JP2002521432A - Methods and compositions for the treatment and prevention of substance abuse using moclobemide - Google Patents

Abstract

  (57) [Summary] Alcohol and drug-related physical dependence, including opioids, other central nervous system antidepressants such as sedatives, central nervous system stimulants such as cocaine and amphetamine and other centrally active drugs Or methods and compositions for using moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions to assist in treating or preventing withdrawal symptoms.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application is related to US patent application Ser. No. 60 / 094,986, filed Jul. 31, 1998.
Is hereby incorporated by reference.

[0002] 1. The present invention relates to the treatment of opioids, other central nervous system antidepressants, such as alcohol and sedatives, as well as conditions associated with withdrawal from the abuse or dependence of, for example, alcohol and sedatives, central nervous system stimulants. It relates to methods and compositions for prevention. The present invention also provides for preventing, controlling or reducing the development of physical dependence on central nervous system depressants such as opioids, alcohol and sedatives, and other central nervous stimulants such as cocaine and amphetamine. And methods and compositions of

[0003] 2. BACKGROUND OF THE INVENTION 2.1. Moclobemide Chemistry and Pharmacokinetics Moclobemide, or p-chloro-N- (2-morpholinoethyl) -benzamide, has the formula

Embedded image Which is described in US Pat. No. 4,210,754 to Burkard et al.

[0004] Moclobemide is a selective and reversible monoamine oxidase (MAO) subtype A inhibitor. Kettler, R. et al., 1990, Acta Psychiatr. Scand., Su
pp. 360 (82): 101-103. Unlike other monoamine oxidases, which bind irreversibly and non-selectively to MAO and may have severe food and drug interactions that limit therapeutic utility, moclobemide is a monoamine oxidase A (MAO-A) or monoamine oxidase It is part of a unique class of selective MAO inhibitors that predominantly or selectively inhibit any of oxidase B (MAO-B). Compounds that selectively inhibit MAO-B, and thereby inhibit dopamine degradation, are useful for treating neurological and neurodegenerative diseases of the dopaminergic pathway, such as Parkinson's disease. Livi
ngston, MG and Livingston, HM, 1996, Drug Safety, 14 (4): 218-227.
Compounds that selectively inhibit MAO-A dominantly affect serotonin and norepinephrine degeneration, thereby increasing the concentration of these neurotransmitters in synapses and may be useful in depression. Livingston and Livingston, 1996
.

[0005] Although the in vitro binding of moclobemide to MAO-A is weak, MAO-B
It is 167 times more selective than the isoenzyme. The in vivo binding of moclobemide to MAO-A is said to be reversible, with sufficient dissociation, and to restore enzyme activity within 16 hours. Fulton, B. and Benfield, P., 1996, Drugs, 52 (3)
: 451. These are older, non-selective and in contrast to irreversible MAO inhibitors (also called "irreversible MAOIs" or "IMAOIs"), MAO
It irreversibly binds to -A and / or MAO-B isoenzymes and enzyme inhibition is seen for several days continuously. Da Prada, M. et al., 1990. MAO-A inhibition is said to be reversible in vivo due to its relatively short duration. Da
Prada et al., 1990, Acta Psychiatr. Scand., Suppl. 360 (82): 103-105.

The effects of moclobemide on monoamine metabolism and / or the activity of monoaminergic neurons are attributed to the catecholamine metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylglycol and serotonin (5-hydroxy It has been indirectly explained in humans by a decrease in the plasma levels of the tryptamine) metabolite 5-hydroxyiodoacetic acid. In vitro, moclobemide is muscarinic, dopaminergic, serotonergic, adrenergic, H 1 _- histaminergic, no apparent affinity for benzodiazepine or opioid receptors. Da Prada et al., 1981, E
xcerpta Medica, 183-196; Da Prada et al., 1983, Mod.Probl. Pharmacopsyc
h., 19: 231-245; Da Prada et al., 1984, Clin. Neuropharmacol., 7 (Suppl. 1
): 684-685.

[0007] Moclobemide is widely distributed in the body and is rapidly cleared from plasma by metabolic conversion of the liver. After a single dose of oral administration, moclobemide is almost completely absorbed, but bioavailability is 44% due to substantial first-pass metabolism.
% To 69%. Guentert, TW et al., 1990, Acta Psychiatr.
Scand., Suppl. 360 (82): 91-93. After multiple doses, moclobemide shows increased bioavailability due to saturation of first pass metabolism. Ibid. Moclobemide is metabolized to at least 19 metabolites, one of which modifies MAO-A inhibitory activity. Jauch, R. et al., 1990, Acta Psychiatr. Sc
and. Suppl. 360 (82): 87-90. Age and renal function have been reported to have no significant effect on the pharmacokinetics of moclobemide, but excretion is impaired in patients with impaired liver function. Stoeckel et al., 1990, Acta Psychiatr. Scand. Suppl. 3
60 (82): 94-97. Therefore, patients suffering from liver damage should have only 50% oral dose. Ibid.

[0008] One of the most interesting features of moclobemide is impressive safety. It has a relatively short-term pharmacokinetic effect, which is a factor in clinical safety, because it inhibits monoamine oxidase continuously. The short plasma half-life of moclobemide (1 to 2 hours) is also a factor in safety as it prevents instantaneous degradation in the tissue and thereby local over-accumulation. Stoeckel et al., 1990. Moclobemide has disadvantageous consequences (adv) over other reversible MAOI compounds in normal clinical use.
erse events). Priest, RG, et al., 1995,
J. Clin. Psychopharm., 15 (4), Suppl. 2: 1s-3s. The most frequently reported adverse consequences are psychiatric, neurological, and gastrointestinal disorders, with only rare cases of hepatobiliary occurring (Hilton, S. et al., 1995, J. Clin. Psychopharmacol., 15 (
4 Suppl. 2): 76S-83S), and the effect of moclobemide on the sleep of healthy volunteers appears to be weak compared to other MAO inhibitors. Blois, R. et al., 1990, Acta
Psychiatr. Scand., Suppl. 360 (82): 73-75.

