| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 31.12.02 |
| PATENT TITLE |
Treatment of stereotypic, self-injurious and compulsive behaviors in man and animals using antagonists of NMDA receptors |
| PATENT ABSTRACT |
NMDA receptor antagonists can be used in methods of treatment, for reducing the frequency of stereotypic behaviors in animals and for reducing the frequency of analogous compulsive behaviors in humans, for example, those that have been said to be a manifestation of, or related to, obsessive-compulsive disorder. Of particular interest are the (+) enantiomers of opioid receptor binding compounds, which can reduce the frequency of the behaviors, while having no effects from binding at the opioid receptor. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 5, 2001 |
| PATENT REFERENCES CITED |
Kim, "Opioid antagonists in the treatment of impulse-control disorders", J. Clin. Psychiatry (1998), 59(4), pp. 159-164 (abstract).* Lijima, I., et al., "Studies in the (+) -Morphinan Series. 5..sup.1 Synthesis and Biological Properties of (+) -Naloxone," J. Med. Chem., 21(4):398-400 (1978). Koyuncuoglu, H. et al., "The treatment of heroin addicts with dextromethorphan: A double-blind comparison of dextromethorphan with chlorprozamine," Int. J. Clin. Pharmacol. Ther. Toxicol., 28 (4) :147-152 (1990). Welch, L. et al., "The treatment of a chronic organic mental disorder with dextromethorphan in a man with severe mental retardation," Br. J. Psychiatry, 161 :118-120 (1992). Pomerleau, O.F., "Endogenous opioids and smoking: A review of progress and problems," Psychoneuroendocrinology, 23 (2) :115-130 (1998). Smith, K.C. et al., "Naltrexone for neurotic excoriations," J. Am. Acad. Dermatol., 20 (5) :860-861 (1989). Dodman, N.H. et al., "Use of narcotic antagonists to modify stereotypic self-licking, self-chewing, and scratching behavior in dogs," JAVMA, 193 (7) :815-819 (1988). Aabech, H.S., "Tourette syndrome: New aspects on pharmacological treatment," Tidsskr. Nor. Laegeforen., 109(9):961-963 (1989). Dodman, N.H. et al., "Investigation into the use of narcotic antagonists in the treatment of a stereotypic behavior pattern (crib-biting) in the horse," Am. J. Vet. Res., 48 (2) :311-319 (1987). Crockford, D.N. et al., "Naltrexone in the treatment of pathological gambling and alcohol dependence," Can. J. Psychiatry, 43 (1) :86 (1998). Keuthen, N.J. et al., "Trichotillomania: Current issues in conceptualization and treatment," Psycother. Psychosom., 67 (4-5) :202-213 (1998). Mills, I.H. et al., "Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions," Q.J. Med., 91 (7) :493-503 (1998). Herling, S. et al., "Discriminative stimulus effects of dextrorphan in pigeions," J. Pharmacol. Exp. Ther., 227 (3):723-731 (1983). Woods-Kettelberger, A. et al., "Animal models with potential applications for screening compounds for the treatment of obsessive-compulsive disorders," Exp. Opin. Invest. Drugs, 6 (10) :1369-1381 (1997). Ghaziuddin, M. et al., "Haloperidol treatment of trichotillomania in a boy with autism and mental retardation," J. Autism and Developmental Disorders, 21 (3) :365-371 (1991). Pulvirenti, L. et al., "Dextromethorphan reduces intravenous cocaine self-administration in the rat," Eur. J. Pharmacol., 321:279-283 (1997). Choi, D. W. et al., "Opioids and non-opioid enantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons," Eur. J. Pharmacol., 155:27-35 (1988). Lipton, S.A. et al., "Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders," N. Engl. J. Med., 330 (9) :613-622 (1994). O'Connor, P.G. et al., "A Preliminary Investigation of the Management of Alcohol Dependence with Naltrexone by Primary Care Providers," Am. J. Med., 103 (6) :477-482 (1997). Overall, K.L., "Recognition, Diagnosis, and Management of Obsessive-Compulsive Disorders," Canine Practice, 17 (4):39-43 (1992). Chatterjie, N. et al., "Dextro-Naloxone Counteracts Amphetamine-Induced Hyperactivity," Pharmacol. Biochem. Behav., 59 (2) :271-274 (1998). Dodman, N.H. et al., "In Search of Animal Models for Obsessive-Compulsive Disorders," CNS, Nov. 1996. White, S.D., "Naltrexone for treatment of acral lick dermatitis in dogs," JAVMA, 196(7) :1073-1076 (1990). Ebert, B. et al., "Opioid Analgesics as Noncompetitive N-Methyl-D-aspartate (NMDA) Antagonists," Biochem. Pharmacol., 56:553-559 (1998). Gorman, A.L. et al., "The d- and 1- isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord," Neurosci. Lett., 223:5-8 (1997). Dodman, N.H. et al., "Veterinary Models of OCD," Obsessive-Compulsive Disorders, Eric Hollander et al., eds (Marcel Dekker, Inc.), pp. 