Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-11-20
2003-09-16
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06620802
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 the glucocorticoid receptor can be used in methods of treating mild cognitive impairment (MCI).
INTRODUCTION
MCI is an impairment in cognition, specifically memory performance, that is frequently associated with aging. The degree and type of impairment distinguishes MCI from dementia in that MCI patients exhibit deficits in secondary tests of memory, but perform normally on standard tests measuring other cognitive domains. Thus, MCI is defined as a clinical disorder that is distinct from early stages of dementia, particularly Alzheimer's type dementia, and can therefore be specifically targeted for treatment intervention.
The underlying causes of memory loss in MCI have not been determined, thus a strategy for treatment has not been easily identified. Although some investigators believe that most MCI patients have neuropathology that is characteristic of Alzheimer's disease, many patients diagnosed with MCI typically do not progress to Alzheimer's Disease, thereby suggesting that MCI has an underlying pathophysiology that is divergent from that of Alzheimer's despite other characteristics that may be shared.
A number of treatments for Alzheimer's disease have been proposed, but there is no consensus regarding the etiology of the disease and it is not clear which, if any, of these treatments would also be effective for MCI. Proposed treatments include the use of various agents such as cholinergic agonists (Asthana et al.,
Clin. Pharmacol. Ther.
60:76-282, 1996), estrogen, Vitamin E (&agr;-tocopherol), nerve growth factors, or calcium blockers to improve memory or slow the rate of neuronal degeneration and death. Alternatively, Alzheimer's disease has been hypothesized to be an inflammatory disease similar to an autoimmune disease and the administration of anti-inflammatory agents has been proposed as a therapy. Ongoing clinical studies based on this hypothesis include those using prednisone, a synthetic cortisol agonist (see, e.g., Aisen,
Drugs Aging
12:1-6, 1998; Aisen,
Gerontology
43:143-149, 1997; and Aisen,
Mol. Chem. Neuropathol.
28:83-88, 1996). In apparent contrast to the latter theory, it has also been observed that patients with dementia can exhibit markedly increased levels of the physiological glucocorticoid cortisol (hydrocortisone) (see, e.g., Davis et al,
Am. J. Psych.
143:3, 1986; Maeda et al.,
Neurobiol Aging
12:161-163, 1991). Moreover, it has been suggested that increased glucocorticoid levels may play a role in pathogenesis.
Cortisol, which is secreted in response to ACTH (corticotropin), shows circadian rhythm variation, and further, is an important element in responsiveness to many physical and psychological stresses. It has been proposed that, with age, the cortisol regulatory system becomes hyperactivated in some individuals, resulting in hypercortisolemia. It has additionally been postulated that high levels of cortisol are neurotoxic, particularly in the hippocampus, a brain structure that is thought to be central to the processing and temporary storage of complex information and memory (see, e.g., Sapolsky et al.,
Ann. NY Acad. Sci.
746:294-304, 1994; Silva, Annu. Rev. Genet. 31:527-546, 1997; de Leon et al.,
J. Clin. Endocrinol & Metab.
82:3251, 1997; Maeda et al., supra).
Studies of human subjects who have received treatment with exogenous glucocorticoids at therapeutic levels have suggested that glucocorticoids may play a role in short-term, reversible memory impairment. (see, e.g., Wolkowitz et al.,
Am J. Psychiatry
147:1297-1303, 1990; Keenan et al.,
Neurology
47:1396-1402, 1996; Newcomer et al.,
Arch Gen. Psychiatry
56:527-533, 1999). Furthermore, it has been suggested that basal levels of cortisol that are chronically at the high end of the normal range, i.e., levels that correspond to peak circadian values or approximate those levels seen during stress, contribute to the impaired cognitive performance and loss of hippocampal-mediated memory function observed in aging (see, e.g., Lupien et al.,
J. Neurosci.
14:2893-2903, 1994; Lupien et al.,
Nat. Neurosci
1:69-73, 1998).
There has been no evidence prior to this invention, however, that a glucocorticoid receptor antagonist can be an effective treatment for memory impairment in a mature population, especially in patients having cortisol levels that fall within a normal range. Many of the actions of cortisol are mediated by binding to the type I mineral-corticoid receptor, which is preferentially occupied, relative to the type II glucocorticoid receptor, at physiological cortisol levels. As cortisol levels increase, more glucocorticoid receptors are occupied and activated. Thus, those mature individuals who have experienced an aging-associated increase in basal cortisol levels can have a level of glucocorticoid activity that, with time, directly or indirectly results in impaired memory function. Inhibition of glucocorticoid receptor activity is therefore desirable in those individuals. Because cortisol plays an essential role in metabolism, inhibition of all cortisol-mediated activities, however, would be fatal. Therefore, antagonists that specifically prevent type II glucocorticoid receptor functions, but do not antagonize type I mineralcorticoid receptor functions are of particular use in this invention. RU486 and similar antagonists are examples of this category of receptor antagonists.
RU486 has been noted as being effective at abrogating some of the age-associated electrophysiological changes in the rat hippocampus (Talmi et al.,
Neurobiol. of Aging
17:9-14, 1996) and also as providing protection against oxidative stress-induced neuronal cell death in the mouse hippocampus (Behl et al.,
European J. of Neuorsci.
9:912-920, 1997). There have been no studies, however, that have shown that RU486 can improve memory function.
The present inventors have determined that glucocorticoid receptor antagonists such as RU486 are effective agents for the specific treatment of age-associated memory impairment that is not affiliated with dementia in mature patients with normal cortisol levels. The present invention therefore fulfills the need for an effective treatment for MCI by providing methods of administering glucocorticoid receptor antagonists to improve memory function in patients diagnosed with MCI.
SUMMARY OF THE INVENTION
The invention provides a method of treating a patient diagnosed with mild cognitive impairment (MCI) who is 45 years or older and has normal cortisol levels. The method comprises administration of a therapeutically effective amount of a glucocorticoid receptor antagonist to the patient, wherein the patient: (i) obtains at least one perfect score on the folstein Mini Mental status Exam in three administrations of the Exam; (ii) has a clinical dementia rating (CDR) of 0.5; and (iii) scores below, preferably by 1.5 or more standard devations, the age- and education-adjusted cutoff on a memory task test, typically, the logical memory II subscale (Delayed Paragraph Recall) of a paragraph test. The amount of glucocorticoid receptor antagonist administered will preferably improve performance on such a memory task test.
In one embodiment of the invention, the method of treating MCI uses a glucocorticoid receptor antagonist comprising a steroidal skeleton with at least one phenyl-containing moiety in the 11-beta position of the steroidal skeleton. The phenyl-containing moiety in the 11-beta position of the steroidal skeleton can be a dimethylaminophenyl moiety. In alternative embodiments, the glucocorticoid receptor antagonist comprises mifepristone, or, the glucocorticoid receptor antagonist is selected from the group consisting of RU009 and RU044.
In other embodiments, the glucocorticoid receptor antagonist is administered in a daily amount of between about 0.5 to about 20 mg per kilogram of body weight per day; between about 1 to about 10
Belanoff Joseph K.
Schatzberg Alan F.
Corcept Therapeutics, Inc.
Hui San Ming
Padmanabhan Sreeni
Townsend and Townsend / and Crew LLP
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