Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-23
2001-07-17
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S307000
Reexamination Certificate
active
06262049
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention is directed at reducing cravings in mammals. More specifically the present invention is directed at reducing the cravings of a mammal to any dopamine mediated cravings including food or addictive substances.
Considerable research has been directed at obesity, nicotine addiction and substance abuse. The cost to society is very high from the health costs associated with obesity, tobacco consumption, and drug and alcohol abuse. While many individuals choose to lose weight, stop smoking and/or cease abusing drugs or alcohol, they frequently relapse into their former patterns of behavior during or shortly after they complete their treatment programs. Often this may be caused by subtle signals in the environment which initiate cravings in the individual for food or the substance which they had abused. Accordingly, it would be desirable to provide a substance which would suppress cravings for food and/or abused substances in a predisposed mammal.
The use of D
1
antagonists in the treatment of drug abuse is known. U.S. Pat. Nos. 4,973,586 and 5,302,716 disclose the use of D
1
antagonists in treating drug dependence. A dosage range of 0.02-10 mg/kg was suggested, with 2.0 mg/kg divided over 1-3 administrations per day being particularly preferred.
Spealman, et al., Neurochem. Int. Vol. 20 Suppl., 99147S-152S (1992) discloses that cocaine is a robust reinforcer and often is used as a standard for evaluating the reinforcing effects of other drugs. When SCH 39166 was administered to monkeys, a 3-fold or greater increase in the dose of cocaine usually was required to restore characteristic self-administration performances.
Barrett-Larimore and Spealman in Society for Neuroscience Abstracts 22(2): 92 5 (1996) reported that several compounds including the D
1
antagonist SCH 39166, a D
2
antagonist and a D
3
/D
4
antagonist all were able to attenuate the cocaine-seeking behavior in a cocaine relapse model. Clifton, 1995 and Clifton, 1991 have indicated that the D
1
antagonists SCH39166 and SCH 23390 have no effect on total food intake, meal size or feeding rate up to 3 mg/kg.
Caine and Koob in The Journal of Pharmacology and Experimental Therapeutics Vol. 270, No. 1 pp. 209-218 (1994) describe tests on D
1
antagonists SCH 39166 and SCH 23390 for cocaine and food self-reinforcement. D1 antagonists were found to affect cocaine self-administration.
Chausmer and Ettenberg in Pharmacology Biochemistry and Behavior Vol. 57, No. 4, pp. 681-685 (1997) conducted tests on D
1
and D2 antagonists in response re-instatement properties of food reward. They found that the D
2
antagonist raclopride was sufficient to block the response-reinstating effects of food reinforcement, but the D
1
antagonist SCH 39166 was not.
Nathan, Breskin and Batki in CNS Drugs Jul. 10, 1998 (1) pp. 43-59 summarize results in treating cocaine addiction with various drugs.
Lancet, Volume 347 pp. 504-508 (Feb. 14, 1996) reports that haloperidol was tested for decreasing desire for an abused substance. However, this compound is reported to have had significant adverse side effects, such as dysphoria, restlessness or stiffness, which reduces the desire for individuals to take them.
It has been difficult to develop substances which inhibit craving in mammals, particularly humans, because of the lack of reliable animal models which correlate well with human behavior.
Substances which are administered to reduce craving should not produce significant physiological effects, such as stimulation of mood or elevate blood pressure or heart rate. This could result in the substitution of one abused substance for another. Compounds which dampen the desire for the abused substance also should not exacerbate the physiological symptoms of the abused substance in the event the individual relapses and takes the abused substance. Substances administered to reduce craving also should not produce significant adverse affects, such as dysphoria, restlessness or stiffness.
Accordingly, it is desirable to provide a compound and method of treatment which will be active in reducing craving for the abused substance, and which does not exacerbate the sympathetic response rate caused by the abused substance and which has favorable pharmacodynamic effects.
It also is desirable to provide a compound and method of treatment which blocks the euphoric and dysphoric effects of the abused substance.
