U.S. patent application number 10/310152 was filed with the patent office on 2004-03-04 for nicotine addiction treatment.
This patent application is currently assigned to Cary Medical Corporation. Invention is credited to Cary, Douglas D..
Application Number | 20040044005 10/310152 |
Document ID | / |
Family ID | 22031798 |
Filed Date | 2004-03-04 |
United States Patent
Application |
20040044005 |
Kind Code |
A1 |
Cary, Douglas D. |
March 4, 2004 |
Nicotine addiction treatment
Abstract
The present invention encompasses methods of treating patients
for tobacco addiction and nicotine addiction, for palliating the
effects of nicotine withdrawal, for providing or facilitating the
effects of smoking cessation therapies and as long-term smoking
cessation maintenance therapy. The invention also includes related
pharmaceutical compositions comprising nicotine receptor
antagonists and either an anti-depressant or an anti-anxiety drug.
Specific combinations of drugs (mecamylamine HCl and bupropion HCl)
as well as mecamylamine in combination with certain drug classes
(e.g., anti-anxiety drugs and anti-depressants) comprise the
pharmaceutical compositions disclosed. These compositions are also
contemplated for use in the treatment of cocaine addiction and the
treatment of alcohol dependence.
Inventors: |
Cary, Douglas D.; (Great
Falls, VA) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
Cary Medical Corporation
|
Family ID: |
22031798 |
Appl. No.: |
10/310152 |
Filed: |
December 5, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10310152 |
Dec 5, 2002 |
|
|
|
09785496 |
Feb 20, 2001 |
|
|
|
09785496 |
Feb 20, 2001 |
|
|
|
09423897 |
Nov 16, 1999 |
|
|
|
6197827 |
|
|
|
|
09423897 |
Nov 16, 1999 |
|
|
|
PCT/US98/20894 |
Oct 2, 1998 |
|
|
|
60060794 |
Oct 3, 1997 |
|
|
|
Current U.S.
Class: |
514/253.04 ;
514/220; 514/317; 514/419; 514/649 |
Current CPC
Class: |
A61K 31/135 20130101;
Y10S 514/812 20130101; A61K 45/06 20130101; A61P 25/34 20180101;
A61P 25/36 20180101; A61P 25/32 20180101; Y10S 514/813 20130101;
Y10S 514/811 20130101; A61K 31/135 20130101; A61K 31/13 20130101;
A61K 31/135 20130101; A61K 2300/00 20130101; A61K 31/135 20130101;
A61K 31/135 20130101 |
Class at
Publication: |
514/253.04 ;
514/649; 514/317; 514/220; 514/419 |
International
Class: |
A61K 031/496; A61K
031/445 |
Claims
What is claimed:
1. A pharmaceutical composition for treating tobacco addiction or
nicotine addiction, palliating nicotine withdrawal symptoms or
facilitating smoking cessation comprising a therapeutically
effective combination of a nicotine receptor antagonist and either
an anti-depressant or an anti-anxiety drug.
2. The pharmaceutical composition of claim 1, wherein said
anti-depressant is selected from the group consisting of bupropion,
doxepin, desipramine, clomipramine, imipramine, nortriptyline,
amitriptyline, protriptyline, trimipramine, fluoxetine,
fluvoxamine, paroxetine, sertraline, phenelzine, tranylcypromine,
amoxapine, maprotiline, trazodone, venlafaxine, mirtazapine, their
pharmaceutically active salts and their optical isomers.
3. The pharmaceutical composition of claim 1, wherein said
anti-depressant is either bupropion or a pharmaceutically
acceptable salt thereof, or doxepin or a pharmaceutically
acceptable salt thereof.
4. The pharmaceutical composition of claim 3, wherein said
pharmaceutically acceptable salt of bupropion is bupropion HCl.
5. The pharmaceutical composition of claim 3, wherein said
pharmaceutically acceptable salt of doxepin is doxepin HCl.
6. The pharmaceutical composition of claim 1, wherein the nicotine
receptor antagonist is selected from the group consisting of:
mecamylamine, amantadine, pempidine, dihydro-beta-erythroidine,
hexamethonium, erysodine, chlorisondamine, trimethaphan camsylate,
tubocurarine chloride, d-tubocurarine, their pharmaceutically
acceptable salts and their optical isomers.
7. The pharmaceutical composition of claim 6, wherein said nicotine
receptor antagonist is mecamylamine or a pharmaceutically
acceptable salt thereof.
8. The pharmaceutical composition of claim 7, wherein said
pharmaceutically acceptable salt of mecamylamine is mecamylamine
HCl.
9. The pharmaceutical composition of claim 1, wherein the
anti-anxiety agent is selected from the group consisting of
hydroxyzine, meprobamate, buspirone, their pharmaceutical salts and
their optical isomers.
10. The pharmaceutical composition of claim 1, wherein said
anti-anxiety agent is buspirone or a pharmaceutically acceptable
salt thereof.
11. The pharmaceutical composition of claim 10, wherein said
pharmaceutically acceptable salt of buspirone is buspirone HCl.
12. The pharmaceutical composition of claim 3, wherein said
bupropion or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 50 mg to about 300
mg.
13. The pharmaceutical composition of claim 3, wherein said
bupropion or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 50 mg to about 150
mg.
14. The pharmaceutical composition of claim 7, wherein said
mecamylamine or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 1 mg to about 25
mg.
15. The pharmaceutical composition of claim 7, wherein said
mecamylamine or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 1 mg to about 10
mg.
16. The pharmaceutical composition of claim 10, wherein said
buspirone or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 5 mg to about 60
mg.
17. The pharmaceutical composition of claim 10, wherein said
buspirone or a pharmaceutically acceptable salt thereof is
formulated to deliver a daily dose of about 5 mg to about 10
mg.
18. A method of treating tobacco addiction or nicotine addiction,
palliating nicotine withdrawal symptoms or facilitating smoking
cessation comprising the step of administering to a patient the
pharmaceutical composition of any of claims 1 to 17.
19. The method of claim 18, comprising the further step of
administering nicotine replacement therapy.
20. The method of claim 19, wherein said nicotine replacement
therapy is a nicotine transdermal patch.
21. A pharmaceutical composition for treating cocaine addiction and
associated withdrawal effects comprising a therapeutically
effective combination of a nicotine receptor antagonist and either
an anti-depressant or an anti-anxiety drug.
