Methods of treating injuries or conditions associated with CNS edema

Abstract

To provide methods of treating injuries or conditions related to CNS edema.SOLUTION: 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 dysfunction 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.SELECTED DRAWING: None

Description

[Background technology]

[0001] After spinal cord injury, cardiac arrest, liver failure, intracranial hemorrhage, neurosurgery, traumatic brain injury, stroke (ischemic and / or hemorrhagic), infection, cerebral malaria, or other similar injury or illness, or any form of cerebral ischemia, subjects may suffer from space-occupying cerebral edema (swelling), or, in the case of spinal cord injury, spinal cord edema. Life-threatening brain swelling occurs in up to 8% of all hospitalized ischemic stroke patients and up to 15% of all middle cerebral artery stroke patients. In subjects suffering from stroke, brain swelling usually appears several days after the stroke, usually peaking on the second or third day.

[0002] Brain swelling can increase intracranial pressure, blocking blood flow to the brain and depriving the brain of oxygen. Brain swelling can also block brain drainage pathways, preventing fluid from leaving the brain. Furthermore, as intracranial pressure increases within the skull, previously healthy brain tissue can be destroyed, resulting in transtentorial or uncal herniation. Swelling in and around the brain can also result in morbidity and brain death, as well as secondary neurological disorders and death of the subject.

[0003] Brain swelling can be associated with two distinct molecular and physiological processes: cellular swelling of neurons and astrocytes, and transcapillary influx of ions and fluids into the injury site. Cellular swelling of neurons and astrocytes results from changes in ion gradients between cells and the extracellular space. One ion channel associated with cell swelling is the NC channel, also known as the SUR1-TRPM4 channel. CA-ATP This channel is a nonselective Ca channel that is activated when intracellular ATP in neuronal cells is depleted. 2+ Activated ATP-sensitive cation channel. NC CA-ATP The channel is thought to consist of a regulatory subunit containing sulfonylurea receptor 1 (SUR1) and a pore subunit related to transient receptor potential cation channel subfamily M member 4 (TRPM4). Summary of the Invention [Means for solving the problem]

[0004] Minimizing the degree of cerebral swelling is the main concern of doctors when treating the subject who suffers from the condition or disease that may cause cerebral edema.But the treatment of cerebral edema is particularly difficult because of the long period of time that swells, the overall function of brain, and the location of brain in the skull.Therefore, providing the treatment that reduces the degree of cerebral edema will be an advancement in the art.

[0005] With this background in mind, the present disclosure relates to methods of reducing or treating CNS edema, eg, brain swelling, spinal cord swelling, and / or related conditions.

[0006] In one embodiment, a method for reducing the occurrence of late neurological deterioration (or death) in a subject following an injury or condition associated with CNS edema. A method is presented, which includes administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to a subject after the subject has experienced an injury or condition associated with CNS edema, and continuing the continuous infusion for at least 72 hours after initiation, thereby reducing late neurological deterioration.

[0007] In another embodiment, a method for reducing the brain midline shift in a subject after the injury or condition associated with cerebral edema is provided.The method comprises: after the subject experiences the injury or condition associated with cerebral edema, administering a SUR1-TRPM4 channel inhibitor to the subject, and performing decompressive craniectomy on the subject.

[0008] In yet another embodiment, a method for improving the degree of disability in a subject suffering from an injury or condition associated with CNS edema is provided. The method comprises administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to the subject after the subject suffers from an injury or condition associated with CNS edema. A further step comprises establishing the subject's initial degree of disability based on a first scoring system or test, and determining a second degree of disability using a second scoring system or test after a period of time has elapsed since the initial degree of disability was determined. In one embodiment, the first and second scoring systems or tests can be the same or different. In a specific embodiment, one scoring system is used for the first scoring system (or test).

[0009] In another embodiment, the method of counteracting a decrease in blood glucose levels in a subject receiving a SUR1-TRPM4 channel inhibitor comprises administering to the subject an SUR1-TRPM The method may include administering to the subject one or more continuous infusions of a 4 channel inhibitor and co-administering to the subject a dextrose solution.

