U.S. patent application number 09/506991 was filed with the patent office on 2001-09-20 for use of sulfamate derivatives for treating impulse control disorders.
Invention is credited to McElroy, Susan L..
Application Number | 20010023254 09/506991 |
Document ID | / |
Family ID | 22396040 |
Filed Date | 2001-09-20 |
United States Patent
Application |
20010023254 |
Kind Code |
A1 |
McElroy, Susan L. |
September 20, 2001 |
Use of sulfamate derivatives for treating impulse control
disorders
Abstract
Impulse Control Disorders (ICD's) are characterized by harmful
behaviors performed in response to irresistible impulses. The
essential feature of an ICD is the failure to resist an impulse,
drive, or temptation and to perform an act that is harmful to the
person or to others. The present invention comprises methods for
the treatment or prevention of ICD's using a class of sulfamates of
the following formula: 1 wherein X is CH.sub.2 or oxygen, and
R.sub.1, R.sub.2, R.sub.3, R4 and R.sub.5 are as herein defined.
Further, pharmaceutical compositions containing a compound of
formula (I) as well as methods for their use and intermediates form
part of the present invention are also disclosed.
Inventors: |
McElroy, Susan L.;
(Cincinnati, OH) |
Correspondence
Address: |
FROST BROWN TODD, LLC
2200 PNC CENTER
201 E. FIFTH STREET
CINCINNATI
OH
45202
US
|
Family ID: |
22396040 |
Appl. No.: |
09/506991 |
Filed: |
February 18, 2000 |
Current U.S.
Class: |
514/439 |
Current CPC
Class: |
A61K 31/7024 20130101;
A61K 31/385 20130101; A61P 25/18 20180101; A61P 25/32 20180101;
A61P 25/34 20180101; A61K 31/18 20130101; A61P 25/28 20180101; A61P
25/30 20180101; A61P 25/00 20180101; A61K 31/36 20130101; A61K
31/351 20130101 |
Class at
Publication: |
514/439 |
International
Class: |
A61K 031/385; A01N
043/26 |
Claims
What is claimed is:
1. A method for treating an Impulse Control Disorder comprising
administering to a mammal afflicted with such condition a
therapeutically effective amount for treating such condition of a
compound of the formula I: 4wherein X is CH.sub.2 or oxygen;
R.sub.1 is hydrogen or alkyl; and R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are independently hydrogen or lower alkyl and, when X is
CH.sub.2, R.sub.4 and R.sub.5 may be alkene groups joined to form a
benzene ring and, when X is oxygen, R.sub.2 and R.sub.3 and/or
R.sub.4 and R.sub.5 together may be a methylenedioxy group of the
following formula (II): 5wherein R.sub.6 and R.sub.7 are the same
or different and are hydrogen, lower alkyl or are alkyl and are
joined to form a cyclopentyl or cyclohexyl ring.
2. The method of claim 1 wherein the compound is selected from the
group consisting of
2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranos- e
sulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-L-fructopyrano- se
sulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyran- ose
methylsulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fruc- topyranose
butylsulfamate, 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta--
D-fructopyranose ethylsulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- -beta-D-fructopyranose
octylsulfamate, 2,3-O-(1-methylethylidene)-4,5-O-su-
lfonyl-beta-D-fructopyranose 2-propenylsulfamate,
2,3-O-(1-methylethyliden- e)-4,5-O-sulfonyl-beta-D-fructopyranose
phenylmethylsulfamate,2,3-O-(1-met-
hylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
cyclopropylsulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
cyclobutylsulfamate,2,3 -O-(1-methylethylidene)-4,
5-O-sulfonyl-beta-D-fructopyranose (2,2,2-trifluoroethyl)sulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
dimethylsulfamate,
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fruct- opyranose
diethylsulfamate, 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-
-D-fructopyranose
azidosulfate,(S)-2,3-O-(1-methylethylidene)-4,5-O-sulfin-
yl-beta-D-fructopyranose sulfamate,
(R)-2,3-O-(1-methylethylidene)-4,5-O-s-
ulfinyl-beta-D-fructopyranose sulfamate,
2,3-O-(1-ethylpropylidene)-4,5-O-- sulfonyl-beta-D-fructopyranose
sulfamate, 2,3-O-(1-methylethylidene)-4,5-O-
-[N-(4-methylbenzenesulfonyl)imidosulfinyl]- beta-D-fructopyranose
sulfamate,2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)
imidosulfonyl]-beta-D-fructopyranose sulfamate,
2,3-O-(cyclohexylidene)-4- ,5-O-sulfonyl-beta-D-fructopyranose
sulfamate,(S)-4,5-O-[N-(1,1-dimethylet-
hoxycarbonyl)imidosulfinyl]-2,3-O-(1- methylethylidene)-beta
-D-fructopyranose sulfamate, and the pharmaceutically acceptable
salts thereof.
3. The method of claim 1 wherein the compound is selected from the
group consisting of
(1R,2R,3S,4S)-(1,2;3,4-di-O-methylethylidenecyclohexan-1,2,-
3,4-tetraol-4-yl)methyl sulfamate and (1R,2S,3 S,4S)-(3
,4-O-methylethylidene-1,2-O-sulfinylcyclohexan
1,2,3,4-tetraol-4-yl)methy- l sulfamate.
4. The method of claim 1 wherein the compound of formula I is
topiramate.
5. The method of claim 1, wherein the therapeutically effective
amount is of from about 15 to about 2000 mg per day.
6. The method of claim 1, wherein the therapeutically effective
amount is of from about 25 to about 750 mg per day.
7. The method of claim 1 wherein the Impulse Control Disorder is
selected from the group consisting of intermittent explosive
disorder (IED), kleptomania, pathological gambling, pyromania,
trichotillomania, compulsive buying or shopping, repetitive
self-mutilation, nonparaphilic sexual addictions, severe nail
biting, compulsive skin picking, personality disorders with
impulsive features, attention deficit/hyperactivity disorder,
eating disorders characterized by binge eating, and substance use
disorders.
8. The method of claim 1 wherein the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of adrenergics, adrenocortical steroids,
adrenocortical suppressants, aldosterone antagonists, amino acids,
analeptics, analgesics, anorectic compounds, anorexics,
anti-anxiety agents, antidepressants, antihypertensives,
anti-inflammatorys, antinauseants, antineutropenics,
antiobsessional agents, antiparkinsonians, antipsychotics, appetite
suppressants, blood glucose regulators, carbonic anhydrase
inhibitors, cardiotonics, cardiovascular agents, choleretics,
cholinergics, cholinergic agonists, cholinesterase deactivators,
cognition adjuvants, cognition enhancers, hormones, memory
adjuvants, mental performance enhancers, mood regulators,
neuroleptics, neuroprotectives, psychotropics, relaxants,
sedative-hypnotics, serotonin antagonists, serotonin inhibitors,
serotonin receptor antagonists, stimulants, thyroid hormones,
thyroid inhibitors, thyromimetics, cerebral ischemia agents,
vasoconstrictors, and vasodilators.
