Methods of treating injuries or conditions related to cns edema

Abstract

The present technology is related to reducing or treating neurological swelling and related conditions with SUR1-TRPM4 channel inhibitors. In some embodiments, the methods include: reducing late neurological deterioration or preventing death, reducing cerebral midline shift, reducing the degree of disability in a subject, counteracting blood glucose levels in a subject receiving a SUR1-TRPM4 channel inhibitor, preventing brain swelling, monitoring liver enzyme activity along with treating injury or conditions related to CNS edema, or monitoring cardiac activity along with treating injury or conditions related to CNS edema.

What is claimed is: 
     
         1 . A method of reducing late neurological deterioration or death in a subject following an injury or condition related to CNS edema, comprising administering a SUR1-TRPM4 channel inhibitor to the subject following the subject experiencing the an injury or condition related to CNS edema, wherein the administering includes one or more continuous infusion of the SUR1-TRPM4 channel inhibitor lasting cumulatively for at least 72 hours after starting the one or more continuous infusion, wherein the SUR1-TRPM4 channel inhibitor reduces late neurological deterioration. 
     
     
         2 . The method of  claim 1 , wherein the CNS edema is cerebral edema. 
     
     
         3 . The method of  claim 2 , wherein the step of administering prevents death of the subject. 
     
     
         4 . The method of  claim 1 , wherein the method reduces the late neurological deterioration or death as determined over a population based on the incidence of late neurological deterioration or death in patients treated with the one or more continuous infusion compared to a similar population that was not treated with the one or more continuous infusion. 
     
     
         5 . The method of  claim 1 , wherein the method of reducing the late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is initially administered within 1 hour following the subject experiencing the injury or condition related to CNS edema. 
     
     
         6 . The method of  claim 1 , wherein the method of reducing the incidence of late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is initially administered within 4½ hours following the subject experiencing the injury or condition related to CNS edema. 
     
     
         7 . The method of  claim 1 , wherein the method of reducing the incidence of late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is initially administered at from 4½ hours to 10 hours following the subject experiencing the injury or condition related to CNS edema. 
     
     
         8 . The method of  claim 1 , wherein the method of reducing the incidence of late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is initially administered at from 6 hours to 12 hours following the subject experiencing the injury or condition related to CNS edema. 
     
     
         9 . The method of  claim 1 , wherein the method of reducing the late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is initially administered prior to about 8 hours following the subject experiencing the injury or condition related to CNS edema. 
     
     
         10 . The method of  claim 1 , wherein administering the one or more continuous infusion of the SUR1-TRPM4 channel inhibitor occurs for at least 96 hours. 
     
     
         11 . The method of  claim 1 , wherein administering the one or more continuous infusion of the SUR1-TRPM4 channel inhibitor occurs for at least 120 hours. 
     
     
         12 . The method of  claim 1 , wherein administering the one or more continuous infusion of the SUR1-TRPM4 channel inhibitor occurs for at least 168 hours. 
     
     
         13 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof, 
     
     
         14 . The method of  claim 1 , wherein the SUR1-TRPM4 channel inhibitor is glyburide. 
     
     
         15 . The method of  claim 1 , wherein the method of treating late neurological deterioration or death is the result of a hemorrhagic stroke. 
     
     
         16 . The method of  claim 1 , wherein the method of treating late neurological deterioration or death is the result of an ischemic stroke. 
     
     
         17 . The method of  claim 16 , wherein the ischemic stroke occurs at a middle cerebral artery, an intracranial carotid artery, an extracranial carotid artery, a combination thereof. 
     
     
         18 . The method of  claim 1 , wherein the method of treating late neurological deterioration is the result of traumatic brain injury. 
     
     
         19 . The method of  claim 1 , wherein the method of treating late neurological deterioration or death is a result of cardiac arrest, liver failure, intraventricular hemorrhage, or neurosurgery. 
     
     
         20 . The method of  claim 1 , wherein the CNS edema is spinal cord edema, and the late neurological deterioration is spinal cord injury. 
     