[0010] In another example, a method for preventing or reducing CNS edema in a subject at high risk for severe brain or spinal cord swelling following an injury or condition associated with CNS edema may include determining whether the subject is at high risk for severe brain or spinal cord swelling, and administering a SUR1-TRPM4 channel inhibitor to the subject if it is determined that the subject is at high risk for severe brain swelling.

[0011] In another example, a method of safely delivering glyburide to a subject can include administering one or more continuous infusions of glyburide to the subject and measuring liver enzyme levels while continuing to administer the glyburide.

[0012] In another example, a method of monitoring cardiac activity when administering a sulfonylurea to a subject can include administering one or more continuous infusions of the sulfonylurea to the subject and performing an electrocardiogram on the subject to monitor the subject's heart.

[0013] In another example, a method of delivering glyburide to a subject can include administering glyburide intravenously to the subject and monitoring blood glucose, liver enzymes, and QTc while the glyburide is administered intravenously to the subject.

[0014] In another example, a method of treating a subject suffering from a large hemispheric infarction can include administering a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor to the subject. The subject can be under 71 years of age, and the treatment can improve functional outcome as measured by one or more outcome scales.

[0015] In another example, a method of treating a subject suffering from a large hemispheric infarction can include administering a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor to the subject. The subject can have a lesion volume of at least about 100 cc, or an ASPECTS score of less than or equal to 5, or both.

[0016] In another example, a method of treating a subject suffering from a large hemispheric infarction can include administering to the subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, which can begin at the time of the index stroke or 9 hours or less from when the subject was last observed normal.

[0017] In another example, a method of treating a subject suffering from a traumatic brain injury can include administering a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor to the subject, who, prior to treatment, can exhibit radiological evidence of intracerebral blood induced by the traumatic brain injury.