22. The pharmaceutical composition for treating cocaine addiction
and associated withdrawal effects of claim 21, wherein the
anti-depressant is selected from the group consisting of: bupropion
or a pharmaceutically active salt thereof, and doxepin or a
pharmaceutically active salt thereof.
23. The pharmaceutical composition for treating cocaine addiction
and associated withdrawal effects of claim 22, wherein the
anti-anxiety drug is buspirone or a pharmaceutically active salt
thereof.
24. A method of treating cocaine addiction and associated
withdrawal effects comprising the step of administering to a
patient the pharmaceutical composition of any of claims 21 to
23.
25. A pharmaceutical composition for treating alcohol dependence
and associated withdrawal effects comprising a therapeutically
effective combination of nicotine receptor antagonist and either an
anti-depressant or an anti-anxiety drug.
26. The pharmaceutical composition for treating alcohol dependence
and associated withdrawal effects of claim 25, wherein the
anti-depressant is selected from the group consisting of: bupropion
or a pharmaceutically active salt thereof, and doxepin or a
pharmaceutically active salt thereof.
27. The pharmaceutical composition for treating alcohol dependence
and associated withdrawal effects of claim 25, wherein the
anti-anxiety drug is buspirone or a pharmaceutically active salt
thereof.
28. A method of treating alcohol dependence and associated
withdrawal effects comprising the step of administering to a
patient the pharmaceutical composition of any of claims 25 to 27.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions
and methods of using these compositions to treat patients for
tobacco addiction and nicotine addiction, to palliate the effects
of nicotine withdrawal and to enhance the outcomes of other smoking
cessation therapies. Each agent of the pharmaceutical compositions
disclosed has an unique mechanism of action, and when administered
concurrently, the combined drugs provide unexpected advantages over
existing therapies.
BACKGROUND OF THE INVENTION
[0002] Tobacco addiction represents the most important preventable
cause of illness and death in our society, responsible for more
than 400,000 deaths each year. Currently, one out of five Americans
smoke cigarettes, representing almost 50 million smokers in the
United States alone. Half of all smokers will die of diseases
directly related to tobacco use, and many smokers will suffer
significant morbidity. Approximately 15 million smokers try to
quit, but only one million of those succeed in smoking cessation
each year.
[0003] A. Nicotine Addiction and Nicotine Addiction Therapy
[0004] A great deal of evidence supports the view that people
continue to smoke because of the reinforcing effects of nicotine.
Relevant findings include the fact that when allowed to control the
nicotine content of each puff, smokers previously deprived of
cigarettes, or administered a centrally acting nicotine antagonist,
select higher nicotine concentrations. Moreover, under certain
conditions, smokers, as well as animals, will self-administer
intravenous nicotine.
[0005] The rewarding psychopharmacologic effects of nicotine are
diverse. They include tranquilization, weight loss, decreased
irritability, reduction in craving for cigarettes and other tobacco
products, increased alertness, and improved cognitive function.
These effects involve to some extent relief of withdrawal symptoms,
which could be considered negative reinforcement by nicotine.
However, some effects (e.g., improved attentiveness) have been
demonstrated in non-dependent animals (Rose, 1996 Rev. Med. 47:
493).
[0006] Nicotine that is inhaled in tobacco smoke is rapidly
absorbed and enters the pulmonary circulation, reaching the brain
within several seconds. One cigarette provides 5-30 ng/ml of
nicotine in venous blood (Rose, 1996). Nicotine has a metabolic
half-life of roughly 2 hours, and cotinine is the main metabolite.
Other mechanisms of nicotine delivery, such as snuff, and smoking
pipes and cigars create the same effects once in the blood
stream.
[0007] Nicotine is a powerful psychoactive drug that activates the
same brain pathway as cocaine, and other psychostimulants,
producing drug associated tolerance and withdrawal effects. In
smokers, nicotine's rapid onset of central nervous system action
and short half-life cause tolerance to develop quickly and provide
an optimal environment for the development of nicotine
dependence.
[0008] Several pharmacotherapies have proven effective for smoking
cessation. These include nicotine replacement therapies (NRTs).
Such NRTs come in the form of gum, the transdermal patch, nasal
spray, and inhaler. The first FDA-approved pharmaceutical to
provide nicotine replacement was Nicorette.RTM. (nicotine
polacrilex), a chewing gum formulation that contained 2 mg, and
later 4 mg, of nicotine in each piece. The gum delivered nicotine
through buccal absorption following chewing.
[0009] Non-nicotine pharmacologic therapies are a more recently
developed method of treating nicotine addiction. Possible reagents
include nicotine blockade therapy, drugs affecting serotonergic
neurotransmission, anti-depressants, anxiolytics, clonidine and
airway sensory replacement (Rose, 1996; and Cinciripini et al.,
1998 Oncology 12: 249-256). Nicotine blockade therapy (also
referred to as nicotine receptor antagonists) utilizes compounds
that occupy nicotine receptors, thereby attenuating the reward
received from tobacco usage (Clarke, 1991 Br. J. Addict. 86:
501-505).
[0010] B. Anti-Depressants and Anxiolytics
[0011] Anti-depressants have oftentimes been used to treat symptoms
of nicotine withdrawal. One such anti-depressant is bupropion.
Wellbutrin.RTM. is the trade name for the bupropion salt, bupropion
HCl, an anti-depressant manufactured by Glaxo Wellcome. A
sustained-release formulation of bupropion HCl, Wellbutrin SR.RTM.,
is also indicated for the treatment of depression. Glaxo Wellcome
also has FDA approval to market a sustained release formulation of
bupropion HCl as an aid to smoking cessation treatment for the
smoking cessation indication. Glaxo Wellcome is marketing this
product under the trade name Zyban.RTM.. Zyban.RTM. can be used
either alone or in combination with a nicotine transdermal system
(NTS). The mechanism of action of bupropion is unknown, but is
thought to influence neurotransmitters. Specifically, bupropion is
believed to operate on the neurochemistry of nicotine addiction by
enhancing dopamine levels in the mesolimbic system and affecting
noradrenergic neurons in the locus ceruleus portion of the brain.
As dopamine had been associated with the rewarding effects of
addictive substances, such as nicotine, inhibition of
norepinephrine re-uptake was contemplated to induce a decrease of
withdrawal symptoms (The Medical Letter 39: 77 (Aug. 15,
1997)).
