Methods of medical treatment with sur1-trpm4 channel inhibitors

Abstract

A method of treating or preventing adverse outcomes associated with tissue plasminogen activator (tPA) administration, cerebral edema-related side effects, cerebral edema associated with radiation therapy, or migraine headaches by administering an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, and optionally the co-administration of a second therapeutically active agent, to a subject in need thereof. Adverse outcomes associated with tPA include cerebral hemorrhage, cerebral edema, physical impairment or death. The administration of the SUR1-TRPM4 channel inhibitors occurs prior to the radiation therapy, during the radiation therapy, after the radiation therapy, or combinations thereof. The SUR1-TRPM4 channel inhibitor is administered prior to surgical excision of a brain tumor, CAR-T therapy, or administration of flutarabine. Alternatively, or in addition, the SUR1-TRPM4 channel inhibitor is administered prior the onset of the cerebral edema-related side effects.

1 . A method of treating or preventing cerebral edema-related side effects induced by a treatment of a patient, comprising administering an effective amount of a SUR1-TRPM4 channel inhibitor to said patient, thereby treating or preventing the cerebral edema-related side effects in the patient,
 wherein the treatment is a CAR-T therapy, surgical excision of a brain tumor, radiation therapy, administration of a therapeutic agent comprising flutarabine, or a combination thereof, and   wherein the SUR1-TMPR4 channel inhibitor is administered via one or more continuous infusions, via injection, via a transdermal patch or gel, orally, or a combination thereof.   
     
     
         2 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, 9-phenantrol, fluflenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3′,5′-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, metabolites that interact with SUR1, or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. 
     
     
         4 . The method of  claim 1 , wherein the treatment at least one course of CAR-T therapy, surgical excision of a brain tumor, radiation therapy or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the treatment inducing cerebral edema-related side effects in the patient is administration of a therapeutic agent comprising flutarabine. 
     
     
         6 . The method of  claim 1 , wherein at least a portion of the effective amount of the SUR1-TRPM4 channel inhibitor is administered prior to onset of the cerebral edema-related side effects. 
     
     
         7 . The method of  claim 1 , wherein at least a portion of the effective amount of the SUR1-TRPM4 channel inhibitor is administered following the onset of the cerebral edema-related side effects. 
     
     
         8 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor is administered for about 1 hours to about 96 hours. 
     
     
         9 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor is administered at a dosage of about 0.05 mg/day to about 3.0 mg/day. 
     
     
         10 . The method of  claim 1 , comprising administering the SUR1-TRPM4 channel inhibitor in an amount sufficient to effect a SUR1-TRPM4 channel inhibitor plasma level of about 0.4 ng/mL to about 5 ng/mL in said patient and to effect a steady-state SUR1-TRPM4 channel inhibitor concentration of about 3.0 ng/mL to about 30.0 ng/mL in the patient. 
     
     
         11 . The method of  claim 1 , comprising administering the SUR1-TRPM4 channel inhibitor in an amount sufficient to effect a C max  of the SUR1-TRPM4 channel inhibitor of about 1 ng/mL to about 30 ng/mL in the patient. 
     
     
         12 . The method of  claim 1 , wherein the treatment is gamma radiation of a brain tumor in the patient. 
     
     
         13 . The method of  claim 1 , wherein the treatment comprises at least one of Cyberknife or Gamma Knife in the patient. 
     
     
         14 . The method of  claim 1 , wherein the treatment is radiation therapy and at least a first portion of the SUR1-TRPM4 channel inhibitor is administered via one or more continuous infusions prior to the radiation therapy, and a second portion of the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch or orally after the radiation therapy. 
     
     
         15 . A method of treating or preventing a migraine headache in a patient in need of treatment, comprising administering to said patient an effective amount of a SUR1-TRPM4 channel inhibitor, thereby treating or preventing the migraine headache in the patient. 
     
     
         16 . The method of  claim 15 , wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, 9-phenantrol, fluflenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3′,5′-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, metabolites that interact with SUR1, or combinations thereof. 
     
     
         17 . The method of  claim 15 , wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. 
     
     
         18 . The method of  claim 15 , further comprising administering a second therapeutically active agent. 
     
     
         19 . The method of  claim 18 , wherein the second therapeutically active agent comprises at least one of a pain reliever, triptan, glucocorticoid, antidepressant, anti-seizure drug, botox, or a combination thereof. 
     
     
         20 . The method of  claim 18 , wherein the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent are administered in a dosage ratio of about 75:25 to about 25:75.