTS: Piracetam/ADVERSE EFFECTS/* THERAPEUTIC USE
Pyrrolidinones/* THERAPEUTIC USE
*Reading
ADDITIONAL Child
MESH Clinical Trials
SUBJECTS: DoubleBlind Method
Female
Human
Male
Random Allocation
Support, Non-U.S. Gov’t
PUBLICATION CLINICAL TRLAL
TYPES: CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
LANGUAGE: Eng
REGISTRY O (Pyrrolidinones)
NUMBERS: 7491 -74-9 (Piracetam)

- ❑ p!R%izlFzEiiqw

2ot_3 310983
:5.3PM
M
r===% TITLE: An overview of pharmacologic treatment of cognitive decline iwthe aged.
.
AUTHOR: Reisberg B; Ferris SH; Gershon S
Y SOURCE: 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 Cognition Disorders/*DRUG THERAPY
SUBJECTS:
ADDITIONAL Anticoagulants/THERAPEUTIC USE
MESH Clinical Trials
SUBJECTS: Comparative Study
Dihydroergotoxine~HERAPEUTIC USE
Human
———__ Hyperbaric Oxygenation
Methylphenidate~HERAPEUTIC USE
Parasympathomimetics/THERAPEUTIC USE
Peptides/THERAPEUTIC USE
PiracetamflHERAPEUTIC USE
Procaine/THERAPEUTIC USE
Support, U.S. Gov’t, P.H.S. Vasodilator Agents~HERAPEUTIC USE
PUBLICATION CLINICAL TRIAL
TYPES: JOURNAL ARTICLE
REVIEW
LANGUAGE: Eng
REGISTRY O(Anticoagulants)
NUMBERS: 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)

2o1-2 3 ‘1098 4:0(’) PM


lltl~.lr lJV. 1+. JL.+L/&~l . ..1V1%llCll L! lU/Jr5WlXill,.4

m
/, TITLE: Profound effects of combining choline and piracetam o~l
() ~~d cholinergic function in aged rats.
AUTHOR: Bartus RT; Dean RL 3d; Sherman KA; Friedman E; Beer B
SOURCE: Neurobiol Aging 1981 SummeG2(2): 105-11
NLM CIT. ID: 82058347

_&=-Q.

.—–.

I of3 3 10:983:50 PM
ABSTRACT: In an attempt to gain some insight into possible approaches to reducing
age-related memory disturbances, aged Fischer 344 rats were administered
n 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 tasb 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 age-related deficits
on this passive avoidance task and that memory disturbances are at least
partially responsible. Those subjects given only choline (100 mgkg) did not
differ on the behavioral task from control animals administered vehicle.
-m~w’-) ~m’m*i.-
*@M~ W“* givl!lithe’plriitititarnkli—’lwmhdfb
,(100mg/kgufeach) exhibited mtentiom WON severdtim-lmtter t-n
~~~- h a second study, it was shown that twice the
dose of piracetam(200 mgkg) or choline (200 mgkg) 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 6-100A). 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
(19VO). No measurable changes in striatum 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 eflects of
combining choline amll!p~racetam are quitell’ifferent lhan’fiose o%takwd
with either drug alone and support the notion that in.order to achieve.
substantial efficacy in ag~ subjeets it may be nmmsary to reduce mWp1c3,
interactive neuroehem~ckm in the brai+er M“ activity in,
more than one pammeter of a deficient metabolic pathway.
MAIN MESH *Aging
SUBJECTS: Choline/ANALYSIS/* PHARMACOLOGY
Memory/*DRUG EFFECTS
Parasympathetic Nervous System/* PHYSIOLOGY
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY

2of3 3110983.50 PM
ADDITIONAL Acetylcholine/ANALYSIS/SECRETION
MESH Animal
.-. SUBJECTS: Brain Chemistry/DRUG EFFECTS
Male
Rats
Rats, Inbred F344
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY O(Pyrrolidinones)
NUMBERS: 51-84-3 (Acetylcholine)
62-49-7 (Choline)
7491 -74-9 (Piracetam)

3of3 310983:50 [’M


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E
TITLE: Piracetam-induced facilitation of interhemispheric transfer of visual
information in rats.
AUTHOR: Buresova O; Bures !
h
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 unaffected but that the secondary trace (in the
ipsilateral hemisphere) was considerably improved and almost equalled the
primary one (savings increased from 20-30% to 50-60%). 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
literalized by 5 days of monocular overtraining, Piracetam facilitated
formation of the secondary engram induced by 3 interocular transfer trials.
It is concluded that Piracetam enhances transcommissural encoding
mechanisms activated in the initial stage of monocular learning and in some
forms of interhemispheric transfer, but does not affect the
transcommissural readout. This effect is interpreted as a special case of the
Piracetam-induced facilitation of the phylogenetically old mechanisms of
redundant information storage which improve Iiminal or subnormal
learning.

10s2 310 %3 3.51 PM


MAIN MESH Form Perception/*DRUG EFFECTS
SUBJECTS: Pattern Recognition, Visual/*DRUG EFFECTS
–—–
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
Transfer (Psychology )/*DRUG EFFECTS
ADDITIONAL Animal
MESH Corpus Callosum/PHYSIOLOGY
SUBJECTS: Discrimination Learning/DRUG EFFECTS
Male
Memory/DRUG EFFECTS
Overlearning/DRUG EFFECTS
Perceptual Masking
Rats
Spreading Cortical Depression
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng

_r—-p

2o1-2 3 10983.51 I’M


E!!
.—.2 TITLE: Some effects ofpiracetam (UCB 6215, Nootropyl) on ~ie
-/ schizophrenia.’
3
AUTHOR: Dimond SJ; Scammell RE; Pryce IG; Huws D; Gray C
SOURCE: Psychopharmacology (Berl) 1979 Sep;64(3):341-8
NLM CIT. ID: 80057401
ABSTRACT: A study is described of effects of a nootropic drug on chronic
schizophrenia. The nootropic drugs act on the central nervous system with
the cerebral cortenslfieir tq@ Chronic schizophrenic patients on the
drug showed’improvement in object namingand in tes@where the patient
was required to indicate the number of times he had been tapped.