[0012] Another anti-depressant successfully used in the treatment
of smoking cessation is doxepin. Doxepin and pharmaceutically
acceptable salts thereof were originally administered as
anti-depressants (THE MERCK INDEX #3425: 539). Additional
anti-depressants considered or utilized for smoking cessation
treatment include imipramine (Nunn-Thompson et al., 1989 Clin.
Pharm. 8: 710-720) and desipramine (Diana et al., 1990 Am. J.
Physiol. 259: H1718-H1729).
[0013] Anxiolytics have also been administered to treat nicotine
withdrawal. Anxiolytics counter the mild anxiety symptoms that
occur during smoking cessation treatment, or the treatment of
alcoholism or other substance abuse. The anxiolytic, isovaleramide,
has been recommended for use in smoking cessation (Balandrin et
al., WO 94/28888). Smoking cessation has also been treated with a
combination of antidepressants and anxiolytics (Glazer, U.S. Pat.
No. 4,788,189).
[0014] C. Nicotine Receptor Antagonists
[0015] Another class of smoking cessation drugs are nicotine
receptor antagonists, which are used to block the nicotinic
receptor (Rose et al., 1997 Psychopharmacology 130: 28-40).
Evidence suggests that smoking cessation may be facilitated by
administration of a nicotinic antagonist having a selective action
on central nicotinic cholinoceptors of the C6 (ganglionic) type
(Clarke, 1987 Psychopharmacology 92: 135-143). Additional nicotinic
receptors exist against which nicotine antagonists can operate. One
nicotine receptor antagonist, mecamylamine and its pharmaceutically
acceptable salts, has been explored as a possible pharmacotherapy
for smoking cessation because it aids smoking cessation in both
animals and humans (Tennant et al., 1984 NIDA Res. Monogr. 55:
291-297). Mecamylamine was patented in 1958 and since has been
marketed as the anti-hypertensive agent, Inversine.RTM., which is
mecamylamine hydrochloride (HCl) (Pfister, U. S. Pat. No.
2,831,027; THE MERCK INDEX #5654: 905). In the context of nicotine
dependence, mecamylamine HCl has been shown to block many of the
physiologic, behavioral, and reinforcing effects of nicotine.
[0016] Low doses of mecamylamine HCl have been shown to enhance
smoking cessation when used in combination with a nicotine
transdermal system (NTS) (Rose et al., 1994 Clin. Pharmacology
& Therapeutics 56: 86; Levin et al., U.S. Pat. Nos. 5,574,052
and 5,316,759). In a double-blind clinical trial, in which nicotine
was administered by skin patch treatment with or without concurrent
mecamylamine (5 mg/bid), a threefold enhancement in continuous
smoking abstinence rates was observed for the combined
mecamylaminenicotine patch group compared to the rate observed for
the transdermal patch alone. Additionally, the therapeutic effect
was sustained for the combined mecamylamine-nicotine patch group,
whereas abstinence decreased four fold over 12 months in the
NTS-only group. Another effect of the combined mecamylamine-NTS
therapy was significantly reduced cravings for cigarettes, negative
effect and appetite (Rose et al., 1994).
[0017] Thus, because drugs such as mecamylamine, or a
pharmaceutically acceptable salt thereof, compete for the same
receptor as nicotine, they have been beneficial in enhancing
currently available smoking cessation therapies. Mecamylamine is a
central and peripheral nicotine antagonist and causes individuals
treated with mecamylamine to crave higher doses of nicotine than
when the same individual is treated with agents which are
peripheral nicotine antagonists only (e.g., trimethaphan) (Perkins
et al., "Effects of Central and Peripheral Nicotinic Blockage on
Human Nicotine Discrimination," Psychopharm. In press).
Mecamylamine blocks the stimulus effects of both cytisine and
nicotine, both of which bind to neuronal nicotinic receptors
(Chandler et al., 1997 Psychopharmacology 129: 257-264).
[0018] Additional nicotinic antagonists include hexamethonium
(Wotring et al., 1995 Neuroscience 67: 293-300),
dihydro-beta-erythroidine (Stolerman et al., 1997
Psychopharmacology 129: 390-397), d-tubocurarine (Wotring et al.,
1995), pempidine (Rapier et al., 1990 J. Neurochem. 54: 937-945),
chlorisondamine (Caggiula et al., 1995 Psychopharmacology 122:
301-306), erysodine (Decker et al., 1995 Eur. J. Pharmacol. 280:
79-80) and trimethaphan camsylate (Hisayama et al., 1988 Br. J.
Pharmacol. 95: 465-472).
[0019] Some nicotinic antagonists have been combined with other
agents to examine the effects on mean arterial pressure and renal
sympathetic nerve activity. Two nicotinic receptor antagonists,
pentolinium and hexamethonium, have been examined in combination
with benextramine, desipramine and prazosin for their ability to
modulate blood pressure (Martin 1997 J. Auton. Pharmacol. 17:
249-259). However, combinations of nicotinic antagonists and either
anti-depressants or anxiolytics have not been previously indicated
for use in the treatment of smoking cessation or for other
substance addiction therapies.
[0020] D. Treatment of Cocaine Addiction
[0021] Cocaine addiction has been treated with some of the drugs
used for smoking cessation as a means of decreasing cocaine
withdrawal symptoms. For example pharmacotherapy with desipramine,
amantadine and bromocriptine was shown in preliminary studies to
minimize the symptoms of cocaine withdrawal (Hall et al., 1990
Pharmacotherapy 10: 47-65; and Kostenetal., 1991 NIDA Res. Monogr.
105: 510-511). Combinations of desipramine and amantadine have
facilitated greater opiate and cocaine abstinence (Oliveto et al.,
1995 J. Subst. Abuse Treat. 12: 423-428).
SUMMARY OF THE INVENTION
[0022] The present invention relates to a pharmaceutical
composition for treating tobacco addiction and nicotine addiction,
for palliating nicotine withdrawal symptoms or facilitating smoking
cessation. The preferred compositions comprise a therapeutically
effective combination of a nicotine receptor antagonist and either
an anti-depressant or an anti-anxiety drug absent supplementation
of nicotine. Contemplated pharmaceutical compositions can be an
admixture of the active agents administered as a single unit (e.g.,
a single tablet or capsule) or can be administered in separate
dosage units (e.g., two capsules).
