Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids

Patent metadata

Field	Value
Publication number	US-10426786-B2
Application number	US-201715649460-A
Country	US
Kind code	B2
Filing date	Jul 13, 2017
Priority date	Aug 13, 2012
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

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.

First claim

What is claimed is:

1. 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 allopregnanolone, wherein both of the benzodiazepine and the allopregnanolone are administered in a subtherapeutic dose, wherein the subject has been exposed to a nerve agent or a pesticide that can cause seizures.

2. The method of claim 1 , wherein the subject has been exposed to an organophosphorous nerve agent or pesticide.

3. The method of claim 1 , wherein the subject has been exposed to tabun, sarin, soman, GF, VR, VX, Acephate (Orthene), Azinphos-methyl (Gusathion, Guthion), Bensulide (Betasan, Lescosan), Bomyl (Swat), Bromophos (Nexion), Bromophos-ethyl (Nexagan), Cadusafos (Apache, Ebufos, Rugby), Carbophenothion (Trithion), Chlorethoxyfos (Fortress), Chlorfenvinphos (Apachlor, Birlane), Chlormephos (Dotan), Chlorphoxim (Baythion-C), Chlorpyrifos (Brodan, Dursban, Lorsban), Chlorthiophos (Celathion), Coumaphos (Asuntol, Co-Ral), Crotoxyphos (Ciodrin, Cypona), Crufomate (Ruelene), Cyanofenphos (Surecide), Cyanophos (Cyanox), Cythioate (Cyflee, Proban), DEF (De-Green), Demeton (Systox), Demeton-S-methyl (Duratox, Metasystoxl), Dialifor (Torak), Diazinon, Dichlorofenthion, (VC-13 Nemacide), Dichlorvos (DDVP, Vapona), Dicrotophos (Bidrin), Dimefos (Hanane, Pestox XIV), Dimethoate (Cygon, DeFend), Dioxathion (Delnav), Disulfoton (Disyston), Ditalimfos, Edifenphos, Endothion, EPBP (S-seven), EPN, Ethion (Ethanox), Ethoprop (Mocap), Ethyl parathion (E605, Parathion, thiophos), Etrimfos (Ekamet), Famphur (Bash, Bo-Ana, Famfos), Fenamiphos (Nemacur), Fenitrothion (Accothion, Agrothion, Sumithion), Fenophosphon (Agritox, trichloronate), Fensulfothion (Dasanit), Fenthion (Baytex, Entex, Tiguvon), Fonofos (Dyfonate, N-2790), Formothion (Anthio), Fosthietan (Nem-A-Tak), Heptenophos (Hostaquick), Hiometon (Ekatin), Hosalone (Zolone), IBP (Kitazin), Iodofenphos (Nuvanol-N), Isazofos (Brace, Miral, Triumph), Isofenphos (Amaze, Oftanol), Isoxathion (E-48, Karphos), Leptophos (Phosvel), Malathion (Cythion), Mephosfolan (Cytrolane), Merphos (Easy Off-D, Folex), Methamidophos (Monitor), Methidathion (Supracide, Ultracide), Methyl parathion (E601, Penncap-M), Methyl trithion, Mevinphos (Duraphos, Phosdrin), Mipafox (Isopestox, Pestox XV), Monocrotophos (Azodrin), Naled (Dibrome), Oxydemeton-methyl (Metasystox-R), Oxydeprofos (Metasystox-S), Phencapton (G 28029), Phenthoate (Dimephenthoate, Phenthoate), Phorate (Rampart, Thimet), Phosalone (Azofene, Zolone), Phosfolan (Cylan, Cyolane), Phosmet (Imidan, Prolate), Phosphamidon (Dimecron), Phostebupirim (Aztec), Phoxim (Baythion), Pirimiphos-ethyl (Primicid), Pirimiphos-methyl (Actellic), Profenofos (Curacron), Propetamphos (Safrotin), Propyl thiopyrophosphate (Aspon), Prothoate (Fac), Pyrazophos (Afugan, Curamil), Pyridaphenthion (Ofunack), Quinalphos (Bayrusil), Ronnel (Fenchlorphos, Korlan), Schradan (OMPA), Sulfotep (Bladafum, Dithione, Thiotepp), Sulprofos (Bolstar, Helothion), Temephos (Abate, Abathion), Terbufos (Contraven, Counter), Tetrachlorvinphos (Gardona, Rabon), Tetraethyl pyrophosphate (TEPP), tetramethylenedisulfotetramine (TETS), Triazophos (Hostathion), and Trichlorfon (Dipterex, Dylox, Neguvon, Proxol).

4. The method of claim 1 , wherein the subject has been exposed to tetramethylenedisulfotetramine (TETS).

5. The method of claim 1 , wherein the benzodiazepine and the allopregnanolone are co-administered together and/or by the same route of administration.

6. The method claim 1 , wherein the benzodiazepine and the allopregnanolone are co-administered separately and/or by different routes of administration.

7. The method claim 1 , wherein one or both of the benzodiazepine and the allopregnanolone are administered by the inhalational or intrapulmonary route of administration.

8. The method claim 6 , wherein one or both of the benzodiazepine and the allopregnanolone are aerosolized particulates having a mass median aerodynamic diameter ranging from about 1 μm to about 3 μm.

9. The method of claim 1 , wherein the benzodiazepine is administered at a dose in the range of 0.3 pg/kg to 3.0 pg/kg.

10. The method of claim 1 , wherein the allopregnanolone is administered at a dose in the range of about 5 mg/kg to about 50 mg/kg.

11. The method 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.

12. The method of claim 1 , further comprising the co-administration of an NMDA receptor antagonist.

Assignees

• Univ California

Inventors

• Rogawski Michael A
• Pessah Isaac N
• Cao Zhengyu
• Lein Pamela J

Classifications

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61K31/57 Primary

  substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title