Methods of treating and preventing/reducing the likelihood of mesial temporal lobe epilepsy (tle)

Abstract

The invention provides methods of treatment that prevent the onset of Mesial temporal lobe epilepsy (TLE) in a subject, or which reduce the severity of TLE in a subject, by administering a NKCC1 inhibitor to the subject after the subject has suffered from an insult known to precipitate TLE.

1 . A method of inhibiting or reducing the likelihood of the onset of Mesial temporal lobe epilepsy (TLE) in a subject, the method comprising administering a therapeutically effective amount of a NKCC1 inhibitor to the subject after the subject has suffered from an insult known to precipitate TLE. 
     
     
         2 . The method of  claim 1 , wherein the insult known to precipitate TLE is selected from the group consisting of status epilepticus (SE), petit mal epilepsy, absence, myoclonic, clonic, tonic, tonic-clonic, and atonic seizures, acquired aphasia, acquired aphasia with epilepsy (Landau-Kleffner syndrome), acquired epileptic aphasia, cortical dysplasia-focal epilepsy syndrome (CDFE), neonatal seizures, hippocampal sclerosis (HS) and hippocampal, cerebral, and cerebellar atrophy, febrile seizures including complex febrile convulsions (CFC), traumatic brain injury, stroke, hypoxic-ischemic event, metabolic disorder and brain tumors. 
     
     
         3 . The method of  claim 1 , wherein the NKCC1 inhibitor is administered to the subject during the latent period following the subject's development of status epilepticus (SE). 
     
     
         4 . The method of  claim 1 , wherein the NKCC1 inhibitor is administered to the subject after the subject suffers an initial seizure of unknown etiology. 
     
     
         5 . The method of  claim 3 , wherein the NKCC1 inhibitor is administered to the subject within around eight to around twenty-four weeks after the subject undergoes one of the insults listed in  claim 2 . 
     
     
         6 . The method of  claim 3 , wherein the NKCC1 inhibitor is administered to the subject within around one to around four weeks after the subject undergoes one of the insults listed in  claim 2 . 
     
     
         7 . The method of  claim 1 , wherein the NKCC1 inhibitor is combined with a second therapeutic agent and co-administered to the subject after the subject has suffered from an insult known to precipitate TLE, wherein the second therapeutic agent comprises a GABA modulating composition, an anticonvulsant agent, an ion channel inactivator, an antidiuretic agent, or a combination thereof. 
     
     
         8 . The method of  claim 1 , wherein the NKCC1 inhibitor is a loop diuretic selected from the group consisting of torasemide, furosemide, azosemide, bumetanide, piretanide, tripamide, etozoline and its metabolite ozolinone, and cicletanine, and pharmaceutically acceptable derivatives, salts and esters thereof. 
     
     
         9 . The method of  claim 1  wherein the NKCC1 inhibitor is a compound selected from the group consisting of 3-Hydrazinopropionic Acid, Aminooxyacetic Acid, Gabaculine, Gabapentin, Isoniazid, Phenelzine, Phenylethylidenehydrazine, Pregabalin, Valnoctamide, Valproic acid, Valpromide, Vigabatrin and mixtures thereof. 
     
     
         10 . The method of  claim 7 , wherein the GABA-modulating composition is selected from the group consisting of barbiturates, benzodiazepines, Gabapentin, Pregabalin, 4-aminobutanoic acid (GABA), 4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), 4-amino-3-phenylbutanoic acid, 4-amino-3-hydroxybutanoic acid, 4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid, 4-amino-3-(thien-2-yl)butanoic acid, 4-amino-3-(5-chlorothien-2-yl)butanoic acid, 4-amino-3-(5-bromothien-2-yl)butanoic acid, 4-amino-3-(5-methylthien-2-yl)butanoic acid, 4-amino-3-(2-imidazolyl)butanoic acid, 4-guanidino-3-(4-chlorophenyl)butanoic acid, (3-aminopropyl)phosphonous acid, (4-aminobut-2-yl)phosphonous acid, sodium butyrate, (3-amino-2-methylpropyl)phosphonous acid, (3-aminobutyl)phosphonous acid, (3-amino-2-(4-chlorophenyl)propyl)phosphonous acid, (3-amino-2-(4-chlorophenyl)-2-hydroxypropyl)phosphonous acid, (3-amino-2-(4-fluorophenyl)propyl)phosphonous acid, (3-amino-2-phenylpropyl)phosphonous acid, (3-amino-2-hydroxypropyl)phosphonous acid, (E)-(3-aminopropen-1-yl)phosphonous acid, (3-amino-2-cyclohexylpropyl)phosphonous acid, (3-amino-2-benzylpropyl)phosphonous acid, [3-amino-2-(4-methylphenyl)propyl]phosphonous acid, [3-amino-2-(4-trifluoromethylphenyl)propyl]phosphonous acid, [3-amino-2-(4-methoxyphenyl)propyl]phosphonous acid, [3-amino-2-(4-chlorophenyl)-2-hydroxypropyl]phosphonous acid, (3-aminopropyl)methylphosphinic acid, (3-amino-2-hydroxypropyl)methylphosphinic acid, (3-aminopropyl)(difluoromethyl)phosphinic acid, (4-aminobut-2-yl)methylphosphinic acid, (3-amino-1-hydroxypropyl)methylphosphinic acid, (3-amino-2-hydroxypropyl)(difluoromethyl)phosphinic acid, (E)-(3-aminopropen-1-yl)methylphosphinic acid, (3-amino-2-oxo-propyl)methylphosphinic acid, (3-aminopropyl)hydroxymethylphosphinic acid, (5-aminopent-3-yl)methylphosphinic acid, (4-amino-1,1,1-trifluorobut-2-yl)methylphosphinic acid, (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid, and 3-aminopropylsulfinic acid and other compositions as described herein. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein the NKCC1 inhibitor is administered to the subject after the subject suffers an initial seizure of unknown etiology. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 11 , wherein the NKCC1 inhibitor is a compound selected from the group consisting of 3-Hydrazinopropionic Acid, Aminooxyacetic Acid, Gabaculine, Gabapentin, Isoniazid, Phenelzine, Phenylethylidenehydrazine, Pregabalin, Valnoctamide, Valproic acid, Valpromide, Vigabatrin and mixtures thereof. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 7 , wherein the antidiuretic agent is a peripherally-acting antidiuretic agent. 
     
     
         25 . The method of  claim 7 , wherein the antidiuretic agent acts by inhibiting the diuretic action of a NKCC1 inhibitor. 
     
     
         26 - 32 . (canceled)