     
         21 . The method of  claim 1 , wherein the one or more continuous infusion is started after a bolus dose administration. 
     
     
         22 . The method of  claim 1 , wherein the one or more continuous infusion comprises two or more continuous infusion dosages, wherein a first continuous infusion dosage is higher than a second continuous infusion dosage. 
     
     
         23 . The method of  claim 1 , wherein the one or more continuous infusion is started after a bolus dose administration, and wherein the one or more continuous infusion comprises two or more continuous infusion dosages, wherein a first continuous infusion dosage is higher than a second continuous infusion dosage. 
     
     
         24 . The method of  claim 1 , wherein administering of the SUR1-TRPM4 channel inhibitor is coupled with a decompressive craniectomy. 
     
     
         25 . The method of  claim 1 , wherein the administering of the SUR1-TRPM4 channel inhibitor reduces cerebral midline shift and cerebral edema in the subject sufficient to prevent the need for the subject to receive a decompressive craniectomy. 
     
     
         26 . A method of reducing cerebral midline shift in a subject following an injury or condition related to cerebral edema, comprising:
 administering to the subject a SUR1-TRPM4 channel inhibitor following the subject experiencing the injury or condition related to cerebral edema, and   performing a decompressive craniectomy on the subject.   
     
     
         27 . The method of  claim 26 , wherein injury or condition related to cerebral edema is a stroke. 
     
     
         28 . The method of  claim 26 , wherein the method reduces the cerebral midline shift as determined over a population based on the degree of cerebral midline shift in patients treated with the one or more continuous infusion compared to a similar population that was not treated with one or more continuous infusion. 
     
     
         29 . The method of  claim 26 , wherein the inhibitor of the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. 
     
     
         30 . The method of  claim 26 , wherein the SUR1-TRPM4 channel inhibitor is glyburide. 
     
     
         31 . The method of  claim 26 , wherein administering the SUR1-TRPM4 channel inhibitor includes one or more continuous infusion lasting cumulative for at least 72 hours. 
     
     
         32 . The method of  claim 26 , wherein administering the SUR1-TRPM4 channel inhibitor includes one or more continuous infusion lasting cumulatively for at least 96 hours. 
     
     
         33 . The method of  claim 26 , wherein administering the SUR1-TRPM4 channel inhibitor includes a bolus dose administration followed by one or more continuous infusion. 
     
     
         34 . The method of  claim 26 , wherein the SUR1-TRPM4 channel inhibitor treats lesional swelling. 
     
     
         35 . The method of  claim 26 , wherein the SUR1-TRPM4 channel inhibitor is first administered to the subject at from immediately following the injury or condition related to the cerebral edema to about 12 hours after the subject experiences the injury or condition related to cerebral edema. 
     
     
         36 . The method of  claim 26 , wherein the SUR1-TRPM4 channel inhibitor is first administered to the subject at from 4½ hours following the injury or condition related to cerebral edema to about 12 hours after the subject experiences the injury or condition related to cerebral edema. 
     
     
         37 . The method of  claim 26 , wherein step of administering occurs prior to or during the decompressive craniectomy. 
     
     
         38 . The method of  claim 26 , wherein the step of administering occurs after decompressive craniectomy. 
     
     
         39 . A method of treating a subject that has suffered an injury or condition related to CNS edema, comprising:
 administering one or more continuous infusion of a SUR1-TRPM4 channel inhibitor to the subject following the subject experiencing the injury or condition related to CNW edema,   establishing an initial degree of disability of the subject following the injury or condition related to CNS edema using a first scoring system or test, and   determining a second degree of disability after a period of time with respect to the initial degree of disability using a second scoring system or test, wherein as a result of the SUR1-TRPM4 channel inhibitor administration, an improved difference in degree of disability is realized.   
     
     
         40 . The method of  claim 39 , wherein the first scoring system or test and the second scoring system or test are the same. 
     
     
         42 . The method of  claim 39 , wherein the first scoring system or test and the second scoring system or test are different. 
     
     
         43 . The method of  claim 39 , wherein the step of administering is prior to the step of establishing. 
     
