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 - 29 . (canceled) 
     
     
         30 . A method for reducing, delaying, or reversing neuronal dysfunction associated with traumatic brain injury in a mammalian subject comprising administering to the mammalian subject an effective amount of at least one huperzine compound, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         31 . The method of  claim 30 , further comprising administering to the mammalian subject an effective amount of at least one anticholinergic compound, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         32 . The method of  claim 31 , wherein the at least one anticholinergic compound is also an antiglutamatergic compound. 
     
     
         33 . The method of  claim 31 , further comprising administering to the mammalian subject an effective amount of an anticonvulsive compound, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         34 . The method of  claim 32 , wherein the at least one anticholinergic compound that is also an antiglutamatergic compound is i) trihexyphynidyl, and ii) another anticholinergic compound or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         35 . The method of  claim 34 , further comprising administering to the mammalian subject an effective amount of an anticonvulsive compound, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         36 . The method of  claim 30 , the at least one huperzine compound is huperzine A. 
     
     
         37 . The method of  claim 30 , wherein the at least one huperzine compound is (−)-huperzine A or (+)-huperzine A. 
     
     
         38 . The method of  claim 30 , wherein the at least one huperzine compound is a combination of (−)-huperzine A and (+)-huperzine A is administered to the mammalian subject. 
     
     
         39 . The method of  claim 31 , wherein the at least one anticholinergic compound is atropine. 
     
     
         40 . The method of  claim 32 , wherein the at least one anticholinergic compound that is also an antiglutamatergic compound is bentactyzine. 
     
     
         41 . The method of  claim 33 , wherein the anticonvulsive compound is diazepam. 
     
     
         42 . The method of  claim 36 , wherein the mammalian subject is not administered an additional acetylcholinesterase inhibitor or an anticholinergic compound. 
     
     
         43 . The method of  claim 36 , wherein the huperzine A is administered at a dose in the range of 1.25 to 5,000 μg/kg/day. 
     
     
         44 . The method of  claim 30 , wherein the mammalian subject has suffered traumatic brain injury, and administration of the at least one huperzine compound, or pharmaceutically acceptable salt or hydrate thereof improves cognitive function of the mammalian subject. 
     
     
         45 . The method of  claim 44 , wherein improving the cognitive function of the mammalian subject comprises improving memory acquisition, storage or retrieval by the mammalian subject. 
     
     
         46 . The method of  claim 44 , wherein improving cognitive function of the mammalian subject comprises improving concentration of the mammalian subject. 
     
     
         47 . The method of  claim 44 , wherein improving cognitive function of the mammalian subject comprises improving the performance of complex tasks by the mammalian subject. 
     
     
         48 . The method of  claim 30 , wherein the mammalian subject is pretreated with the at least one huperzine compound, or pharmaceutically acceptable salt or hydrate thereof. 
     
     
         49 . A method for reducing, delaying, or reversing neuronal dysfunction associated with traumatic brain injury in a mammalian subject comprising adjunctively administering to the mammalian subject (a) at least one huperzine compound, or a 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.