Improvements were also noted inhrning aud ~~ @ dichotic
listening the patients showed a reduction in the amount of incorrect verbal
responses produced&llwcw wev! no impmw-tsio ~~-1
social behaviour ra~These results suggest some cognitive improvement
I!hitlittle if any change in the disease state of the patient.
MAIN MESH Piracetam/*THERAPEUTIC USE
SUBJECTS: Pyrrolidinones/* THERAPEUTIC USE
Schizophrenia/* DRUG THERAPY
ADDITIONAL Adult
MESH Chronic Disease
--- SUBJECTS: Clinical Trials
Dichotic Listening Tests
DoubleBlind Method
Female
Human
Male
Middle Age
Motor Skills/DRUG EFFECTS
Psychiatric Status Rating Scales
Schizophrenic Psychology
PUBLICATION CLINICAL TRIAL
TYPES: JOURNAL ARTICLE
LANGUAGE: Eng

--

2of2 3/10/98 3:57 PM


National Library of Medicine: IGM Full Record Screen

_-—_
•1 000
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!?3
TITLE: Increase in the power of human memorf in ❑ormal man through the use
of drugs.
AUTHOR: Dimond SJ; Brouwers EM
k SOURCE: Psychopharmacology (Bet-l) 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 capsulu @ 400 mg per dayr~n a double blind
study. Each subject learned series of words presented as stimuli upon a
memory drum. No effects were observed after 7 days but -14 day~.
Vdld learning had signifkan~ increati
MAIN MESH Memory/*DRUG EFFECTS
SUBJECTS: Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL Female
MESH SUBJECTS: Human
Male
Stimulation, Chemical
Verbal Learning/DRUG EFFECTS
PUBLICATION CLINICAL TRIAL
TYPES: CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
LANGUAGE: Eng

Iofl
National Library of Medicine: [GM Full Record Screen

----
•1 000
00000

TITLE: Piracetam facilitates retrieval but does not impair extinction of


bar-pressing in rats.
AUTHOR: Sara SJ; David-Remacle M; Weyers M; Giurgea C

t-
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. Diwg4zaa&d
@reals had signifkantly shorter xmsponsc Jatcndcs than sali.netreattdl
@malu~,q{wulti arc rnteqn@ed as a fhcditatim<oftial pwcesses
_——_
after fo~e@ii& Zhe 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 Conditioning, Operant./*DRUG EFFECTS
SUBJECTS: Extinction (Psychology )/*DRUG EFFECTS
Memory/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidinones/* PHARNIACOLOGY
ADDITIONAL Animal
MESH Male
SUBJECTS: Rats
Water Deprivation
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng

lofl 310,984:11 PM
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.“ ,, ..... . .. . .. – .,

El
TITLE: Piracetam impedes hippocampal neuronal 10SSduring withdrawal after
–~.

v AUTHOR:
AUTHOR
AFFILIATION:
Brandao F; Paula-Barbosa MM; Cadete-Leite A
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 prokmgd @had
consumption induced hippocampal ncnrondloss. 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 hippocampal formation 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 withdrawaLThac data suggcat that piracct.am treatment
imped~ during withdrawa~ the purming of mmronal degeneration.
MAIN MESH Ethanol/* ADVERSE EFFECTS
SUBJECTS: Hippocampus/*DRUG EFFECT!YPATHOLOGY
Neurons/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Substance Withdrawal Syndrome/* PATHOLOGY
ADDITIONAL Analysis of Variance
MESH Animal
SUBJECTS: Cell Count/DRUG EFFECTS
Diet
Male
Rats
Rats, Sprague-Dawley
Support, Non-U.S. Gov’t
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY 64-17-5 (Ethanol)
NUMBERS: 7491 -74-9 (Piracetam)
—_

2of3 3:1 1;98 12.03 PM


TITLE: Does piracetam counteract the ECT-induced memory dysfunctions in
//
depressed patients?
‘J AUTHOR: Mindus P; Cronholm B; Levander SE
SOURCE: Acts Psychiatr Stand 1975 Jun;51(5):319-26
NLM CIT. ID: 75201625
ABSTRACT: A double-blind, intra-individual cross-over comparison of the effect of
piracetam on retrograde memory impairment as measured by the KS
memory test battery was performed in connection with second and third
Bi-ECT in 18 patients diagnosed as suffering from depression. The seizure
duration and the post-ECT EGG patterns were examined visually and the
post-ECT confusion time was measured. Piracetam was given orally in the
dose of 4.8 g/dsy for 3 days. No significant effects were obtained on memory
scores, electrical stimulus duration, EEG pattern or post-ECT confusion
time. The fmdiqp. mq Mkalc.thaLtlm-@kct of.piracetam
shown Enanimai ekctroconvuslive stimulation (ECS) is due to a
Wmtemdm of tbe disturbing ~ hypoxia on iuemM@mdonw’It is
concluded that more information is needed as regards the pharmacokinetics
and the mode of action of the drug.
MAIN MESH Depression/* THERAPY
SUBJECTS: Electroconvulsive Therapy/* ADVERSE EFFECTS
Memory/*DRUG EFFECTS
—_ Memory Disorders/’ ETIOLOGY/PREVENTION & CONTROL
Piracetam/*PHARMACOLOGY/THERAPEUTIC USE
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL Adult
MESH Aged
SUBJECTS: Clinical Trials
Drug Evaluation
English Abstract
Female
Human
Male
Middle Age
Placebos
PUBLICATION CLINICAL TRIAL
TYPES: CONTROLLED CLINICAL TRIAL
JOURNAL ARTICLE
LANGUAGE: ??, :

__-—..

2ot-2 310984:25 PM
1%
TITLE: Effects of oxiracetam on learning and memory in animals: comparison
~ with piracetam.