[0009] Moclobemide is not widely used in the United States, but is used in Europe and other countries and is known to cause any clinically relevant interactions with commonly prescribed drugs. Not been. Zimmer, R. et al., 1990, Acta Ps
ychiatr. Scand., Suppl. 360 (82): 84-86. In addition, moclobemide appears to be much less than typical MAO inhibitors with concomitant administration of sympathomimetics or eliciting a hypertensive response by consuming tyramine-rich foods. Hilton
, SE, 1997, Eur. Arch.Psychiatry Clin. Neurosci., 247: 113-119; Zimme
r, 1990, Acta Psychiatr.Scand., Suppl. 360 (82): 81-83; Zimmer, Fischbach
et al., 1990, Acta Psychiatr. Scand., Suppl. 360 (82): 76-77; Zimmer, Pue.
ch et al., 1990, Acta Psychiatr.Scand., Suppl. 360 (82): 78-80; Da Prada
et al., 1990, Acta Psychiatr. Scand., Suppl. 360 (82): 106-107. Many studies also suggest that moclobemide is more tolerated than other compounds with anti-suppressive activity. Priest, RG, et al., 1995. Perhaps most impressively, the fatal toxicity index for moclobemide is
Approaches zero. Hilton et al., 1995.

[0010] Initially, the recommended dose for moclobemide therapy (ie, depression treatment) was about 100 mg to 150 mg, three times a day. Guentert, TW et al., 19
90. Subsequent experience has suggested that, in terms of the positive dose response curve seen with moclobemide, doses as high as 600 mg per day produce a gradual effect and remain well tolerated. Fitton, A. et al., 1992, Drugs, 43 (4): 561-596.

[0011] Moclobemide is characterized by its excellent safety and positive tolerability profile
It has become a popular antidepressant in Canada, Europe, Australia, New Zealand, South Africa and Latin America. Angst J. et al., 1
996, Int.Clin. Psychopharmacol., 11 (Suppl. 3): 3-7; Glick, ID et al.,
1995 Schatzberg, AF and Nemeroff, CB (Ed.), The American Psychiat
ric Press Textbook of Psychopharmacology, Washington, DC, pp. 839-846))
. Prescribing medications with harmful and potentially fatal side effects, such as irreversible MAOIs, to treat depression is among the physicians many medications that they are just about to prescribe. This has been a cause of some concern because depressed patients may attempt suicide. Moclobemide is a MAO inhibitor as an antidepressant, but is not prone to lethal drug and food interactions,
Overdose appears to be less toxic. Patients taking other MAO inhibitors must adhere to dietary restrictions that need to avoid red wine, beer, old cheese and meat, liver, yeast extract and fava or broad bean, among others .

[0012] Further, since the side effect profile of moclobemide is benign, the compliance rate is good. Priest, RG, 1990, Acta Psychiatr. Scand., Suppl.
360 (82): 39-41. Compliance is a critical component of successful treatment because of the higher morbidity and mortality for untreated psychiatric disorders. If a patient continually refuses medical treatment for a psychiatric disorder due to poor initial experience in pharmacological response, the prognosis will be inadequate as if the patient had not been treated at all. When used in the treatment of major depression, moclobemide proves to be an effective, slow, patient-friendly drug.

2.2. Therapeutic effects of moclobemide Moclobemide (F. Hoffman-La Roche, Basel, Switzerland), sold under the trademark AURORIX or MANERIX, has been found to be effective in the treatment of various psychiatric disorders. For example, moclobemide is marketed as an antidepressant in Canada, Europe, Australia, New Zealand, South America, and Latin America, which has shown significant therapeutic effects in a number of patient groups. Angst J. et al., 1996; Glick, ID et a
l., 1995. A review of the pharmacological properties and therapeutic uses of moclobemide in depression is a revision of the previous review of Fitton et al., 1992, Drugs, 43 (4): 561-596, F.
Issued in Drugs, 52 (3): 450-478, 1996 by ulton and Benfield.

The formulation and use of moclobemide as an antidepressant is described in US Pat. No. 4,210,754 to Burkard et al. In the treatment of depression, moclobemide is a tricyclic antidepressant (TCA), a selective serotonin reuptake inhibitor (SSR)
I), and have similar potency as non-selective irreversible MAO inhibitors. Fulton and Benfield, 1996; Fitton et al., 1992. In particular, moclobemide has been shown to be effective in treating elderly patients with depression or age-related dementia. Wesnes, K. et al., 1990, Acta Psychiatr. Scand., Suppl. 360 (82
): 71-72; U.S. Patent No. 4,906,626 to Amrein et al.

[0015] Moclobemide is used in tobacco addiction (PCT publication WO 95/28934; PCT publication WO 90/04387), attention deficit disorder (Trott, GE et al., 1992, Psychop).
harmocol., 106 Suppl .: 134-136), and anxiety disorders such as social phobia, obsessive-compulsive disorder and fear (US Pat. No. 5,371,082 by Versiani et al .; Liebo
witz, MR et al., 1990, Acta Psychiatr. Scand., Suppl. 360 (82): 29-34;
Angst, J. et al., 1996, Int.Clin. Psychopharm., 11 (Suppl.3): 3-7; Polla
ck, MH and Gould, RA, 1996, Int.Clin. Psychopharm., 11 (Suppl.3): 7
1-75) has also been reported to be effective.

The use of irreversible monoamine oxidase inhibitors (MAOIs) is limited by a wide range of MAOI drugs and MAOI food interactions that can produce a hypertensive response, especially with sympathomimetics or tyramine-containing foods. ing. This has led to a decrease in the use of the drug, despite its clinical advantages. Even when MAOI's efficacy is documented in certain conditions, many physicians reluctant to prescribe this class of drugs because of the risk of serious adverse reactions. This seems to be the case even when the MAOI is more effective than other available treatments. Moclobemide has not been widely studied in the United States, presumably because it was classified as a monoamine oxidase inhibitor. In fact, moclobemide has not been approved by the US Food and Drug Administration. Furthermore, in the field of psychiatry, Diagnostic and Statist
ical Manual of Mental Disorders, Ed. 4, (DSM-IV), American Psychiatric A
ssociation, 1994, Washington, DC, and there is a great need for alternative therapies to better treat the growing number of psychiatric and psychological disorders.

