Pharmaceutical compositions and methods for preventing, treating, or reversing neuronal dysfunction

Abstract

The present invention provides compositions and methods for preventing, treating or reversing neuronal dysfunction in a mammal resulting from exposure to organophosphate nerve agents, organophosphate insecticides and incapacitating agents of the central nervous system (CNS); CNS injury, including traumatic brain injury, neurologic complications of cardiac surgery, perinatal asphyxia, and stroke, spinal cord injury, and peripheral nerve injury; and neuronal disorders associated with the loss of motor function including post-polio syndrome, amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease and Rett syndrome; neurodegenerative disorders including Alzheimer's disease, mild cognitive impairment and schizophrenia; and cognitive impairment associated with aging. The compositions of the invention preferably comprise in effective amounts (a) at least one acetylcholinesterase inhibitor, (b) at least one compound with anticholinergic properties or both anticholinergic and antiglutamatergic properties, (c) optionally an anticonvulsive compound, and a pharmaceutically acceptable carrier.

1 - 48 . (canceled) 
     
     
         49 . A method for treating a mammalian subject at risk of organophosphate poisoning comprising administering to the mammalian subject in need thereof a therapeutically effective amount of a galanthamine compound or pharmaceutically acceptable salt or hydrate thereof. 
     
     
         50 . The method of  claim 49 , further comprising administering to the mammalian subject a therapeutically effective amount of an anticholinergic compound or pharmaceutically acceptable salt or hydrate thereof. 
     
     
         51 . The method of  claim 50 , wherein the organophosphate is an organophosphate nerve agent which is cyclosarin, sarin, soman, tabun, VR, VX, Novichok-5 or Novichok-7, or an organophosphate insecticide which is azinphos-methyl, bornyl, dimefos, methamidophos, or methyl parathion. 
     
     
         52 . The method of  claim 51 , wherein the organophosphate is an organophosphate insecticide. 
     
     
         53 . The method of  claim 51 , wherein the organophosphate is an organophosphate nerve agent. 
     
     
         54 . The method of  claim 53 , wherein the organophosphate nerve agent and the agent is soman. 
     
     
         55 . The method of  claim 50 , wherein the anticholinergic compound is atropine. 
     
     
         56 . The method of  claim 50 , wherein the anticholinergic compound is also an antiglutamatergic compound. 
     
     
         57 . The method of  claim 51 , wherein the anticholinergic and antiglutamatergic compound is caramiphen. 
     
     
         58 . The method of  claim 50 , wherein the galanthamine compound is (−)-galanthamine or (+)-galanthamine. 
     
     
         59 . The method of  claim 54 , wherein the anticholinergic compound is atropine. 
     
     
         60 . The method of  claim 54 , wherein the anticholinergic compound is also an antiglutamatergic compound. 
     
     
         61 . The method of  claim 59 , wherein the anticholinergic and antiglutamatergic compound is caramiphen. 
     
     
         62 . The method of  claim 54 , wherein the galanthamine compound is (−)-galanthamine or (+)-galanthamine. 
     
     
         63 . The method of  claim 50 , wherein the active ingredients (a) and (b) are administered prior to exposure to the organophosphate. 
     
     
         64 . The method of  claim 50 , wherein the active ingredients (a) and (b) are administered after exposure to the organophosphate. 
     
     
         65 . The method of  claim 54 , wherein the active ingredients (a) and (b) are administered prior to exposure to the organophosphate. 
     
     
         66 . The method of  claim 54 , wherein the active ingredients (a) and (b) are administered after exposure to the organophosphate. 
     
     
         67 . A method for treating a mammalian subject at risk of poisoning by an incapacitating agent of the central nervous system comprising adjunctively administering to the mammalian subject in need thereof (a) a galanthamine compound or pharmaceutically acceptable salt or hydrate thereof, and (b) an anticholinergic compound or pharmaceutically acceptable salt or hydrate thereof, wherein the active ingredients (a) and (b) are each administered in an amount that renders the combination of two active ingredients more effective compared to the efficacy of each ingredient administered in the same amount alone. 
     
     
         68 . A method for treating a mammalian subject at risk of poisoning by an incapacitating agent of the central nervous system comprising adjunctively administering to the mammalian subject in need thereof (a) 2.0 to 50,000 μg/kg/day of a galanthamine compound or pharmaceutically acceptable salt or hydrate thereof, and (b) 0.005 to 100 mg/kg/day of an anticholinergic compound or pharmaceutically acceptable salt or hydrate thereof.