‘/’AUTHOR: Mondadori C; Classen W; Borkowski J; Ducret T; Buerki H; Schade A
u SOURCE: Clin Neuropharmacol 1986;9 Suppl 3: S27-38
NLM CIT. ID: 87244092
ABSTRACT: The effects of oxiracetam and piracetam were compared in learning and
memory tests in rats and mice. In the dose range examined, the two
nootropics were equally active in reducing the amnesia induced by
cerebral electroshock in the mouse. Step-down retention performance,
however, was distinctly improved by oxiracetam but unaffected by
piracetam, no matter whether it was given before or immediately after the
learning trial. Oxiracetam also improved acquisition performance in aged
(24- to 27-month-old) rats in an active-avoidance situation at doses of 30
and 100 mg/kg i.p. whereas piracetam showed no effect at 100 mg/kg i.p.
MAIN MESH Avoidance Learnin~DRUG EFFECTS
SUBJECTS: Memo~/*DRUG EFFECTS
Piracetam/*PHARMACOLOGY
Pyrrolidines/*PHARMACOLOGY
Pyrrolidinones/* PHARMACOLOGY
ADDITIONAL Aging/PHYSIOLOGY
MESH Animal
-. SUBJECTS: Comparative Study
Drug Administration Schedule
Electroshock
Mice
Rats
PUBLICATION JOURNAL ARTICLE
TYPES:
LANGUAGE: Eng
REGISTRY O(Pyrrolidines)
NUMBERS: O(Pyrrolidinones)
62613-82-5 (oxiracetam)
7491 -74-9 (Piracetam)

20f2 310’9X 42X PM


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National Library of Medicine: IGM Full Record Screen

_—_ ❑

l??
TITLE: Effect of chronic trwatment with phwetam and tacrinc m some changes
/(
u AUTHOR:
caused by thymectomy in the rat brain.
Song C; Earley B; Leonard BE
AUTHOR Department of Pharmacology, University College Galway, Ireland.
AFFILIATION:
SOURCE: Pharmacol Biochem Behav 1997 Apfi56(4):697-704
NLM CIT. ID: 97276543

-. —.
—.

.—.

1 et-3 3/1 19812:04 PM


ILL+J,,, lJU. LW,JA. WU/&~l. ,,%llVlll: L701Y~UC1411-+J U.,p.r? ,Jv . ..4-. .“! w& “U” .. . . . “!. W.... . . . . . ““.... . . .

ABSTRACT: Thymectomized rats, 5 weeks after surgery, showed a significant


impairment in learning and memory as shown by deficits in passive
avoidance and in the Morris water maze test. The behaviour of the
————.
thymectomized rats in the “open field” apparatus was largely unchanged.
Following treatment for 20 days with either piracetam (500 mg/kg) or
tacrine (3.0 mg/kg), the deficit in passive avoidance learning was largely
reversed. Chronic treatment with tacrine also reversed the deficit in the
behaviour of the thymectomized rats in the Morris water maze. The effects
of thymectomyon the biogenic aminesand some of their metabolizesin the
amygdaloidcortex, hypothalamus,striatum and olfactory bulbs were also
determined.Relative to the sham-operatedcontrols,thymectomy resulted
in a reduction in the noradrenaline concentration in the amygdala,
hypothalamus, and olfactory bulbs. This effect was reversed by chronic
piracetamand tacrine treatments. The concentration of dopamine was also
reduced in the olfactory bulbs after thymectomy whereas in the striatum
the concentrationof 5-hydroxytryptamine(5-HT; serotonin) was increased.
The concentrationof gamma amino butyric acid (GABA) was determined
in amygdaloid cortex and hippocampus only. The only significant change
occurred following chronic treatmentof thymectomizedrats with tacrine,
when a significant elevation of GABA was found. Neither piracetam nor
tacrine produced any change in the amines of their metabolizes in the
sham-operated controls. Tacrine, however, elevated the dopamine and
reduced the 5-HT content of the hypothalamus and increased the
3,4-dihydroxylphenylacetic acid concentration of the striatum of
——___
thymectomized rats. Examination of the differential white blood cell count
of the thymectomized rats showed that the percentage of lymphocytes was
decreased, and the percentage of neutrophils increased, relative to the
sham-operated controls. Chronic Iacrine, but not piracetam, treatment
reversed the lesion-induced changes.
MAIN MESH Behavior, Animal/*DRUG EFFECTS
SUBJECTS: Brain/DRUG EFFECTS/* METABOLISM
Nootropic Agents/* PHARMACOLOGY
Piracetam/*PHARMACOLOGY
Tacrine/*PHARMACOLOGY
Thymus Gland/* IMMUNOLOGY
ADDITIONAL Animal
MESH Avoidance Learning/DRUG EFFECTS
SUBJECTS: Corticosterone/BLOOD
Leukocyte Count/DRUG EFFECTS
Male
Maze Learning/DRUG EFFECTS
Neslrotransmitters/METABOLISM
Rats
Rats, Sprague-Dawley
Thymectomy
PUlfLICATION JOURNAL ARTICLE
.—-.—.
.—- TYPES:

2of3 3/’11/98 12.04 PM


Lif~A3%ension Foundation Offshore Drugs Page 120f13

.4=%=
Picamilon appears to be more effectivethan Hydergineor vinpocetinin
improvingblood flow to the cerebral vessels. Picarnilon 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 amdog (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 between the niacin and GABA molecules.

Suggested dose: One tablet, two to three times a day.


If cognitive enhancing results do not occur in 30 days, double the dose.
-“...>~’”

PIRACETAI$I

Piracetamis a derivativeof the aminoacidGABAthatincreasesthe


sensitivityof receptorsinthe braininvolvedinmemoryandlearning.
..?= .
.-—- Piracetamis 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, memo~, and creativity. It has been shown
to harmonize and synchronize the spheres of the brain by anchoring
itiormation within the brain.