9. The method of claim 1 wherein the Impulse Control Disorder is an
eating disorder and the compound is used in conjunction with one or
more other drug compounds selected from the group consisting of
serotonin re-uptake inhibitors, antidepressants, psychostimulants,
and orlistat.
10. The method of claim 1 wherein the Impulse Control Disorder is
an overweight/obesity condition and the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of sibutramine, psychostimulants, and
orlistat.
11. The method of claim 1 wherein the Impulse Control Disorder is a
nicotine addiction condition and the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of bupropion, serotonin reuptake inhibitors,
nicotine, and antidepressants.
12. The method of claim 1 wherein the Impulse Control Disorder is
an alcohol abuse/dependence condition and the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of naltrexone, serotonin reuptake inhibitors, and
other antidepressants.
13. The method of claim 1 wherein the Impulse Control Disorder is a
behavioral addiction condition and the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of serotonin reuptake inhibitors, lithium,
valproic acid or divalproex sodium, other antidepressants,
naltrexone, atypical antipsychotics, and other mood
stabilizers.
14. The method of claim 1 wherein the Impulse Control Disorder is a
paraphilias/sexual addiction condition and the compound is used in
conjunction with one or more other drug compounds selected from the
group consisting of serotonin reuptake inhibitors, lithium,
divalproex sodium/valproic acid, antiandrogen agents, other
antidepressants, and other mood stabilizers.
Description
[0001] This application is based on U.S. Provisional Patent
Application Ser. No. 60/121,339, McElroy, filed Feb. 24, 1999.
TECHNICAL FIELD
[0002] The present invention generally relates to the use of drugs
for the treatment of mental disorders. More specifically, the
invention describes methods for the treatment and prevention of
Impulse Control Disorders (ICD's) by administering sulfamate
derivatives.
BACKGROUND OF THE INVENTION
[0003] Sulfamate derivatives having useful pharmaceutical activity
in the areas of epilepsy, glaucoma, peptic ulcers and male
infertility are disclosed in U.S. Pat. Nos. 4,075,351, 4,513,006,
4,591,601, 4,792,569, and 5,760,007. One of these compounds
2,3;4,5-bis-O-(1-methylethylidene)- beta -D-fructopyranose
sulfamate known as topiramate has been demonstrated in clinical
trials of human epilepsy to be effective as adjunctive therapy or
as monotherapy in treating simple and complex partial seizures and
secondarily generalized seizures and is currently marketed for the
treatment of simple and complex partial seizure epilepsy with or
without secondary generalized seizures.
[0004] Binge eating disorder (BED) is characterized by discrete
periods of binge eating during which large amounts of food are
consumed in a discrete period of time and a sense of control over
eating is absent. Persons with bulimia nervosa have been reported
to have electroencephalographic abnormalities and to display
reduced binge eating in response to the anti-epileptic drug
phenytoin. Also, in controlled trials in patients with epilepsy,
topiramate was associated with suppression of appetite and weight
loss unreleated to binge eating.
[0005] Binge eating disorder is a subset of a larger classification
of mental disorders broadly defined as Impulse Control Disorders
(ICDs) characterized by harmful behaviors performed in response to
irresistible impulses. It has been suggested that ICDs may be
related to obsessive-compulsive disorder or similarly, maybe forms
of obsessive-compulsive disorders. It has also been hypothesized
that ICDs may be related to mood disorder or may be forms of
affective spectrum disorder, a hypothesized family of disorders
sharing at least one common physiologic abnormality with major
depression. In the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV), the essential feature of an ICD is the failure
to resist an impulse, drive, or temptation to perform an act that
is harmful to the person or to others. For most ICDs, the
individual feels an increasing sense of tension or arousal before
committing the act, and then experiences pleasure, gratification,
or release at the time of committing the act. After the act is
performed, there may or may not be regret or guilt. ICDs are listed
in a residual category, the ICDs Not Elsewhere Classified, which
includes intermittent explosive disorder (IED), kleptomania,
pathological gambling, pyromania, trichotillomania, and ICD not
otherwise specified (NOS). Examples of ICDs NOS are compulsive
buying or shopping, repetitive self-mutilation, nonparaphilic
sexual addictions, severe nail biting, compulsive skin picking,
personality disorders with impulsive features, attention
deficit/hyperactivity disorder, eating disorders characterized by
binge eating, and substance use disorders.
SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to describe the use
of sulfamate derivatives for the treatment of Impulse Control
Disorders.
[0007] The present invention comprises methods for the treatment or
prevention of Impulse Control Disorders using the compounds of
formula (I), pharmaceutical compositions containing one or more of
the compounds of formula (I), or pharmaceutical compositions
containing one or more of the compounds of formula (I) in addition
to a safe and effective amount of one or more additional agents to
treat related symptoms and conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The sulfamates of use in the present invention are of the
following formula (I): 2
[0009] wherein
[0010] X is CH.sub.2 or oxygen;
[0011] R.sub.1 is hydrogen or alkyl; and R.sub.2, R.sub.3, R.sub.4
and R.sub.5 are independently hydrogen or lower alkyl and, when X
is CH.sub.2, R.sup.4 and R.sub.5 may be alkene groups joined to
form a benzene ring and, when X is oxygen, R.sub.2 and R.sub.3
and/or R.sub.4 and R.sub.5 together may be a methylenedioxy group
of the following formula (II): 3
[0012] wherein
[0013] R.sub.6 and R.sub.7 are the same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form a
cyclopentyl or cyclohexyl ring. R.sub.1 in particular is hydrogen
or alkyl of about 1 to 4 carbons, such as methyl, ethyl and
iso-propyl. Alkyl throughout this specification includes straight
and branched chain alkyl. Alkyl groups for R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are of about 1 to 3 carbons
and include methyl, ethyl, iso-propyl and n-propyl. When X is
CH.sub.2, R.sub.4 and R.sub.5 may combine to form a benzene ring
fused to the 6-membered X-containing ring, i.e., R.sub.4 and
R.sub.5 are defined by the alkatrienyl group
.dbd.C--CH.dbd.CH--CH.dbd..