2.3 Opiates and Addictions Opiates are drugs derived from opiates, such as morphine, heroin and codeine, and many natural and semi-synthetic compounds. The term "opioid" applies more broadly to all agonists and antagonists having morphine-like activity, as well as to more natural and synthetic opioid peptides,
More comprehensive. Opiate addiction (drowning, addiction) is both a psychological and physiological situation. In recent years, despite advances in the fields of opiate receptors, endogenous opiate-like hormones and neurotransmitters, the mechanics and mechanisms of poisoning and withdrawal are poorly understood. Apparently, opiate withdrawal is a highly active state of adrenaline that causes the locus of the locus (in the brain) to become significantly activated. There are also three classes of opiate receptors,
It is known that there are σ, κ and μ, and that there is a subdivision within each classification as well.

[0018] Morphine and other morphine-like opioid agonists are used clinically to treat acute pain. They are initially analgesic by mu opioid receptors and also produce anxiolytic and euphoric effects. Such rejoicing and euphoria can result in opioid-poisoned individuals, people making absolutely illegal use,
Escalated people whose use was medical instruction at first time, people who were given opiate in the context of medical treatment (eg, chronic pain) but no longer needed such treatment Arouse abusers in groups, including,.

The mortality of street heroin users is very high, and opiate selection is due to its convenience and low cost. Criminal involvement in support of this habit includes uncertainties about the dose, purity or identity of drugs purchased on the street, serious infections associated with the sharing of unsterile drugs and injectable drug brace, Premature death of the user. In general, heroin users are associated with skin tumors, pulmonary infections, bacterial infections that cause endocarditis, and viral infections that cause hepatitis and AIDS (AIDS). Clearly, there is a need for an effective detoxification method that will actually be used by the addict population, ie with minimal pain and anxiety. Known detoxification methods are inconsistent with this need. Instead, there is a need for less painful and less euphoric drugs to help mitigate detoxification. Moreover, there is currently no method for preventing and controlling or alleviating physical opiate addiction, a satisfactory way by reducing the stimulus to its intake.

2.4 Physical opiate dependence and discontinuation With the prolonged use of opiates, mental dependence, physical dependence and tolerance develop. Physical dependence is a condition that develops as a result of adaptation that occurs by resetting the homeostasis mechanism in response to repeated use of a drug.

Opiates affect a number of mechanistic systems that were previously in equilibrium, most notably those endogenous opioid-mediated systems, and the presence of opiate-induced inhibition or stimuli in these systems. You need to find a new balance below. A person in this condition requires continuous administration of the drug to maintain normal function. If the drug is suddenly stopped, the previously affected mechanism must cause a new imbalance and re-adjust itself to a new equilibrium. In the case of opiates and other central nervous system drugs such as nicotine and alcohol, central nervous system hyperarousal is understood as a readaptation mechanism used by the body without addictive drugs.

[0022] The appearance of withdrawal symptoms upon discontinuation of a drug is the only practical evidence of physical dependence. It has been estimated that 25% of humans who use opiates sporadically (unusually) become addictive or addictive. Physical dependence is a function of the opiate dose schedule, but can occur with very low levels of opiate exposure, can persist for prolonged periods after drug discontinuation, and can occur in all exposed patients. Typically,
Most of those who have gone on a twice daily use become physically dependent within 6-8 weeks. Clearly, each opiate has its own ability to induce dependence.

In patients who are physically dependent on opiates, sudden withdrawal of opiates leads to the appearance of a withdrawal syndrome of opiates. The signs and symptoms of this syndrome have been described in detail. They are for the first 24 hours
Insomnia, lacrimation, rhinorrhea, uncontrollable yawning, sweating, piloerectio
n), showing insomnia and dilated pupils. As the syndrome progresses, these symptoms become more severe, with convulsions and muscle twitching, kick-up movements, severe back, abdominal and leg pain; abdominal and muscular spasms; sensations of heat and cold,
Insomnia, nausea, vomiting and diarrhea; nasal cold and severe sneezing; may be accompanied by increased body temperature, increased blood pressure, respiratory rate, increased heart rate (alone or in combination with respect to "withdrawal symptoms" or "withdrawal" See herein). Some of these signs and syndromes have been incorporated into the DSM-IV-R standard for opiate withdrawal. The severity of discontinuation is a function of which opiate was administered, at what dose, and for how long. Therefore, in general,
The degree of physical dependence is affected by the severity of the discontinuation syndrome.

The half-life of an opiate drug determines when to begin discontinuation and is usually within two to three times the half-life after the last opiate administration. Thus, for short half-life opiates such as morphine, discontinuation begins at 6-12 hours, while for long half-life opiates such as methadone, it begins at 36-48 hours. . Opiate withdrawal symptoms usually reach their maximum intensity in 36-72 hours.
Without treatment, the craving for the drug lasts for months (Fraser et al., 1961), but the syndrome follows its course in 5-7 days. Prolonged physical effects of opiate withdrawal can appear up to six months after resolution of acute symptoms.

2.5 Detoxification Methods Until very recently, opiate detoxification is a relatively standard method whose primary purpose is to slowly minimize or eliminate the signs and symptoms of opiate withdrawal symptoms. The most common methods for treating withdrawal symptoms of opiate addiction are
Methadone, a synthetic anesthetic developed during World War I, was substituted for the opiate in question, followed by a gradual discontinuation of methadone for 5-12 days. This technique was followed in 1948 by Isbell and Vogel (Isbell, H. an.
d Vogel, VH, 1948, Amer. J. Psvchiat., 105: 909-914).

The first two alternatives to methadone treatment that have been tried without overwhelming success have been propanolol treatment and propoxyphene treatment. Propanolol is a beta-adrenergic inhibitor that is thought to reduce the euphoric effect (effect of feeling euphoric) after cessation of anesthetic and medication (Grosz HJ, 1972, Lancet 2: 564566). But,
Controlled dosing was found to have only modest effects and it was decided to eliminate propanolol as an aid in the treatment of opiate withdrawal (Hollister LE
., Prusmack JJ, 1974, Arch. Gen. Psychiatry, 31: 695-698).

