Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids

Abstract

Provided are compositions comprising a benzodiazepine and a neurosteroid, containing one or both of the benzodiazepine and the neurosteroid in a subtherapeutic dose, and administration of such compositions for mitigation of an epileptic seizure. Further provided are compositions comprising a benzodiazepine, a neurosteroid, and an NMDA blocker, and administration of such compositions for mitigation of an epileptic seizure.

1 . A composition comprising a benzodiazepine and a neurosteroid, wherein the composition comprises one or both of the benzodiazepine and the neurosteroid in a subtherapeutic dose. 
     
     
         2 . The composition of  claim 1 , further comprising a NMDA receptor antagonist. 
     
     
         3 . The composition of  claim 1 , wherein the composition is formulated for oral or transmucosal delivery or administration. 
     
     
         4 . The composition of  claim 1 , wherein the composition is formulated for parenteral delivery. 
     
     
         5 . The composition of  claim 4 , wherein the parenteral delivery or administration is via a route selected from the group consisting of inhalational, intrapulmonary, intramuscular, subcutaneous, transmucosal and intravenous. 
     
     
         6 . The composition of  claim 1 , wherein the benzodiazepine is an agonist of the benzodiazepine recognition site on GABA A  receptors and stimulates endogenous neurosteroid synthesis. 
     
     
         7 . The composition of  claim 1 , wherein the benzodiazepine is selected from the group consisting of bretazenil, clonazepam, cloxazolam, clorazepate, diazepam, fludiazepam, flutoprazepam, lorazepam, midazolam, nimetazepam, nitrazepam, phenazepam, temazepam and clobazam. 
     
     
         8 . The composition of  claim 1 , wherein the benzodiazepine is selected from the group consisting of midazolam, lorazepam and diazepam. 
     
     
         9 . The composition of  claim 1 , wherein the neurosteroid is selected from the group consisting of allopregnanolone, allotetrahydrodeoxycorticosterone, ganaxolone, alphaxolone, alphadolone, hydroxydione, minaxolone, and Althesin. 
     
     
         10 . The composition of  claim 1 , wherein the neurosteroid is allopregnanolone. 
     
     
         11 . The composition of  claim 1 , wherein the composition comprises allopregnanolone and a benzodiazepine selected from the group consisting of midazolam, lorazepam and diazepam. 
     
     
         12 - 17 . (canceled) 
     
     
         18 . The composition of  claim 2 , wherein the NMDA receptor antagonist is selected from the group consisting of dizocilpine (MK-801), meperidine, methadone, dextropropoxyphene, tramadol, ketobemidone, ketamine, dextromethorphan, phencyclidine, nitrous oxide (N 2 O), AP5 (R-2-amino-5-phosphonopentanoate), AP7 (2-amino-7-phosphonoheptanoic acid), CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid), selfotel, amantadine, dextrallorphan, dextromethorphan, dextrorphan, ethanol, eticyclidine, gacyclidine, ibogaine, magnesium, memantine, methoxetamine, rolicyclidine, tenocyclidine, methoxydine, tiletamine, xenon, neramexane, eliprodil, etoxadrol, dexoxadrol, WMS 2539, NEFA, remacemide, delucemine, 8A-PDHQ, aptiganel, HU-211, remacemide, rhynchophylline, 1 Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate, DCKA (5,7-dichlorokynurenic acid), kynurenic acid, and lacosamide. 
     
     
         19 . The composition of  claim 2 , wherein the NMDA receptor antagonist is dizocilpine (MK-801). 
     
     
         20 . A method of preventing or terminating a seizure in a subject in need thereof, comprising administration to the subject of an effective amount of a composition of  claim 1 . 
     
     
         21 . A method of accelerating the termination or abortion of an impending seizure in a subject in need thereof, comprising administration to the subject of an effective amount of a composition of  claim 1 . 
     
     
         22 - 31 . (canceled) 
     
     
         32 . A method of preventing or terminating a seizure in a subject in need thereof, comprising administration to the subject of an effective amount of a benzodiazepine and a neurosteroid, wherein one or both of the benzodiazepine and the neurosteroid are administered in a subtherapeutic dose. 
     
     
         33 . A method of accelerating the termination or abortion of an impending seizure in a subject in need thereof, comprising administration to the subject of an effective amount of a benzodiazepine and a neurosteroid, wherein one or both of the benzodiazepine and the neurosteroid are administered in a subtherapeutic dose. 
     
     
         34 - 63 . (canceled) 
     
     
         64 . A kit comprising a benzodiazepine and a neurosteroid, wherein one or both of the benzodiazepine and the neurosteroid are provided in unit dosage forms comprising a subtherapeutic dose. 
     
     
         65 - 128 . (canceled)