Treating of side-effects resulting from chemodenervation

Abstract

The present disclosure relates generally to methods of restoring neuromuscular transmission by locally administering an effective dose of a composition comprising an anticholinesterase to a non-responsive muscle. The disclosure also relates to methods of reversing a neurotoxin-induced muscle paralysis or muscle weakness, the method comprising locally administering a composition comprising an anticholinesterase to the patient.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A method of treating a botulinum toxin induced muscle paralysis or muscle weakness, the method comprising locally administering a composition comprising an anticholinesterase to a patient's muscle that has been previously exposed to the botulinum toxin. 
     
     
         5 . The method of  claim 4 , wherein the botulinum toxin is botulinum toxin type A. 
     
     
         6 . The method of  claim 4 , wherein the anticholinesterase is a reversible anticholinesterase having one or more of groups selected from carbamate, tertiary ammonium, and quaternary ammonium. 
     
     
         7 . The method of  claim 4 , wherein the anticholinesterase is selected from one or more of neostigmine, edrophonium, pyridostigmine, physostigmine, rivastigmine, donepezil, galantamine, ambenonium, and combinations thereof. 
     
     
         8 . The method of  claim 4 , wherein the anticholinesterase is pyridostigmine. 
     
     
         9 . The method of  claim 4 , wherein the anticholinesterase is of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Y is CR 3  or N + X − R 4 , wherein X is a halogen; 
         R 1  is selected from hydrogen, C 1 -C 6  alkyl, —CO(OH), —CO(C 1 -C 6  alkoxy), —CO(NH 2 ), —CONH(C 1 -C 6  alkyl), and —CON(C 1 -C 6  alkyl) 2 ; 
         R 2  is hydrogen, or R 2  and R 3  together with the atoms to which they are attached form an optionally substituted heterocycle; 
         R 3  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy C 1 -C 6  alkyl, amino C 1 -C 6  alkyl, (C 1 -C 6  alkylamino) C 1 -C 6  alkyl, (di C 1 -C 6  alkylamino) C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl —OH, —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , and —N + (C 1 -C 6  alkyl) 3 X − ; and 
         R 4  is selected from C 1 -C 6  alkyl, hydroxy C 1 -C 6  alkyl, or C 1 -C 6  alkoxy C 1 -C 6  alkyl. 
       
     
     
         10 . The method of  claim 4 , wherein the composition is administered directly to the muscle affected. 
     
     
         11 . The method of  claim 4 , wherein the composition is administered parenterally. 
     
     
         12 . The method of  claim 4 , wherein the composition is administered transdermally. 
     
     
         13 . The method of  claim 12 , wherein the transdermal administration is transdermal patch or transdermal gel. 
     
     
         14 . The method of  claim 4 , wherein the composition is a sustained-release composition. 
     
     
         15 . The method of  claim 14 , wherein the release is over a period of 1-day, 7-day, or 30-day, or any combination of these. 
     
     
         16 . The method of  claim 4 , wherein the composition is a dissolvable in-situ gel or drug depot. 
     
     
         17 . The method of  claim 16 , wherein the gel composition is extrudable through a needle having about 30 gauge to about 33 gauge. 
     
     
         18 . The method of  claim 4 , wherein anticholinesterase is administered in a dose of about 0.05-0.5 mg/kg. 
     
     
         19 . The method of  claim 4 , wherein anticholinesterase is administered in a low dose. 
     
     
         20 . The method of  claim 19 , wherein the low dose is about ⅘ to 1/50 of the clinical dose of the anticholinesterase when dosed for said anticholinesterase's oral or intravenous use. 
     
     
         21 . The method of  claim 4 , wherein the anticholinesterase is administered immediately after the botulinum toxin. 
     
     
         22 . The method of  claim 4 , wherein the anticholinesterase is administered at any time following an evidence of unwanted side effects of the botulinum toxin. 
     
     
         23 . The method of  claim 16 , wherein the composition is a sustained-release composition, optionally having the release over a period of 1-day, 7-day, or 30-day, or any combination of these.