SUMMARY OF THE INVENTION
The present invention is directed at a method for reducing cravings to food or an addictive substance in a mammal comprising administering an anti-craving effective amount of a D
1
/D
5
antagonist, a D
1
/D
5
partial agonist, or mixtures thereof, alone or in combination with other CNS compounds. The method is particularly adapted to reducing cravings to food or addictive substances, such as tobacco, alcohol or abused drugs. In a preferred embodiment, the D
1
/D
5
antagonist or D
1
/D
5
partial agonist is administered in a range of about 0.01 to about 500 mpk per day preferably about 1-150 mpk per day, to a mammal predisposed to cravings. Preferred D
1
/D
5
antagonists are SCH 23390, SCH39166, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 and A69024, with SCH 39166 being particularly preferred. A preferred D
1
/D
5
partial agonist is SKF 38393.
The D1/D5 antagonists or D
1
/D
5
partial agonists may be used in combination with compounds selected from the following CNS classes:
A. anti-obesity compounds;
B. serotonin receptor agonists and antagonists;
C. antipsychotics/anxiolytics;
D. antidepressants;
E. dopaminergic agonists;
F. anticonvulsants/ mood stimulants;
G. cocaine-like agonists;
H. cocaine catalytic antibodies; and
I. alcohol and opiate antagonist drugs.
REFERENCES:
patent: WO 96/13257 (1996-05-01), None
patent: WO 97/46239 (1997-12-01), None
patent: WO 99/15161 (1999-04-01), None
Panocka et al, Derwent Drug File Abstracts, abstract no. 1995-39814.*
Ng et al, Medline Abstracts, abstract no. 95203333, 1994.*
Dyr et al, Biological Abstracts, abstract no. 1993:323964.*
Archer et al, Derwent Drug File Abstracts, abstract no. 1996-21249.*
Caine et al, Derwent Drug File Abstracts, abstract no. 1994-38611.*
Guse et al, Derwent Drug File Abstracts, abstract no. 1993-19338.*
Cervo L., et al., Brain Research 673:2 pp. 242-250 (Mar. 6, 1995).
Bednar, et al., American J. of Physiology 269:4 pt. 2 R896-902 (Oct., 1995).
Cervo, et al., Brain Research 731:31-38 (1996).
Nielsen, et al., European Journal of Pharmacology, 11:167-176 (1985).
Corrigall, et al., Pharmacology Biochemistry and Behavior, 48:3 pp. 817-820 (1994).
W. Dry, et al., “Effects of D1and D2Dopamine Receptor Agents on Ethanol Consumption in the High-Alcohol-Drinking (HAD) Line of Rats,” Alcohol, 10:207-212 (1993).
Samochowiec et al., Pharmazie 50 pp. 815-818 (1995).
I. Panocka et al., “Effects of the dopamine D1receptor antagonist SCH 39166 on the ingestive behaviour of alcohol-preferring rats,” Psychopharmacology 120:227-235 (1995).
Gordon YK. Ng, et al., “Dopamine receptor agonist reduces ethanol self-administration in the ethanol-preferring C57BL/6J inbred mouse,” European Journal of Pharmacology, Section 269 pp. 365-374 (1994).
Sydney Archer, et al., Suppression of Morphine and cocaine Self-Administration in Rats by Mixed Mu Antagonist-Kappa Agonist (N-CBM-TAMO) and a Long-Acting Selective D1Antagonist (AS0300), Bioorganic & Medicinal Chemistry Letters 6:10 pp. 1139-1144 (1996).
S. Barak Caine, et al., “Effects of Dopamine D-1 and D-2 Antagonists on Cocaine Self-Administration Under Different Schedules of Reinforcement in the Rat,” The Journal of Pharmacology and Experimental Therapeutics, 270:1 pp. 209-218, 1994.
Paul A. Guse, et al., “Attentuation of Arrhythmogenic Effects of Cocaine by a Dopaminergic Antagonist Schering 39166,” JACC 21:2 Feb. 1993, Abstract.
Coffin Vicki L.
Glue Paul W.
Jarvis William R. A.
Mazer Edward H.
Schering Corporation
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