[0014] A particular group of compounds of formula (I) is that
wherein X is oxygen and both R.sub.2 and R.sub.3 and R.sub.4 and
R.sub.5 together are methylenedioxy groups of the formula (II),
wherein R.sub.6 and R.sub.7 are both hydrogen, both alkyl or
combine to form a spiro cyclopentyl or cyclohexyl ring, in
particular where R.sub.6 and R.sub.7 are both alkyl such as methyl.
A second group of compounds is that wherein X is CH.sub.2 and
R.sub.4 and R.sub.5 are joined to form a benzene ring. A third
group of compounds of formula (I) is that wherein both R.sub.2 and
R.sub.3 are hydrogen.
[0015] The compounds of formula 1: may be made by the processes
disclosed in U.S. Pat. Nos. 4,075,351, 4,513,006, 4,591,601,
4,792,569, 5,242,942, 5,387,700, which are incorporated in their
entirety herein by reference.
[0016] The compounds of formula I include the various individual
isomers as well as the racemates thereof. For treating ICDs, a
compound of formula (I) may be employed at a daily dosage in the
range of about 15 to 1400 mg administered orally, for an average
adult human.
[0017] To prepare the pharmaceutical compositions of this
invention, one or more sulfamate compounds of formula (I) are
intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending on the form of
preparation desired for administration, e.g., oral, by suppository,
or parenteral. In preparing the compositions in oral dosage form,
any of the usual pharmaceutical media may be employed. Thus, for
liquid oral preparations, such as for example, suspensions, elixirs
and solutions, suitable carriers and additives include water,
glycols, oils, alcohols, flavoring agents, preservatives, coloring
agents and the like; for solid oral preparations such as, for
example, powders, capsules and tablets, suitable carriers and
additives include starches, sugars, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like. Because of
their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated or enteric coated by standard techniques.
Suppositories may be prepared, in which case cocoa butter could be
used as the carrier. For parenterals, the carrier will usually
comprise sterile water, though other ingredients, for example, for
purposes such as aiding solubility or for preservation, may be
included. Injectable suspensions may also be prepared in which case
appropriate liquid carriers, suspending agents and the like may be
employed. Topiramate is currently available for oral administration
in round tablets containing 25 mg, 100 mg or 200 mg of active
agent. The tablets contain the following inactive ingredients:
lactose hydrous, pregelatinized starch, microcrystalline cellulose,
sodium starch glycolate, magnesium stearate, purified water,
carnauba wax, hydroxypropyl methylcellulose, titanium dioxide,
polyethylene glycol, synthetic iron oxide, and polysorbate 80.
[0018] The pharmaceutical compositions herein will contain, per
dosage unit, e.g., tablet, capsule, powder injection, teaspoonful,
suppository and the like from about 5 to about 1000 mg of the
active ingredient.
[0019] The activity of the compounds of formula I in treating ICD's
was first evidenced in clinical studies conducted to evaluate the
efficacy of topiramate in treating mood disorders. Several patients
who coincidentally had binge eating disorder reported that there
was a marked reduction in their binging and a concurrent loss in
weight.
[0020] Examples of specific compounds of formula (I) are:
[0021] 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose
sulfamate
[0022]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
sulfamate;
[0023]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-L-fructopyranose
sulfamate;
[0024]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
methylsulfamate;
[0025]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
butylsulfamate;
[0026]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
ethylsulfamate;
[0027]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
octylsulfamate;
[0028]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
2-propenylsulfamate;
[0029]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
phenylmethylsulfamate;
[0030]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
cyclopropylsulfamate;
[0031]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
cyclobutylsulfamate;
[0032]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
(2,2,2-trifluoroethyl)sulfamate;
[0033]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
dimethylsulfamate;
[0034]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
diethylsulfamate;
[0035]
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
azidosulfate;
[0036]
(S)-2,3-O-(1-methylethyldene)-4,5-O-sulfinyl-beta-D-fructopyranose
sulfamate;
[0037]
(R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D-fructopyranose
sulfamate;
[0038]
2,3-O-(1-ethylpropylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
sulfamate;
[0039]
2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidos-
ulfinyl]-beta-D-fructopyranose sulfamate;
[0040]
2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidos-
ulfonyl]-beta-D-fructopyranose sulfamate;
[0041] 2,3-O-(cyclohexylidene)-4,5-O-sulfonyl-beta-D-fructopyranose
sulfamate;
[0042]
(S)-4,5-O-[N-(1,1-dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-me-
thylethylidene)-beta-D-fructopyranose sulfamate;
[0043] and the pharmaceutically acceptable salts thereof.
[0044] Included within the scope of this invention are the various
individual anomers, diastereomers and enantiomers as well as
mixtures thereof. Such compounds are included within the definition
of formula (I). In addition, the compounds of this invention also
include any pharmaceutically acceptable salts, for example: alkali
metal salts, such as sodium and potassium; ammonium salts;
monoalkylammonium salts; dialkylammonium salts; trialkylammonium
salts; tetraalkylammonium salts; and tromethamine salts. Hydrates
and other solvates of the compound of the formula (I) are included
within the scope of this invention.
[0045] Pharmaceutically acceptable salts of the compounds of
formula (I) can be prepared by reacting the sulfamate of formula
(I) with the appropriate base and recovering the salt.
[0046] The sulfamate derivatives may be used in conjunction with
one or more other drug compound and used according to the methods
of the present invention so long as the pharmaceutical agent has a
use that is also effective in treating ICD's and/or concurrent
illnesses. Pharmaceutical agents include the following categories
and specific examples. It is not intended that the category be
limited by the specific examples. Those of ordinary skill in the
art will be able to identify readily those pharmaceutical agents
that have utility with the present invention. Those of ordinary
skill in the art will recognize also numerous other compounds that
fall within the categories and that are useful according to the
invention.
[0047] Adrenergic: Adrenalone; Amidephrine Mesylate; Apraclonidine
Hydrochloride; Brimonidine Tartrate; Dapiprazole Hydrochloride;
Deterenol Hydrochloride; Dipivefrin; Dopamine Hydrochloride;
Ephedrine Sulfate; Epinephrine; Epinephrine Bitartrate; Epinephryl
Borate; Esproquin Hydrochloride; Etafedrine Hydrochloride;
Hydroxyamphetamine Hydrobromide; Levonordefrin; Mephentenrine
Sulfate; Metaraminol Bitartrate; Metizoline Hydrochloride;
Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxidopamine;
Oxymetazoline Hydrochloride; Phenylephrine Hydrochloride;
Phenylpropanolamine Hydrochloride; Phenylpropanolamine Polistirex;
Prenalterol Hydrochloride; Propylhexedrine; Pseudoephedrine
Hydrochloride; Tetrahydrozoline Hydrochloride; Tramazoline
Hydrochloride; Xylometazoline Hydrochloride.