Similarly, propoxyphene was an incomplete treatment protocol and is itself addictive and appears to lead to severe respiratory depression when mixed with alcohol (Tenet, FS, 1973). , JAMA, 226: 1012; Inaba D. et al. 1974, Am. J. Dru
g Alcohol Abuse, 1: 67-78; Tennat FS et al., JAMA, 232: 10191022). Acupuncture and moxibustion therapy (Wen HL and Cheung SYC, 1973, Am. J. Acupuncture, 1: 71-75
; Whitehead, PC, 1978, Int. J. Addict., 13: 1-16; 1) and vitamin C treatment (Libby A. and Stone I., 1977, J. Orthomolecular Psychiatr., 6: 300308).
; Free V., Sanders P., 1978, J. Orthomolecular Psychiatr., 7: 264-270; V.
S. Patent No. 4,500,515 to Libby, Age.) Was also studied as a potential opiate withdrawal restoration, but with less success.

[0028] The development of new drug therapeutics, such as clonidine and naltrexone, to help withdraw withdrawal offers an opportunity for significant advances in opiate detoxification protocols, and various protocols have been published in the literature. However, there remains a need for methods to prevent, control or alleviate physical dependence on addictive drugs and alcohol.

2.6 Alcohol Intoxication High alcohol users not only acquire the above-mentioned tolerance for opiates, but also develop a state of physical dependence. Alcohol withdrawal is not as severe as withdrawing opiates, but has many of the same symptoms: drug craving, tremors,
Includes irritability, vomiting, sleep disorders, tachycardia, hypertension, sweating, sensory distortions, and stroke. In addition, other health problems, malnutrition, infectious diseases, or electrolyte imbalance combine to predispose to delirium. Delirium is severe excitement, confusion,
Includes visual hallucinations, fever, tachycardia, heavy sweating, vomiting, diarrhea and dilated pupils.

Alcohol withdrawal symptoms have been reported for moderate daily alcohol users for 7 to 34 days, with delirium appearing 48 to 87 days after ingestion and withdrawal (Isbell, H. et al. 1955, OJ Stud. Alcohol, 16: 1). As expected, more severe withdrawal symptoms usually include more alcohol drinking per day,
Associated with recent alcohol use, and longer-term alcoholic tolerance, more drug use with alcohol, and further medical problems (Schuckit, M.
A. et al., 1995, Addiction, 90: 1335-1347).

Clonidine has been shown to be useful in treating alcohol withdrawal symptoms (Baumgartner, GR, and Rowen, RC, 1987, Arch. Intern. Med. 147: 12).
twenty three). Naltrexone has been used as an adjunct for the treatment of alcoholism and alcohol withdrawal, and has recently been approved by the FDA as a chemical treatment for alcoholism. Naltrexone appears to block some of the enhancing properties of alcohol, leading to a reduced rate of reversion in clinical trials.

2.7 Cocaine and Other Central Nervous System Stimulators 2.7. 1 Cocaine It is estimated that over 4 million Americans occasionally use cocaine, and the number of addicts is about 1,700,000. Estimated (Gawin, FH and Ell
inwood, Jr., EH, 1988, N. Enal. J. Med., 318: 1173-1182). Addiction usually leads to medical, mental, social and economic damage (Cregler, LL, and Mark,
H., 1986, N. Enal. J. Med., 315: 1495-1500; Isner, JM et al., 1986, N.
Enal. J. Med., 315: 1438-1443; Lesko, LM et al., 1982, N. Engl. J. Med.
., 307: 1153).

The main factor in the spread of cocaine is the widespread availability of relatively inexpensive cocaine in the form of alkaloids (free salt, “crack”) suitable for smoking and powdered hydrochloride suitable for nasal and intravenous use Is possible (Gawin, FH and Ellinwoo
d, Jr., EH, 1988). Drug addiction in men was about twice that of women. However, the use of smoking cocaine is particularly common in young women with children,
They may use cocaine in the same way men do (Go
odman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Ed.,
1996, Hardman, JG et al., Eds., McGraw Hill, pp. 569-571).

Cocaine provides a dose-dependent increase in heart rate and blood pressure, resulting in increased alertness, improved performance and improved confidence and well-being in sleep-absence and alert-waiting tasks (Wi
lson, MC et al., 1971, Psychopharmacoloqia, 22: 271-281; Fischman, MW
, 1988, J. Clin.PsYchiatrY, 49 (Suppl. 2): 7-10; Fischman, MW et al.,
1985, J. Pharmacol. EXP. Ther., 235: 677-682). High doses result in euphoria, which is often short-lived followed by a desire for more drugs. Involuntary motor muscle activity, routine behavior, and paranoia appear after repeated administration. Increased irritability and risk of violence have been seen among severe chronic users.

The half-life of cocaine in plasma is about 50 minutes, but crack users usually desire more cocaine after 10 to 30 minutes. Nasal and intravenous users also produce a much shorter persistence than expected with plasma cocaine levels, which suggests that a decrease in plasma levels is associated with higher levels of termination and reintake of cocaine cravings. Suggested (Johanson, CE, and Fischman, MW, 1989
, Pharm. Rev., 41: 3-52).

[0036] Addiction is the most common complication of cocaine use. Some users, especially nasal users, may continue to use it intermittently for years. Another patient becomes a compulsive user despite elaborate methods of maintaining control. Stimulants tend to be used more irregularly than opioids, nicotine and alcohol. Use in the feast is very common; the feast lasts hours and days and ends only when the drug is exhausted.

Since cocaine is usually used intermittently, even severe users spend frequent discontinuations or “crashes”. It consists of withdrawal symptoms, dysthymia, depression, sleep preferences, fatigue, cocaine craving, and bradycardia seen by users admitted to the hospital. Careful studies of discontinued cocaine users have shown a gradual reduction in these symptoms over one to three weeks (Satel, SL, et. Al.
al., 1991, Am. J. Psychiatry, 148: 1712-1716).

Cocaine is frequently used in combination with another drug, for example, heroin.
Alcohol is another drug that cocaine users take to reduce the excitement they experience while using large amounts of cocaine. Some people develop alcoholism in addition to their cocaine addiction.

Other risks of cocaine use include arrhythmias, myocarditis, arteriotomy, brain, vasoconstriction and stroke, beyond the potential for intoxication. Death from traumatic trauma is also associated with cocaine use (Marzuk, PM, et al., 1995, N. Enal. J. Med., 332: 17S3-17
57). Cocaine users during pregnancy may also experience preterm delivery and premature exfoliated placenta (Chasnoff, IJ, et al., 1989, JAMA. 261: 1741-1744). Reports of abnormal growth in children born to women using cocaine have been confused with premature birth, various types of drug exposure, and lack of nursing before and after childbirth.

