Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-29
2001-04-10
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S415000
Reexamination Certificate
active
06214855
ABSTRACT:
TECHNICAL FIELD
This invention relates to the use of N-heterocyclic glyoxylamide compounds for the treatment of stroke.
BACKGROUND ART
This invention is directed to reducing or preventing nerve cell death and subsequent neurological dysfunction normally occurring in a stroke.
Strokes are a major cause of death and disablement. Multiple mechanisms may cause stroke. Hemorrhagic stroke occurs when rupture of an artery in the brain causes a hemorrhage (viz., an aneurysm). Occlusive stroke occurs when a thrombosis or embolism restrict blood flow to part of the brain. For occlusive stroke the reduction of blood flow leads to death of brain tissue. Thrombosis occurs when a blood clot forms and blocks blood flow in an artery supplying blood to the brain. Embolism occurs when a moving clot settles in an artery supplying blood the brain, causing a stroke.
Many of those affected with strokes never recover full neurologic function or even a substantial measure of the neurologic function initially lost.
Conventional treatment consists of controlling blood pressure, administration, of blood thinners, and etc. None of the presently used techniques or therapeutic agents is without drawbacks. A great need remains to develop new methods of treating occlusive stroke by the use of improved therapeutic agents.
DISCLOSURE OF INVENTION
It is an object of this invention to provide a method of treatment of a mammal, including a human, currently afflicted with a stroke or previously afflicted with a stroke, said method comprising administering to said mammal a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
It is also an object of this invention to use an N-heterocyclic glyoxylamide compound for the manufacture of a medicament for treating stroke in a mammal, including a human, currently afflicted with a stroke or previously afflicted with a stroke.
It is also an object of this invention to provide a composition for treatment of a stroke in a mammal, including a human, currently afflicted with a stroke or previously afflicted with a stroke, said composition comprising administering to said mammal a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
It is also an object of this invention to provide a method of reducing the occurrence of neuronal damage and associated neurological dysfunction in a stroke in a human compared to that which normally occurs by administering a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
It is also an object of this invention to use N-heterocyclic glyoxylamide compounds to reduce neurological degeneration such as can be induced by a stroke and the associated functional impairment which can result in a human by administering a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
It is also an object of this invention to provide a composition of reducing the occurrence of neuronal damage and associated neurological dysfunction in a stroke in a human compared to that which normally occurs by administering a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
The term “stroke” is used herein to mean occlusive stroke, e.g., an ischemic event, resulting in the loss of oxygen supply to the brain caused by means inclusive of thrombosis or embolism.
The term, “subject” is used herein to mean mammals including humans.
BEST MODE FOR CARRYING OUT THE INVENTION
Treatment can be remedial or therapeutic as by administering an N-heterocyclic glyoxylamide compound following an ischemic event to mitigate the effects of that event. Treatment can also be prophylactic or prospective by administering a compound in anticipation that an ischemic event may occur, for example, in a patient who is prone to stroke.
Cells known to be destroyed during a stroke include hippocampal neurons, cortical neurons, caudate and putaminous neurons, cerebellar neurons and brain stem neurons. Since these hippocampal neurons are known to be the most sensitive to strokes, the therapeutically effective amount of N-heterocyclic glyoxylamide compound is preferably a hippocampal neuron protecting amount, i.e., an amount which reduces hippocampal neuron death compared that which would occur if the stroke were untreated.
(A) Procedure for Subjects During or Soon After a Stroke:
Treatment for a subject currently afflicted with a stroke using the method of the invention should occur within 6 hours of onset of the stroke, preferably within 4 hours, and most preferably as soon as stroke diagnosis occurs. In order to obtain a rapid response with minimum risk, the administration of the N-heterocyclic glyoxylamide compound, for example, 1H-indole-3-glyoxylamide compound or indolizine compound should preferably be via a parenteral route in a neuronal cell protecting amount (i.e., an amount which reduces neuronal cell death compared to that which would occur if the stroke were not treated).
In general, N-heterocyclic glyoxylamide compound will be administered to a mammal such as man so that an effective dose is received, for example an intravenous dose in the range of about 0.1 to about 10 mg/kg of body weight.
(B) Procedure for Subjects in Danger of a Stroke:
Treatment of a subject for prevention of a stroke, where the subject is determined to be at a high risk for a stroke, but who does not currently have a stroke, is to provide a level of N-heterocyclic glyoxylamide compound such that on the occurrence of cerebral ischemia, there will be sufficient N-heterocyclic glyoxylamide compound already present in the subject to protect neuronal cells (i.e., an amount which would reduce neuronal cell death compared to that which would occur if a stroke occurred and was untreated). Administration of N-heterocyclic glyoxylamide compound is preferably carried out orally on a daily basis.
Since the occurrence of ischemia could come at any time, therapeutically sufficient plasma levels of N-heterocyclic glyoxylamide compound should be present. In general, the plasma level of N-heterocyclic glyoxylamide compound is a non-toxic concentration in the range of from about 0.01 micromolar to 1000 micromolar. The amount administered to obtain such plasma level depends on the method of administration and the half-life of the N-heterocyclic glyoxylamide compound. Preferably, administration is on a daily basis so that the dose of N-heterocyclic glyoxylamide compound can be minimized.
General Aspects of the Method:
It will be apparent to those skilled in the art that a compound of the present invention can be co-administered with other therapeutic or prophylactic agents and/or medicaments that are not medically incompatible therewith.
The regimen for treatment may stretch over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to three oral doses per day, each from about 0.01 to about 50 mg/kg of body weight are used with preferred doses being from about 0.04 to about 5.0 mg/kg.
The specific dose of N-heterocyclic glyoxylamide compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the size and age of the patient, the severity of the stroke, and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
Method of Administration.
This can be by any method such as parenteral or oral dosing wherein the N-heterocyclic glyoxylamide compound crosses the blood brain barrier in sufficient amount to protect neuronal cells from death. The N-heterocyclic glyoxylamide compounds are most often used in the method of the invention in the form of pharmaceutical formulation, as described infra. Other forms of administration may be used in both human and veterinary contexts. Such alternative forms include the use of suppositories, transdermal patches, and com
Gemba Takefumi
Hori Yozo
Foley & Lardner
Henley III Raymond
Shionogi & Co. Ltd.
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