Suggested dose: Piracetam should be used in doses ranging from 1600 to


2400 mg a day taken first thing in the morning.

RETIN A

Retin A is a highly publicized vitamin A derivative that stimulates skin cell


renewal, increasing the creation of youthfld cells at the skin’s surface. Retin A
may produce side effects such as minor irritation, People using Retin A
.>.. .,...
should stay out of the sun and use a sunblock for normal sunlight exposure,
.L.. ,,J,
,, ....-.
, .:.:7 -.;-:?.q~
because Retin A increases skin sensitivity to sunlight.

http: //lef.org/cgi-local/shop, pl/page=offshore html 3/10/98


—., ,
A. INGREDIE NT NAME:

CRINE HYDROCHLO RIDE

B. Chemical Name:

3-Ctioro-7-methoW-9-( l-methyl+-diethyltinobutyltino)acfidine Dihydrochloride;


Mepacrine Hydrochloride; Quinacrinium Chloride
2-Ctioro-5-(Omega-Diethyltino-Mpha-Methylbu&ltino)-7-Metho~actidine
Dihydrochloride
3-Ctioro-9-(4'-Diethyltino-l'-Methylbutyltio)-7-MtihoWacfidine Dihydrochloride
6-Chloro-9-((4-(Diethylamino)- 1-Methylbutyl)Amino)-2-Methoxyacridine
Dihydrochloride
3-CNoro-7-MethoW-9-( l-Methy14-Diethylatinobutyltino)Actidine Dihydrochloride
2-Methoxy-6-Chloro-9-(4-Diethylamino- 1-Methylbutylamino)

C. Common Name:

Acrichine, Acriquine, Akrichin (Czech), Arichi~ Atabrine, Atabrine Dihydrochloride,


Atabrine Hydrochloride, Atebrin, Atebrine, AtebrinHydrochloride, Chemiochin, Chinacri%
Chinacrin Hydrochloride, Crinodor~ Dial, Erio~ Italchi~ malaricida, Mecryl, Mepacrine
Dihydroch.loride, Mepacrine Hydrochloride, Methoquine, Acridine Dihydrochloride,
Metochi~ Metoqui~ Metoquine, Palacri~ Palusan, Pentilen, Quinacrine Dihydrochloride,
Quinacrine Hydrochloride

D. Chemical grade or description of the strength, quality, and purity of


the ingredient:

Assay: 100.12%
98 yO

E. Information about how the ingredient is supplied:


Bright Yellow, Crystalline Powder. It is odorless and has a bitter taste.

F. Information about recognition of the substance in foreign


pharmacopoeias:

Pharmacopoeias.In Arg., Belg., Br., Braz., Eur., Fr., Ger., Hung., Ind., It., Mex., Neth.,
Nerd., Po]., Rus., Span., Swiss., Turk., and U. S.
.
-.
G. Bibliography of available safety and efficacy data including peer
reviewed medical literature:

H. Information about dosage forms used:

Tablets

L Information about strength:

100mg - 900mg

J. Information about route of administration:

Orally

K. Stability data:

Melting Point: 257 C (DEC)


—— Incompatible with alkalis, nitrates, and oxidizing agents.

L. Formulations:

M. Miscellaneous Information:

Page -2-
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QUALI~ CONTROL REPORT

cHEMICAL NAME. :QUINAcRINE Hydrochloride ‘Sp

MANUFACTURE LOT NO. :025

PHYSICAL TEST

SPECIFICATION TEST STANDARD...usP — /BP_/t4ERcK_/NF_/MART ._/CO. SPECS._.

l)DESCRIPTION .:
P - BRIGHT YELLOW, CRYSTALLINE POWDER. IS ODORLESS AND HAS A BITTER
~ TASTE.

2)S0LUB1LIT% .:
SPARINGLY SOLUBLE IN WATER; SOLUBLE IN ALCOHOL.

3)MELTING POINT.:
MELTS AT ABOUT 250 DEGREES WITH DECOMPOSITION.
.—=
4)SPECIFIC GRAVITY. :

5)IDENTIFICATION .:
A)COMPLIES (A) AS PER IR SPEcTRuM USP xXII.
B)COMPLIES (C) As PER USP XxII”
c)A SOLUTION 1 IN 100 HAS A PH ABOUT 4.5.

FAILS .:
PASSES. :

COMMENTS.:QUINACRINE DIHYDROCHLORIDE IS ALSO KNOWN AS QUINACRINE HCL.

ANALYST SIGNATURE. : DATE .:

DATE .: INITIAL. :
PRJ3PACK TEST. :

RETEST .: DATE .: INITIAL. :


---- ------------------ IDENTIFICATION -------------------
PRODUCT #: 22299-2 NAME: QUINACRINE DIHYDROCHLOIUDE HYDRATE,
98?4.