In general, withdrawal of cocaine is modest and treatment of withdrawal symptoms has not been well explored. Desipramine is a tricyclic antidepressant tested in several double-blind clinical trials of cocaine addiction. Although desipramine, like cocaine, inhibits reabsorption of monoamine psychotransmitters, its primary effect is on reabsorption of norepinephrine. It has been hypothesized that desipramine can relieve some withdrawal symptoms of cocaine dependence and reduce the desire for cocaine during vulnerable periods following cocaine withdrawal. This drug has shown efficacy in a group of patients who were primarily white-collar intranasal cocaine users (Gawin, FH, et al. 1989, Arch of Gen Psychiatry L 46: 117l- 12l). Most of the desipramine series of studies using more severely ill cocaine addicts were negative. Goodman and Gilman, p. 571. Several other types of treatment have been tried in this disease. Examples include: Amantadine and doopaminergic drugs with reported detoxification effects (Alterm
an, AI et al., 1992, Drug alcohol Depend., 31: 19-29); fluoxetine, a selective serotonin reabsorption antagonist reported to reduce cocaine use (Batki, SL, et al., 1993, J. Clin. PsychoDharmacol., 13: 243-250);
And a partial opioid agonist found to reduce cocaine self-administration in monkeys and monkeys (Mello, NK et al., 1989, Sc
ience, 245: 859-862). Thus, all studies of therapeutic methods that help treat the addiction and prevent relapse to cocaine dependence have at best revealed moderate value. Thus, there is still a need for compounds that can be reliably used in the treatment of cocaine addiction.

2.7.2 Other CNS Stimulators This effect, similar to cocaine, is produced, for example, by amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate hydrochloride and diethylproprion (sometimes collectively And referred to herein as "CNS stimulants"). Amphetamine, like in cocaine, increases synaptic dopamine by stimulating presynaptic release rather than inhibiting reabsorption (Goodman and Gilman, p571). Methamphetamine, intravenously or smoked, produces addiction / dependence symptoms similar to those of cocaine.

In contrast, mouth irritants, such as those mentioned in the weight loss program, have a short-term effect on tolerance gain. Only a few patients who are directed to such stimulants to promote weight loss show a drug craving behavior that captures the stimulating effect of a method of treating anorexia. These patients will meet diagnostic criteria for abuse or addiction.

Cathinone, a compound similar to amphetamine, is widely used in Africa because of its stimulant properties. In recent years, a similar substance metacathinone with similar effects has been synthesized in the United States. Also, there is still a need for compounds that can be reliably used to treat, prevent and control addiction to CNS stimulants and withdrawal symptoms from CNS stimulants.

3. SUMMARY OF THE INVENTION The present invention relates to the discontinuation of abuse or dependence on CNS stimulants such as opioids, alcohols and other central nervous system (CNS) sedatives, including sedatives, cocaine and amphetamine. It is useful in treating and preventing symptoms associated with.

The present invention also relates to marijuana, barbiturates, and lysergic acid diethylamide (LSD), which act on the central nervous system but are not generally classified as pure "irritants" or "antidepressants" ), Treatment and prevention of symptoms associated with abuse or discontinuation of other substances including hallucinogens such as phencyclidine (PCP) methylenedioxymethamphetamine (MDMA, Ecstasy), N, N-dimethylamine and psilocybin Useful when The present invention is also useful in preventing, controlling or alleviating the development of physical dependence on drugs and alcohol.

The present invention relates to the use of moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions for treating and preventing certain mental and medical conditions. The moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition of the present invention may exist in the form of a pharmaceutically acceptable salt, or a hydrate or a solvate (sorbate). In the description,
The term "moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition" is moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition; moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition, or moclobemide; Pharmaceutically acceptable salts or hydrates or solvates (sorbate) forms of metabolites, moclobemide derivatives or moclobemide compositions; or prodrugs thereof. The invention also includes the use of a composition in the methods of the invention, wherein the composition includes moclobemide, moclobemide metabolite, moclobemide derivative together with a pharmaceutically acceptable carrier. The moclobemide metabolite of the present invention is a substance having MAO-A inhibitory activity, for example, clovemide N-oxide.

The present invention treats or prevents the symptoms associated with substance abuse and withdrawal, including abuse or dependence on other CNS inhibitors such as opioids, alcohol and sedatives and CNS stimulants such as cocaine and amphetamine. The use of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition. Thus, certain embodiments of the present invention relate to the treatment of such withdrawal symptoms by administering to a human a therapeutically effective amount of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition.

The present invention also includes the use of moclobemide or moclobemide compositions in preventing, controlling or alleviating the development of physical dependence on drugs and alcohol.
That is, one embodiment of the present invention relates to administering a therapeutically effective amount of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition to a human in need of prevention of physical drug and alcohol dependence. Another aspect of the invention provides a method for administering an therapeutically effective amount of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition to a human in need of such treatment by administering to the human in need thereof the opioid, CNS inhibitor or CNS stimulant. Methods for controlling ingestion or reabsorption.

Also, the use of other benzamide derivatives to treat or prevent physical dependence, or to treat or prevent withdrawal symptoms, or to control intake, is encompassed by the present invention. Particularly, p-iodo-N- (2-morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, 4-chloro The use of -N- (2-morpholinoethyl) -benzamide, and p-chloro-N- (2-morpholinoethyl) -benzamide-N'-oxide is contemplated. Each of these compounds and their salts is structurally similar to moclobemide, although moclobemide is preferred, but can be used in the present methods.

The present invention further provides for treating or preventing abstinence symptoms in humans by administering to said human before, during or after other detoxification methods, moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. Moclobemide, moclobemide metabolites, along with conventional or known detoxification methods to
Includes the use of moclobemide derivatives or moclobemide compositions.
The invention also encompasses the use of moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions with a pharmaceutically active compound, such as a known antidepressant, preferably a tricyclic antidepressant. . Also, such known antidepressant compounds include tricyclic antidepressants such as amitriptin, clomipramine, doxepin, imipramine, (+)-tripramine, amixapine, desipramine, maprotin, nortriptyline, and protriptyline; Absorption inhibitors such as (±) -fluoxetine, flavoxamine, paroxetine, sertraline, and (±) -venlafaxine; amorphous antidepressants such as bupropion, nefazoton and trazodone; and other monoamine oxidase inhibitors such as phenelzine; It includes tranylcypromine and (-)-sergyline triptyline, including one or a combination. In particular, the present invention encompasses the use of moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions with other known antidepressants without the widespread negative drug interactions associated with MAOI's.