[0048] Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone
Acetate; Desoxycorticosterone Pivalate; Dexamethasone Acetate;
Fludrocortisone Acetate; Flumoxonide; Hydrocortisone Hemisuccinate;
Methylprednisolone Hemisuccinate; Naflocort; Procinonide;
Timobesone Acetate; Tipredane.
[0049] Adrenocortical suppressant: Aminoglutethimide;
Trilostane.
[0050] Alcohol deterrent: Disulfiram.
[0051] Aldosterone antagonist: Canrenoate Potassium; Canrenone;
Dicirenone; Mexrenoate Potassium; Prorenoate Potassium;
Spironolactone.
[0052] Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride;
Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate;
Lysine Hydrochloride; Methionine; Phenylalanine; Proline; Serine;
Threonine; Tryptophan; Tyrosine; Valine.
[0053] Analeptic: Modafinil.
[0054] Analgesic: Acetaminophen; Alfentanil Hydrochloride;
Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime;
Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride;
Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine
Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride;
Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride;
Butacetin; Butixirate; Butorphanol; Butorphanol Tartrate;
Carbamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride;
Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol
Hydrochloride; Clonixeril; Clonixin; Codeine; Codeine Phosphate;
Codeine Sulfate; Conorphone Hydrochloride; Cyclazocine; Dexoxadrol
Hydrochloride; Dexpemedolac; Dezocine; Diflunisal; Dihydrocodeine
Bitartrate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride;
Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate;
Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen;
Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal;
Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone;
Fluradoline Hydrochloride; Flurbiprofen; Hydromorphone
Hydrochloride; Tbufenac; Indoprofen; Ketazocine; Ketorfanol;
Ketorolac Tromethamine; Letimide Hydrochloride; Levomethadyl
Acetate; Levomethadyl Acetate Hydrochloride; Levonantradol
Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride;
Lofentanil Oxalate; Lorcinadol; Lomoxicam; Magnesium Salicylate;
Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride;
Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl
Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate;
Mimbane Hydrochloride; Mirfentanil Hydrochloride; Molinazone;
Morphine Sulfate; Moxazocine; Nabitan Hydrochloride; Nalbuphine
Hydrochloride; Nalmexone Hydrochloride; Namoxyrate; Nantradol
Hydrochloride; Naproxen; Naproxen Sodium; Naproxol; Nefopam
Hydrochloride; Nexeridine Hydrochloride; Noracymethadol
Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Olvanil;
Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride; Oxycodone
Terephthalate; Oxymorphone Hydrochloride; Pemedolac; Pentamorphone;
Pentazocine; Pentazocine Hydrochloride; Pentazocine Lactate;
Phenazopyridine Hydrochloride; Phenyramidol Hydrochloride;
Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam
Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol
Hydrochloride; Propirarn Fumarate; Propoxyphene Hydrochloride;
Propoxyphene Napsylate; Proxazole; Proxazole Citrate; Proxorphan
Tartrate; Pyrroliphene Hydrochloride; Remifentanil Hydrochloride;
Salcolex; Salethamide Maleate; Salicylamide; Salicylate Meglumine;
Salsalate; Sodium Salicylate; Spiradoline Mesylate; Sufentanil;
Sufentanil Citrate; Talmetacin; Talniflumate; Talosalate;
Tazadolene Succinate; Tebufelone; Tetrydamine; Tifurac Sodium;
Tilidine Hydrochloride; Tiopinac; Tonazocine Mesylate; Tramadol
Hydrochloride; Trefentanil Hydrochloride; Trolamine; Veradoline
Hydrochloride; Verilopam Hydrochloride; Volazocine; Xorphanol
Mesylate; Xylazine Hydrochloride; Zenazocine Mesylate; Zomepirac
Sodium; Zucapsaicin.
[0055] Anorectic compounds including dexfenfluramine.
[0056] Anorexic: Aminorex; Amphecloral; Chlorphentermine
Hydrochloride; Clominorex; Clortermine Hydrochloride;
Diethylpropion Hydrochloride; Fenfluramine Hydrochloride;
Fenisorex; Fludorex; Fluminorex; Levamfetamine Succinate; Mazindol;
Mefenorex Hydrochloride; Phenmetrazine Hydrochloride; Phentermine;
Sibutramine Hydrochloride.
[0057] Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem;
Binospirone Mesylate; Bretazenil; Glemanserin; Ipsapirone
Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron
Hydrochloride; Panadiplon; Pancopride; Pazinaclone; Serazapine
Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.
[0058] Antidepressant: Adatanserin Hydrochloride; Adinazolam;
Adinazolam Mesylate; Alaproclate; Aletamine Hydrochloride; Amedalin
Hydrochloride; Amitriptyline Hydrochloride; Amoxapine; Aptazapine
Maleate; Azaloxan Fumarate; Azepindole; Azipramine Hydrochloride;
Bipenamol Hydrochloride; Bupropion Hydrochloride; Butacetin;
Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ciclazindol;
Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon
Hydrochloride; Clomipramine Hydrochloride; Cotinine Fumarate;
Cyclindole; Cypenamine Hydrochloride; Cyprolidol Hydrochloride;
Cyproximide; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol
Maleate; Dazepinil Hydrochloride; Desipramine Hydrochloride;
Dexamisole; Deximafen; Dibenzepin Hydrochloride; Dioxadrol
Hydrochloride; Dothiepin Hydrochloride; Doxepin Hydrochloride;
Duloxetine Hydrochloride; Eclanamine Maleate; Encyprate;
Etoperidone Hydrochloride; Fantridone Hydrochloride; Fehmetozole
Hydrochloride; Fenmetramide; Fezolamine Fumarate; Fluotracen
Hydrochloride; Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan
Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride;
Imiloxan Hydrochloride; Imipramine Hydrochloride; Indeloxazine
Hydrochloride; Intriptyline Hydrochloride; Iprindole;
Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride;
Lortalamine; Maprotiline; Maprotiline Hydrochloride; Melitracen
Hydrochloride; Milacemide Hydrochloride; Minaprine Hydrochloride;
Mirtazapine; Moclobemide; Modaline Sulfate; Napactadine
Hydrochloride; Napamezole Hydrochloride; Nefazodone Hydrochloride;
Nisoxetine; Nitrafudam Hydrochloride; Nomifensine Maleate;
Nortriptyline Hydrochloride; Octriptyline Phosphate; Opipramol
Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine;
Phenelzine Sulfate; Pirandamine Hydrochloride; Pizotyline;
Pridefine Hydrochloride; Prolintane Hydrochloride; Protriptyline
Hydrochloride; Quipazine Maleate; Rolicyprine; Seproxetine
Hydrochloride; Sertraline Hydrochloride; Sibutramine Hydrochloride;
Sulpiride; Suritozole; Tametraline Hydrochloride; Tampramine
Fumarate; Tandamine Hydrochloride; Thiazesim Hydrochloride;
Thozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride;
Trebenzomine Hydrochloride; Trimipramine; Trimipramine Maleate;
Venlafaxine Hydrochloride; Viloxazine Hydrochloride; Zimeldine
Hydrochloride; Zometapine.