CAS #: 69-05-6
MF: C23H30CLN30
SYNONYMS
ACRICHINE * ACRIQUTNE * AKRICHIN (CZECH) * ARICHIN * ATABRINE *
~[ ATABRINE DIHYDROCHLORIDE * ATABRINE HYDROCHLORIDE * ATEBRIN *
i

ATEBRINE * ATEBRIN HYDROCHLORIDE * CHEMIOCHIN * CHINACRIN *


CHINACRIN
t HYDROCHLORIDE *
2-CHLORO-5-(OMEGA-DIETHYLANIINO-ALPHA-METHYLBUTYLAMlNO)
@(
-7-METHOXYACRIDINE DIHYDROCHLORIDE “]
3-cHLoRo-9-(4’-DrETHYLAMrNo- 1‘-
METHYLBUTYLAMINO)-7-METHOXYACRIDINE DIHYDROCHLOIUDE *
6-CHLORO-9-((4-
(DIETHYLAMINO)- I-METHYLBUTYL)AMINO)-2-METHOXYACRIDINE
DIHYDROCHLORIDE
*
3-CHLORO-7-METHOXY-9-(1-METHYL-4-DIETHYLAMINOBUTYLAMINO)ACRIDINE

DIHYDROCHLORIDE~CRINODORA * DIAL * ERION * ITALCHIN* MALARICIDA *

MECRYL * MEPACRINEDIHYDROCI-ILORIDE
* MEPACRINEHYDROCHLORIDE*

METHOQUINE~ C
~ [2-METHOXY-6-CHLORO-9-{4-DETHYLAMIN0-I-~THyLBUTyLAMIN0)]
ACRIDINEDU-HYDROCHLORIDE * METOCHIN* METOQUIN * METOQUINE*
PALACRIN
b< * PALUSAN* PENTILEN * QUINACRINEDIHYDROCHLORIDE* QUINACRINE

HYDROCHLORIDE * 866 R.P, * SN 390 *


------------------ TOXICITY HAZARDS -------------------
RTECS NO: AR7875000
ACRIDTNE, 6-CHLORO-9-((4-(DIETHYLAMINO)-1 -METHYLBUTYL)AMINO)-2-

METHOXY-,DIHYDROCHLORIDE
TOXICITYDATA
ORL-RATLD50.660MG/KG JPETAB91,157,47
IVN-RATLD50:29MG/KG JPETAB91,157,47
IUT-RATLD50:100MG/KG UEBA6 16,1074,78
ORL-MUSLD50:557MG/KG JPETAB91,157,47
IPR-MUSLD50:189MG/KG JPETAB91,133,47
SCU-MUSLD50:212MG/KG ABEMAV1,317,41
IVN-MUS LD50:38 MG/’KG JPETAB 91,157,47
ORL-RBT LD50:433 MG/KG JPETAB 91,157,47
IVN-RBT LD50:9 MG/KG 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 (FLACCID PARALYSIS WITHOUT
ANESTHESIA)
BEHAVIORAL (ALTERED SLEEP TIME)
BEHAVIORAL (SOMNOLENCE)
BEHAVIORAL (TOXIC PSYCHOSIS)
BEHAVIORAL (CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD)
VASCULAR (OTHER CHANGES)
LUNGS, THOW4.X 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 FERTLLITY INDEX)
EFFECTS ON FERTILITY (PRE-IMPLANTATION MORTALITY)
EFFECTS ON FERTILITY (POST-IMPLANTATION MORTALITY)
ONLY SELECTED REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES
(RTECS)
DATA IS PRESENTED HERE, SEE ACTUAL ENTRY IN RTECS FOR COMPLETE
INFORMATION.
------------------ HEALTH HAZARD DATA -----------------
ACUTE EFFECTS
HARMFUL IF SWALLOWED, INHALED, OR ABSORBED THROUGH SKIN.
MAY CAUSE EYE IRRITATION.
MAY CAUSE SKIN IRRITATION.
TO THE BEST OF OUR KNOWLEDGE, THE CHEMICAL, PHYSICAL, AND
TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY INVESTIGATED.

FIRST AID
.-——%. IN CASE OF CONTACT, IMMEDIATELY FLUSH EYES WITH COPIOUS AMOUNTS
OF
WATER FOR AT LEAST 15 MINUTES.
..-.,
IN CASE OF CONTACT, IMMEDIATELY WASH SKIN WITH SOAP AND COPIOUS

AMOUNTS OF WATER,
IF INHALED, REMOVE TO FRESH AIR, IF NOT BREATHING GIVE ARTIFICIAL
RESPIRATION, IF BREATHING IS DIFFICULT, GIVE OXYGEN,
IF SWALLOWED, WASH OUT MOUTH WITH WATER PROVIDED PERSON IS
CONSCIOUS.
CALL A PHYSICIAN
WASH CONTAMINATED CLOTHING BEFORE REUSE.
\l -------------------- PHYSICAL DATA --------------------
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-CONTAINED BREATHING APPARATUS AND PROTECTIVE CLOTHING
TO
PREVENT CONTACT WITH SKIN AND EYES
=-. UNUSUAL FIRE AND EXPLOSIONS HAZARDS
EMITS TOXIC FUMES UNDER FIRE CONDITIONS
------------------- REACTIVITY DATA -------------------
INCOMPATIBILITIES
STRONG OXIDIZING AGENTS
STRONG ACIDS
MAY DISCOLOR ON EXPOSURE TO LIGHT
HAZARDOUS COMBUSTION OR DECOMPOSITION PRODUCTS
TOXIC FUMES OF
CARBON MONOXIDE, CARBON DIOXIDE
NITROGEN OXIDES
HYDROGEN CHLORIDE GAS
--------------- SPILL OR LEAK PROCEDURES --------------
STEPS TO BE TAKEN IF MATERIAL IS RELEASED OR SPILLED
EVACUATE AREA
WEAR SELF-CONTAINED BREATHING APPARATUS, RUBBER BOOTS AND HEAVY

RUBBER GLOVES.
SWEEP UP, PLACE IN A BAG AND HOLD FOR WASTE DISPOSAL
AVOID RAISING DUST.
VENTILATE AREA AND WASH SPILL SITE AFTER MATERIAL PICKUP IS
_— COMPLETE.