Except where certain central nervous system sedative addiction or withdrawal symptoms have been used for treatment or prevention, administration of additional sedatives has a counteracting effect, as readily determined by those skilled in the art. If so, the present invention further provides moclobemide, moclobemide, moclobemide, moclobemide, moclobemide, moclobemide, moclobemide, mozorebide with benzodiazipine, including without limitation alprazolam, chlordiazepoxide, clonazepan, chlorazepate, diazepan, estazolam, flurazepan, halazepan, lorazepan, midazolam, oxazepan, quazepan, temazepan or triazolam. Includes the use of moclobemide derivatives or moclobemide compositions.

The present invention relates to a method of treating moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions alone or in other detoxifications to treat or prevent physical dependence or to treat or prevent withdrawal symptoms. Along with the means,
Includes use for all human patients, including men, women, children and the elderly. The present invention is further directed to simultaneously treating, preventing or alleviating physical dependence on multiple types of addictive substances, or treating, preventing or alleviating symptoms associated with concurrent discontinuation from dependence on multiple types of substances. Moclobemide,
It includes using moclobemide metabolites, moclobemide derivatives or moclobemide compositions.

4. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the prevention of abuse or dependence on opioids, alcohol and other CNS antidepressants such as sedatives, or CNS stimulants such as cocaine and amphetamine in humans. A method for treating a condition associated with discontinuation of a drug, the method comprising: administering a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to the human suffering from withdrawal. Include.

The present invention also provides a method for preventing the development of withdrawal symptoms in humans that is dependent on other central nervous system antidepressants such as opioids, alcohol and sedatives, or CNS stimulants such as cocaine and amphetamine. Wherein the method comprises administering a therapeutically effective amount of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition to said human who is likely to suffer from withdrawal symptoms.

The present invention is further directed to a method for preventing, controlling or ameliorating a physical dependence on a drug or alcohol in a human, comprising the steps of: providing said human with moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition Administering a therapeutically effective amount of the substance.

Furthermore, the present invention encompasses a method of controlling the intake of the above substances by administering moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions. Moclobemide, as well as certain other moclobemide derivatives, are described by Burkard et al.
al., US Pat. No. 4,210,754, and Amerian et al., US Pat. No. 4,906,626, which are incorporated by reference in their entirety. formula:

Embedded image The moclobemide metabolite, also known as moclobemide-N-oxide, has been shown to have MAO-A inhibitory activity and has been shown to have opioids, central nervous system antidepressants, alcohols and sedatives. The present invention also encompasses abuse of central nervous system antidepressants, or substance abuse involving discontinuation of use from abuse or dependence on CNS stimulants such as cocaine and amphetamine, and use in the treatment or prevention of the symptoms.

Prodrugs, ie, drugs that are metabolized in vivo to become active ingredients, and prodrugs.
Methods for making drugs are readily known in the art (eg, Balant,
L.P., "Prodrugs for the Improvement of Drug Absorption Via Different Rou
tes of Administration, "Eur. J. Drug Metab. Pharmacokinet.15: 143-153 (1
990); and Bundgaard, H., "Novel Chemical Approaches in Prodrug Design," Drugs of the Future 16: 443-458 (1991); incorporated herein by reference). is there
In embodiments, the derivatives of the present invention have MAOI activity.

The prophylactic as well as therapeutic doses of an active ingredient (eg, moclobemide, a metabolite of moclobemide, a derivative of moclobemide) in the treatment or prevention of physical dependence or withdrawal symptoms will vary with the pain of patient intake. Dosage and frequency of dosing will also vary depending on the age, weight, and responsiveness of each patient. In general, the recommended daily dose range for the conditions described herein is approximately 50 per day.
mg and about 1200 mg, and generally is divided equally into 1 to 4 doses per day. Preferably, a daily dose range should be between 150 mg and 900 mg, usually divided equally between two and four doses per day. In some cases, it may be necessary to use doses outside these ranges, but the physician will know how to increase, decrease, or discontinue treatment based on patient response. The various terms described above, eg, “therapeutically effective amount,” are encompassed by the above dosages and dosing frequency schedules.

For use in the treatment or prevention of physical dependence or withdrawal symptoms, the physician
The duration of treatment and the frequency of use of moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions will generally be prescribed for each patient. However, in general, the treatment or prevention of substance abuse or dependence with moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide compositions can be performed for the required period, a single, uninterrupted period or a separate period. .
More specifically, the treatment with moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is performed for at least 4 weeks.

The moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition may be administered before, during, or after conventional methods used to detoxify substance abuse or dependence patients.

When used to prevent, control or alleviate physical dependence on a substance, treatment with moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition should temporarily overlap the duration of ingestion of the addictive substance. But,
It can begin prior to the period and / or continue after the period ends. In addition, moclobemide, moclobemide metabolites, moclobemide derivatives or moclobemide composition treatments are used to control or alleviate physical dependence that is already present but very low and therefore unlikely to cause clinically significant withdrawal symptoms. be able to. For example, a normal alcohol drinker who has a small physical dependence on alcohol can be used to prevent physical dependence even for individuals who are not likely to develop withdrawal symptoms after stopping alcohol drinking. The use of metabolites, moclobemide derivatives or moclobemide composition treatment would benefit.

[0062] Any suitable route of administration may be employed for providing a patient with an effective dose of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. For example, oral, rectal, parenteral, transdermal, subcutaneous, sublingual, intranasal, intramuscular,
Intrathecal and similar routes are employed as appropriate. Dosage forms include tablets, coated tablets, caplets, capsules (eg, hard gelatin capsules), troches, dragees, dispersions, suspensions, solutions, patches, and the like. Sustained-release preparations well known in the art. For example, Introduction to Pharmaceut
ical Dosage Forms , 1985, Ansel, HC, Lea and Febiger, Philadelphia, PA
; Remington's Pharmaceutical Sciences , 1995, Mack Publ. Co., Easton, PA.
reference.