[0059] Antihypertensive: Alfuzosin Hydrochloride; Alipamide;
Althiazide; Amiquinsin Hydrochloride; Amlodipine Besylate;
Amlodipine Maleate; Anaritide Acetate; Atiprosin Maleate;
Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumethiazide;
Benzthiazide; Betaxolol Hydrochloride; Bethanidine Sulfate;
Bevantolol Hydrochloride; Biclodil Hydrochloride; Bisoprolol;
Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide;
Buthiazide: Candoxatril; Candoxatrilat; Captopril; Carvedilol;
Ceronapril; Chlorothiazide Sodium; Cicletanine; Cilazapril;
Clonidine; Clonidine Hydrochloride; Clopamide; Cyclopenthiazide;
Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril
Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydrochloride;
Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril;
Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine Mesylate;
Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldopam Mesylate;
Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril Sodium;
Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanacline Sulfate;
Guanadrel Sulfate; Guancydine; Guanethidine Monosulfate;
Guanethidine Sulfate; Guanfacine Hydrochloride; Guanisoquin
Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz;
Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride;
Hydralazine Polistirex; Hydroflumethiazide; Indacrinone;
Indapamide; Indolaprif Hydrochloride; Indoramin; Indoramin
Hydrochloride; Indorenate Hydrochloride; Lacidipine; Leniquinsin;
Levcromakalim; Lisinopril; Lofexidine Hydrochloride; Losartan
Potassium; Losulazine Hydrochloride; Mebutamate; Mecamylamine
Hydrochloride; Medroxalol; Medroxalol Hydrochloride;
Methalthiazide; Methyclothiazide; Methyldopa; Methyldopate
Hydrochloride; Metipranolol; Metolazone; Metoprolol Fumarate;
Metoprolol Succinate; Metyrosine; Minoxidil ; Monatepil Maleate;
Muzolimine; Nebivolol; Nitrendipine; Ofornine; Pargyline
Hydrochloride; Pazoxide; Pelanserin Hydrochloride; Perindopril
Erbumine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril;
Polythiazide; Prazosin Hydrochloride; Primidolol; Prizidilol
Hydrochloride; Quinapril Hydrochloride; Quinaprilat; Quinazosin
Hydrochloride; Quinelorane Hydrochloride; Quinpirole Hydrochloride;
Quinuclium Bromide; Ramipril; Rauwolfia Serpentina; Reserpine;
Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside;
Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride;
Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren;
Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen; Tinabinol;
Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide;
Trimazosin Hydrochloride; Trimethaphan Camsylate; Tnimoxamine
Hydrochloride; Tripamide; Xipamide; Zankiren Hydrochloride;
Zofenoprilat Arginine.
[0060] Anti-inflammatory: Aldlofenac; Alclometasone Dipropionate;
Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac
Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen;
Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine
Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen;
Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;
Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide;
Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium;
Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium;
Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole;
Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac;
Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort;
Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin
Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone;
Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen;
Furobufen; Halcinonide; Halobetasol Propionate; Halopredone
Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen
Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen;
Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam;
Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; Loteprednol
Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone
Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone;
Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Naproxen;
Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein;
Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride;
Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate;
Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine;
Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;
Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex;
Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone;
Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin;
Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium;
Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol
Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate;
Zidometacin; Zomepirac Sodium.
[0061] Antinauseant: Buclizine Hydrochloride; Cyclizine Lactate;
Naboctate Hydrochloride.
[0062] Antineutropenic: Filgrastim; Lenograstim; Molgramostim;
Regramostim; Sargramostim.
[0063] Antiobsessional agent: Fluvoxamine Maleate.
[0064] Antiparkinsonian: Benztropine Mesylate; Biperiden; Biperiden
Hydrochloride; Biperiden Lactate; Carmantadine; Ciladopa
Hydrochloride; Dopamantine; Ethopropazine Hydrochloride;
Lazabemide; Levodopa; Lometraline Hydrochloride; Mofegiline
Hydrochloride; Naxagolide Hydrochloride; Pareptide Sulfate;
Procyclidine Hydrochloride; Quinetorane Hydrochloride; Ropinirole
Hydrochloride; Selegiline Hydrochloride; Tolcapone; Trihexyphenidyl
Hydrochloride. Antiperistaltic: Difenoximide Hydrochloride;
Difenoxin; Diphenoxylate Hydrochloride; Fluperamide; Lidamidine
Hydrochloride; Loperamide Hydrochloride; Malethamer; Nufenoxole;
Paregoric.
[0065] Antipsychotic: Acetophenazine Maleate; Alentemol
Hydrobromide; Alpertine; Azaperone; Batelapine Maleate; Benperidol;
Benzindopyrine Hydrochloride; Brofbxine; Bromperidol; Bromperidol
Decanoate; Butaclamol Hydrochloride; Butaperazine; Butaperazine
Maleate; Carphenazine Maleate; Carvotroline Hydrochloride;
Chlorpromazine; Chlorpromazine Hydrochloride; Chlorprothixene;
Cinperene; Cintriamide; Clomacran Phosphate; Clopenthixol;
Clopimozide; Clopipazan Mesylate; Cloroperone Hydrochloride;
Clothiapine; Clothixamide Maleate; Clozapine; Cyclophenazine
Hydrochloride; Droperidol; Etazolate Hydrochloride; Fenimide;
Flucindole; Flumezapine; Fluphenazine Decanoate; Fluphenazine
Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene;
Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol;
Haloperidol Decanoate; Iloperidone; Imidoline Hydrochloride;
Lenperone; Mazapertine Succinate; Mesoridazine; Mesoridazine
Besylate; Metiapine; Milenperone; Milipertine; Molindone
Hydrochloride; Naranol Hydrochloride; Neflumozide Hydrochloride;
Ocaperidone; Olanzapine; Oxiperomide; Penfluridol; Pentiapine
Maleate; Perphenazine; Pimozide; Pinoxepin Hydrochloride;
Pipamperone; Piperacetazine; Pipotiazine Palniitate; Piquindone
Hydrochloride; Prochlorperazine Edisylate; Prochlorperazine
Maleate; Promazine Hydrochloride; Remoxipride; Remoxipride
Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrochloride;
Sertindole; Setoperone; Spiperone; Thioridazine; Thioridazine
Hydrochloride; Thiothixene; Thiothixene Hydrochloride; Tioperidone
Hydrochloride; Tiospirone Hydrochloride; Trifluoperazine
Hydrochloride; Trifluperidol; Triflupromazine; Triflupromazine
Hydrochloride; Ziprasidone Hydrochloride.
