Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-08-15
2002-03-26
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06362173
ABSTRACT:
FIELD OF THE INVENTION
This invention generally pertains to the field of psychiatry. In particular, this invention pertains to the discovery that agents which inhibit the binding of cortisol to its receptor can be used in methods of ameliorating psychosis, including the psychotic component of pathologies or conditions with psychotic symptoms.
INTRODUCTION
This invention is directed to a method for treating psychosis whose pathogenesis is related to glucocorticoid regulatory dysfunction. The types of psychosis treated by the methods of the invention must be distinguished from the older definition of psychosis, which referred to schizophrenia and manic states. Schizophrenia and manic states are not associated with dysfunction of the glucocorticoid regulatory pathway and there is no basis to believe that possibility. Thus, the treatment methods of the invention encompass the modem usage of the term psychosis, i.e., non-schizophrenia and non-manic state associated psychosis.
There has been historic confusion in the definition of psychosis. This is, in part, based on a lack of understanding of a common pathophysiologic mechanism causing psychosis in various conditions. For example, Oberlander, et al., WO 98/26785, teaches use of an anti-glucocorticoid to treat schizophrenia and manic states. However, schizophrenia and manic states are are believed to be the result of abnormal nerve structure, i.e., “hard-wiring” problems. In contrast, it is believed that the pathophysiology of psychosis (the term used in its modem sense, as used in the instant invention) is related to neurochemical (glucocorticoid regulatory) problems. This theory is extended by the instant invention, in which it was surprisingly discovered that agents which inhibit the binding of cortisol to its receptor can be used to treat psychosis.
Today it is known that psychotic patients can be distinguished from other psychiatric problems in that they have a glucocorticoid regulatory dysfunction. In contrast, patients with schizophrenia and manic states do not have glucocorticoid regulatory dysfunction (see, e.g., Rothschild (1982)
Br. J. Psychiatry
141:471-474; Clower (1986)
J. Clin. Psychopharmacol.
6:363-365). Thus, schizophrenia and manic states are not within the scope of the definition of “psychosis” (as defined either by the medical profession, or, as used herein), and thus are not treated by the methods of the invention.
In most species, including man, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which shows both circadian rhythm variation and elevations in response to stress and food. Cortisol levels are responsive within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and acts by binding to an intracellular, glucocorticoid receptor (GR). In man, glucocorticoid receptors are present in two forms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-beta isoform which differs in only the last fifteen amino acids. The two types of GR have high affinity for their specific ligands, and are considered to function through the same transduction pathways.
The biologic effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor antagonists. Several different classes of agents are able to block the physiologic effects of GR-agonist binding. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984)
J. Clin. Endocrinol. Metab.
59:25). Mifepristone binds to the GR with high affinity, with a K of dissociation ≦10
−9
M (Cadepond (1997)
Annu. Rev. Med.
48:129).
Patients with some forms of psychiatric illnesses have been found to have increased levels of cortisol (Krishnan (1992)
Prog. Neuro-Psychopharrnacol. & Biol. Psychiat.
16:913-920). For example, some patients with depressed mood have had their mood improve with treatments which lower the levels of cortisol. In some individuals, reversing increased cortisol levels using inhibitors of steroid biosynthesis can be effective in treating depression (Murphy (1991)
J. Steroid Biochem. Mol. Biol.
39:239; Murphy (1991)
J. Clin. Psychopharmcol.
11:121; Dhar (1989)
Clin. Invest. Med.
12:B27). Alternatively, some depressed individuals can be responsive to treatments which block the effect of cortisol, as by administering GR antagonists (Van Look (1995)
Human Reproduction Update
1:19-34). In one study, a patient with depression secondary to Cushing's Syndrome (hyperadrenocorticism) was responsive to a high dose, up to 1400 mg per day, of GR antagonist mifepristone (Nieman (1985)
J. Clin Endocrinol. Metab.
61:536). Another study which used mifepristone to treat Cushing's syndrome found that it improved the patients' conditions, including their psychiatric status (Chrousos, pp 273-284, In: Baulieu, ed. The Antiprogestin Steroid RU 486 and Human Fertility Control. Plenum Press, New York (1989), Sartor (1996)
Clin. Obstetrics and Gynecol.
39:506-510). Mifepristone has been used to treat major depression. Using from about 2.5 to 4.4 mg/kg per day for periods up to eight weeks, one group found that four patients with chronic severe depression, who were resistant to conventional therapies, responded to treatment (Murphy (1993)
J. Psychiatr. Neurosci.
18:209).
Psychosis has also been associated with Cushing's syndrome (Gerson (1985)
Can. J. Psychiatry
30:223-224; Saad (1984)
Am. J. Med.
76:759-766). Mifepristone has been used to treat acute psychiatric disturbances secondary to Cushing's syndrome. One study showed that a relatively high dose of mifepristone (400 to 800 mg per day) was useful in rapidly reversing acute psychosis in patients with severe Cushing Syndrome due to adrenal cancers and ectopic secretion of ACTH from lung cancer (Van der Lely (1991)
Ann. Intern. Med.
114:143; Van der Lely (1993)
Pharmacy World & Science
15:89-90; Sartor (1996) supra).
Psychotic major depression has long been recognized as a distinct psychiatric illness, having both psychotic and depressive components. In a differential diagnosis, it is important that psychotic major depression be distinguished from nonpsychotic major depression, because effective treatments and patterns of response to pharmacologic therapies for psychotic major depression are very different from those relating to non-psychotic major depression. Successful treatment depends on the accuracy of the initial diagnosis. (Glassman (1981)
Arch. Gen. Psychiatry
38:424-427, Schatzberg (1992)
Am. J. Psychiatr.
149:733-745, Schatzberg (1988)
Annals N.Y. Acad. of Sci.
537:462). Psychotic major depression is very common. It has been estimated that twenty five percent of depressed patients admitted to the hospital have psychotic major depression (Coryell (1984)
J. Nerv. Ment. Dis.
172:521).
Before this invention, there was to fast-acting effective treatment without significant side effects for the treatment of psychosis or the psychotic component of illnesses and conditions associated with psychosis, such as psychotic major depression. Individuals suffering from psychotic major depression have a low placebo response rate and respond poorly to antidepressant therapy alone, i.e., without concurrent treatment with antipsychotic medication (Glassman (1975)
Am. J. Psychiatry
132:716-719; Avery (1979)
Am. J. Psychiatry
135:559-562). While psychotic depression can respond to electroconvulsive therapy (ECT), this form of treatment is controversial, can have significant side effects, has a relatively slow response rate and has a high level of related morbidity. Similarly, another commonly used treatment for psychotic major depression, a combination therapy of currently available antipsychotic and antidepressant medications, has a slow onset of acti
Belanoff Joseph K.
Schatzberg Alan F.
Bozicevic, Field & Francis
Field Bret E.
Jarvis William R. A.
The Board of Trustees of the Leland Stanford Junior University
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