[0023] The anti-depressant of the pharmaceutical composition
contemplated for this invention can be bupropion or a
pharmaceutically acceptable salt thereof, or doxepin or a
pharmaceutically acceptable salt thereof. Additional
anti-depressants contemplated for combination with a nicotinic
antagonist include: doxepin, desipramine, clomipramine, imipramine,
nortriptyline, amitriptyline, protriptyline, trimipramine,
fluoxetine, fluvoxamine, paroxetine, sertraline, phenelzine,
tranylcypromine, amoxapine, maprotiline, trazodone, venlafaxine,
mirtazapine, their pharmaceutically active salts or their optical
isomers.
[0024] One pharmaceutically acceptable salt of bupropion
contemplated for the invention to be used in combination with a
nicotine receptor antagonist is bupropion hydrochloride (HCl). The
amount of bupropion or its pharmaceutically acceptable salt to be
administered with a nicotine receptor antagonist is formulated so
as to provide a dose of about 50 mg to about 300 mg per day.
[0025] One pharmaceutically acceptable salt of doxepin contemplated
for the invention to be used in conjunction with a nicotine
receptor antagonist is doxepin hydrochloride (HCl). It is further
contemplated that the amount of doxepin or pharmaceutically
acceptable salt thereof to be administered with a nicotine receptor
antagonist is formulated so as to provide a dose of about 10 mg to
a dose of about 300 mg of doxepin per day. The total daily dose can
be administered in several dosages over the course of the day
(e.g., 1 to 6 tablets).
[0026] It is also contemplated that the nicotine receptor
antagonist component of the pharmaceutical composition is
mecamylamine and pharmaceutically acceptable salts thereof as well
as optical isomers. One pharmaceutically acceptable salt of
mecamylamine disclosed herein is mecamylamine hydrochloride (HCl).
It is further contemplated that the amount of mecamylamine, or
pharmaceutically acceptable salt thereof, to be administered with
either an anti-depressant or an anti-anxiety drug is formulated to
provide a dose of about 1 mg to about 25 mg of mecamylamine per
day.
[0027] The invention further relates to the use of the anti-anxiety
drug, buspirone or pharmaceutically acceptable salts thereof in
combination with a nicotine receptor antagonist. It is contemplated
that buspirone hydrochloride (HCl) in combination with a nicotine
receptor antagonist be utilized. The invention also relates to the
use of an amount of buspirone or pharmaceutically acceptable salt
thereof to be administered with a nicotine receptor antagonist that
is formulated so as to provide a dose of about 5 mg to a dose of
about 60 mg per day. More preferred is the use of a nicotine
receptor antagonist in a dosage range of about 1 mg to about 25 mg
of mecamylamine (HCl) to be administered in conjunction with a
dosage of buspirone (HCl) of about 5 mg to about 10 mg per tablet.
These dosages may be administered as one tablet to six tablets per
day. Anxiolytics other than buspirone contemplated for
coadministration with a nicotinic antagonist for the treatment of
smoking cessation include: hydroxyzine or meprobamate.
[0028] This invention further provides compositions containing
nicotinic antagonists, other than mecamylamine, and either an
anxiolytic or an anti-depressant. The nicotinic antagonists
include: central nicotinic antagonists, central and peripheral
nicotinic antagonists and peripheral nicotinic antagonists.
Specific nicotinic antagonists contemplated include: mecamylamine,
amantadine, pempidine, dihydro-beta-erythroidine, hexamethonium,
erysodine, chlorisondamine, trimethaphan camsylate, tubocurarine
chloride, d-tubocurarine, their pharmaceutically acceptable salts
or their optical isomers.
[0029] The invention additionally relates to a method of treating
tobacco addiction or nicotine addiction, palliating nicotine
withdrawal symptoms, or facilitating smoking cessation comprising
the step of administering to a patient any one of the
aforementioned pharmaceutical compositions.
[0030] The invention further relates to a method of treating
tobacco addiction or nicotine addiction, palliating nicotine
withdrawal symptoms, or facilitating smoking cessation comprising
the added step of administering the pharmaceutical compositions
disclosed above in combination with a nicotine replacement or
supplementation therapy. The nicotine transdermal patch is such a
contemplated nicotine replacement therapy.
[0031] It is further contemplated that the described pharmaceutical
compositions can be administered to treat individuals for cocaine
addiction, to ameliorate cocaine withdrawal symptoms and to treat
individuals for alcohol addiction and ameliorate the effects
associated with alcohol withdrawal. The methods of delivery and
dosages administered for treatment of cocaine addiction and alcohol
dependence may be similar to those suggested for treatment of
nicotine addiction.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0032] I. General Description
[0033] Although non-prescription nicotine replacement therapies
dominate the market, their effectiveness in preventing
nicotine-dependent individuals from relapsing is not as great as
that demonstrated for non-nicotine dependent pharmacological
agents, such as bupropion HCl. Success rates for nicotine gum is
less than 10% at 12 months and for nicotine transdermal patches
only 10-30% at 12 months (Rose et al., 1994). Therefore,
identifying reagents that possess low failure rates are a goal for
both the industry and for smokers desiring to quit their addictive
habit.
[0034] The present invention encompasses methods of treating
patients for tobacco addiction, nicotine addiction, palliating the
effects of nicotine withdrawal, enhancing the outcomes of other
smoking cessation therapies, as well as providing long term smoking
cessation maintenance treatment. The invention also includes
related pharmaceutical compositions used to treat patients
administered in therapeutically effective amounts. Specific
combinations of drugs, such as an anti-anxiety agent in combination
with a nicotine receptor antagonist are disclosed. Additionally,
the pharmaceutical composition of an antidepressant in combination
with a nicotine receptor antagonist is also contemplated. Preferred
nicotinic receptor antagonists are those that are both a central
and peripheral nicotine antagonist (e.g., mecamylamine) or a
central nicotinic agonist. Less preferred nicotinic receptor
antagonists are those antagonists which are only peripheral
nicotine antagonists. These compositions are also contemplated for
use in treating individuals for cocaine addiction and its
associated withdrawal effects, and alcohol dependence and its
associated withdrawal effects.