     
         44 . The method of  claim 39 , wherein the step of establishing is prior to the step of administering. 
     
     
         45 . The method of  claim 39 , wherein the injury or condition related to CNS edema is a stroke. 
     
     
         46 . The method of  claim 45 , wherein one or both of the first scoring system or test or the second scoring system or test is selected from the group consisting of a National Institutes of Health Stroke Scale (NIHSS), an Alberta Stroke Program Early CT Score (ASPECTS); a magnetic resonance imaging (MRI); and a CT Scan. 
     
     
         47 . The method of  claim 45 , wherein the first scoring system or test is based upon a National Institutes of Health stroke score system, and the second scoring system or test is based on a modified Rankin Scale or Barthel Index. 
     
     
         48 . A method of counteracting a decline in blood glucose levels in a subject that is receiving a SUR1-TRPM4 channel inhibitor, comprising:
 administering one or more continuous infusion of the SUR1-TRPM4 channel inhibitor to the subject, and   co-administering a dextrose solution to the subject.   
     
     
         49 . The method of  claim 48 , wherein the administering step is for treatment of an injury or condition unrelated to CNS edema. 
     
     
         50 . The method of  claim 48 , wherein the administering step is for treatment of an injury or condition related to cerebral edema. 
     
     
         51 . The method of  claim 48 , wherein the dextrose solution comprises saline or water, and from about 3 wt % to about 12 wt % dextrose. 
     
     
         52 . The method of  claim 48 , further comprising measuring blood glucose levels before or during the administering step. 
     
     
         53 . The method of  claim 52 , wherein the dextrose solution is administered initially when the blood glucose levels in the subject is at or below about 120 mg/dL. 
     
     
         54 . The method of  claim 52 , wherein the dextrose solution is administered initially when the blood glucose levels in the subject is at or below about 100 mg/dL. 
     
     
         55 . The method of  claim 52 , wherein when the blood glucose level is from greater than about 80 mg/dL to 100 mg/dL, a 3 wt % to 8 wt % solution of dextrose is administered to the subject at from about 50 cc/hr to about 120 cc/hr. 
     
     
         56 . The method of  claim 52 , wherein when the blood glucose level is from about 55 mg/dL to 80 mg/dL, an 8 wt % to 12 wt % solution of dextrose is administered to the subject at from 50 cc/hr to 120 cc/hr. 
     
     
         57 . The method of  claim 52 , wherein when the blood glucose level is less 55 mg/dL, an 8 wt % to 12 wt % solution of dextrose is administered to the subject at from 50 cc/hr to 120 cc/hr. 
     
     
         58 . The method of  claim 52 , wherein when the blood glucose level is below 55 mg/dL, administering of the SUR1-TRPM4 channel inhibitor is reduced or ceased. 
     
     
         59 . The method of  claim 52 , wherein the blood glucose level is first verified either by performing another measurement at the bedside or by laboratory test prior to ceasing or reducing the administration of the SUR1-TRPM4 channel inhibitor. 
     
     
         60 . The method of  claim 52 , further comprising hourly monitoring of blood glucose levels for at least 12 hours. 
     
     
         61 . The method of  claim 52 , further comprising hourly monitoring of blood glucose levels for 24 hours, monitoring blood of blood glucose every two hours for the next 24 hours, and monitoring blood glucose levels every four hours while the step of administering continues. 
     
     
         62 . The method of  claim 52 , wherein when if the blood glucose level of the subject drops below a predetermined level, the method further comprises co-administering a bolus of dextrose solution to the subject. 
     
     
         63 . The method of  claim 52 , wherein if the blood glucose level of the subject is greater than about 80 mg/dL, then the co-administering of the dextrose solution is ceased. 
     
     
         64 . The method of  claim 52 , wherein if the blood glucose level of the subject is greater than about 100 mg/dL, then the co-administering of the dextrose solution is ceased. 
     
     
         65 . The method of  claim 52 , wherein if the blood glucose level of the subject is greater than about 120 mg/dL, then the co-administering of the dextrose is ceased. 
     
