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(12) Patent Application Publication (10) Pub. No.: US 2009/0258844 A1 HOCHMAN (43) Pub US 20090258844A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0258844 A1 HOCHMAN (43) Pub. Date: Oct. 15, 2009 (54) COMPOSITIONS AND METHODS FOR THE (60) Provisional application No. 60/263,830, filed on Jan. TREATMENT OF DISORDERS OF THE 23, 2001, provisional application No. 60/113,620, CENTRAL AND PERPHERAL NERVOUS filed on Dec. 23, 1998. SYSTEMS Publication Classification (75) Inventor: Daryl W. HOCHMAN, Bahama, (51) Int. Cl. NC (US) A6II 3/196 (2006.01) A613/60 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) HUNTON & WILLIAMS LLP (52) U.S. Cl. ......................................... 514/162: 514/562 INTELLECTUAL PROPERTY DEPARTMENT 1900 KSTREET, N.W., SUITE 1200 (57) ABSTRACT WASHINGTON, DC 20006-1109 (US) The present invention relates to methods and compositions for treating selected conditions of the central and peripheral (73) Assignee: NeuroTherapeutics Pharma, Inc., nervous systems employing non-synaptic mechanisms. More Chicago, IL (US) specifically, one aspect of the present invention relates to methods and materials for treating seizure and seizure disor (21) Appl. No.: 12/424,172 ders, epilepsy, status epilepticus, migraine, spreading depres Sion, intracranial hypertension; for treating the pathophysi Filed: Apr. 15, 2009 ological effects of head trauma, stroke, ischemia and hypoxia; (22) for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol; and for treating neurop Related U.S. Application Data sychiatric disorders and central nervous system edema by (60) Division of application No. 1 1/259,532, filed on Oct. administering agents that modulate ionic concentrations and/ 25, 2005, now abandoned, which is a continuation of or ionic gradients in the brain, particularly ion-dependent or application No. 10/056,528, filed on Jan. 23, 2002, cation-chloride cotransporter antagonists. Electrolyte now Pat. No. 7,214,711, which is a continuation-in cotransportantagonists and combinations of Such composi part of application No. 09/470,637, filed on Dec. 22, tions with other agents for treating various conditions are 1999, now Pat. No. 6,495,601. disclosed. Patent Application Publication Oct. 15, 2009 Sheet 1 of 8 US 2009/0258844 A1 s Patent Application Publication Oct. 15, 2009 Sheet 2 of 8 US 2009/0258844 A1 vauvoor gala, wowra-Per-Mtarterwortwrotterstowsrogress rW es W rerra wearineralaaaaaaaaaa as awa-ars : sawwas i 3-tra ''' Ways a rur, swapw say WW saw Fawn wess ... ...a... ...wiswavy vs - was skys a vs. vs. rers we wrt Bs. A r s r. saw is Dr w• PP v t c2. Patent Application Publication Oct. 15, 2009 Sheet 3 of 8 US 2009/0258844 A1 irr-WM 'm : WMMa. Y. W.Vava * : : N : i : : : : k 8.-WWwww. r Patent Application Publication Oct. 15, 2009 Sheet 4 of 8 US 2009/0258844 A1 5%. 25 5%z. a6 N-N-N-N-N-N- z. 22 H 32. a6 - 92. 227 .52. 22 - .572. 22- ----- 572. 27 -wry (52. a 5 mV Patent Application Publication Oct. 15, 2009 Sheet 5 of 8 US 2009/0258844 A1 Patent Application Publication Oct. 15, 2009 Sheet 6 of 8 US 2009/0258844 A1 w!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!?m?n?????????????????????????????????????????????????????????????????i??????????????????????????????????????????i????????????????????????????????????????????????????????????????????????????????36°?? ###############################øgºg Patent Application Publication Oct. 15, 2009 Sheet 7 of 8 US 2009/0258844 A1 TWIT“) S05 Patent Application Publication Oct. 15, 2009 Sheet 8 of 8 US 2009/0258844 A1 FUR0SEMIDE BLOCKADE o CHLORIDE COTRANSPORT NEURONA, DEPOLORIZATION US 2009/0258844 A1 Oct. 15, 2009 COMPOSITIONS AND METHODS FOR THE epileptiform from non-epileptiform activity, is referred to as TREATMENT OF DISORDERS OF THE “hypersynchronization” because it describes the state in CENTRAL AND PERPHERAL NERVOUS which individual neurons become increasingly likely to dis SYSTEMS charge in a time-locked manner with one another. 0005 Epilepsy is one of the most common neurological REFERENCE TO RELATED APPLICATIONS disorders, affecting about 1% of the population. There are 0001. This application is a continuation of U.S. patent various forms of epilepsy, including idiopathic, symptomatic application Ser. No. 10/056,528, filed Jan. 23, 2002, which and cryptogenic. Genetic predisposition is thought to be the claims priority under 35 U.S.C. S 119(e) to U.S. Patent Appli predominant etiologic factor in idiopathic epilepsy. Symp cation No. 60/263,830, filed Jan. 23, 2001, and is a continu tomatic epilepsy usually develops as a result of a structural ation-in-part of U.S. patent application Ser. No. 09/470,637, abnormality in the brain. filed Dec. 22, 1999, now U.S. Pat. No. 6,495,601, which 0006 Status epilepticus is a particularly severe form of claims