[0035] II. Specific Description
[0036] In one embodiment, the pharmaceutical compositions of this
invention that are used to treat tobacco addiction and palliate the
withdrawal symptoms associated with cessation of tobacco use,
preferably include the following combinations:
[0037] (1) mecamylamine or a pharmaceutically acceptable
mecamylamine salt such as mecamylamine hydrochloride (HCl) and
bupropion or a pharmaceutically acceptable bupropion salt, such as
bupropion hydrochloride (HCl);
[0038] (2) mecamylamine or a pharmaceutically acceptable
mecamylamine salt, such as mecamylamine HCl and buspirone or a
pharmaceutically acceptable buspirone salt, such as buspirone
hydrochloride (HCl);
[0039] (3) mecamylamine or a pharmaceutically acceptable
mecamylamine salt such as mecamylamine HCl and doxepin or a
pharmaceutically acceptable doxepin salt, such as doxepin
hydrochloride (HCl); and
[0040] (4) a nicotine receptor antagonist and either an
anti-depressant or an anti-anxiety agent.
[0041] The patents that exist for the anti-depressants,
anti-anxiety drugs (also known as anxiolytics), and nicotine
antagonists, such as mecamylamine, identified below discuss other
uses for these agents. These patents describe the pharmaceutical
compositions and their pharmaceutically acceptable salt
derivatives, methods of producing the pharmaceuticals and methods
of using them.
[0042] Although large dosage ranges are contemplated for the
nicotine receptor antagonist-anti-depressant and nicotine receptor
antagonist-anxiolytic combinations, due to the unexpected
advantages created by the combination therapy, preferred dosages
may lie in the low to mid range for each drug. These lower dosages
will reduce the incidence of side effects and adverse
reactions.
[0043] Mecamylamine was used initially as an anti-hypertensive, but
also can act as a nicotine receptor antagonist. U.S. Pat. No.
2,831,027 describes the synthesis of mecamylamine. The mecamylamine
salt, mecamylamine HCl, has the chemical formula of
C.sub.11H.sub.22ClN. Mecamylamine and pharmaceutically or
physiologically acceptable salts thereof (e.g., mecamylamine HCl)
and optical isomers are contemplated in this invention to be used
in combination with an anti-anxiety drug or an anti-depressant to
treat tobacco addiction and nicotine addiction, ameliorate nicotine
withdrawal effects, in conjunction with nicotine replacement
therapies (NRTs), and to treat cocaine addiction and alcohol
dependence.
[0044] Nicotinic antagonists, in addition to mecamylamine,
contemplated for use in combination with an anxiolytic or an
anti-depressant include dihydro-beta-erythroidine (also known as
dihydro-.beta.-erythroidine;
3.beta.-1,6-didehydro-14,17-dihydro-3-methoxy-16(15H)-oxaerythrinan-15-on-
e; 12,13-didehydro-2,7,13,14-tetrahydro-.alpha.-erythroidine) (THE
MERCK INDEX, #3158: 500; 1989); tubocurarine chloride (also known
as 7',12'-dihydroxy-6,6-dimethoxy-2,2',2'-trimethyltubocuraranium
chloride hydrochloride) (THE MERCK INDEX, #9717: 1542, 1989);
d-tubocurarine (Wotring et al., 1995); amantadine (also known as
tricyclo[3.3.1.1.sup.3,- 7]decan-1-amine; 1-adamantanamine;
1-aminoadamantane; 1-aminodiamantane;
1-aminotricyclo[3.3.1.1.sup.3,7]decane) (THE MERCK INDEX #380: 60,
1989); pempidine (also known as 1,2,2,6,6-pentamethylpiperidine)
(THE MERCK INDEX #7022: 1120, 1989); erysodine (an erythrine
alkaloid related to dihydro-beta-erythroidine; see Decker et al.,
1995; and Singh et al., 1969 Experientia 25: 785); chlorisondamine
(also known as chlorisdondamine chloride;
4,5,6,7-tetrachloro-2,3-dihydro-2-methyl-2-[tr-
imethylammonio)ethyl]-2H-isoindolium dichloride;
4,5,6,7-tetrachloro-2-(2--
dimethylaminoethyl)-2-methylisoindolinium chloride methochloride)
(THE MERCK INDEX #2101: 324-325, 1989); hexamethonium (also known
as N,N,N,N',N',N'-hexamethyl-1,6-hexanediaminium;
hexmethylenebis(trimethyla- mmonium) (THE MERCK INDEX #4609: 741,
1989); and trimethaphan camsylate (also known as
decahydro-2-oxo-1,3-bis(phenylmethyl)thienol[1',2':
1,2]thieno[3,4]imidazol-5-ium (THE MERCK INDEX #9621: 1527, 1989).
The pharmaceutical salts of these compounds are also contemplated
for use in the treatment of smoking cessation. One example using a
nicotinic antagonist other than mecamylamine is amantadine HCl and
bupropion, wherein about 150 mg to about 300 mg of bupropion is
co-administered with about 50 mg to about 150 mg of amantadine HCl
to treat smoking cessation, as well as other conditions involving
withdrawal symptoms.
[0045] This invention also relates to use of an anti-depressant,
such as bupropion, in conjunction with a nicotine receptor
antagonist. U.S. Pat. Nos. 3,819,706 and 3,885,046 describe the
synthesis of bupropion. The various forms of bupropion have been
used to treat psychosexual dysfunction in men and women, to reduce
cholesterol levels, to treat attention deficit disorder (ADD), to
suppress prolactin levels in animals, to treat depression, to treat
tardive dyskinesia in mammals, and to overcome the mental alertness
impairments created by alcohol consumption. Patents encompassing
the aforementioned methods of using bupropion are disclosed
respectively in U.S. Pat. Nos. 4,507,323; 4,438,138; 4,435,449;
4,347,257; 3,885,046; 4,425,363; and 4,393,078. One
pharmaceutically acceptable salt of bupropion, bupropion HCl, which
is marketed under the names of Wellbatrin.RTM. and Wellbutrin.RTM.,
has the chemical formula of C.sub.11H.sub.19Cl.sub.2NO.
[0046] Another anti-depressant contemplated for administration with
a nicotine receptor antagonist is doxepin or pharmaceutically
acceptable salts thereof. U.S. Pat. Nos. 3,438,981 and 3,420,851
describe the synthesis, pharmaceutical composition and use of
doxepin. Doxepin has the chemical formula of C.sub.19H.sub.21NO.