99-143 (1997). Moon-Fanelli, Alice A. et al., "Description and development of compulsive tail chasing in terriers and response to clomipramine treatment," JAVMA, 212 (8) :1252-1257 (1998). Moon-Fanelli, Alice A. et al., "Veterinary Models of Compulsive Self-Grooming: Parallels with Trichotillomania," In Trichotillomania, Dan J. Stein eds. et al., eds., (American Psychiatric Press, Inc.), pp. 63-92 (1997). Rapoport, J.L. et al., "Drug treatment of canine acral lick. An animal model of obsessive-compulsive disorders," Archives of General Psychiatry, 49 (7) :517-521 (1992) [on line] [Aug. 17, 2000] Retrieved form the Internet: http://gateway.ovid.com/rel410/server1/ovidweb.cqi. Rapoport, J.L., "Animal models of obsessive compulsive disorders," Clinical Neuropharmacology, 15 Suppl 1 Pt A:261A-262A (1992) [on line] [Aug. 17, 2000] Retrieved form the Internet: http://gateway.ovid.com/re1410/server1/ovidweb.cqu. Shuster, Louis et al., "Basic Mechanisms of Compulsive and Self-Injurious Behavior," N.H. Dodman eds. et al., Psychopharmacology of animal Behavior Disorders, pp. 185-202 (1998). Stein, Dan J. et al., "Use of the Selective Serotonin Reuptake Inhibitor Citalopram in a Possible Animal Analogue of Obsessive-Compulsive Disorder," Depression and Anxiety, 8 :39-42 (1998). Stein, Dan J. et al, "Obsessive-Compulsive Spectrum Disorders," J. Clin. Psychiatry, 56 (6) :265-266 (1995). Swedo, Susan E. et al., "Trichotillomania An Obsessive Compulsive Spectrum Disorder?," Psychiatric Clinics of North America, 15 (4) :777-790 (1992). Swedo, Susan E. et al., "Long-Term Treatment of Trichotillomania (Hair Pulling)," The New England Journal of Medicine, 329 (2) :141-142 (1993). "Obsessive-Compulsive Disorder," Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-R, 4th ed. Washington, American Psychiatric Association, pp. 417-423 (1994). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for treating obsessive-compulsive disorder in a human, comprising administering to the human an effective amount of a composition comprising one or more NMDA receptor antagonists. 2. The method of claim 1 wherein the NMDA receptor antagonist is (+) methadone. 3. The method of claim 1 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 .mu.M and less than or equal to 100 .mu.M. 4. The method of claim 1 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 1 .mu.M and less than or equal to 10 .mu.M. 5. The method of claim 1 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.d in an NMDA receptor binding assay greater than 100 nM and 1ess than or equal to 1 .mu.M. 6. The method of claim 1 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 nM and less than or equal to 100 .mu.M. 7. The method of claim 1 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay loss than or equal to 10 nM. 8. The method of claim 1 wherein the composition does not comprise haloperidol. 9. The method of claim 1 wherein the obsessivc-compulsive disorder is manifested by one or more behaviors selected from the group consisting of checking, counting and washing to remove contamination. 10. The method of claim 1 wherein the composition further comprises a pharmeceutical carrier. 11. A method for treating obsessive-compulsive disorder in a human, comprising administering to the human an effective amount of a composition comprising one or more NMDA receptor antagonists, wherein the composition does not comprise primarily (-) enantiomer of an opioid receptor agonist or antagonist. 12. The method of claim 11 wherein the NMDA receptor antagonist is (+) methadone. 13. The method of claim 11 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 .mu.M and less than or equal to 100 .mu.M. 14. The method of claim 11 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 1 .mu.M and less than or equal to 10 .mu.M. 15. The method of claim 11 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 100 nM and less than or equal to 1 .mu.M. 16. The method of claim 11 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 nM and less than or equal to 100 nM. 17. The method of claim 11 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay less than or equal to 10 nM. 18. The method of claim 11 wherein the composition does not comprise haloperidol. 19. The method of claim 11 wherein the obsessive-compulsive disorder is manifested by one or more behaviors selected from the group consisting of checking, counting and washing to remove contamination. 20. The method of claim 11 wherein the composition further comprises a pharmeceutical carrier. 