[0018] In another example, a method of testing a treatment for treating LHI can include enrolling subjects at least 18 years of age with radiologically defined LHI, treating the subjects with a SUR1-TRPM4 channel inhibitor or a matching placebo for up to about 72 hours starting 9 hours or less from the stroke or from the last observed normal time point, and assessing the mRS. The method can be considered successful if a statistically significant result in favor of the drug is detected in subjects 70 years of age or younger, or if a descriptive benefit is detected in subjects over 70 years of age. In certain embodiments, for example, the following items are provided: (Claim 1) A method for reducing late neurological deterioration or death in a subject after an injury or condition associated with CNS edema, comprising administering a SUR1-TRPM4 channel inhibitor to the subject after the subject has experienced the injury or condition associated with CNS edema, wherein the administering step comprises one or more continuous infusions of the SUR1-TRPM4 channel inhibitor continuing cumulatively for at least 72 hours after the start of the one or more continuous infusions, and wherein the SUR1-TRPM4 channel inhibitor reduces late neurological deterioration. (Claim 2) 10. The method of claim 1, wherein the CNS edema is cerebral edema. (Claim 3) 3. The method of claim 2, wherein the administering step prevents death of the subject. (Claim 4) 10. The method of claim 1, wherein the method reduces late neurological deterioration or death as determined for a population based on the occurrence of late neurological deterioration or death in patients treated with the one or more continuous infusions compared to a similar population not treated with the one or more continuous infusions. (Claim 5) 2. The method of claim 1, wherein the method of reducing late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is first administered within one hour after the subject experiences the injury or condition associated with CNS edema. (Claim 6) 2. 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 first administered within 4.5 hours after the subject experiences the injury or condition associated with CNS edema. (Claim 7) 2. 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 first administered 4.5 to 10 hours after the subject experiences the injury or condition associated with CNS edema. (Claim 8) 2. 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 first administered 6 to 12 hours after the subject experiences the injury or condition associated with CNS edema. (Claim 9) 2. The method of claim 1, wherein the method of reducing late neurological deterioration or death is effective when the SUR1-TRPM4 channel inhibitor is first administered more than about 8 hours after the subject experiences the injury or condition associated with CNS edema. (Claim 10) 2. The method of claim 1, wherein the administration of the one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is for at least 96 hours. (Claim 11) 2. The method of claim 1, wherein the administration of the one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is for at least 120 hours. (Claim 12) 2. The method of claim 1, wherein the administration of the one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is carried out for at least 168 hours. (Claim 13) 2. 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, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 14) 2. The method of claim 1, wherein the SUR1-TRPM4 channel inhibitor is glyburide. (Claim 15) 10. The method of claim 1, wherein said method of treating late neurological deterioration or death is the result of hemorrhagic stroke. (Claim 16) 10. The method of claim 1, wherein said method of treating late neurological deterioration or death is the result of an ischemic stroke. (Claim 17) 17. The method of claim 16, wherein the ischemic stroke occurs in the middle cerebral artery, the intracranial carotid artery, the extracranial carotid artery, or a combination thereof. (Claim 18) 10. The method of claim 1, wherein said method of treating late neurological deterioration is the result of traumatic brain injury. (Claim 19) 10. The method of claim 1, wherein the method of treating late neurological deterioration or death is the result of cardiac arrest, liver failure, intracranial hemorrhage, or neurosurgery. (Claim 20) 10. The method of claim 1, wherein the CNS edema is spinal cord edema and the late neurological deterioration is spinal cord injury. (Claim 21) 10. The method of claim 1, wherein the one or more continuous infusions begin after administration of a bolus dose. (Claim 22) 10. The method of claim 1, wherein the one or more continuous infusions comprise two or more continuous infusion dosages, a first continuous infusion dosage being greater than a second continuous infusion dosage. (Claim 23) 2. The method of claim 1, wherein the one or more continuous infusions are initiated after administration of a bolus dose, and the one or more continuous infusions comprise two or more continuous infusion dosages, a first continuous infusion dosage being greater than a second continuous infusion dosage. (Claim 24) 10. The method of claim 1, wherein the step of administering the SUR1-TRPM4 channel inhibitor is combined with decompressive craniectomy. (Claim 25) 10. The method of claim 1, wherein administering the SUR1-TRPM4 channel inhibitor reduces brain midline shift and cerebral edema in the subject sufficiently to obviate the need for the subject to undergo decompressive craniectomy. (Claim 26) administering a SUR1-TRPM4 channel inhibitor to a subject after the subject has experienced an injury or condition associated with cerebral edema; and performing a decompressive craniectomy on the subject. 20. A method for reducing midline brain shift in said subject following said injury or condition associated with cerebral edema, comprising: (Claim 27) 27. The method of claim 26, wherein the injury or condition associated with cerebral edema is stroke. (Claim 28) 27. The method of claim 26, wherein the method reduces brain midline shift as determined for a population based on the degree of brain midline shift in patients treated with one or more serial infusions compared to a similar population not treated with the one or more serial infusions. (Claim 29) 27. The method of claim 26, 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, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 30) 27. The method of claim 26, wherein the SUR1-TRPM4 channel inhibitor is glyburide. (Claim 31) 27. The method of claim 26, wherein administering the SUR1-TRPM4 channel inhibitor comprises one or more continuous infusions cumulatively lasting for at least 72 hours. (Claim 32) 27. The method of claim 26, wherein administering the SUR1-TRPM4 channel inhibitor comprises one or more continuous infusions cumulatively lasting for at least 96 hours. (Claim 33) 27. The method of claim 26, wherein the step of administering the SUR1-TRPM4 channel inhibitor comprises a bolus dose followed by one or more continuous infusions. (Claim 34) 27. The method of claim 26, wherein the SUR1-TRPM4 channel inhibitor treats swelling of the lesion. (Claim 35) 27. The method of claim 26, wherein the SUR1-TRPM4 channel inhibitor is initially administered to the subject immediately after the injury or condition associated with the cerebral edema until about 12 hours after the subject experiences the injury or condition associated with cerebral edema. (Claim 36) 27. The method of claim 26, wherein the SUR1-TRPM4 channel inhibitor is initially