[0066] Appetite suppressant: Dexfenfluramine Hydrochloride;
Phendimetrazine Tartrate; Phentermine Hydrochloride.
[0067] Blood glucose regulators: Human insulin; Glucagon;
Tolazamide; Tolbutamide; Chloropropamide; Acetohexamide and
Glipizide.
[0068] Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide
Sodium, Dichlorphenamide; Dorzolamide Hydrochloride; Methazolamide;
Sezolamide Hydrochloride.
[0069] Cardiac depressant: Acecainide Hydrochloride; Acetylcholine
Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine
Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride;
Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine
Hydrochloride; Capobenate Sodium; Capobenic Acid; Cifenline;
Cifenline Succinate; Clofilium Phosphate; Disobutamide;
Disopyramide; Disopyramide Phosphate; Dofetilide; Drobuline;
Edifolone Acetate; Emilium Tosylate; Encainide Hydrochloride;
Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride;
Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcainide
Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride;
Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride;
Pirolazamide; Pranolium Chloride; Procainamide Hydrochloride;
Propafenone Hydrochloride; Pyrinoline; Quindonium Bromide;
Quinidine Gluconate; Quinidine Sulfate; Recainam Hydrochloride;
Recainam Tosylate; Risotilide Hydrochloride; Ropitoin
Hydrochloride; Sematilide Hydrochloride; Suricainide Maleate;
Tocainide; Tocainide Hydrochloride; Transcainide.
[0070] Cardiotonic: Actodigin; Amrinone; Bemoradan; Butopamine;
Carbazeran; Carsatrin Succinate; Deslanoside; Digitalis; Digitoxin;
Digoxin; Dobutamine; Dobutamine Hydrochloride; Dobutamine
Lactobionate; Dobutamine Tartrate; Enoximone; Imazodan
Hydrochloride; Indolidan; Isomazole Hydrochloride; Levdobutamine
Lactobionate; Lixazinone Sulfate; Medorinone; Milrinone; Pelrinone
Hydrochloride; Pimobendan; Piroximone; Prinoxodan; Proscillaridin;
Quazinone; Tazolol Hydrochloride; Vesnarinone.
[0071] Cardiovascular agent: Dopexamine; Dopexamine
Hydrochloride.
[0072] Choleretic: Dehydrocholic Acid; Fencibutirol; Hymecromone;
Piprozolin; Sincalide; Tocamphyl.
[0073] Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol;
Demecarium Bromide; Dexpanthenol; Echothiophate Iodide;
Isoflurophate; Methacholine Chloride; Neostigmine Bromide;
Neostigmine Methylsulfate; Physostigmine; Physostigmine Salicylate;
Physostigmine Sulfate; Pilocarpine; Pilocarpine Hydrochloride;
Pilocarpine Nitrate; Pyridostigmine Bromide.
[0074] Cholinergic agonist: Xanomeline; Xanomeline Tartrate.
[0075] Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime
Chloride; Pralidoxime Iodide; Pralidoxime Mesylate.
[0076] Coccidiostat: Arprinocid; Narasin; Semduramicin;
Semduramicin Sodium.
[0077] Cognition adjuvant: Ergoloid Mesylates; Piracetam;
Pramiracetam Hydrochloride; Pramiracetam Sulfate; Tacrine
Hydrochloride.
[0078] Cognition enhancer: Besipirdine Hydrochloride; Linopirdine;
Sibopirdine.
[0079] Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy
progesterone; Medroxyprogesterone; Norgestrel; Norethynodrel;
Estradiol; Megestrol (Megace); Norethindrone; Levonorgestrel;
Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 alpha
dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17 alpha
estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon;
Testolactone; Clomiphene; Han memopausal gonadotropins; Human
chorionic gonadotropin; Urofollitropin; Bromocriptine; Gonadorelin;
Luteinizing hormone releasing hormone and analogs; Gonadotropins;
Danazol; Testosterone; Dehydroepiandrosterone; Androstenedione;
Dihydroestosterone; Relaxin; Oxytocin; Vasopressin;
Folliculostatin; Follicle regulatory protein; Gonadoctrinins;
Oocyte maturation inhibitor; Insulin growth factor; Follicle
Stimulating Hormone; Luteinizing hormone; Tarnoxifen.; Corticorelin
Ovine Triftutate; Cosyntropin; Metogest; Pituitary, Posterior;
Seractide Acetate; Somalapor; Somatrem; Somatropin; Somenopor;
Somidobove.
[0080] Memory adjuvant: Dimoxamine Hydrochloride; Ribaminol.
[0081] Mental performance enhancer: Aniracetam.
[0082] Mood regulator: Fengabine.
[0083] Neuroleptic: Duoperone Fumarate; Risperidone.
[0084] Neuroprotective: Dizocilpine Maleate.
[0085] Psychotropic: Minaprine.
[0086] Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride;
Aminophylline; Azumolene Sodium; Baclofen; Benzoctamine
Hydrochloride; Carisoprodol; Chlorphenesin Carbamate;
Chlorzoxazone; Cinflumide; Cinnamedrine; Clodanolene;
Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium;
Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride;
Flavoxate Hydrochloride; Fletazepam; Flumetramide;-Flurazepam
Hydrochloride; Hexafluorenium Bromide; Isomylamine Hydrochloride;
Lorbamate; Mebeverine Hydrochloride; Mesuprine Hydrochloride;
Metaxalone; Methocarbamol; Methixene Hydrochloride; Nafomine
Malate; Nelezaprine Maleate; Papaverine Hydrochloride; Pipoxolan
Hydrochloride; Quinctolate; Ritodrine; Ritodrine Hydrochloride;
Rolodine; Theophylline Sodium Glycinate; Thiphenamil Hydrochloride;
Xilobam.