-=
.-—- WASTE DISPOSAL METHOD
DISSOLVE OR MIX THE MATERIAL WITH A COMBUSTIBLE SOLVENT AND BURN


INA
CHEMICAL INCINERATOR EQUIPPED WITH AN AFTERBURNER AND SCRUBBER,

OBSERVE ALL FEDERAL, STATE, AND LOCAL LAWS


--- PRECAUTIONS TO BE TAKEN IN HANDLING AND STORAGE ---
CHEMICAL SAFETY GOGGLES
RUBBER GLOVES
NIOSW’MSHA-APPROVED RESPIRATOR
SAFETY SHOWER AND EYE BATH
USE ONLY IN A CHEMICAL FUME HOOD
DO NOT BREATHE DUST
DO NOT GET IN EYES, ON SKIN, ON CLOTHING
WASH THOROUGHLY AFTER HANDLING
TOXIC
KEEP TIGHTLY CLOSED
LIGHT SENSITIVE
STORE IN A COOL DRY PLACE
HARMFUL BY INHALATION, IN CONTACT WITH SKIN AND IF SWALLOWED

WEAR SUITABLE PROTECTIVE CLOTHING


THE ABOVE INFORMATION IS BELIEVED TO BE CORRECT BUT DOES NOT
_—_ PURPORT TO BE
ALL INCLUSIVE AND SHALL BE USED ONLY AS A GUIDE SIGMA ALDRICH SHALL
NOT BE
HELD LIABLE FOR ANY DAMAGE RESULTING FROM HANDLING OR FROM
CONTACT WITH THE
ABOVE PRODUCT SEE REVERSE SIDE OF INVOICE OR PACKING SLIP FOR
ADDITIONAL
TERMS AND CONDITIONS OF SALE
Ii UNITED ST.~TES OF .{ MERICA .5!]!)

Packaging and storage-Preaerve Pyrox31in loosely packed in cartons, protected


from light.
CATEGoRl”—Pharmaceutic necessity fOr COLLODION.

Quinacrine Hydrochloride
A %
1
r! QUINACRISE HYDROCHLORIDE
A ‘-”
3-Chloro-7-methoxv-9-f l-met hd-1-diethvlaminobutvlamino)acridine
b’” ‘--
Dfiydnxh[oride; ~lep&rine ~ydrochlo~ide; Quin&nnium’ Chloride

NH—CH(CH3)—CH2C H2CH2—N+(C2H5)2

\cH30@@c, H ]2C-.2H20

C=H~OCIYSO 2HC1 2Hz0 Mol. wt. 508.94


Quinacrine HydrochIonde
CzsHwCl~oO 2HC1. 2H,0.
contains not less than 98 per cent of
!Q
/

-_ E sommy=a&b “nacrine Hydrochloride occurs as a bn~


a bitter taste.
rq Umacrui=>-drochlonde
crystalline powder.

diaaolves in about 35 ml. of water.


It k soluble in alco~ol.
Identification-
.1: To 5 mf. of a solution of Quinacrine Hy@hloride (1in4L)), add a sl~ght excess
LIX ofammonia T.S.: a yellowtoorange, ody precipitate ofqumacnne baseis
formedwhichadherestothewallofthevessel and iasoluble in ether. I
)tton B: To 5 ml. of a solution of Quinacrine Hydrochloride (1 in 40), add 1 ml. of di- I
luted nitric acid: a yellow crystalline precipitate ia formed.
he action
ofa mixtureofnitric C: To 5 ml. of a solution of Quinacrine Hy#roc~oride (1 in 40), add 1 ml. of
mercuricchlorideT.S.:
schiefly
ofcellulose
tetranitrate D: The titrate from the preapltate,
a ‘euowoV’P’U*
tamed m M‘owed””
Zdent@zhon test
A, acidified
with nitric acid, responds to the tests for Ch.fode,. page 901.
pH—The pH of a solution of Quinacrine Hydrochloride (1 m 100) ia about 4.5.
, matted mam of filaments, resembling water, page 942-Determine the water content of Qtirine Hydrochloride by
e touch. [tisexceedingly flarnrrwble, drying at 105 ❑ for 4 hours or by the Karl Fischer method: it containa not less than
witha luminous flame. When kept in
is decomposed -with the evolution of Restdue
‘.wr Centmdnot
on I?nttlon, ‘ore
page ‘bans
9 12—Tr e remdws
‘*t ‘f on
‘awr”
Igtutlon
“ of 200 mg. of Quinacrine
ue. Hydrochloride is negligible.
Jwly but completely in 25 parta of a Assay—Transfer to a 100-ml. volumetric &wk about 250 mg. of Quinacrine Hydrw
f alcohol. It is soluble in acetone and chloride, accurately weighed,. diescke it in 10 ml. of water, then add 10 ml. of a
n these solutions by water. solution Prepared by dissohng 25 Gm. of sodium acetaw and 10 ml. of g]acid
ut 500 mg. of Pyro Iin, accurately acetic acid in water to make 100 ml. Add exactly 50 ml. of 0.1 N taasium bi-
id wateq, and ignite Tt e Pyroxyhn at chromate and water tQ make 100 ml., s~pper the flask, mix choroug E’y, and filter
it the dtsh to redness, and cool: not through a dry titer aper into a dry flask, rejecting the first 15 ml. of the tiltmte.
>Ieaaure 50 ml. of J e subsequent filtrate into a glaas-stippered &k, add 1,5 ml.
lm. of Pyroxylin with 20 ml. of water
not have an acid reaction to litmus. contents
‘f gently, acid
‘yticMOric and and
allow20”to
Wan‘f~-ium the dark‘o&de
for 5 T”S”’
rrunutes.
‘mp~dh%%~ofvat$
on a steam bath, and dry the rmidue and titrate the liberated iodine with 0.1 N sodium thioaulfatil adding starch T.S~
of residue remaina. aa the end-point is neared. Perform a blank determination with the same quanti-
600 THE PEARXACOPEM OF TEE

tiea of the same magenta and in the same manner (see Reaidwd ZWutti, material. Make the s
S32). Each ml. of 0.1 Npotiu d.ichromate is equivalent to 8.4S2 mg. of ~~ pletely with successive
CINaO . 2HC!I 2HZ0. ~ct is colorless. 1
Packaging and storage—P~e Quinambe Hydrochloride in tight, light-reaist,ant cotton moistened with
cent.ainem.