administered to the subject from 4.5 hours after the injury or condition associated with cerebral edema to about 12 hours after the subject experiences the injury or condition associated with cerebral edema. (Claim 37) 27. The method of claim 26, wherein the administering step occurs before or during the decompressive craniectomy. (Claim 38) 27. The method of claim 26, wherein the administering step occurs after decompressive craniectomy. (Claim 39) administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to a subject after the subject has experienced an injury or condition associated with CNW edema; establishing an initial degree of disability in the subject following the injury or condition associated with CNS edema using a first scoring system or test; and determining a second degree of disability using a second scoring system or test after a period of time related to said first degree of disability. a method of treating said subject suffering from said injury or condition associated with CNS edema, comprising administering said SUR1-TRPM4 channel inhibitor resulting in varying degrees of improvement in disability. (Claim 40) 40. The method of claim 39, wherein the first scoring system or test and the second scoring system or test are the same. (Claim 42) 40. The method of claim 39, wherein the first scoring system or test and the second scoring system or test are different. (Claim 43) The method of claim 39, wherein the administering step precedes the establishing step. (Claim 44) The method of claim 39, wherein the establishing step occurs before the administering step. (Claim 45) The method of claim 39, wherein the injury or condition associated with CNS edema is stroke. (Claim 46) The first scoring system or test or the second scoring system or test, or both, may be based on the National Institutes of Health Stroke Scale (NIHSS), Alberta Stroke Scale (AMS), or the National Institutes of Health Stroke Scale (NIHSS). 46. ​​The method of claim 45, wherein the method is selected from the group consisting of Program Early CT Score (ASPECTS), magnetic resonance imaging (MRI), and CT scan. (Claim 47) 46. ​​The method of claim 45, wherein the first scoring system or test is based on the National Institutes of Health Stroke Scoring System and the second scoring system or test is based on a modified Rankin Scale or Barthel Index. (Claim 48) administering to the subject one or more continuous infusions of a SUR1-TRPM4 channel inhibitor; and co-administering a dextrose solution to said subject. a method for neutralizing a decrease in blood glucose levels in said subject receiving said SUR1-TRPM4 channel inhibitor, comprising: (Claim 49) 49. The method of claim 48, wherein the administering step is for the treatment of an injury or condition not associated with CNS edema. (Claim 50) 49. The method of claim 48, wherein the administering step is for the treatment of an injury or condition associated with cerebral edema. (Claim 51) 49. The method of claim 48, wherein the dextrose solution comprises saline or water and about 3% to about 12% dextrose by weight. (Claim 52) 49. The method of claim 48, further comprising measuring blood glucose levels before or during said administering step. (Claim 53) 53. The method of claim 52, wherein the dextrose solution is initially administered if the blood glucose level of the subject is about 120 mg / dL or less. (Claim 54) 53. The method of claim 52, wherein the dextrose solution is initially administered if the blood glucose level of the subject is about 100 mg / dL or less. (Claim 55) 53. The method of claim 52, wherein a 3% to 8% by weight dextrose solution is administered to the subject at about 50 cc / hour to about 120 cc / hour when the blood glucose level is greater than about 80 mg / dL to 100 mg / dL. (Claim 56) 53. The method of claim 52, wherein an 8% to 12% by weight dextrose solution is administered to the subject at 50 cc / hour to 120 cc / hour when the blood glucose level is between about 55 mg / dL and 80 mg / dL. (Claim 57) 53. The method of claim 52, wherein an 8% to 12% by weight dextrose solution is administered to the subject at 50 cc / hour to 120 cc / hour if the blood glucose level is below 55 mg / dL. (Claim 58) 53. The method of claim 52, wherein administration of the SUR1-TRPM4 channel inhibitor is reduced or stopped if the blood glucose level falls below 55 mg / dL. (Claim 59) 53. The method of claim 52, wherein the blood glucose level is first verified, either by performing a separate bedside measurement or by clinical testing, and then administration of the SUR1-TRPM4 channel inhibitor is stopped or reduced. (Claim 60) 53. The method of claim 52, further comprising monitoring blood glucose levels hourly for at least 12 hours. (Claim 61) 53. The method of claim 52, further comprising the steps of monitoring blood glucose levels every hour for 24 hours, monitoring blood glucose every two hours for the next 24 hours, and monitoring blood glucose levels every four hours while continuing the administering step. (Claim 62) 53. The method of claim 52, further comprising co-administering a bolus of a dextrose solution to the subject when the blood glucose level of the subject falls below a predetermined level. (Claim 63) 53. The method of claim 52, wherein if the subject's blood glucose level is greater than about 80 mg / dL, then the step of co-administering the dextrose solution is stopped. (Claim 64) 65. The method of claim 52, wherein the co-administering of the dextrose solution is stopped if the subject's blood glucose level is greater than about 100 mg / dL. 53. The method of claim 52, wherein if the subject's blood glucose level is greater than about 120 mg / dL, then the step of co-administering the dextrose is stopped. (Claim 66) 67. The method of claim 52, wherein the co-administering of the dextrose solution is stopped if the subject's blood glucose level is greater than about 140 mg / dL. 53. The method of claim 52, wherein the rate of dextrose administration is increased after blood glucose has tended to decline rapidly. (Claim 68) 68. The method of claim 67, wherein the trend toward a rapid decline in blood glucose is defined as a decrease of > 10 mg / dL from the last measurement. (Claim 69) 68. The method of claim 67, wherein the trend toward a rapid decline in blood glucose is defined as a decrease of > 30 mg / dL from the last measurement. (Claim 70) 49. 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, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 71) 49. The method of claim 48, wherein the inhibitor of the SUR1-TRPM4 channel is glyburide. (Claim 72) The method of claim 50, wherein the injury or condition associated with CNS edema is stroke. (Claim 73) determining whether the subject is at high risk for severe brain or spinal cord swelling, and administering a SUR1-TRPM4 channel inhibitor to the subject if the subject is determined to be at high risk for severe brain or spinal cord swelling. 