[0063] The compositions of the present invention can also include other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from acids, including pharmaceutically acceptable non-toxic inorganic and organic acids.

Because the compounds of the present invention are basic, salts can be prepared from acids, including non-toxic inorganic and organic acids. These acids include maleic acid, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, bromic acid, hydrochloric acid, isethionic acid, lactic acid, Includes malic acid, mandelic acid, methanesulfonic acid, mucus acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are bromic acid, hydrochloric acid, maleic acid, phosphoric acid and sulfuric acid.

The compositions include compositions suitable for oral, rectal, transdermal, sublingual, and parenteral (including transdermal, intramuscular, intrathecal, and intravenous) administration, including any given In any given case, the most suitable route will depend on the nature and severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. 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.

When employing oral compositions, a suitable dosage range for use is, for example, from about 50 mg to about 1200 mg per day, generally divided equally into 1 to 4 doses per day, preferably Is usually from about 150 mg to about 900 mg per day, usually divided into 2 to 4 doses daily, most preferably about 150 mg per day.
mg to about 600 mg, usually in 2 or 4 divided doses daily.
To do. Evaluate the patient from the lower end and titrate upwards to within this dose range to achieve satisfactory control of symptoms or appropriate prevention

In practical use, moclobemide, a metabolite of moclobemide, a derivative of moclobemide or a moclobemide composition is prepared according to conventional pharmaceutical dispensing techniques.
It can be used in combination as the active ingredient in an intimate mixture with a pharmaceutical carrier. The carrier may take a wide variety of forms depending on the desired dosage form, eg, oral or parenteral (including intravenous injection or infusion). In preparing oral dosage forms, any of the usual pharmaceutical media, for example, water, glycols,
Oils, alcohols, fragrances, preservatives, coloring agents and the like, oral solutions,
For example, suspensions, elixirs and solutions; or can be employed in the case of aerosols; also, starches, sugars, microcrystalline cellulose, stabilizers, diluents, granulating agents, lubricants, binders, fillers. Carriers such as agents, disintegrants and the like can be employed with oral solid dosage forms such as powders, capsules and tablets (solid oral dosage forms are preferred over liquid dosage forms). A preferred solid oral dosage form is a tablet. The most preferred solid oral formulation is a coated tablet. Because of their ease of administration, tablets and capsules represent the most convenient dosage unit, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets are coated by standard aqueous or non-aqueous techniques. Containing moclobemide as an active ingredient, coated tablets, sachets,
And the preparation of hard gelatin capsules is described in US Patent No. 4,906,626, which is hereby incorporated by reference.

In addition to the common dosage forms set out above, the compounds of the present invention may also be administered in controlled or sustained release means and / or, for example, in US Patent Nos. 3845770; 3916899; 3536809; 35981
23; 3630200, 4008719, 4687660, and 4769027 (the disclosures of which are incorporated herein by reference). Preferred controlled release or sustained release tablets suitable for use with moclobemide are described in US Pat. No. 5,427,798, which is incorporated herein by reference.

Pharmaceutical stabilizers can also be used to stabilize compositions containing moclobemide, moclobemide metabolites or moclobemide derivatives or salts thereof; -Includes, but is not limited to, cysteine hydrochloride, glycine hydrochloride, malic acid, sodium pyrosulfite, citric acid, tartaric acid and L-dicysteine hydrochloride. For example, U.S. Patent No.
See 5358970 (incorporated herein by reference).

Compositions of the present invention suitable for oral administration include powders as discrete units, each containing a predetermined amount of the active ingredient, such as capsules, cachets, or tablets or spray sprays. Or as granules, or as solutions or suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, these compositions involve uniformly and intimately bringing the active ingredient into association with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into the desired appearance. Prepared by For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally with one or more binders, fillers, stabilizers, lubricants, inert diluents, And / or mixed with a surfactant or dispersant and compressed. Molded tablets may be made by molding in a suitable machine a powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 50 mg to about 300 mg of the active ingredient, and each cachet or capsule contains from about 50 mg to about 300 mg of the active ingredient. In a preferred embodiment, these tablets, each cachet or capsule contain about 50 mg of the active ingredient.
, About 70 mg, about 100 mg and about 150 mg.

The present invention is further defined with reference to the following examples, which further describe the preparation of the compounds and compositions of the present invention, but there are many modifications, both materials and methods, that Can be implemented without departing from the objects and advantages of the present invention.

[0072] 5. Example 5.1 Example 1 Oral formulation coated tablet:

[Table 1] * Water evaporates during manufacture.

The active ingredient (moclobemide, moclobemide metabolite or moclobemide derivative) is mixed with lactose until a homogeneous mixture is obtained. A small amount of corn starch is mixed with an appropriate amount of water to form a corn starch paste. This is then mixed with the homogeneous mixture to form a wet uniform mass. To the resulting wet mass, add the remaining corn starch and mix until uniform granules are obtained. The granules are then sieved through a suitable mill using a 1/4 inch stainless steel screen. The ground granules are then dried in a suitable dryer to the desired moisture content. Next, the dried granules are sieved with a suitable mill using a 1/4 mesh stainless steel screen. The magnesium stearate is then mixed and the resulting mixture is tabletted into tablets of desired shape, thickness, hardness and disintegration degree.

The tablets are coated by standard aqueous or non-aqueous techniques. For example, 2.5 mg of hydroxypropyl methylcellulose can be dissolved in 25 mg of deionized water. In this solution, 1.88 mg of talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0 mg of red iron oxide
Mix in a .02 mg aqueous suspension (10 mg). The coating suspension is sprayed on the tablets and the coated tablets are dried at 45 ° C. overnight.

5.2 Example 2 Oral Formulation Capsules:

[Table 2]

Mix the active ingredient (moclobemide), lactose and corn starch until homogeneous; mix the resulting powder with magnesium stearate.
The resulting mixture is encapsulated in a suitably sized, two-piece hard gelatin capsule.

5.3 Example 3 Oral Formulation Tablet:

[Table 3]

The active ingredient (moclobemide) is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized maize starch BP. Add an appropriate amount of purified water to granulate the powder. After drying, the granules are sieved and mixed with magnesium stearate. Next, the granules are compressed into tablets using a punch.

