Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-06-14
2001-11-06
Dees, Jose G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C424S457000
Reexamination Certificate
active
06312717
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved method for treating anxious and/or depressed patients. Concurrent administration of certain azapirones with a 5-HT1A autosomal receptor antagonist provides faster onset of anxiolytic and antidepressant actions. By administering the azapirone in such a manner that formation of the 1-(2-pyrimidinyl)piperazine metabolite (1-PP) is minimized, a more robust therapeutic effect is achieved.
Certain azapirqne compounds and their pharmaceutically acceptable salts have been described as being useful in treating anxiety and depression disorders. These compounds have general structure (I) and are identified below.
(I)
Compound
Z
Reference
buspirone
U.S. Pat. No. 3,717,634
gepirone
U.S. Pat. No. 4,423,049
ipsapirone
EP 129,128
tandospirone
U.S. Pat. No. 4,507,303
zalospirone
J. Med. Chem., 1988, 31:1382-1392
These particular azapirones containing the pyrimidinylpiperazine moiety as an integral part of their molecular structure give rise to 1-(2-pyrimidinyl)piperazine (1-PP) as their major metabolite. This metabolite is seen in greatest abundance following oral administration. The most studied and well-known member of this compound class is buspirone, an important antianxiety agent first approved for use in anxious patients in 1986. Although buspirone has been disclosed as having antidepressant properties by Robinson, et al.,
J. Clin. Psychopharmacol
. , 1990, 10:675-765; it has not been generally considered to be as efficacious as classical antidepressant agents.
However, Blier, et al. in
Neuropsychopharmacol
. , 1997, 16:333-338; reported that buspirone exhibited both an efficacy and onset of action that was superior to classical antidepressants when the buspirone was combined with the 5-HT1A autosomal receptor blocker, pindolol. Both agents were administered separately by the oral route to a group of depressed patients in the study described by Blier.
SUMMARY OF THE INVENTION
The invention concerns an improved method for treating anxiety and/or depression. The method involves concomitant administration of an azapirone, such as buspirone, gepirone, ipsapirone, tandospirone or zalospirone, and a 5-HT1A autosomal receptor antagonist such as pindolol. An improvement in rapidity of onset and efficacy of this combination of agents is provided by administration of the azapirone in a manner that suppresses formation of the major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP).
REFERENCES:
patent: 3717634 (1973-02-01), Wu et al.
patent: 4423049 (1983-12-01), Temple, Jr.
patent: 4507303 (1985-03-01), Ishizumi et al.
patent: 4818756 (1989-04-01), Seidel et al.
patent: WO 99/61014 (1999-02-01), None
Magid Aboud-Gharbia, et al., “Polycyclic Aryl- and Heteroarylpiperazinyl Imides as 5-HT1A Receptor Ligands and Potential Anxiolytic Agents: Synthesis and Structure-Activity Relationship Studies,”J. Med. Chem.,1988, 31:1382-1392.
Donald S. Robinson, et al., “Clinical Effects of the 5-HT1A Partial Agonists in Depression: A Composite Analysis of Buspirone in the Treatment of Depression,”Journal of Clinical Psychopharmacology,1990, 10:67S-76S.
Pierre Blier, et al., “Selective Activation of Postsynaptic 5-HT1A Receptors Induces Rapid Antidepressant Response,”Neuropsychopharmacology,1997, 16:333-338.
Dunbar Geoffrey C.
Molinoff Perry B.
Bristol--Myers Squibb Company
Dees Jos,e G.
Ryan Richard P.
Williamson Michael A.
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