Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-03
2003-10-21
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S617000, C514S652000, C514S655000
Reexamination Certificate
active
06635667
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods of treatment using MAO-A or MAO-B inhibitors such as L-deprenyl.
L-Deprenyl, also known as selegiline or Eldepryl, is a selective inhibitor of mitochondrial monoamine oxidase type B (MAO-B). It belongs to a class of enzyme-activated irreversible inhibitors also described as “suicide” inhibitors, because the compound acts as a substrate for monoamine oxidase, the action of which on the compound results in irreversible inhibition. L-Deprenyl forms a monovalent complex with monoamine oxidase as an initial, reversible step. Subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavine-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. The oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner.
L-Deprenyl has been used clinically as an MAO-B inhibitor in combination with levo-dopa (L-dopa) to treat Parkinson's disease. L-Dopa treatment alone is optimally effective only for the first few years of therapy. The anti-Parkinson's disease action of L-deprenyl was based on the theory that MAO-B was the predominant form of MAO in the brain and that brain MAO rather than peripheral enzyme activity was to be selectively inactivated. Use of L-deprenyl in conjunction with L-dopa therapy enhances dopaminergic transmission. This permits a lowering of the dosage of L-dopa, which prolongs the effect of L-dopa and decreases adverse side effects of L-dopa.
L-Deprenyl has been reported to enhance catecholaminergic activity and diminish serotoninergic activity in the brain, by mechanisms unrelated to MAO-B inhibition. In rats it has been shown to reduce brain damage after exposure to transient hypoxia-ischemia, the proposed mechanism being either a prevention of the rise of H
2
O
2
or an increase in enzymatic radical scavenging capacity, particularly by facilitating superoxide dismutase activity. Indeed, some of these additional mechanisms may contribute to L-deprenyl's mode of action in Parkinson's disease.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method of increasing nitric oxide production.
It is a further object of the present invention to provide a method of treating diseases of brain and blood vessels related to a deficiency in nitric oxide production.
It is yet another object of the present invention to provide a method of protecting the vascular endothelium.
It is a further object of the present invention to provide a method of relaxing non-vascular smooth muscle.
It is another object of the present invention to provide a method of treating neuronal disorders.
It is a further object of the present invention to provide a method of treating cellular disorders of platelets, RBC, WBC, mast cells, macrophages, and glial cells.
These and other objects of the invention are provided by a method of treating a disorder of the vasculature, comprising administering to a subject suffering from such a disorder an effective amount of an MAO-A or MAO-B inhibitor. The disorder of the vasculature may be a disorder of the cerebral or peripheral vasculature. Specific vasculature disorders which can be treated include essential, renovascular, pulmonary, and ocular hypertension, myocardial infarction, and cerebrovascular stroke.
The disorder of the vasculature may be associated with a deficiency in NO production, with the MAO-A or MAO-B inhibitor exerting an endothelium-dependent effect on the vasculature. Alternatively, the disorder may be a disorder of the vasculature associated with a toxic effect of &bgr;-amyloid on the vasculature, in which case the MAO-A or MAO-B inhibitor protects the endothelium of the vasculature from P-amyloid. The disorder also may be one not associated with a deficiency in NO production, in which case the MAO-A or MAO-B inhibitor exerts an endothelium-independent effect on the vasculature.
The present invention also provides a method of treating a neuronal disorder other than Parkinson's Disease or Alzheimer's Disease, comprising administering to a subject suffering from such a disorder an effective amount of an MAO-A or MAO-B inhibitor. The disorder may be associated with a deficiency in NO production, in which case the MAO-A or MAO-B inhibitor stimulates production of NO. Alternatively, the neuronal disorder may be caused by a toxic effect of &bgr;-amyloid on neurons.
Also provided according to the invention is a method of treating a disorder of the non-vascular smooth muscle, comprising administering to a subject suffering from such a disorder an effective amount of an MAO-A or MAO-B inhibitor. Disorders of the non-vascular smooth muscle that can be treated include airway obstruction or another respiratory disorder and a gastrointestinal motility disorder.
The present invention also provides a method of treating a cellular disorder of platelets, RBC, WBC, mast cells, macrophages, or glial cells, comprising administering to a subject suffering from such a disorder an effective amount of an MAO-A or MAO-B inhibitor. In a preferred embodiment, the MAO-A or MAO-B inhibitor acts as an anti-platelet agent or an anti-inflammatory agent.
In preferred embodiments, the MAO-A or MAO-B inhibitor is selected from the group consisting of L-deprenyl, clorgyline, pargyline, N-(2-aminoethyl)-4-chlorobenzamide hydrochloride, N-(2-aminoethyl)-5(3-fluorophenyl)-4-thiazolecarboxamide hydrochloride, and derivatives thereof. A dose of 1-100 mg/day, preferably 1-10 mg/day, of the MAO-A or MAO-B inhibitor is used in accordance with the present invention.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DESCRIPTION OF PREFERRED EMBODIMENTS
It has been discovered, surprisingly, that MAO-A or MAO-B inhibitors such as L-deprenyl display many modes of action which are totally unrelated to their mode of action as selective inhibitors of MAO-A and/or MAO-B. For example, it has been found that MAO-A or MAO-B inhibitors such as L-deprenyl exert effects on both cerebral and peripheral vasculature, some of which are mediated by nitric oxide (NO) and others of which are NO-independent. More particularly, MAO-A or MAO-B inhibitors such as L-deprenyl have been found to stimulate NO production rapidly and stereospecifically when administered in vitro or in vivo to peripheral or cerebral blood vessels. They also have been found to blunt the vasoconstriction caused by a number of vasoconstrictors.
For example, L-deprenyl at low doses (≦10 &mgr;M) causes a rapid NO-mediated endothelium-dependent vasodilation. At higher doses L-deprenyl produces a slow progressive NO—and endothelium-independent direct relaxation of vascular smooth muscle. The NO-mediated, endothelial-dependent effects of L-deprenyl and other MAO-A or MAO-B inhibitors on the cerebral and peripheral vasculature makes them useful in treating a variety of disorders, including essential, renovascular and pulmonary hypertension, glaucoma (by reduction of intraocular pressure), macular degeneration, and erectile impotence all of which result from a significant reduction of endothelium-dependent relaxation. The NO-mediated, endothelial-dependent effects also are useful in preserving organs for transplantation. The blood-brain barrier is composed of endothelial cells, and by protecting the endothelium L-deprenyl and other MAO-A or MAO-B inhibitors protect the integrity of the blood-brain barrier. They also are useful in cases of myocardial infarction and cerebrovascular stroke which result from an alteration of endothelial function. The endothelium-independent direct relaxation of vascular smooth muscle by MAO-A or MAO-B inhibitors such
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