[0087] Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam;
Amobarbital Sodium; Bentazepam; Brotizolam; Butabarbital;
Butabarbital Sodium; Butalbital; Capuride; Carbocloral; Chloral
Betaine; Chloral Hydrate; Chlordiazepoxide Hydrochloride;
Cloperidone Hydrochloride; Clorethate; Cyprazepam; Dexclamol
Hydrochloride; Diazepam; Dichloralphenazone; Estazolam;
Ethchlorvynol; Etomidate; Fenobam; Flunitrazepam; Fosazepam;
Glutethimide; Halazepam; Lormetazepam; Mecloqualone; Meprobamate;
Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pentobarbital
Sodium; Perlapine; Prazepam; Quazepam; Reclazepam; Roletamide;
Secobarbital; Secobarbital Sodium; Suproclone; Thalidomide;
Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos
Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride;
Zolpidem Tartrate.
[0088] Serotonin antagonist: Altanserin Tartrate; Amesergide;
Ketanserin; Ritanserin.
[0089] Serotonin inhibitor: Cinanserin Hydrochloride; Fenclonine;
Fonazine Mesylate; Xylamidine Tosylate.
[0090] Serotonin receptor antagonist: Tropanserin
Hydrochloride.
[0091] Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampyzine
Sulfate; Arbutamine Hydrochloride; Azabon; Caffeine; Ceruletide;
Ceruletide Diethylamine; Cisapride; Dazopride Fumarate;
Dextroamphetamine; Dextroamphetamine Sulfate; Difluanine
Hydrochloride; Dimefline Hydrochloride; Doxapram Hydrochloride;
Etryptamine Acetate; Ethamivan; Fenethylline Hydrochloride;
Flubanilate Hydrochloride; Flurothyl; Histamine Phosphate;
Indriline Hydrochloride; Mefexamide; Methamphetamine Hydrochlo
ride; Methylphenidate Hydrochloride; Pemoline; Pyrovalerone
Hydrochloride; Xamoterol; Xamoterol Fumarate. Synergist: Proadifen
Hydrochloride.
[0092] Thyroid hormone: Levothyroxine Sodium; Liothyronine Sodium;
Liotrix.
[0093] Thyroid inhibitor: Methimazole; Propyithiouracil.
[0094] Thyromimetic: Thyromedan Hydrochloride.
[0095] Cerebral ischemia agents: Dextrorphan Hydrochloride.
[0096] Vasoconstrictor: Angiotensin Amide; Felypressin;
Methysergide; Methysergide Maleate.
[0097] Vasodilator: Alprostadil; Azaclorzine Hydrochloride;
Bamethan Sulfate; Bepridil Hydrochloride; Buterizine; Cetiedil
Citrate; Chromonar Hydrochloride; Clonitrate; Diltiazem
Hydrochloride; Dipyridamole; Droprenilamine; Erythrityl
Tetranitrate; Felodipine; Flunarizine Hydrochloride; Fostedil;
Hexobendine; Inositol Niacinate; Iproxamine Hydrochloride;
Isosorbide Dinitrate; Isosorbide Mononitrate; Isoxsuprine
Hydrochloride; Lidoflazine; Mefenidil; Mefenidil Fumarate;
Mibefradil Dihydrochloride; Mioflazine Hydrochloride; Mixidine;
Nafronyl Oxalate; Nicardipine Hydrochloride; Nicergoline;
Nicorandil; Nicotinyl Alcohol; Nifedipine; Nimodipine; Nisoldipine;
Oxfenicine; Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate;
Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol;
Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; Terodiline
Hydrochloride; Tipropidil Hydrochloride; Tolazoline Hydrochloride;
Xanthinol Niacinate.
[0098] Specifically, topiramate may be administered in combination
with other medications to treat certain symptoms and disorders
including:
[0099] I. Treatment of Binge Eating (Binge Eating Disorder, Bulimia
Nervosa, Anorexia Nervosa with Binge eating) with serotonin
re-uptake inhibitors (e.g., citalopram (CELEXA), clomipramine
(ANAFRANIL)), fluoxetine (PROZAC), fluvoxamine (LUVOX), venlafaxine
(EFFEXOR), other antidepressants (e.g., bupropion (WELLBUTRIN)
nefazodone (SERZONE), tricyclics (e.g., NORPRAMIN and PAMELOR),
trazodone (DESYREL), Substance P antagonists), psychostimulants,
(e.g., d-amphetamine, phentermine; and sibutramine (MERIDIA)) and
orlistat.
[0100] II. Treatment of overweight/obesity condition with
sibutramine (MERIDIA); psychostimulants, (e.g., d-amphetamine,
phentermine) and orlistat.
[0101] III. Treatment of nicotine addiction/smoking cessation with
bupropion (ZYBAN), serotonin reuptake inhibitors, nicotine patches
and gum, and other antidepressants.
[0102] IV. Treament of alcohol abuse/dependence (alcoholism) with
naltrexone (REVIA), serotonin reuptake inhibitors, and other
antidepressants.
[0103] V. Treatment of other impulse control disorders (behavioral
addictions) with serotonin reuptake inhibitors, lithium, valproic
acid or divalproex sodium (e.g., DEPAKENE or DEPAKOTE), other
antidepressants, naltrexone, atypical antipsychotics, (e.g.,
olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone
(RISPERDAL), ziprasidone) and other mood stabilizers (e.g.,
carbamazepine)
[0104] VI. Treatment of paraphilias/sexual addictions with
serotonin reuptake inhibitors, lithium, divalproex sodium/valproic
acid, antiandrogen medications (e.g., medroxyprogesterone,
gonadotropin-releasing hormone (GnRH) agonists), other
antidepressants, and other mood stabilizers (e.g.,
carbamazepine).
[0105] When administered, the formulations of the invention are
applied in pharmaceutically acceptable amounts and in
pharmaceutically acceptable compositions. Such preparations may
routinely contain salts, buffering agents, preservatives,
compatible carriers, and optionally other therapeutic ingredients.
When used in medicine the salts should be pharmaceutically
acceptable, but non-pharmaceutically acceptable salts may
conveniently be used to prepare pharmaceutically acceptable salts
thereof and are not excluded from the scope of the invention. Such
pharmacologically and pharmaceutically acceptable salts include,
but are not limited to, those prepared from the following acids:
hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic,
acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane
sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and
benzene sulfonic. Also, pharmaceutically acceptable salts can be
prepared as alkaline metal or alkaline earth salts, such as sodium,
potassium or calcium salts.
[0106] Suitable buffering agents include: acetic acid and a salt
(1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a
salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V).
Suitable preservatives include benzalkonium chloride (0.003-0.03%
W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and
thimerosal (0.004-0.02% W/V).