21. A method for treating obsessive-compulsive disorder in a human, comprising administering to the human an effective amount of a composition comprising one or more compounds selected from the group consisting of: dextromethorphan, dextrorphan, naltrexone, naloxone, methadone, pentazocine, nalmefene, diprenorphine, nalorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine, butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine, and a combination of any of the preceding, wherein the compounds are predominantly (+) enantiomer. 22. The method of claim 21 wherein the compound is methadone. 23. The method of claim 21 wherein the compound is dextromethorphan. 24. The method of claim 21 wherein the compound is dextrorphan. 25. The method of claim 21 wherein the compound is naltrexone. 26. The method of claim 21 wherein the compound is naloxone. 27. The method of claim 21 wherein the compound is nalmefene. 28. The method of claim 21 wherein the obsessive-compulsive disorder is manifested by one or more behaviors selected from the group consisting of checking, counting and washing to remove contamination. 29. The method of claim 21 wherein the composition comprises greater than 50% to 60% (+) enantiomer. 30. The method of claim 21 wherein the composition comprises greater than 60% (+) enantiomer 31. The method of claim 21 wherein the composition comprises greater than 70% (+) enantiomer. 32. The method of claim 21 wherein the composition comprises greater than 80% (+) enantiomer. 33. The method of claim 21 wherein the composition comprises greater than 90% (+) enantiomer. 34. The method of claim 21 wherein the composition further comprises a pharmeceutical carrier. 35. The method of claim 22 wherein the methadone is (+) methadone. 36. A method for treating obsessive-compulsive disorder in a human, comprising administering to the human an effective amount of a composition comprising one or more NMDA receptor antagonists, wherein the composition does not comprise an opioid receptor agonist or an opioid receptor antagonist. 37. The method of claim 36 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 .mu.M and less than or equal to 100 .mu.M. 38. The method of claim 36 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 1 .mu.M and less than or equal to 10 .mu.M. 39. The method of claim 36 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 100 nM and less than or equal to 1 .mu.M. 40. The method of claim 36 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay greater than 10 nM and less than or equal to 100 nM. 41. The method of claim 36 wherein the composition comprising one or more NMDA receptor antagonists has a K.sub.D in an NMDA receptor binding assay less than or equal to 10 nM. 42. The method of claim 36 wherein the obsessive-compulsive disorder is manifested by one or more behaviors selected from the group consisting of checking, counting and washing to remove contamination. 43. The method of claim 36 wherein the composition further comprises a pharmaceutical carrier. -------------------------------------------------------------------------------- |
| PATENT EXAMPLES |
EXAMPLE 1 Treatment of Cribbing in Horses Horses were admitted to the Large Animal Hospital of Tufts University School of Veterinary Medicine or were tested in their home barn. Cribbing straps and food were removed prior to testing. Control rates of crib-biting were observed and recorded for 5 minute intervals for one hour or more after an intravenous injection of 0.15 M saline. Test drugs were administered orally (by gavage) or by injection into the jugular vein. Solutions were made up with physiological saline and sterilized by filtration through a 0.2 micron filter (Millipore). For the experimental data shown in FIG. 1, after establishment of a stable control rate of approximately 10 crib-bites per minute, 50 mg of D-methadone-HCl in 25 ml saline was injected i.v. In FIG. 1, the cumulative number of crib-bites was plotted against time as was the rate per 5 minute interval (Shuster, L. and N. H. Dodman, pp. 185-202, In Psychopharmacology of Animal Behavior Disorders, (N. H. Dodman and L. Shuster, eds.), Blackwell Scientific, Malden, Mass., 1998). The rate decreased between the second and the fifth 5-minute interval following injection. The control rate then resumed during the next 80 minutes of observation. Horses were observed continuously during scoring for side effects that might be attributed to the treatment. These included changes in posture, disposition and motor activity. See also Table 1. |
| PATENT PHOTOCOPY | Available on request |
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