One pharmaceutically acceptable salt of doxepin, doxepin HCl, has
the chemical formula of C.sub.19H.sub.22ClNO and is marketed under
the names Adapin.RTM., Aponal.RTM., Curatin.RTM., Novoxapin.RTM.,
Quitaxon.RTM. and Sinequan.RTM.. Doxepin and pharmaceutically or
physiologically acceptable salts have been administered as
anti-depressants or anti-pruritics (THE MERCK INDEX, #3425: 539).
As contemplated for use in this invention, doxepin is to be
administered with a nicotine receptor antagonist to treat the
effects of tobacco addiction and nicotine addiction, to palliate
nicotine withdrawal effects, and to potentiate other smoking
cessation therapies. These pharmaceutical compositions may also be
used to treat cocaine addiction or to treat alcohol dependence.
[0047] Additional anti-depressants contemplated for administration
with nicotine receptor antagonists include: amitriptyline (100-30
mg per day), clomipramine (200-250 mg per day), desipramine
(100-300 mg per day), imipramine (100-300 mg per day),
nortriptyline (50-200 mg per day), protriptyline (20-60 mg per
day), trimipramine (100-300 mg per day), fluoxetine (10-80 mg per
day), fluvoxamine (100-300 mg per day), paroxetine (20-50 mg per
day), sertraline (50-200 mg per day), phenelzine (45-90 mg per
day), tranylcypromine (2-50 mg per day), amoxapine (200-600 mg per
day), maprotiline (150-200 mg per day), trazodone (200-600 mg per
day), nefazodone (300-600 mg per day), venlafaxine (75-375 mg per
day), and mirtazapine (15-45 mg per day); and their
pharmaceutically acceptable salts and optical isomers. The
preferred dosage ranges for the pharmaceutical composition
comprising a nicotine receptor antagonist and one of the above
listed anti-depressants would likely lie in the low to mid-range
dosages suggested for each agent.
[0048] In addition to anti-depressants, anxiolytics can be
administered with nicotine receptor antagonists either in admixture
or administered separately. One anxiolytic agent contemplated is
buspirone and pharmaceutically acceptable salts thereof, such as
buspirone HCl. U.S. Pat. Nos. 3,717,634 and 4,182,763 describe the
synthesis, pharmaceutical composition and use of buspirone as an
anxiolytic. Buspirone has its the chemical formula of
C.sub.21H.sub.31N.sub.5O.sub.2. Its synthesis is described in U.S.
Pat. No. 3,717,634. Buspirone and its pharmaceutically acceptable
salts, such as buspirone HCl, are useful as non-benzodiazepine
anxiolytics and as 5-hydroxytryptamine (5-HT.sub.1) receptor
agonists (THE MERCK INDEX, #1493: 539). Buspirone HCl has the
chemical formula of C.sub.21H.sub.32ClN.sub.5O.sub.2 and
commercially is marketed under such names as Bespar.RTM.,
Buspar.RTM., Buspinol.RTM., Censpar.RTM., Lucelan.RTM. and
Travin.RTM..
[0049] Other non-benzodiazepine anxiolytics are also contemplated
for use in conjunction with a nicotine receptor antagonist to treat
smoking cessation. Additional anxiolytics include: hydroxyzine
(50-400 mg per day) and meprobamate (400-1600 mg per day). The
preferred dosage range for such drug combinations may lie in the
low to mid-range of the suggested ranges due to simultaneous
administration with a nicotinic antagonist. In turn, these lower
dosages reduce the risk of adverse side effects.
[0050] A preferred embodiment of the invention is the
pharmaceutical composition comprising a dose formulated to deliver
about 1 mg mecamylamine HCl to about 25 mg mecamylamine HCl per day
and from about 50 mg bupropion HCl to about 300 mg bupropion HCl
per day. A more preferred embodiment would be a pharmaceutical
composition comprising a dose formulated to deliver about 1 mg
mecamylamine HCl to about 10 mg mecamylamine HCl per day and a dose
formulated to deliver about 50 mg bupropion HCl to about 300 mg
bupropion HCl. The most preferred embodiment comprises a dose
formulated to deliver about 1 mg mecamylamine HCl to about 5 mg
mecamylamine HCl per day and from about 50 mg bupropion HCl to
about 300 mg bupropion HCl per day. These formulations could be
administered either in one pill once a day or via several pills, up
to about 6 formulated units (e.g.,( tablets or capsules) per day.
The maximum recommended daily dose suggested for mecamylamine HCl
and bupropion HCl are generally 25 mg and 300 mg respectively.
Alternatively, another contemplated embodiment is a formulated
pharmaceutical composition that releases the active ingredients
over time. Such pharmaceutical compositions are also contemplated
for use in treating cocaine addiction and withdrawal symptoms
associated with cocaine addiction, and alcohol dependence and its
associated withdrawal effects.
[0051] Another preferred embodiment is the pharmaceutical
composition of buspirone HCl (Buspar.RTM., Mead Johnson) in
combination with mecamylamine HCl to be used to treat tobacco
addiction, nicotine addiction, to palliate the side effects of
nicotine withdrawal, to improve long term withdrawal from smoking,
or to enhance nicotine replacement therapies. The pharmaceutical
composition preferably comprises a dose of buspirone HCl of about 5
mg to about 10 mg per day and a dose of mecamylamine HCl of about 1
mg to about 25 mg per day. These formulations could be administered
either in one pill once a day or via several pills, up to about 6
formulated units (e.g., tablets or capsules) per day; the maximum
recommended daily dosages of buspirone HCl and mecamylamine HCl are
generally 60 mg and 25 mg respectively. Another contemplated
embodiment is a formulated time release pharmaceutical composition
that releases the active ingredients over time. This would include
formulations comprising a buspirone HCl dose of about 5 mg per day
and a dose of about 25 mg per day of mecamylamine HCl, as well as a
dose of buspirone HCl of about 10 mg per day and a dose of about 1
mg per day of mecamylamine HCl. Other possible combinations will be
apparent to an individual schooled in the art in light of the
dosage range suggested herein. These formulations are also
considered for treating withdrawal effects related to cocaine
addiction, and alcohol dependence and its associated withdrawal
effects.