[0107] In the present invention, the sulfamide derivatives are
administered in safe and effective amounts. An effective amount
means that amount necessary to delay the onset of, inhibit the
progression of, halt altogether the onset or progression of or
diagnose the particular condition being treated. In general, an
effective amount for treating an ICD will be that amount necessary
to inhibit mammalian symptoms of the particular ICD in-situ. When
administered to a subject, effective amounts will depend, of
course, on the particular condition being treated; the severity of
the condition; individual patient parameters including age,
physical condition, size and weight; concurrent treatment;
frequency of treatment; and the mode of administration. These
factors are well known to those of ordinary skill in the art and
can be addressed with no more than routine experimentation. It is
preferred generally that a minimum dose be used, that is, the
lowest safe dosage that provides appropriate relief of
symptoms.
[0108] Dosage may be adjusted appropriately to achieve desired drug
levels, locally or systemically. Generally, daily oral doses of
active compounds will be from about 0.01 mg/kg per day to 2000
mg/kg per day. It is expected that IV doses in the range of about 1
to 1000 mg/cm.sup.3 per day will be effective. In the event that
the response in a subject is insufficient at such doses, even
higher doses (or effective higher doses by a different, more
localized delivery route) may be employed to the extent that
patient tolerance permits. Continuous IV dosing over, for example
24 hours or multiple doses per day is contemplated to achieve
appropriate systemic levels of compounds.
[0109] A variety of administration routes are available. The
particular mode selected will depend of course, upon the particular
drug selected, the severity of the disease state(s) being treated
and the dosage required for therapeutic efficacy. The methods of
this invention, generally speaking, may be practiced using any mode
of administration that is medically acceptable, meaning any mode
that produces effective levels of the active compounds without
causing clinically unacceptable adverse effects. Such modes of
administration include oral, rectal, sublingual, topical, nasal,
transdermal or parenteral routes. The term "parenteral" includes
subcutaneous, intravenous, intramuscular, or infusion. Intravenous
routes are preferred.
[0110] The compositions may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. In general, the compositions are prepared by
uniformly and intimately bringing the compounds into association
with a liquid carrier, a finely divided solid carrier, or both, and
then, if necessary, shaping the product.
[0111] Compositions suitable for oral administration may be
presented as discrete units such as capsules, cachets, tablets, or
lozenges, each containing a predetermined amount of the active
compound. Other compositions include suspensions in aqueous liquors
or non-aqueous liquids such as a syrup, an elixir, or an
emulsion.
[0112] Other delivery systems can include time-release, delayed
release or sustained release delivery systems. Such systems can
avoid repeated administrations of the active compounds of the
invention, increasing convenience to the subject and the physician.
Many types of release delivery systems are available and known to
those of ordinary skill in the art. They include polymer based
systems such as polylactic and polyglycolic acid, polyanhydrides
and polycaprolactone; nonpolymer systems that are lipids including
sterols such as cholesterol, cholesterol esters and fatty acids or
neutral fats such as mono-, di and triglycerides; hydrogel release
systems; silastic systems; peptide based systems; wax coatings,
compressed tablets using conventional binders and excipients,
partially fused implants and the like. In addition, a pump-based
hardware delivery system can be used, some of which are adapted for
implantation.
[0113] A long-term sustained release implant also may be used.
"Long-term" release, as used herein, means that the implant is
constructed and arranged to deliver therapeutic levels of the
active ingredient for at least 30 days, and preferably 60 days.
Long-term sustained release implants are well known to those of
ordinary skill in the art and include some of the release systems
described above.
EXAMPLES
[0114] In the examples, patients were treated with open-label
topiramate starting at 25 mg/qHS and the dosage increased by the
patient in 25 mg increments as tolerated by the subjects until a
response is seen up to a maximum of 1200 mg.
1TABLE 1 Patients with Binge Eating Disorder (BED) Treated
Clinically with Open-Label Topiramate (as of 12/16/98) Reasons Max
Pt Topiramate Dose # Pt ID Begun (mg/day) Response 1 LJM BD 1200
Remission of BD (BED) Remission of BED (Obesity) Loss of 107 lbs. 2
CEJ BD 150 Mild improvement of BD, BED Moderate decrease of BED,
Overweight Loss of 5 lbs. Discontinued due to sedation, cognitive
dulling 3 JAC BD 1200 Moderate improvement of BD. BED Remission of
BED Obesity Loss of 50.5 lbs 4 JEB BD 900 Moderate improvement of
BD, BED Marked improvement of BED, Overweight Loss of 30.5 lbs. 5
KCW BED 100 First trial: No response of BED, Obesity discontinued
due to GI distress Compulsive Buying (BD, in 100 Second Trial:
Worsening of BD remission) Remission of BED Loss of 11 lbs.
Remission of Compulsive Buying 6 JB BED 100 No response of BED
Overweight No weight change Key: BD = Bipolar Disorder; BED = Binge
Eating Disorder; Pt. = patient; D/C = topiramate treatment
discontinued; Cont. = topiramate treatment continued; GI =
gastrointestinal
[0115]
2TABLE 2 Patients with Overeating, Overweight, and Obesity Treated
Clinically with Topiramate (as of 12/16/98) Pt. Reasons Max dose #
Pt. ID Topiramate Begun (mg/day) Response 1 BAA BD 700 No response
of BD Obesity Loss of 9 lbs. (293-284) (BED, in remission) 2 HTB BD
300 Remission of BD Overeating Remission of overeating Overweight
Loss of 16 lbs. (248-232) Discontinued 2.degree. illness in
remission 3 ADJ BD 400 Moderate improvement of BD Overeating,
Moderate improvement of overeating Overweight Loss of 7 lbs.
(239-232) 4 TK BD 350 No response of BD Overeating Mild improvement
in overeating Overweight Loss of 5 lbs. (238-233) 5 JCJ BD 1. 250
First Trial: Worsening of BD Overeating 2. 200 Mild decrease of
overeating Overweight Loss of 7 lbs. (152-145) Second Trial Mild
improvement of BD Mild decrease of overeating Gain of 1 lb.
(154-155 lbs.) 6 KDC Overeating 800 Worsening of BD Overweight Loss
of 9 lbs. (208-199 lbs) (BD, in remission) 7 NLR BD 300 Worsening
of BD Overweight Loss of 46 lbs. (196-150 lbs.) Discontinued due to
anorexia 8 PR BD 700 Moderate improvement of BD Overeating Marked
improvement in overeating Overweight Loss of 19 lbs. (185-166)
Discontinued due to G.I. Distress Key: Pt. = patient; BD = Bipolar
Disorder; BED = Binge Eating Disorder; D/C = topiramate treatment
discontinued; cont = topiramate treatment continued; GI =
gastrointestinal
* * * * *