Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-02-04
2002-04-09
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S169000
Reexamination Certificate
active
06369046
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 treating dementia.
BACKGROUND OF THE INVENTION
Dementia is loss of one's ability to think and remember. This condition afflicts many thousands of individuals, especially the elderly, and is becoming more common as our population ages. Typically, this loss of cognitive skills and memory is slow and progressive, taking many months or years. To date, there are no effective treatments which can stop, slow or reverse this process.
What causes dementia is controversial, resulting in many different and contrasting proposed theories of causation and methods of treatment. While dementia is commonly associated with Alzheimer's disease and multi-infarct, or vascular, dementia, it is also seen with a variety of other conditions. One generally agreed upon theory proposes that the death or injury of brain neurons, especially those in the hippocampus, leads to dementia. Dementia has also been associated with increased levels of cortisol. There is conflicting evidence as to whether this hypercortisolemia causes the brain damage or is the result of it. For example, not all conditions characterized by hypercortisolemia, such as Cushing's syndrome, are associated with dementia. One group proposed that brain damage may hyperactivate the cortisol regulatory system, resulting in hypercortisolemia. They suggested that elevated cortisol might be a biological marker of dementia and may have a value in diagnosis of dementia. They also suggested that this activation relates generally to cognitive decline itself, not to an etiology of dementia (Maeda (1991)
Neurobiol Aging
12:161-163). Another theory proposes that increased levels of cortisol is 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 (Sapolsky (1994)
Ann. NY Acad. Sci.
746:294-304); Silva (1997)
Annu. Rev. Genet.
31:527-546). Hippocampal atrophy has been proposed to be a predictor of future Alzheimer's disease (de Leon (1997)
Int. Psychogeriatr.
9 Suppl 1:183-190).
Yet another theory is exactly opposite our invention's. We propose that inhibition of cortisol activity (using receptor antagonists) will prevent dementia-inducing brain damage. In direct contrast, the alternative theory proposes that brain damage leading to dementia is caused by inflammation, such as that seen in autoimmunity. On this basis, it proposes that Alzheimer's disease is an autoimmune reaction directed against pathological brain tissue (e.g., senile plaques containing dystrophic neurites, Tau protein and condensed beta amyloid deposits; Gasiorowski (1997)
Med. Hypotheses
49:319-326; Hull (1996)
Neurobiol. Aging.
17:795-800). Thus, on the premise that it is a neurodegenerative disease mediated by inflammation, Alzheimer's disease is being treated by immunosuppression with synthetic cortisols. Ongoing clinical studies are using prednisone, a synthetic cortisol (agonist) (Aisen (1998)
Drugs Aging
12:1-6; Aisen (1997)
Gerontology
43:143-149; Aisen (1996)
Mol. Chem. Neuropathol.
28:83-88). Other anti-inflammatory drugs (e.g., hydroxychloroquine and colchicine) are also undergoing clinical trials as treatments for Alzheimer's disease (Aisen (1998) supra).
To add to the confusion in the field, several additional theories and methods of treating dementia and Alzheimer's disease are being pursued. One believes that dementia is caused by death of cells which produce a memory-inducing neurotransmitter (forebrain cholinergic neurons). Thus, Alzheimer's disease is also being treated using cholinergic agonists in an effort to improve memory (Asthana (1996)
Clin. Pharmacol Ther.
60:76-282). Another group proposes using estrogen to promote the growth of the memory-inducing neurons. Yet another theory to treat dementia proposes using Vitamin E (alpha-tocopherol), as it slows nerve cell death. Nerve growth factors have been proposed for the same reason. Calcium blockers (e.g., nimodipine) have also been evaluated as a treatment for Alzheimer's disease on the basis that blocking the increase in intracellular free calcium may retard the process of neuronal death and slow the progression of the disease (Brodaty (1997)
Med. J. Aust.
167:447-449).
Thus, it is clear that to date there is no consensus as to the etiology or treatment of dementia. Before this invention, there was no effective treatment to treat dementia or to diminish the rate of cognitive decline in diseases such as Alzheimer's disease or multi-infarct dementia. Thus, there exists a great need for an effective and safe treatment for dementia, especially one that can decrease the rate and severity of the cognitive decline. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
The invention provides a method of treating dementia in an individual diagnosed as having symptoms of dementia by administration of an amount of a glucocorticoid receptor antagonist effective to treat the dementia. In one embodiment, the glucocorticoid receptor antagonist is administered when the individual scores less than 30 on the Folstein Mini Mental Status Exam. In another embodiment, the glucocorticoid receptor antagonist is administered when the individual is diagnosed with early in the course of Alzheimer's disease, as indicated by a score of between about 21 and 29 on the Folstein Mini Mental Status Exam. The dementia can be associated with a condition selected from the group consisting of Alzheimer's disease and multi-infarct dementia. The dementia can be associated with Alzheimer's disease wherein the dementia is accompanied by absence of the apolipoprotein E4 allele or lack of expression of apolipoprotein E4.
In one embodiment, the invention's method of treating dementia 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 mg per kilogram of body weight per day; or between about 1 to about 4 mg per kilogram of body weight per day. The administration can be once per day. In alternative embodiments, the mode of glucocorticoid receptor antagonist administration is oral, or by a transdermal application, by a nebulized suspension, or by an aerosol spray.
The invention also provides a kit for the treatment of dementia in a human, the kit comprising a glucocorticoid receptor antagonist; and, an instructional material teaching the indications, dosage and schedule of administration of the glucocorticoid receptor antagonist. In alternative embodiments, the instructional material indicates that the glucocorticoid receptor antagonist can be administered in a daily amount of about 0.5 to about 20 mg per kilogram of body weight per day, of about 1 to about 10 mg per kilogram of body weight per day, or about 1 to about 4 mg per kilogram of body weight per day. The instructional material can indicate that corticol contributes to the rate of cognitive decline in patients with dementia, and that the glucocorticoid receptor antagonist can be used to treat dementia. The kit's instructional material can further indicate that the glucocorticoid receptor antagonist can be used for the treatment of early in the course of Alzheimer's disease in patients who do not have the apolipoprotein
Belanoff Joseph K.
Schatzberg Alan F.
Bozicevic Field & Francis LLP
Criares Theodore J.
Field Bret E.
The Board of Trustees of the Leland Stanford Junior University
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