10. A method of preventing or reducing CNS edema in a subject at high risk of severe brain or spinal cord swelling following an injury or condition associated with CNS edema, comprising: (Claim 74) 74. The method of claim 73, wherein the subject has experienced a stroke and the CNS edema is cerebral edema. (Claim 75) 75. The method of claim 74, wherein the subject is considered to be at high risk for severe brain swelling if 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 of greater than 50 cc, poor collateral circulation as determined by CT angiography, and a CT scan showing hypodensity involving at least 33% of the middle cerebral artery territory. (Claim 76) 76. The method of claim 75, wherein the subject is considered at high risk for severe brain swelling if the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 82 cc. (Claim 77) 76. The method of claim 75, wherein the subject is considered at high risk for severe brain swelling if the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 145 cc. (Claim 78) 76. The method of claim 75, wherein the subject is considered at high risk for severe brain swelling if the subject exhibits a magnetic resonance imaging (MRI) diffusion weighted image (DWI) of greater than 145 cc. (Claim 79) 76. The method of claim 75, wherein the subject is considered at high risk for severe brain swelling if the subject exhibits a CT perfusion score of greater than 70 cc. (Claim 80) 76. The method of claim 75, wherein the subject is considered at high risk for severe brain swelling if the subject exhibits a CT scan showing hypodensity involving at least 50% of the middle cerebral artery territory. (Claim 81) 74. The method of claim 73, wherein the administering step is by one or more continuous infusions of the SUR1-TRPM4 channel inhibitor for a cumulative period of at least 72 hours. (Claim 82) 74. 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, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 83) 74. The method of claim 73, wherein the SUR1-TRPM4 channel inhibitor is glyburide. (Claim 84) 74. The method of claim 73, wherein said administering is within 12 hours of said injury or condition associated with said CNS edema. (Claim 85) administering one or more continuous infusions of glyburide to the subject; and measuring liver enzyme levels while continuing to administer the glyburide. A method for delivering glyburide to a subject, comprising: (Claim 86) 86. The method of claim 85, wherein the administering step is for the treatment of an injury or condition associated with spinal cord edema. (Claim 87) 87. The method of claim 86, wherein said administering is for the treatment of an injury or condition associated with cerebral edema. (Claim 88) 88. The method of claim 87, wherein the injury or condition associated with cerebral edema is stroke. (Claim 89) 86. The method of claim 85, further comprising the preceding step of measuring liver enzyme levels prior to administering said glyburide. (Claim 90) 86. The method of claim 85, wherein said step of measuring liver enzyme levels comprises measuring said liver enzyme levels a specified period of time after initiating said administering step. (Claim 91) 91. The method of claim 90, wherein the specified period of time is about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 168 hours, the day the subject is discharged from the hospital, or a combination thereof. (Claim 92) 86. The method of claim 85, wherein the liver enzyme measured is aspartate aminotransferase (AST). (Claim 93) 86. The method of claim 85, wherein the liver enzyme measured is alanine aminotransferase (ALT). (Claim 94) 85. The method of claim 84, wherein the administering step is modified or discontinued based on the results of the measuring step. (Claim 95) 86. The method of claim 85, wherein the step of administering glyburide is discontinued if the subject's ALT level rises above about 8 times the upper limit of normal ALT levels as determined by the administering physician. (Claim 96) 61. The method of claim 60, wherein the step of administering glyburide is discontinued if the subject develops cholestatic jaundice or hepatitis. (Claim 97) administering to the subject one or more continuous infusions of a sulfonylurea; and performing an electrocardiogram on the subject to monitor the subject's heart; A method for monitoring cardiac activity when glyburide is administered to said subject, comprising: (Claim 98) 98. The method of claim 97, wherein the administering step is for the treatment of an injury or condition associated with spinal cord edema. (Claim 99) 98. The method of claim 97, wherein said administering is for the treatment of an injury or condition associated with cerebral edema. (Claim 100) 98. The method of claim 97, wherein the injury or condition associated with cerebral edema is stroke. (Claim 101) 98. The method of claim 97, wherein said step of performing said electrocardiogram comprises the preceding step of performing said electrocardiogram on said subject prior to administering said sulfonylurea. (Claim 102) 98. The method of claim 97, wherein said step of performing an electrocardiogram comprises performing an electrocardiogram on the subject a specified period of time after starting said administering step. (Claim 103) 98. The method of claim 97, wherein the specified period of time is about 4 hours to about 6 hours, about 24 hours, about 48 hours, about 60 hours to about 72 hours, about 168 hours, the day the subject is discharged from the hospital, or a combination thereof. (Claim 104) 98. The method of claim 97, wherein said step of administering said sulfonylurea is discontinued if the QTc of said electrocardiogram exceeds about 550 ms. (Claim 105) 98. The method of claim 97, wherein the injury or condition associated with cerebral edema is stroke. (Claim 106) administering glyburide intravenously to the subject; and monitoring blood glucose, liver enzymes, and QTc during the step of intravenously administering the glyburide to the subject. A method for delivering glyburide to a subject, comprising: (Claim 107) 107. The method of claim 106, further comprising administering dextrose to the subject. (Claim 108) A method of treating a subject suffering from a massive cerebral hemispheric infarction, comprising administering to the subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein the subject is under 71 years of age and the treatment improves functional outcome as measured by one or more outcome scales. (Claim 109) A method of treating a subject suffering from a massive cerebral hemispheric infarction, comprising administering to the subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein the subject has a lesion volume of at least about 100 cc or an ASPECTS score of ≦5, or both. (Claim 110) A method of treating a subject suffering from a massive cerebral hemispheric infarction, comprising administering to the subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor, wherein the administering step is initiated 9 hours or less from the time of confirmed stroke or from the time the subject was last observed to be normal. (Claim 111) A method of treating a subject suffering from a traumatic brain injury, comprising administering to the subject a therapeutically effective amount of an intravenous SUR1-TRPM4 channel agent, wherein the subject shows radiological evidence of intracerebral blood induced by the traumatic brain injury prior to treatment. (Claim 112) enrolling subjects at least 18 years of age who are radiologically defined as having LHI; treating the subject with a SUR1-TRPM4 channel inhibitor or matching placebo for up to about 72 hours starting 9 hours or less from the stroke or from the last observed normal time point; assessing the mRS; A method for testing a treatment for large hemispheric cerebral infarction, comprising: detecting a statistically significant result in favor of the drug in subjects 70 years of age or younger, or detecting a descriptive benefit in subjects over 70 years of age, and the method is deemed successful if a statistically significant result in favor of the drug is detected in subjects 70 years of age or younger, or detecting a descriptive benefit in subjects over 70 years of age.