[0052] Another preferred embodiment using a nicotine receptor
antagonist in conjunction with an anti-depressant is the
pharmaceutical composition of doxepin HCl in combination with
mecamylamine HCl. Contemplated pharmaceutical compositions comprise
a dose of doxepin HCl of about 10 mg to about 300 mg per day and a
dose of mecamylamine HCl of about 1 mg to about 25 mg per day
administered either separately (e.g., each drug is dispensed in
separate capsules or tablets) or in one unit, such as one capsule
or tablet. These formulations could be administered either in one
pill once a day or via several pills, up to 6 formulated units
(e.g., tablets or capsules) per day. A more preferred formulation
would comprise a dose of about 10 mg to about 150 mg per day of
doxepin and a dose of mecamylamine HCl of about 1 mg to about 25 mg
per day. The most preferred formulation would comprise a dosage of
5 mg mecamylamine HCl and a dosage of about 75 mg of doxepin HCl
administered twice daily (e.g., morning and evening).
Alternatively, another contemplated embodiment is a formulated time
release pharmaceutical composition that would deliver the active
ingredients over time. This would include formulations comprising a
doxepin HCl dose of about 50 mg per day and a dose of about 25 mg
per day of mecamylamine HCl. Other possible combinations will be
apparent to an individual schooled in the art in light of the
dosage range suggested herein. The recommended maximum daily dose
for mecamylamine HCl and doxepin HCl are generally 25 mg and 300 mg
respectively. Such pharmaceutical compositions are also
contemplated for use in treating cocaine addiction and withdrawal
effects associated with cocaine addiction, and alcohol dependence
and its associated withdrawal effects.
[0053] The contemplated combinations of pharmaceutical compositions
discussed above can be prepared for oral, parenteral, rectal or
buccal administration, or in a form suitable for administration by
inhalation or insufflation to the average adult human for treatment
of tobacco addiction and nicotine addiction, to treat the effects
of nicotine and tobacco withdrawal, to improve long term abstinence
from smoking, or to enhance smoking cessation therapies (e.g.,
nicotine replacement therapies, such as the nicotine transdermal
patch or Nicorette.RTM. gum). The pharmaceutical compositions may
further be formulated using one or more pharmaceutically acceptable
carriers and excipients. The drugs can be administered in a single
unit (e.g., one tablet) or as two or more separate drugs.
[0054] For oral administration, the pharmaceutical compositions
disclosed may take the form of, for example, tablets or capsules
prepared by conventional means in admixture with pharmaceutically
acceptable excipients such as binding agents (e.g., pregelatinised
maize starch, polyvinylpyrrolidone or hydroxypropyl
methylcellulose); fillers (e.g., lactose, microcrystalline
cellulose or calcium phosphate); lubricants (e.g., magnesium
stearate, talc or silica); disintegrants (e.g., potato starch or
sodium starch glycolate); or wetting agents (e.g., sodium lauryl
sulphate); glidants; artificial and natural flavors and sweeteners;
artificial or natural colors and dyes; and solubilizers. The
pharmaceutical compositions may be additionally formulated to
release the active agents in a time-release manner as is known in
the art and as discussed in U.S. Pat. Nos. 4,690,825 and 5,055,300.
The tablets may be coated by methods well known in the art.
[0055] Liquid preparations for oral administration may take the
form of, for example, solutions, syrups or suspensions, or they may
be presented as a dry product for reconstitution with water or
other suitable vehicles before use. Such liquid preparations may be
prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup, methyl
cellulose or hydrogenated edible fats); emulsifying agents (e.g.,
lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily
esters or ethyl alcohol); preservatives (e.g., methyl or propyl
p-hydroxybenzoates or sorbic acid); and artificial or natural
colors and/or sweeteners.
[0056] For buccal administration, the composition may take the form
of tablets or lozenges formulated in conventional manners.
[0057] The active compounds may be formulated for parenteral
administration by injection, which include using conventional
catheterization techniques or infusion. Formulations for injection
may be presented in unit dosage form, e.g., in ampules or in
multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulating agents such as
suspending, stabilizing and/or dispersing agents. Alternatively,
the active ingredients may be in powder form for reconstitution
with a suitable vehicle, e.g., sterile pyrogen-free water, before
use.
[0058] The active compounds may also be formulated in rectal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0059] For intranasal administration or administration by
inhalation, the active compounds are conveniently delivered in the
form of a solution or suspension from a pump spray container that
is squeezed or pumped by the patient, or as an aerosol spray
presentation from a pressurized container or nebulizer, with the
use of a suitable propellant (e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethan- e, carbon dioxide
or other suitable gas). In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. The pressurized container or nebulizer may contain
a solution or suspension of the active compound. Capsules and
cartridges (made, for example, from gelatin) for use in an inhaler
or insufflator may be formulated containing a powder mix of an
active compound and a suitable powder base such as lactose or
starch.
[0060] Without further description, it is believed that one of
ordinary skill in the art, using the preceding description and the
following illustrative examples, can make and utilize the compounds
of the present invention and practice the claimed methods.
Additionally, all of the preceding pharmaceutical compositions
comprising a nicotine receptor antagonist and either an
anti-depressant or an anti-anxiety drug to treat nicotine
dependence and smoking cessation can be used in conjunction with a
nicotine replacement therapy (e.g., nicotine transdermal patch).
These compositions and methods of administration are also
contemplated for use in treating both cocaine addiction and alcohol
dependence. The following working examples therefore, specifically
point out preferred embodiments of the present invention, and are
not to be construed as limiting in any way the remainder of the
disclosure.) Other generic configurations will be apparent to one
skilled in the art.
EXAMPLES
Example 1
[0061] A formulation comprising about 1.0 mg mecamylamine and about
50 mg bupropion is combined into a single tablet or capsule and is
administered orally at a dose frequency between one to six tablets
daily.
Example 2
[0062] A formulation comprising about 1.0 mg mecamylamine and about
150 mg bupropion is combined into a single tablet or capsule and is
administered orally at a dose frequency between one to six tablets
daily.
Example 3
[0063] A formulation comprising about 5 mg mecamylamine and about
50 mg bupropion is combined into a single tablet or capsule and is
administered orally at a dose frequency between one to six tablets
daily.
Example 4
[0064] A formulation comprising about 5 mg mecamylamine and about
150 mg bupropion is combined into a single tablet or capsule and is
administered orally at a dose frequency between one to six tablets
daily.
Example 5
[0065] A formulation comprising about 25 mg mecamylamine and about
300 mg bupropion is combined into a single tablet or capsule and is
administered orally in one dose. This dosage is also contemplated
to be administered in a pharmaceutical composition that releases
the active ingredients over time (e.g., 24 hours).
