Treatment and prevention of stroke and other neurological disorders

Abstract

Using high-throughput screening, in an oxygen-glucose deprivation (OGD) model, isoxsuprine hydrochloride was identified as a potent neuroprotective compound. In an animal middle artery occlusion (MCAO) model of transient focal ischemia, isoxsuprine significantly reduced infarct volume compared to vehicle. The invention, therefore, provides methods of treatment and pharmaceutical compositions that are useful in the treatment and prevention of a wide-variety of ischemia-related injuries, including stroke.

1 .- 18 . (canceled) 
     
     
         19 . A method of treating or preventing a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition selected from the group consisting of isoxsuprine, chlorphenesin and the pharmaceutically acceptable salts, analogs and derivatives thereof, wherein the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Parkinsonism, Huntington's disease, Binswanger's disease, vascular cognitive impairment, vascular dementia, amyotrophic lateral sclerosis or multiple sclerosis, glaucoma, light-induced retinal degeneration or macular degeneration, retinitis pigmentosa, HIV-associated dementia (acquired immunodeficiency syndrome dementia complex) and HIV-associated neuropathy, encephalitis, causalgia or peripheral neuropathies, olivopontocerebellar atrophy, mitochondrial abnormalities, MELAS syndrome, MERRF, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperhomocysteinemia, hyperprolinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, hepatic encephalopathy, Tourette's syndrome, drug addiction and drug dependency, drug withdrawal, depression and anxiety syndromes. 
     
     
         20 . A method of protecting neuronal cells from ischemia- or hypoxia-induced cell death comprising administering to a subject in need thereof a therapeutically effective amount of at least composition selected from the group consisting of isoxsuprine, chlorphenesin and the pharmaceutically acceptable salts, analogs and derivatives thereof. 
     
     
         21 . The method of  claim 21 , wherein the subject is at risk of suffering, or is suffering from, or has suffered an ischemic or hemorrhagic stoke, a transient ischemic attack (TIA), head trauma, a brain hemorrhage, cardiac arrest, cerebral edema, hydrocephalus, asphyxia, thrombosis, embolism, thromboembolism, atherosclerosis, prolonged severe hypotension, intrauterine hypoxia, birth hypoxia, cardiac surgery complications or neurosurgery complications. 
     
     
         22 . The method of  claim 21 , wherein the subject is at risk of suffering, or is suffering from, or has suffered focal cerebral ischemia or global cerebral ischemia. 
     
     
         23 . The method of  claim 20 , wherein the subject is administered from about 0.001 to about 0.75 mg/kg (often about 0.001 to about 0.1 mg/kg) of isoxsuprine or a pharmaceutically acceptable salt, analog or derivative thereof. 
     
     
         24 .- 26 . (canceled) 
     
     
         27 . A method of treating or preventing reperfusion injury comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition selected from the group consisting of isoxsuprine, chlorphenesin and the pharmaceutically acceptable salts, analogs and derivatives thereof. 
     
     
         28 . The method of  claim 27 , wherein the subject is at risk of suffering, or is suffering from, or has suffered an ischemic or hemorrhagic stoke. 
     
     
         29 . The method of  claim 27 , wherein the subject is at risk of suffering, or is suffering from, or has suffered focal cerebral ischemia or global cerebral ischemia. 
     
     
         30 . The method of  claim 29 , wherein isoxsuprine, chlorphenesin or a pharmaceutically acceptable salt, analog or derivative thereof is administered to the subject intravenously at around 15-30 minutes up to about 12 hours, often about sixty to around one hundred twenty minutes after the subject expresses an occlusion of a cerebral artery. 
     
     
         31 . The method of  claim 29 , wherein isoxsuprine, chlorphenesin or a pharmaceutically acceptable salt, analog or derivative thereof is administered to the subject intravenously within about 15-30 minutes up to about 12 hours, often about fifteen to about thirty minutes after the onset of reperfusion of an occluded cerebral artery. 
     
     
         32 . The method of  claim 29 , wherein isoxsuprine, chlorphenesin or a pharmaceutically acceptable salt, analog or derivative thereof is administered intravenously at the onset of reperfusion of an occluded cerebral artery. 
     
     
         33 . The method of  claim 27 , wherein the subject is administered from about 0.001 to about 0.75 mg/kg, often about 0.001 to about 0.1 mg/kg of isoxsuprine or a pharmaceutically acceptable salt, analog or derivative thereof. 
     
