Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1999-06-03
2002-08-20
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06437003
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[Not Applicable ]
BACKGROUND OF THE INVENTION
Calcium channel blockers are a relatively recently discovered class of compounds which possess a wide spectrum of properties useful in the treatment of cardiovascular, cerebrovascular, intraocular, and other disorders. Calcium channel blockers were initially identified as a method for the control of hypertension (Fleckenstein et al. (1967)
Z. Kreislaufforsch
, 56: 716), and are routinely used in the control of hypertension and other disorders. In particular, calcium blockers have shown some useful therapeutic properties in the treatment of classic exertional angina, vasospastic angina, angina pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies. In addition, calcium channel blockers have shown therapeutic properties in the treatment of various cerebrovascular disorders, including but not limited to migraine headaches, and convulsive epilepsy.
Several structural classes of compounds are known which exhibit calcium channel blocking utility and have been used as therapeutics in a variety of contexts. The three major classes include dihydropynidines (e.g., nifedipine, felodipine, isradipine, and amlodipine), the benzothiazepines (e.g., diltiazem), and the phenylalkylamines (e.g., verapamil). Three calcium channel blockers are currently of primary clinical significance in the United States, verapamil, nifedipine and diltiazem. All three achieve their antihypertensive effect by inhibiting the entry of calcium ions into vascular smooth muscle. The ultimate effect is vasodilation. These calcium blockers are, however, contraindicated in various circumstances (e.g., where there is impaired left ventricular function). Thus, there is a need for other calcium blocking agents.
SUMMARY OF THE INVENTION
The present identifies previously unknown calcium channel blocking properties of retinoids, in particular retinol, and provides methods of treating pathological conditions characterized by and ameliorated by inhibition of cellular calcium influx using retinoids. Retinoids (e.g., vitamin A and analogues) are lipid-soluble and can therefore achieve extensive distribution within body tissues. They are also rapidly absorbed after oral or intravenous administration and, because of their affinity for fatty tissues, provide a reservoir that maintains elevated retinoid levels for some time after administration. In addition, the physiological tolerance for many retinoids (e.g., vitamin A) has been repeatedly demonstrated and well characterized.
Thus, in one embodiment, this invention provides a method of treating a disease in a mammal where the said disease is characterized by a symptom ameliorated by inhibition of cellular calcium influx. The method typically involves administering to the mammal an effective amount of a retinoid and a pharmacologically acceptable excipient. It will be appreciated that while a major application of the method involves treatment of humans, the methods are not so limited and treatment of virtually any mammal is contemplated. In a particularly preferred embodiment, the mammal is selected from the group of mammals having a disease characterized by one or more symptoms responsive to (ameliorated by) inhibition of calcium influx into a cell.
It is primarily contemplated that the methods will be practiced for the primary purpose of treatment of a condition one or more symptoms of which are responsive to calcium channel blockage. The methods do not contemplate administration of a retinoid for the purpose of diet supplementation. Thus, the retinoid is not a dietary supplement. The methods may thus additionally involve the step of assaying for retinoid-mediated amelioration of a symptom of a disease state. Typically the symptom will be one expected to be responsive to a calcium channel blocker. Similarly, the methods may additionally involve identifying a subject mammal (e.g., a patient) having a disease state expected to prove responsive to a calcium channel blocker.
The methods can be used to treat a wide variety of diseases including, but not limited to essential hypertension, hypertension associated with end stage renal failure, hypertension associated with pregnancy (preeclampsia), salt sensitivity hypertension, type II diabetes hypertension, hypertension associated with alcohol abuse, obesity associated hypertension, systolic hypertension in elderly, asthma, allergies, migraine headache, gastrointestinal motility disorders, Alzheimer's disease, senile dementia, angina pectoris, premature labor, cerebrovascular diseases, and convulsive epilepsy. The methods, however, are particularly well suited for treatment of essential hypertension and intra-ocular hypertension.
Any of a variety of retinoids are suitable. Particularly preferred retinoids include retinoic acid and retinol, with retinol being most preferred. The pharmacologically acceptable excipient is preferably lipid compatible. A most preferred retinoid inhibits cellular influx of calcium through inhibition of voltage gated channels in particular L-type voltage-gated calcium channels.
In another embodiment, this invention provides a method of treating a disorder which is responsive to the partial or complete blockade of calcium channels of the central nervous system of a living mammal. Again the method involves administering to such a living mammal in need thereof, a therapeutically effective amount of a retinoid as described herein. The disorder can include stroke, anoxia, ischemia, migraine or epilepsy, psychosis, Parkinsonism, depression, or any other convulsive disorder. In still another embodiment, the method involves treating the degenerative changes, connected with stroke, anoxia, ischemia, migraine, Parkinsonism, epilepsy or any other convulsive disorder, responsive to the partial or complete blockade of calcium channels of the central nervous system of a living animal body, by administering to a living animal body in need thereof a therapeutically-effective amount of a retinoid as described herein.
In still another embodiment, this invention provides methods of inhibiting calcium influx into a mammalian cell. The methods involve contacting the cell with a retinoid. The retinoid is present in an amount sufficient to inhibit, partially or fully, a calcium channel, more preferably a L-type voltage-gated calcium channel. Virtually any retinoid is suitable, however in a preferred embodiment, the retinoid is retinol or retinoic acid, more preferably retinol. The cell can be virtually any mammalian cell, however preferred cells include muscle cells, more preferably smooth muscle cells, most preferably vascular muscle cells, or cells of the nervous system, more preferably cells of the central nervous system. The cell can be in vivo or in vitro.
In yet another embodiment this invention provides kits for the treatment of a disease in a mammal where the disease is characterized by a symptom ameliorated by inhibition of cellular calcium influx. The kits typically comprising a container containing a retinoid in a pharmaceutically acceptable excipient and instructional materials teaching the use of a retinoid to inhibit calcium influx in the treatment of a disease characterized by a symptom ameliorated by inhibition of cellular calcium influx. The disease includes, but is not limited to any essential hypertension, hypertension associated with end stage renal failure, hypertension associated with pregnancy (preeclampsia), salt sensitivity hypertension, type II diabetes hypertension, hypertension associated with alcohol abuse, obesity associated hypertension, systolic hypertension in elderly, asthma, allergies, migraine headache, gastrointestinal motility disorders, Alzheimer's disease, senile dementia, angina pectoris, premature labor, cerebrovascular diseases, and convulsive epilepsy. Any of the retinoids described herein is suitable and a preferred retinoid is retinol.
DEFIN
McCarron David A
Roullet Jean-Baptiste
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