Example 6
[0066] A 2.5 mg tablet of mecamylamine is taken orally three times
daily, and a 150 mg tablet of bupropion is taken twice daily, in
the morning and evening.
Example 7
[0067] Use of Mecamylamine with Other Anti-Depressants
[0068] Other anti-depressants, such as but not limited to doxepin
HCl (Sinequan.RTM., Pfizer), may also be used in combination with
mecamylamine. Doxepin HCl in a dose range between about 10 mg and
about 150 mg is administered in combination with mecamylamine HCl
in a dose range between about 1 mg and about 25 mg. These dosages
can be administered in several smaller unit formulations over the
course of day (e.g., 1 to 6 capsules).
Example 8
[0069] Use of Mecamylamine with Anti-Anxiety Agents
[0070] The anxiolytic, buspirone HCl (Buspar.RTM., Mead Johnson), a
5-hydroxytryptamine (5-HT.sub.1) agonist, has also demonstrated
effectiveness in combating nicotine-related withdrawal symptoms and
increasing short-term smoking abstinence. This agent, as well as
other anti-anxiety drugs, may also be utilized in combination with
mecamylamine HCl to improve long term withdrawal from smoking.
Buspirone HCl in a dose of about 5 mg to about 10 mg is used in
combination with mecamylamine HCl in a dose of about 1 mg to about
25 mg. This would include a buspirone HCl dose of about 5 mg with
approximately 25 mg of mecamylamine HCl, as well as a dose of
buspirone HCl of about 10 mg and a dose of about 1 mg mecamylamine
HCl. These dosages would likely be administered twice daily, i.e.,
morning and evening, but can be administered more or less
frequently as needed. Other possible combinations will be apparent
to an individual schooled in the art in light of the dosage range
suggested herein.
[0071] References
[0072] This application also incorporates in its entirety, the U.S.
Provisional Application 60/060,794 filed Oct. 3, 1997. The
following references and all articles, texts and patents referred
to above and below, are hereby incorporated by reference in their
entirety:
[0073] A. W. Peck, U.S. Pat. No. 4,393,078 (1983)
[0074] B. M. Bloom et al., U.S. Pat. No. 3,420,851 (1969)
[0075] Balandrin et al., WO 94/28888
[0076] Bupropion HCl, THE MERCK INDEX Eleventh Edition #1488
(1989): 228
[0077] Bupropion (Zyban.RTM.) for Smoking Cessation, The Medical
Letter 39(1007): 77 (August 15, Buspirone, THE MERCK INDEX Eleventh
Edition #1493 (1989): 229
[0078] Caggiula et al., 1995 Psychopharmacology 122: 301-306
[0079] Casten et al., U.S. Pat. No. 4,182,763 (1980)
[0080] Chandler et al., 1997 Psychopharmacology 129: 257-264
[0081] Cinciripini et al., 1998 Oncology 12: 249-256
[0082] Clarke, 1991 Br. J. Addict. 86: 501-505
[0083] Clarke, 1987 Psychopharmacology 92: 135-143
[0084] Decker et al., 1995 Eur. J. Pharmacol. 280: 79-89
[0085] Diana et al., 1990 Am. J. Physiol. 259: H1718-H1729)
[0086] Doxepin, THE MERCK INDEX Eleventh Edition #3425 (1989):
539
[0087] Glazer, U.S. Pat. No. 4,788,189
[0088] Gupta, U. S. Pat. No. 5,055,300 (1991)
[0089] Hall et al., 1990 Pharmacotherapy 10: 47-65
[0090] Hisayama et al., 1988 Br. J. Pharmacol. 95: 465-472
[0091] Kosten et al., 1991 NIDA Res. Monogr. 105: 510-511
[0092] Martin 1997 J. Auton. Pharmacol. 17: 249-259
[0093] Mecamylamine HCl, THE MERCK INDEX Eleventh Edition #5654
(1989): 905
[0094] Mehta, U.S. Pat. No. 3,819,706 (1974)
[0095] Mehta, U.S. Pat. No. 3,885,046 (1975)
[0096] THE MERCK INDEX #380: 60 (1989)
[0097] THE MERCK INDEX #2101: 324-325 (1989)
[0098] THE MERCK INDEX #3158: 500 (1989)
[0099] THE MERCK INDEX #4609: 741 (1989)
[0100] THE MERCK INDEX #7022: 1120 (1989)
[0101] THE MERCK INDEX #9621: 1527(1989)
[0102] THE MERCK INDEX, #9717: 1542 (1989)
[0103] Nunn-Thompson et al., 1989 Clin. Pharm. 8: 710-720
[0104] Oliveto et al., 1995 J. Subst. Abuse Treat. 12: 423-428
[0105] Perkins et al., "Effects of Central and Peripheral Nicotinic
Blockage on Human Nicotine Discrimination," Psychopharm. In
press
[0106] Pfister, U.S. Pat. No. 2,831,027 (1958)
[0107] Rapier et al., 1990 J. Neurochem. 54: 937-945
[0108] Rose, "Nicotine addiction and treatment," 1996 Annu. Rev.
Med. 47: 493
[0109] Rose et al., "Mecamylamine combined with nicotine skin patch
facilitates smoking cessation beyond nicotine patch treatment
alone," 1994 Clin. Pharmacology & Therapeutics. 56: 86-99
(1994)
[0110] Rose et al., 1997 Psychopharmacology 130: 28-40
[0111] Singh et al., 1969 Experientia 25: 785
[0112] Stach, U.S. Pat. No. 3,438,981 (1969)
[0113] Stern, U.S. Pat. No. 4,507,323 (1985)
[0114] Stern, U.S. Pat. No. 4,425,363 (1984)
[0115] Stern, U.S. Pat. No. 4,435,449 (1984)
[0116] Stern, U.S. Pat. No. 4,438,138 (1984)
[0117] Stern, U.S. Pat. No. 4,347,257 (1982)
[0118] Stolerman et al., 1997 Psychopharmacology 129: 390-397
[0119] Tennant et al., 1984 NIDA Res. Monogr. 55: 291-297
[0120] Won, U. S. Pat. No. 4,690,825 (1987)
[0121] Wotring et al., 1995 Neuroscience 67: 293-300
[0122] Wu et al., U.S. Pat. No. 3,717,634 (1973)
* * * * *