%’%ml&Y’K&’%
CATEGoRY—hthetintic; antima]aria]; antiprotozoan. ~~ bath until the q
ple~ly with the aid of 2
DosE—usuAL—SUppti\,&
procwrJ as directed in 1
Antimalanal-100 mg. @g with “then add 10 t
rs equivalent to 8.48? n
Therapeutic-
Packaging and storage-
Antimalarial and antiprotozoan-200 mg. every 6
hours for S dosw, then 100 mg. three times a
Ta~t~avai1able+2Ujna
following amounta ofqu
day for 6 days.
CATEGORY and DOE
Anthehniritie--5OO mg. with S00 mg. of sodium
bicarbonate in a single dose.

Quirtacrine Hydrochloride Tablets


Qm~AcRIh= ~ROCFILORIDE T.4BLETS Q
QuinacrineHydrochlorideTablets containnot lessthan 93 per certt
andnotmorethan 107per cent of tilelabeled amount of CS3HWC1NT30, -
2HC1 . 2H20.
ldentification—
.*: Powder a sufficient number of QuinacrinP Hydrochloride Tablets, equivalent
to about 2.50 mg. of uinnmine hydrochloride, and extract with two I.$ml.
Porticmofhot~a~r,%lknng~~r
add ammonia
wchextmction. T05ml.ofthe extract
T. S., and remove the oilv precipitate so formed by extraction
with two IO-ml. portions of ether. The water layer, acidified with nitric
.:
‘<
[0 CH30

(czoH24s202)2
,

,1

H2s~4

acid, responds to the teata for Chloride, page 901. Quinidine Sulfatei:
B: To the remaining portion of the water extract obtained in Identi@ion teat .4 species of Cirtchom a
add 2 ml. of ammonia T.S.: a ~ellow, oily precipitate forma. Shake the
mixture with ~everal 10-ml. pomons of chloroform until the water layer is INuckiger (Fare. Ruhi(
practically colorless. Evaporate the combined chloroform solutions on a
steam bath in a smafl beaker, and add to the maid ue 3 m L of hot water and Description--Cltiti&e S
2 ml. of diluted hydrochloric acid,moistening thesidesofthebeakerwith cohering in masses. lt
theliquid and stirring witha glass rod. .4I1ow tostandfor30 minutes, then @ light. lta solutions 8
filter,washthecrystals withice-cold water until the last washing is practicall~. ,.. Volubility-one Gm. of c
neutral to litmus, and dry at 1050 for 2 hours: the CWEW]SSIoob~ine~ ,, about10 ml,ofa]cobol.
respond to Io?enti~ion tcsk B and C under Quidru Hydrochlor-rdc, Identification—
page 599.
. .$: .kcjdify a solution ~
Disintegration-Quimcrine Hydrochloride Tableta meet the requirements of the .. ingsolution has
Disintegration Teat for Tableti, page 936, in not more than1 hour. ... B: TO 5 m],ofa solut
Weight variation-Qtinactie Hydrochloride Table@ meet the requirements of the mine T.S.,and C;
lVeight Irariution T-t forTobti, page 945. greencolordue 1
.Assay—Weigh a counted number of not less than 20 Quinscrine Hydrochloride Tab- C!: TO 5 ml. of a soiutI
T.S., and stir WI
lets, and reduce them to a tie powder without appreciable loss. Weigh accurately .:. interval (distinct
a Potion of the powder, equrvahmt toabout 203m of uinacrine hydrochloride, .... D: Quinidine &dfate r
and place it in a eeparator with 25 ml. of w-ata an 3?3 m of diluted hydrochloric .,
acid. Extract the suspension with two I/km]. portions of chloroform, and wash the Specific rotation, page 80’
chloroform extrac~ in a second sepaxator with 10 ml. of water. Discard the washed the, anhydroua basis, d
chloroform, and add the water in the second separator to the suspension of tablet Qtumdine Sulfate in a{

.
Amopyroquine/ A4epacrine 399

1378-W chloroquine base. Soluble I in 5 of water: practi- 1381-v


cally insoluble in alcohol, chloroform, and ether,
-qttine. Cyclochin; Haloquine. 4.(7 -ChIom-4-
A 1% solution in water has a pH of 3.5 to 5.5.
Mefloqrsine Hydrochloride. WR 142490
!amino)-2.6-bis( dihexylaminomct hyl)phertol.
Protect from light. ( ~ )-@-[ 2.8-Bia(trifluoromethy l)-4-quinolyi]-cx-
L. ,CIN,0-497. I.
[2-piperidyi)methanol hydrochloride.
CAS — 14394-]3-3, Adverse Effeets, Treattstens, Preemrtiotr.% ad C17H@6N20, HCI=414.8.
A yellow crystalline a bi[ter taste. Practi.
powder with Reaistmxce. As for Chloroquine. CAS — 53230-10-7 p.395,
(mefloquirre); 5/773-92-3
cdly imakubk in water: readily soluble in dilute acids Hydroxychloroquinc waa given in an average dose of (hydrochloride).
,Nluble in dilute alkalis. Protect
from light.
800 mg daily for up to 4fi years to 94 patients with
Adverse Effects. Epigastric discomfort has been
USCS. Cycloquine resembles chloroquine in its action and lupus crythcmatoaus, rheumatoid aflhritis, or SCIC.
has been used in the USSR for the mppresaion and roderma. The pattcnts had not previously received chl~
reported after doses of I g. and nausea and dizzi-
treatment of malaria. A dose of 300 mg has been given roquinc. amodiaquinc. mcpacrinc, os quinine. Corned
ness after dosea of 1.75 or 2 g.
~cckly for the suppreaaion of malaria and NM mg has
deposition occurred in 26 Patimu it waa reversible in Uses. Metlcquine hydrochloride is a 4-quino-
teen given daily for three days in the treatment of acute
juacks.