Tablets of other strengths can be prepared by varying the ratio of active ingredient to lactose and the compressed weight, and by using suitable punches. Those skilled in the art, in particular,
Single dose forms of 50, 100, 150 and 200 mg of moclobemide can be selected and easily manufactured. For example, tablets of the following composition, as described in US Patent No. 4210754, which is incorporated herein in its entirety, can be prepared by methods known to those skilled in the art: tablets

[Table 4]

The above-described embodiments of the present invention are intended to be merely exemplary, and those skilled in the art will recognize that there are many equivalents to the specific operations described herein. Or, it can be confirmed without going through an experiment more than usual. All such equivalent methods are within the scope of the present invention and are intended to be covered by the appended claims.

The contents of all references cited herein are hereby incorporated by reference. Throughout this specification and the claims, the term "comprising", or a variant thereof, "comprising" is to be understood to mean the inclusion of the recited members and members of the group It is. Other embodiments are also within the claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/32 A61P 25/32 25/36 25/36 // C07D 295/12 C07D 295/12 Z (81 ) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Seth Lehderman United States 10128 East Ninetyfifth Street 143, Sweet, New York, NY 1A F term (reference) 4C086 AA01 AA02 BC56 BC73 CB11 MA01 MA02 MA04 MA35 MA37 MA52 ZC39 4C206 AA01 AA02 KA01 KA06 MA02 MA04 MA55 MA57 MA72 ZC39

Claims (27)

[Claims] 1. A method for treating or preventing a symptom associated with discontinuation of a drug or alcohol from taking in a human, comprising treating a therapeutically effective amount of moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition in a human. The method comprising administering to a human who is physically dependent on the drug or alcohol. 2. A method for preventing, controlling or alleviating physical dependence on a drug or alcohol in a human, comprising administering to a human in need of prevention, control or alleviation moclobemide, moclobemide metabolite, moclobemide derivative or A method comprising administering an amount of a moclobemide composition, wherein the amount is sufficient to prevent, control or alleviate physical dependence. 3. The method according to claim 1, wherein the moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is administered orally or parenterally. 4. The method of claim 3, wherein the moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is administered orally as a tablet or capsule. 5. The method of claim 1, wherein the moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is administered transdermally as a transdermal patch. 6. The method of claim 1, wherein the dose is about 50 mg to about 1200 mg.
Or the method of 2. 7. The dose of claim 6, wherein the dose is about 150 mg to about 900 mg.
The described method. 8. The dosage of claim 7, wherein the dosage is from about 150 mg to about 600 mg.
The described method. 9. The method of claim 1 or 2, wherein moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is administered with a pharmaceutically acceptable carrier. 10. The method of claim 1, wherein the moclobemide, moclobemide metabolite, moclobemide derivative or moclobemide composition is administered in a sustained release or controlled release formulation. 11. The method according to claim 1, wherein the administration is performed 1 to 4 times per day. 12. The method according to claim 1, wherein the administration is continued for at least 4 weeks.
The described method. 13. The method of claim 1, further comprising treating the human with an antidepressant.
Or the method of 2. 14. The method of claim 13, wherein said depressant is a tricyclic antidepressant. 15. The method of claim 15, wherein the tricyclic antidepressant is selected from the group consisting of amitriptin, clomipramine, doxepin, imipramine, (+)-tripramine, amixapine, desipramine, maprotin, nortriptyline, and protriptyline. 15. The method according to 14. 16. The antidepressant may be (±) -fluoxetine, flavoxamine, paroxetine, sertraline, (±) -venlafaxine, (±) -venlafaxine, bupropion, nefazoton, trazodone, phenelzine, tranylcypromine. 14. The method of claim 13, wherein the method is selected from the group consisting of and (-)-sergiline triptyline. 17. The method of claim 1 or 2, further comprising treating said human with benzodiadipine. 18. The method of claim 17, wherein the zenzothiazepine is selected from the group consisting of alprazolam, chlordiazepoxide, clonazepan, chlorazepate, diazepan, estazolam, flurazepan, halazepan, lorazepan, midazolam, oxazepan, quazepan, temazepan or triazolam. 19. The method according to claim 1, wherein the drug is a central nervous system antidepressant.
The described method. 20. The method of claim 19, wherein said central nervous system antidepressant is selected from the group consisting of opioids, sedatives, marijuana and inhibitors. 21. The method according to claim 1, wherein the drug is a central nervous system stimulant. 22. The method of claim 21, wherein said drug is selected from the group consisting of cocaine, amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate hydrochloride, and diethylproprion. 23. The method according to claim 14, wherein the drug is selected from marijuana, barbiturate, lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine (MDMA, Ecstasy), N, N-dimethylamine and psilocybin. The method according to claim 1 or 2, wherein the method is selected from the group 24. A method of controlling alcohol or drug intake in a human comprising administering to the human a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. 25. The drug, wherein the drug is an opioid, a sedative, marijuana, an inhibitor, cocaine, amphetamine, dextroamphetamine, methamphetamine,
Phenmetrazine, methylphenidate hydrochloride, diethylproprion, barbiturate, diethyl lysergic acid (LSD), phencyclidine (PCP)
25. The method of claim 24, wherein the method is selected from the group consisting of, methylenedioxymethamphetamine (MDMA, Ecstasy), N, N-dimethylamine and psilocybin. 26. A method for treating or preventing a symptom associated with discontinuation of a drug or alcohol dependence in a human, comprising administering to the human a p-iodo-N-
(2-morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, 4-chloro-N- (2-morpholinoethyl ) -Benzamide, pharmaceutically acceptable salts thereof and p-chloro-N- (2-morpholinoethyl) -benzamide-N
A method comprising administering a therapeutically effective amount of a compound selected from '-oxide. 27. A method for preventing, controlling or alleviating physical dependence of a drug or alcohol in a human, comprising the steps of: providing p-iodo-N- (2-morpholinoethyl) -benzamide, p-fluoro -N- (2-morpholinoethyl)
-Benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, 4-
Therapeutically effective selected from chloro-N- (2-morpholinoethyl) -benzamide, pharmaceutically acceptable salts thereof and p-chloro-N- (2-morpholinoethyl) -benzamide-N'-oxide A method comprising administering an amount of a compound.