[0019] Reference will now be made to the illustrated exemplary embodiments, and specific terminology is used herein to describe the same, with the understanding, however, that these drawings depict only exemplary embodiments and are therefore not to be considered limiting of the scope thereof. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the incidence rate of mortality in individuals suffering from injuries or conditions associated with cerebral edema according to clinical studies performed and presented herein. [Figure 2] FIG. 2 shows the incidence of deaths in individuals suffering from injuries or conditions associated with cerebral edema who underwent decompressive craniectomy and were treated with either the study drug or a placebo in the clinical studies conducted and presented herein. [Figure 3] FIG. 3 shows the distribution of mRS scores for individuals in the clinical study. [Figure 4] FIG. 4 shows the median 90-day Barthel Index scores of individuals in the clinical study performed and presented herein. [Figure 5] FIG. 5 shows the mean percent reduction in brain midline shift for study participants. [Figure 6] FIG. 6 shows the FLAIR ratios of individuals in the clinical study performed and presented herein. [Figure 7] FIG. 7 shows the blood-brain barrier disruption in individuals in the clinical studies performed and presented herein. [Figure 8] Figure 8 shows an analysis of mRS outcomes according to lesion size in extensive hemispheric infarction. DETAILED DESCRIPTION OF THE INVENTION

[0021] Before particular embodiments of the present invention are disclosed and described, it is to be understood that this invention is not limited to the particular process and materials disclosed herein, as such may vary to some extent. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be defined only by the appended claims and equivalents thereof.

