Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-01-27
2003-01-07
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06503947
ABSTRACT:
INTRODUCTION
Stroke is the third most common cause of death in the United States. Intravenous injection of the serine protease tissue plasminogen activator (tPA) has been approved by the U.S. Food and Drug Administration as the first agent that combats focal cerebral infarction or stroke. Studies have shown that tPA administered as a thrombolytic agent within 3 hours of the insult can dissolve the blood clot(s) responsible for initiating cerebral damage (rt-PA Stroke Study Group, N.Engl. J. Med. 333, 1581-1587 (1995) and Hacke et aL JAMA 274, 1017-1025 (1995)). However, the use of tPA in acute ischemic stroke is reported to carry substantial risk of intracerebral hemorrhage.
SUMMARY
The present invention is based, at least in part, on the discovery that complement activation and free radical formation contribute to cytotoxic damage associated with stroke and other neurological disorders. In addition, it was found that fibrinolytic agents such as tPA, which can be used as a thrombolytic agent, contribute to cytotoxic damage associated with stroke and other neurological disorders. Accordingly, in one aspect, the invention features a method of treating cytotoxic damage associated with non-thrombotic conditions in a subject. The method includes administering to the subject a substance which is complement inhibitor, a free radical scavenger, or both, to thereby ameliorate cytotoxic damage associated with non-thrombotic conditions in the subject. In a preferred embodiment the subject is a mammal, e.g., a human.
In a preferred embodiment, the non-thrombotic condition is a neurodegenerative disease, e.g., Huntington's disease, AIDS dementia complex, neuropathic pain syndromes, Olivopontocerebellar atrophy, Parkinsonism, amyotrophic lateral sclerosis, mitochondrial abnormalities, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperhomocysteinemia, hyperprolinemia, nonketotic hyperglicinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Alzheimer's disease, hepatic encephalopathy, and Tourette's syndrome. In another preferred embodiment, the non-thrombotic condition is an acute neurologic disorder, e.g., hypoglycemia, hypoxia, anoxia, poisoning by carbon monoxide, poisoning by manganese, poisoning by cyanide, mechanical trauma to the brain, mechanical trauma to the spinal cord, and epilepsy. In another preferred embodiment, the subject is suffering from: a convulsive disorder; neuropathic pain; glaucoma. In another preferred embodiment, a non-thrombotic condition includes a drug related condition, e.g., a condition associated with drug addiction, drug dependence, drug withdrawal, or drug tolerance.
In a preferred embodiment, the invention comprises identifying an individual at risk for cytotoxic damage associated with a non-thrombotic condition. In a preferred embodiment, the individual is at risk for cytotoxic damage associated with: a neurodegenerative disease; an acute neurologic disorder; a drug related condition; a convulsive disorder; neuropathic pain; glaucoma.
In a preferred embodiment, the substance is a complement inhibitor such as a soluble complement re mptor type 1 protein. In another preferred embodiment, the substance is a complement inhibitor, a free radical scavenger, or both, which can cross the blood-brain barrier, e.g., the substance is a hydroxamic acid derivative, e.g., salicylhydroxamic acid (SHA) or acetohydroxamic acid (AHA); a substituted amide; a substituted hydroxylamine; an aldoxime, e.g., salicylaldoxime; a hydroxyphenyl compound, e.g., catechin or a derivative thereof or hydrocaffic acid or a derivative thereof; a terpene; oleanolic acid; or an ephedra. In a preferred embodiment, the substance is a complement inhibitor, a free radical scavenger, or both, which has a molecular weight of 600 or less.
In a preferred embodiment, the substance is a complement inhibitor, a free radical scavenger, or both which is administered in a pharmaceutically acceptable formulation. In a preferred embodiment, the substance which is a complement inhibitor, a free radical scavenger or both is administered intraperitoneally, orally, intravascularly, subcutaneously, intradermally, intramuscularly, intranasally, intracerebralventricularly (ICV), or intratracheally.
In a preferred embodiment, the substance which is a complement inhibitor, a free radical scavenger, or both is administered at a level of approximately 40-4,000 mg/Kg, 200-2000 mg/Kg or 400-1,000 mg/Kg.
In a preferred embodiment, the cytotoxic damage is mediated through glutamate receptors.
In another aspect, the invention features a method of treating cytotoxic damage in a subject. The method includes administering to the subject a substance which is a complement inhibitor, a free radical scavenger, or both, wherein the substance is able to cross the blood-brain barrier and thereby treat cytotoxic damage in the subject, e.g., a mammal, e.g., a human. In a preferred embodiment, the method further includes administering a thrombolytic agent to the subject. In a preferred embodiment, the thrombolytic agent is a fibrinolytic agent, e.g. a plasminogen activator (e.g., a tissue plaminogen activator (t-PA) or Desmodus salivary plasminogen activator (dsPA)), a streptokinase, and/or a urokinase. The thrombolytic agents can be produced recombinantly.
In a preferred embodiment, the subject includes a subject suffering from stroke, ischemia, e.g., cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxia ischemia. In a preferred embodiment, the invention comprises identifying an individual at risk for a cytotoxic damage associated with stroke. In the preferred embodiment, the individual is at risk of developing cytotoxic damage associated with one or more of the following: stroke, ischemia, e.g., cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxia ischemia.
In a preferred embodiment, the subject suffers from a neurodegenerative disease, e.g., Huntington's disease, AIDS dementia complex, neuropathic pain syndromes, Olivopontocerebellar atrophy, Parkinsonism, amyotrophic lateral sclerosis, mitochondrial abnormalities, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperhomocysteinemia, hyperprolinemia, nonketotic hyperglicinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Alzheimer's disease, hepatic encephalopathy, and Tourette's syndrome. In another preferred embodiment, the subject is suffering from an acute neurologic disorder, e.g., hypoglycemia, hypoxia, anoxia, poisoning by carbon monoxide, poisoning by manganese, poisoning by cyanide, mechanical trauma to the brain, mechanical trauma to the spinal cord, and epilepsy. In another preferred embodiment, the subject is suffering from: a convulsive disorder; neuropathic pain; glaucoma; or a drug related condition, e.g., a condition associated with drug addiction, drug dependence, drug withdrawal, and drug tolerance.
In the preferred embodiment, the individual is at risk of developing cytotoxic damage associated with: a neurodegenerative disorder; an acute neurologic disorder; a convulsive disorder; a drug-related condition; neuropathic pain; glaucoma.
In a preferred embodiment, the substance is a complement inhibitor, e.g., a soluble complement receptor type 1 protein. In another preferred embodiment, the substance is a complement inhibitor, a free radical scavenger, or both, which can cross the blood-brain barrier, e.g., the complement inhibitor, free radical scavenger, or both is a hydroxamic acid derivative, e.g., salicylhydroxamic acid (SHA) or acetohydroxamic acid (AHA); a substituted amide; a substituted hydroxylamine; an aldoxime, e.g., salicylaldoxime; a hydroxyphenyl compound, e.g., catechin or a derivative thereof, or hydrocaffic acid or a derivative thereof; a terpene; oleanolic acid; or an ephedra. In a preferred embodiment, the substance is a complement i
Kaul Marcus
Le Dean
Lipton Stuart A.
Stamler Jonathan S.
Brigham and Women's Hospital
Fish & Richardson P.C.
Spivack Phyllis G.
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