Compositions and methods for the treatment of disorders of the central and peripheral nervous systems

Abstract

The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and materials for treating seizure and seizure disorders, epilepsy, status epilepticus, migraine, spreading depression, intracranial hypertension; for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia; for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol; and for treating neuropsychiatric disorders and central nervous system edema by administering agents that modulate ionic concentrations and/or ionic gradients in the brain, particularly ion-dependent or cation-chloride cotransporter antagonists. Electrolyte cotransport antagonists and combinations of such compositions with other agents for treating various conditions are disclosed.

1 . A method for treating a condition in a mammalian subject in need thereof, comprising administering an effective amount of a treatment composition comprising at least one component selected from the group consisting of: bumetanide and ethacrinic acid, wherein the condition is selected from the group consisting of: seizures; seizure disorders; epilepsy; and status. 
   
   
       2 . The method of  claim 1 , wherein the treatment composition has cation-chloride cotransporter antagonist activity. 
   
   
       3 . The method of  claim 1 , wherein the treatment composition further comprises a component selected from the group consisting of: phenytoin; carbamazepine; barbiturates; Phenobarbital; pentobarbital: mephobarbital: trimethadione: mephenytoin; paramethadione; phenthenylate; phenacemide; metharbital; benzchlorpropamide; phensuximide; primidone; methsuximide; ethotoin; aminoglutethimide; diazepam; clonazepam; clorazepate; fosphenytoin; ethosuximide; valporate; felbamate; gabapentin; lamotrigine; topiramate; vigrabatrin; tiagabine; zonisamide; clobazam; thiopental; midazoplam; propofol; levetiracetam; oxcarbazepine; CCPene; GYK152466; sumatriptan; non-steroidal anti-inflammatory drugs; neuroleptics; corticosteroids; vasoconstrictors; beta-blockers; antidepressants; anticonvulsants; Depakote; Ergot alkaloids; tryptans; Acetaminophen; caffeine; Ibuprofen; Proproxyphene; oxycodone; codeine; isometheptene; serotonin receptor agonists; ergotamine; dihydroergotamine; sumatriptan; propranolol; metoprolol; atenolol; timolol; nadolol; nifeddipine; nimodipine; verapamil; aspirin; ketoprofen; tofenamic acid; mefenamic acid; naproxen; methysergide; paracetamol; clonidine; lisuride; iprazochrome; butalbital; benzodiazepines; and divalproex sodium. 
   
   
       4 . The method of  claim 1 , additionally comprising administering an effective amount of a blood brain barrier permeability enhancer. 
   
   
       5 . The method of  claim 1 , additionally comprising administering a hyperosmotic agent. 
   
   
       6 . The method of  claim 1 , wherein the treatment composition is administered by at least one of the following: intracranial administration; local intracerebral administration; administration into the cerebral spinal fluid; or administration in a sustained release formulation. 
   
   
       7 . The method of  claim 1 , wherein the treatment composition is formulated to facilitate crossing of the blood brain barrier. 
   
   
       9 . A method for treating a condition in a mammalian subject in need thereof, comprising administering an effective amount of a treatment composition comprising at least one component selected from the group consisting of: thiazide and thiazide-like compositions, wherein the condition is selected from the group consisting of: seizures; seizure disorders; epilepsy; and status. 
   
   
       10 . The method of  claim 9 , wherein the treatment composition has cation-chloride cotransporter antagonist activity. 
   
   
       11 . The method of  claim 9 , wherein the treatment composition further comprises a component selected from the group consisting of: phenytoin; carbamazepine; barbiturates; Phenobarbital; pentobarbital: mephobarbital: trimethadione: mephenytoin; paramethadione; phenthenylate; phenacemide; metharbital; benzchlorpropamide; phensuximide; primidone; methsuximide; ethotoin; aminoglutethimide; diazepam; clonazepam; clorazepate; fosphenytoin; ethosuximide; valporate; felbamate; gabapentin; lamotrigine; topiramate; vigrabatrin; tiagabine; zonisamide; clobazam; thiopental; midazoplam; propofol; levetiracetam; oxcarbazepine; CCPene; GYK152466; sumatriptan; non-steroidal anti-inflammatory drugs; neuroleptics; corticosteroids; vasoconstrictors; beta-blockers; antidepressants; anticonvulsants; Depakote; Ergot alkaloids; tryptans; Acetaminophen; caffeine; Ibuprofen; Proproxyphene; oxycodone; codeine; isometheptene; serotonin receptor agonists; ergotamine; dihydroergotamine; sumatriptan; propranolol; metoprolol; atenolol; timolol; nadolol; nifeddipine; nimodipine; verapamil; aspirin; ketoprofen; tofenamic acid; mefenamic acid; naproxen; methysergide; paracetamol; clonidine; lisuride; iprazochrome; butalbital; benzodiazepines; and divalproex sodium. 
   
   
       12 . The method of  claim 9 , additionally comprising administering an effective amount of a blood brain barrier permeability enhancer. 
   
   
       13 . The method of  claim 9 , additionally comprising administering a hyperosmotic agent. 
   
   
       14 . The method of  claim 9 , wherein the treatment composition is administered by at least one of the following: intracranial administration; local intracerebral administration; administration into the cerebral spinal fluid; or administration in a sustained release formulation. 
   
   
       15 . The method of  claim 9 , wherein the treatment composition is formulated to facilitate crossing of the blood brain barrier.