Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-09
2002-08-20
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S282000, C514S327000, C514S649000
Reexamination Certificate
active
06436938
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of treating depression, especially refractory depression, in a mammal, including a human, by administering to the mammal a sigma receptor ligand in combination with a Serotonin Reuptake Inhibitor (SRI). It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a sigma receptor ligand and a Serotonin Reuptake Inhibitor (SRI).
Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes also occur, especially in severe or “melancholic” depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.
Serotonin Selective Reuptake Inhibitors (SSRIs) currently provide efficacy in the treatment of major depressive disorder (MDD) and are generally perceived by psychiatrists and primary care physicians as effective, well-tolerated and easily administered. However, they are associated with undesirable features, such as high incidence of sexual dysfunction, delayed onset of action and a level of non-responsiveness estimated to be as high as 30% (see M. J. Gitlin,
Journal of Clinical Psychiatry
, 1994, 55, 406-413 and R. T. Segraves,
Journal of Clinical Psychiatry
, 1992, 10(2), 4-10). Preclinical and clinical evidence has indicated that the sexual dysfunction associated with SSRI therapy can be reduced through the use of monoamine reuptake inhibitors (SRI) and dopamine reuptake inhibitors (DRIs), such as bupropion (see A. K. Ashton,
Journal of Clinical Psychiatry
, 1998, 59(3), 112-115). Furthermore, the combination of SRI and DRI may hasten the onset of action as well as offering relief to refractory patients, possibly through a synergistic mechanism (see R. D. Marshall et al,
Journal of Psychopharmacology
, 1995, 9(3), 284-286) and prove beneficial in the treatment of substance abuse and attention deficit hyperactivity disorder (ADHD) according to Barrickman et al,
Journal of the American Academy of Child and Adolescent Psychology
, 1995, 34(5), 649 and Shekim et al,
Journal of Nervous and Mental Disease
, 1989, 177(5), 296.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition for the treatment of depression, especially refractory depression, comprising: (a) a compound that exhibits activity as a serotonin reuptake inhibitor, or a pharmaceutically acceptable salt thereof; (b) a sigma receptor ligand or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active agents “a” and “b” above are present in amounts that render the composition effective in treating, respectively, anxiety or depression, especially refractory depression.
This invention also relates to a method of treating depression in a mammal, comprising administering to said mammal, respectively, an antidepressant effective amount of a pharmaceutical composition comprising: (a) a serotonin reuptake inhibitor (SRI) compound that exhibits activity as an antidepressant, or a pharmaceutically acceptable salt thereof; (b) a sigma receptor ligand or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active agents “a” and “b” above are present in amounts that render the composition effective in treating, respectively, anxiety or depression, especially refractory depression.
This invention also relates to a method of treating depression in a mammal, comprising administering to said mammal: (a) a serotonin reuptake inhibitor (SRI) compound that exhibits activity as an antidepressant, or a pharmaceutically acceptable salt thereof; and (b) a sigma receptor ligand or pharmaceutically acceptable salt thereof; wherein the active agents “a” and “b” above are present in amounts that render the combination of the two agents effective in treating, respectively, anxiety or depression, especially refractory depression.
It will be appreciated that when using a combination method of the present invention, referred to immediately above, both the sigma receptor ligand and the SRI antidepressant agent will be administered to a patient within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms that are taken simultaneously. The term combination, as used above, also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the SRI antidepressant agent may be administered as a tablet and then, within a reasonable period of time, the sigma receptor ligand may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a “fast dissolving oral formulation” is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about seconds.
The compositions of the present invention that contain a sigma receptor ligand and an SRI antidepressant are useful for the treatment of depression, especially refractory depression. As used herein, the term “depression” includes depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias, seasonal affective disorder, or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
Other mood disorders encompassed within the term “depression” include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood, disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
The compositions of the present invention are especially useful for the treatment of refractory depression where the use of an antidepressant is generally prescribed. By the use of a combination of a sigma receptor ligand and an SRI antidepressant agent in accordance with the present invention, it is possible to treat refractory depression in patients for whom conventional antidepressant therapy might not be wholly successful.
Examples of Serotonin Reuptake Inhibitors (SRI) that may be used in the methods and pharmaceutical compositions of this invention are compounds of the formula
wherein phenyl ring A and phenyl ring B can each, independently, be replaced by a naphthyl group, and wherein when phenyl ring A is replaced by a naphthyl group, the ethereal oxygen of structure I and the carbon to which R
3
, R
4
and NR
1
R
2
are attached, are attached to adjacent ring carbon atoms of the naphthyl group and neither of said adjacent ring carbon atoms is also adjacent to a fused ring carbon atom of said naphthyl group;
n and m are, selected, independently, from one, two and three;
R
1
and R
2
are selected, independently, from hydrogen (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, and (C
2
-C
4
)alkynyl, or R
1
and R
2
, together with the nitrogen to which they are attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R
1
and R
2
are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at
Appleman Jolene W.
Ginsburg Paul H.
Henley III Raymond
Pfizer Inc.
Richardson Peter C.
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