20, persistent in 3, and 3 were last IO follow-up. There Iinemethanol compound which has schizonticidal
was a rapid rise in incidence after 150 g had bn given. activity against malaria parasites. It is active
one paticru who had received 770 g over 261h months against chloroquine-resistant falciparum malaria.
developed retinopathy. A second case of probable rc!irro-
Maf~i& A preliminary study in 17 subje.c~s of the usc
pathy was subsequently seen in a funher patient.— R,
of mefloquinc hydrochloride in single l-g dote.v as a
1379-e V Shearer and E. L. Dubois. Am. J. Ophthal. 1967, ~~;ccic againat drug-resistant malaria.— K. H.
64, 245, nnet al., Bull. WId Hlth Org.. 1974, 5f. 375.
Dif_Ylds~tte. DFD: DFDDS; Diformyidiamirrodi-
phenylssdphone. 4.4’-Sulphonylbisformanilide. Ocular :oxicit y in 3 of 99 patients after !avg-tcrrn m.. i - Thiriy-tivc non.immune volunteers infected with I of 3
c,4H, ]f’J@,5-304.3. mcm with hydroxychlorcquinc.— R. 1. Rynca et al., atraina of Pfasrvrodium jafciporum, 2 of them drug-reais-
Arthriris Rheum,, 1979, 22, 832. tam, were treated wiih a single oral dose of mctloquine
CAS — 6784-2$4. hydrochloride 0.4, 1, or 1.5 The infection was cured
A crysullk solid. M.P. 2674tO 2694.Practicallyirxaol- Uses. Hydroxychloroquinc sulphate has an anti- in 2 of 12 given 0.4g, 13 0 f 15 gwen I g. and 8 of 8
ubk in Wauc soluble I k about 200 of dimcthyl sul- malarial action simdar to that of chioroqttine given I,5 g. In 5 partially-immune volunteers infected
phoxide. II is moat stable at pH 6. wllh P, viva-r cures were achieved with single doses of
(ace p.396) but it is mainly used in the treatment
0.4 or I g in IWO. but infection rearrtxcarcd in the
Uws.Diformyidapsortehas keen used as an antimalarial of systemic and discoid lupus erythcmatoaua and remaining ‘3 subjects and was su~ucn~ly cured with
(n dwea of 400 to 800 mg weekly, but is given with rheumatoid arthritis. Treatment is usually atatted chloroquinc and primaquirte.— G. .W. Trenholmc et al..
chloroqume. primaquine, or pyrimethamirre. since it has Science. 1975, 190.792.
with about 400 to 800 mg daily in divided doaea
no acttotr on gametocytea.
with meals and the dose is reduced to about 200 None of 21 volunte,ra bitten by 10 to 15 mosquitoes
Diformyldapsone had an a proximate half-life of 84 heavily infceted with P. Jiifcipurum developed malaria
hours.— W. Peters, Po$[gra1 wed. J.. 1973, 49, 573. to 400 mg when a r=porrse occurs. In malaria, a
when given mcfloquinc hydrochloride 250 or 500 mg
Dlformyldapsonc in daccs of 3.2 g twice weekly for 4 suppressive dose of 400 mg every 7 days is used, weekly, 500 mg every 2 wcek.v. or I g fiery 4 WWIC.S.
weeks damaged !he red blmtt cells in 25 subjects. and in treating an acute attack a dose of 800 mg Dtne.a of 250 mg weekly suppressed P. viva.x infections
Smaller doses did not appear to cause baemolysis.— S. has been used, followed after 6 to 8 houra by during drug administration but malaria appeared when
A, Cucinell et al., J. clin. Pharmac., 1974, [4, 51. treatment ceased.— D. F, Clyde ●t al,, Antimicrob. Ag.
400 mg and a further 400 mg on each of the 2
Wdwia. Diformyldapsonc waa considered to protect
Chemother.. 1976, 9, 384.
following days. Children may be given a weekly
volunteers more effectively against tbe Vietnam Smith Of 39 patients with chioroquine-reaisrant falciparum
strain of P. fafciparum than against the Chcason strain
suppressive dose equivalent to 5 mg of base per tstalaria. 36 (92%) were cleared of infection with no
0(.+-a vivax. ‘Tlwre were no reports of met. kg body-weight, while for treatment an initial rccrudcaccncc zfter treatment with quinine. sulfadoxinc,
h?- “binacmia in patients receiving diformyldapamre and fimcthaminc, by the regimen of A.P, Hall ( Br.
dose of 10 mg per kg may be given, following by
al\ m conjunction with chioroquine,— Clyde. D.F. med. J.. 1975, 2, 15; see under Quinine, p.405), while
5 mg per kg 6 hours later and again on the all of 35 were cleared by treatment with quinine fol-
et m., Ailit. Med., 1971, 136. 836, per Trop. Dis. Bull.,
1972, 69, 593. See also idcm, h4ilit. Med., 1970, /35, second and third days. lowed by a single dose Of mcfloquine hydrochloride t.5 g
527, In the ireatment of giardiasis, the usual dose is (orrc patient received only 1 g). Side-.ffcccs in 40
patients given ,mefloq”inc wc~ abdominal pain (7),
Diformyldapsone 100 to 800 mg weekly given with chl~ 200 mg thrice daily for 5 days.
anorexh” (6), dlarrhoca (6), dizxincsa (9), nausea (3),
rcquine alone. or with chloroquine and primaquine. sup Hydroxychloroquine sulphate has been used in vomiting (9), and weakness (3). Side-effects were mini-
pressed the Smith swain of falciparum malaria in 41 of
the treatment of polymorphous light eruptions. mal or absent if al least 12 hours elapsed after the last
45 mm and the Brai, strain in 9 men. The combination
The dose is as for rheumatoid arthritis. dose of quinine.— A. P, Hall er a/., #z. med. J, 1977.
Jpp+red (O bC ,morc ,cffcctivc than treatment with chlo. 1. 1626,
mqumc and prlmaqume, or than pyrimcthaminc 25 mg PorpAyriu. Hydroxychlorcquine, 400 mg weekly for seve.
,4m”maf studies of the anttmalaria] activities of 4-quin~
weekly which MC pressed the Brai. but not the Smith ral months, had been reported to be safe and effectwe
slraln, — D. F. ?Iydc