     
         66 . The method of  claim 52 , wherein if the blood glucose level of the subject is greater than about 140 mg/dL then the co-administering of the dextrose solution is ceased. 
     
     
         67 . The method of  claim 52 , wherein the rate of dextrose administration is increased after a rapid downward trend in blood glucose. 
     
     
         68 . The method of  claim 67 , wherein the rapid downward trend in blood glucose is defined as a reduction of 10 mg/dL since the last measurement. 
     
     
         69 . The method of  claim 67 , wherein the rapid downward trend in blood glucose is defined as a reduction of 30 mg/dL since the last measurement. 
     
     
         70 . The method of  claim 48 , wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. 
     
     
         71 . The method of  claim 48 , wherein the inhibitor of the SUR1-TRPM4 channel is glyburide. 
     
     
         72 . The method of  claim 50 , wherein the injury or condition related to CNS edema is a stroke. 
     
     
         73 . A method of preventing or reducing CNS edema in a subject at a high risk of severe brain or spinal cord swelling following an injury or condition related to CNS edema, comprising:
 determining whether the subject is at a high risk for severe brain or spinal cord swelling, and   administering a SUR1-TRPM4 channel inhibitor to the subject once the subject is determined to be at high risk for severe brain or spinal cord swelling.   
     
     
         74 . The method of  claim 73 , wherein the subject has experienced a stroke and the CNS edema is cerebral edema. 
     
     
         75 . The method of  claim 74 , wherein the subject is considered to be at a high risk for severe brain swelling when the subject exhibits at least one factor or score selected from the group consisting of: a National Institutes of Health Stroke Scale (NIHSS) score of at least 10, an Alberta Stroke Program Early CT Score (ASPECTS) of 7 or less; an Alberta Stroke Program Early CT Score (ASPECTS) of 4 or less; a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 70 cc; a CT perfusion score greater than 50 cc; poor collateral circulation determined by CT angiography; and a CT scan that shows a hypodensity covering at least 33% of a middle cerebral artery territory. 
     
     
         76 . The method of  claim 75 , wherein the subject is considered to be at the high risk for severe brain swelling when the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 82 cc. 
     
     
         77 . The method of  claim 75 , wherein the subject is considered to be at the high risk for severe brain swelling when the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 145 cc. 
     
     
         78 . The method of  claim 75 , wherein the subject is considered to be at the high risk for severe brain swelling when the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 145 cc. 
     
     
         79 . The method of  claim 75 , wherein the subject is considered to be at the high risk for severe brain swelling when the subject exhibits a CT perfusion score greater than 70 cc. 
     
     
         80 . The method of  claim 75 , wherein the subject is considered to be at the high risk for severe brain swelling when the subject exhibits a CT scan that shows a hypodensity covering at least 50% of the middle cerebral artery territory. 
     
     
         81 . The method of  claim 73 , wherein administering is by one or more continuous infusion of a SUR1-TRPM4 channel inhibitor for a cumulative period of at least 72 hours. 
     
     
         82 . The method of  claim 73 , wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. 
     
     
         83 . The method of  claim 73 , wherein the SUR1-TRPM4 channel inhibitor is glyburide. 
     
     
         84 . The method of  claim 73 , wherein the step of administering is within 12 hours of the injury or condition related to the CNS edema. 
     
     
         85 . A method delivering glyburide to a subject, comprising:
 administering one or more continuous infusion of glyburide to the subject, and   measuring liver enzyme levels while continuing administration of the glyburide.   
     
     
         86 . The method of  claim 85 , wherein the administering step is for treatment of an injury or condition related to spinal cord edema. 
     
     
         87 . The method of  claim 86 , wherein the administering step is for treatment of an injury or condition related to cerebral edema. 
     
     
         88 . The method of  claim 87 , wherein the injury or condition related to cerebral edema is a stroke. 
     
     
         89 . The method of  claim 85 , wherein the method further comprises the preliminary step of measuring liver enzyme levels prior to administering the glyburide. 
     