priority under 35 U.S.C. S 119(e) to U.S. Patent Appli seizure, which is manifested as multiple seizures that persist cation 60/113,620, filed Dec. 23, 1998. for a significant length of time, or serial seizures without any recovery of consciousness between seizures. The overall TECHNICAL FIELD OF THE INVENTION mortality rate among adults with status epilepticus is approxi 0002 The present invention relates to methods and com mately 20 percent. Patients who have a first episode are at positions for treating selected conditions of the central and substantial risk for future episodes and the development of peripheral nervous systems employing non-synaptic mecha chronic epilepsy. The frequency of status epilepticus in the nisms. More specifically, one aspect of the present invention United States is approximately 150,000 cases per year, and relates to methods and compositions for treating seizures and roughly 55,000 deaths are associated with status epilepticus seizure disorders, epilepsy, status epilepticus, migraine head annually. Acute processes that are associated with status epi ache, cortical spreading depression, intracranial hyperten lepticus include intractable epilepsy, metabolic disturbances Sion, neuropsychiatric disorders, central nervous system (e.g. electrolyte abnormalities, renal failure and sepsis), cen edema; for treating or protecting from the pathophysiological tral nervous system infection (meningitis or encephalitis), effects of toxic agents such as ethanol and certain infectious stroke, degenerative diseases, head trauma, drug toxicity and agents; for treating the pathophysiological effects of head hypoxia. The fundamental pathophysiology of status epilep trauma, stroke, ischemia and hypoxia; and for improving ticus involves a failure of mechanisms that normally abortan certain brain functions, such as cognition, learning and isolated seizure. This failure can arise from abnormally per memory; by administering agents that modulate ionic con sistent, excessive excitation or ineffective recruitment of inhi centrations and ionic balances in the central nervous system. bition. Studies have shown that excessive activation of exci Specific treatment compositions, including loop diuretics, tatory amino acid receptors can cause prolonged seizures and thiazide-like diuretics, analogs and derivatives of Such com Suggest that excitatory amino acids may play a causative role. positions, as well as combinations of such compositions with Status epilepticus can also be caused by penicillin and related other agents for modulating ionic concentrations and gradi compounds that antagonize the effects of Y-aminobutyric acid ents, and for treating various conditions, are disclosed. Com (GABA), the primary inhibitory neurotransmitter in the positions and methods for treating pain by administering brain. agents that modulate ionic concentrations and gradients in the 0007. One early diagnostic procedure for epilepsy involved the oral administration of large quantities of water peripheral nervous system are also disclosed. together with injections of vasopressin to prevent the accom BACKGROUND OF THE INVENTION panying diuresis. This treatment was found to induce seizures in epileptic patients, but rarely in non-epileptic individuals 0003 Conventional treatments for neuronal disorders, (Garland et al., Lancet, 2:566, 1943). Status epilepticus can Such as seizure disorders, epilepsy, and the like, target Syn be blocked in kainic acid-treated rats by intravenous injection aptic mechanisms that affect excitatory pathways, such as by of mannitol (Baran et al., Neuroscience, 21:679, 1987). This modulating the release or activity of neurotransmitters or effect is similar to that achieved by intravenous injection of inhibitors. Conventional treatment agents and regimen for urea in human patients (Carter, Epilepsia, 3:198, 1962). The seizure disorders diminish neuronal excitability and inhibit treatment in each of these cases increases the osmolarity of synaptic firing. One serious drawback of this approach is that the blood and extracellular fluid, resulting in water efflux while seizures are generally localized, the treatment affects from the cells and an increase in extracellular space in the (diminishes) neuronal activity indiscriminately. For this rea brain. Acetazolamide (ACZ), another diuretic with a different son, there are serious side effects and repeated use of conven mechanism of action (inhibition of carbonic anhydrase), has tional medications may result in unintended deficiencies in been studied experimentally as an anticonvulsant (White et normal and desirable brain functions, such as cognition, al., Advance Neurol., 44.695, 1986; and Guillaume et al., learning and memory. More detailed information concerning Epilepsia,
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