     
         34 . The method of  claim 27 , wherein the subject is treated concomitantly with one or more compositions or therapies selected from the group consisting of aspirin, intercellular adhesion molecule (ICAM)-1 and LFA-1 antagonists, anti-CD18 and anti-CD11a antibodies, human anti-leukocytic antibodies, glycoprotein IIb IIIa antagonists, direct thrombin inhibitors, external or local ultrasound, mechanical clot retrieval or inaceration, fibrinolytic agents, neuronal wound healing agents, neuroprotective agents, calcium and sodium channel blocking agents, beta-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid antagonist, a serotonin agonist, a transmembrane potassium channel modulator, agents that inhibit astrocyte activation, antioxidants, anti-adhesion monoclonal antibodies and antagonists and antibodies inhibiting platelet aggregation, phenyloin, nitrogen oxides, CNS-protective therapies, free-radical scavengers, reactive oxygen metabolites, antioxidants, other acylated plasminogen-streptokinase activator complex (APSAC), single-chain urokinase-plasminogen activator (scu-PA), thrombin-like enzymes from snake venoms, streptokinase, urokinase, anistreplase, alteplase, saruplase, reteplase, lanoteplase, plasmin, a truncated form of plasmin, a direct-acting thrombolytic with non-thrombolytic-related neuroprotective activities, recombinant  desmodus rotundus  salivary plasminogen activator (rDSPA) alpha-1 (Schering/Teijin Pharmaceuticals), a mutant fibrin-activated human plasminogen (BB10153; British Biotech Inc.), staphylokinase, fibrolase, prourokinase (intra-arterial administration directly into M1 or M2 arterial thrombus), monteplase (modified rtPA), pamiteplase, tisokinase, and vampire bat plasminogen activator, an astrocyte-function-improving agent such as that disclosed in US 2004/0176347, a spin-trap agent such as NXY-059 (cerovive), clopidogrel, n-methyl-dextro-aspartic acid receptor blocking agent, an anticonvulsive agent, a caspase 3 inhibitor, ((tert butylimino)methyl) 1,3 (benzenedisulfonate disodium n oxide), ebselen, glutathione peroxidase, norphenazone, rovelizurnab, lactacystin beta-lactone, tsukubaenolide, 4 phosphonomethylpipecolic acid, eliprodil, antibodies to ganglioside GM1, thrombolytic agents and biologically active variants, salts, and derivatives of any of the above. 
     
     
         35 . A method of treating or preventing an acute neurodegenerative disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition selected from the group consisting of isoxsuprine, chlorphenesin and the pharmaceutically acceptable salts, analogs and derivatives thereof. 
     
     
         36 . The method of  claim 35 , wherein the subject is at risk of suffering, or is suffering from, or has suffered cerebral ischemia or infarction, reperfusion following acute ischemia, perinatal hypoxic-ischemic injury, cardiac arrest, intracranial hemorrhage, and intracranial and intravertebral lesions, whiplash or shaken infant syndrome. 
     
     
         37 . (canceled) 
     
     
         38 . A pharmaceutical composition which is useful in protecting neuronal cells from ischemia- or hypoxia-induced cell death and which comprises:
 (a) a therapeutically effective amount of isoxsuprine or a pharmaceutically acceptable salt, analog or derivative thereof;   (b) a therapeutically effective amount of chlorphenesin or a pharmaceutically acceptable salt, analog or derivative thereof; and, optionally,   (c) a pharmaceutically-acceptable excipient.   
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the composition further comprises one or more therapeutic agents selected from the group consisting of aspirin, intercellular adhesion molecule (ICAM)-1 and LFA-1 antagonists, anti-CD18 and anti-CD11a antibodies, human anti-leukocytic antibodies, glycoprotein IIb IIIa antagonists, direct thrombin inhibitors, external or local ultrasound, mechanical clot retrieval or inaceration, fibrinolytic agents, neuronal wound healing agents, neuroprotective agents, calcium and sodium channel blocking agents, beta-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid antagonist, a serotonin agonist, a transmembrane potassium channel modulator, agents that inhibit astrocyte activation, antioxidants, anti-adhesion monoclonal antibodies and antagonists and antibodies inhibiting platelet aggregation, phenyloin, nitrogen oxides, CNS-protective therapies, free-radical scavengers, reactive oxygen metabolites, antioxidants, other acylated plasminogen-streptokinase activator complex (APSAC), single-chain urokinase-plasminogen activator (scu-PA), thrombin-like enzymes from snake venoms, streptokinase, urokinase, anistreplase, alteplase, saruplase, reteplase, lanoteplase, plasmin, a truncated form of plasmin, a direct-acting thrombolytic with non-thrombolytic-related neuroprotective activities, recombinant  desmodus rotundus  salivary plasminogen activator (rDSPA) alpha-1 (Schering/Teijin Pharmaceuticals), a mutant fibrin-activated human plasminogen (BB10153; British Biotech Inc.), staphylokinase, fibrolase, prourokinase (intra-arterial administration directly into M1 or M2 arterial thrombus), monteplase (modified rtPA), pamiteplase, tisokinase, and vampire bat plasminogen activator, an astrocyte-function-improving agent such as that disclosed in US 2004/0176347, a spin-trap agent such as NXY-059 (cerovive), clopidogrel, n-methyl-dextro-aspartic acid receptor blocking agent, an anticonvulsive agent, a caspase 3 inhibitor, ((tert butylimino)methyl) 1,3 (benzenedisulfonate disodium n oxide), ebselen, glutathione peroxidase, norphenazone, rovelizurnab, lactacystin beta-lactone, tsukubaenolide, 4 phosphonomethylpipecolic acid, eliprodil, antibodies to ganglioside GM1, thrombolytic agents and biologically active variants, salts, and derivatives of any of the above. 
     
     
         40 .- 49 . (canceled)