     
         90 . The method of  claim 85 , wherein the step of measuring liver enzyme levels includes measuring the liver enzyme levels as specified time periods after starting the administering step. 
     
     
         91 . The method of  claim 90 , wherein the specified time periods are at about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 168 hours, the day the subject is discharged, or combination thereof. 
     
     
         92 . The method of  claim 85 , wherein the liver enzyme that is measured is aspartate transaminase (AST). 
     
     
         93 . The method of  claim 85 , wherein the liver enzyme that is measured is alanine transaminase (ALT). 
     
     
         94 . The method of  claim 84 , wherein the step of administering is altered or stopped based on results from the step of measuring. 
     
     
         95 . The method of  claim 85 , wherein the step of administering glyburide is discontinued if the subject's ALT level rises to greater than about 8 times an upper limit of normal ALT levels as determined by an administering practitioner. 
     
     
         96 . The method of  claim 60 , wherein the step of administering glyburide is discontinued if the subject develops cholestatic jaundice or hepatitis. 
     
     
         97 . A method of monitoring cardiac activity when glyburide is administered to a subject, comprising:
 administering one or more continuous infusion of a sulfonylurea to the subject, and   performing an electrocardiogram on the subject to monitor the subject's heart.   
     
     
         98 . The method of  claim 97 , wherein the administering step is for treatment of an injury or condition related to spinal cord edema. 
     
     
         99 . The method of  claim 97 , wherein the administering step is for treatment of an injury or condition related to cerebral edema. 
     
     
         100 . The method of  claim 97 , wherein the injury or condition related to cerebral edema is a stroke. 
     
     
         101 . The method of  claim 97 , wherein the step of performing the electrocardiogram comprises a preliminary step of performing the electrocardiogram on the subject prior to administering the sulfonylurea. 
     
     
         102 . The method of  claim 97 , wherein the step of performing the electrocardiogram comprises performing electrocardiograms on the subject at specified time periods after starting the administering step. 
     
     
         103 . The method of  claim 97 , wherein the specific time periods are at about 4 hours to about 6 hours, about 24 hours, about 48 hours, about 60 hours to about 72 hours, about 168 hours, a day the subject is discharged, or a combination thereof. 
     
     
         104 . The method of  claim 97 , wherein the administering of the sulfonylurea is stopped when a QTc of the electrocardiogram is greater than about 550 ms. 
     
     
         105 . The method of  claim 97 , wherein the injury or condition related to cerebral edema is a stroke. 
     
     
         106 . A method delivering glyburide to a subject, comprising:
 intravenously administering glyburide to the subject, and   monitoring blood glucose, liver enzymes, and QTc during while intravenously administering the glyburide to the subject.   
     
     
         107 . The method of  claim 106 , further comprising administering dextrose to the subject. 
     
     
         108 . A method of treating a subject suffering from a large hemispheric infarction, comprising administering to said subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein said subject is less than 71 years of age and said treating results in improved functional outcomes as measured by one or more outcomes scales. 
     
     
         109 . A method of treating a subject suffering from a large hemispheric infarction, comprising administering to said subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein said subject has a lesion volume of at least about 100 cc or an ASPECTS score of <=5, or both. 
     
     
         110 . A method of treating a subject suffering from a large hemispheric infarction, comprising administering to said subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein said administering is initiated in 9 hours or less from the time of the index stroke or when the subject was last observed as normal. 
     
     
         111 . A method of treating a subject suffering from a traumatic brain injury, comprising administering to said subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein said subject, prior to treatment shows radiological evidence of intracerebral blood induced by said traumatic brain injury. 
     
     
         112 . A method of testing a treatment for large hemispheric infarction, comprising:
 enrolling subjects at least 18 years old with radiologically defined LHI;   treating said subjects with a SUR1-TRPM4 channel inhibitor or matching placebo for up to about 72 hours, beginning 9 hours or less from the stroke or the last time observed normal;   assessing the mRS, wherein said method is considered successful if a statistically significant result favoring drug is detected in subjects 70-years old or younger, or a descriptive benefit is detected in subjects greater than 70-years old.