# US 2019/0167632 A1 · Methods of treating and preventing/reducing the likelihood of mesial temporal lobe epilepsy (tle) > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0167632 A1 - Document ID: US20190167632A1 - Status: Published application - Kind: A1 - Application number: 16/269,167 - Filed: 2019-02-06 - Published: 2019-06-06 - Earliest claimed: 2009-07-24 - Assignees: Wolfgang S. Mueller - Inventors: Wolfgang S. Mueller; John A. Connor; Steven Peterson; Denis Bragin - Web page: https://patentgrep.com/patent/US20190167632A1 ## CPC - A61K 31/34: having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide - A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil - A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole - A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/08: Antiepileptics; Anticonvulsants - A61P 25/10: for petit-mal - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) 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). ### Claim 4 (depends on 1) The method of claim 1, wherein the NKCC1 inhibitor is administered to the subject after the subject suffers an initial seizure of unknown etiology. ### Claim 5 (depends on 2, 3) 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. ### Claim 6 (depends on 2, 3) 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. ### Claim 7 (depends on 1) 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. ### Claim 8 (depends on 1) 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. ### Claim 9 (depends on 1) 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. ### Claim 10 (depends on 7) 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. ### Claim 11 (canceled) ### Claim 12 (canceled) ### Claim 13 (canceled) ### Claim 14 (depends on 11) The method of claim 11, wherein the NKCC1 inhibitor is administered to the subject after the subject suffers an initial seizure of unknown etiology. ### Claim 15 (canceled) ### Claim 16 (canceled) ### Claim 17 (canceled) ### Claim 18 (canceled) ### Claim 19 (depends on 11) 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. ### Claim 20 (canceled) ### Claim 21 (canceled) ### Claim 22 (canceled) ### Claim 23 (canceled) ### Claim 24 (depends on 7) The method of claim 7, wherein the antidiuretic agent is a peripherally-acting antidiuretic agent. ### Claim 25 (depends on 7) The method of claim 7, wherein the antidiuretic agent acts by inhibiting the diuretic action of a NKCC1 inhibitor. ### Claim at position 26 26-32. (canceled)