[0022] In describing and claiming the present invention, the following terminology will be used.

[0023] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a SUR1-TRPM4 channel inhibitor" includes a reference to one or more of such SUR1-TRPM4 channel inhibitors.

[0024] As used herein, the term "active agent" refers to an agent added to a composition. It refers to a compound or mixture of compounds that tends to produce a particular therapeutic effect when combined.

[0025] As used herein, the term "large hemispheric infarction" or "LHI" refers to a large hemispheric infarction that occurs in adjacent (e.g., 、 Refers to an ischemic stroke affecting the entire or subtotal territory of the middle cerebral artery (MCA), with or without involvement of the anterior cerebral artery [ACA] and / or posterior cerebral artery [PCA] territories.

[0026] As used herein, "late neurological deterioration" refers to neurological deterioration that occurs after injury or condition that causes neurological swelling. The deterioration begins after the injury or condition occurs, but can occur up to 72 hours, 96 hours, 120 hours, 144 hours, 168 hours or longer after the underlying injury or condition.

[0027] The term "lesion" refers to an abnormality in the tissue of the brain. In some cases, a lesion may be a space-occupying lesion that has a discernible volume and may affect nearby tissue and blood vessels.

[0028] As used herein, the term "placebo" refers to a formulation that does not contain a SUR1-TRPM4 antagonist, or a formulation that is similar in composition except that the amount (wt%) of a SUR1-TRPM4 channel inhibitor is replaced with an equal amount (wt%) of another inactive ingredient, such as water. Furthermore, a "placebo" may have typical minor formulation differences due to the absence of a drug, as will be understood by those skilled in the art.

[0029] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and most typically refers to a human patient.

[0030] The term "sulfonylurea" includes sulfonylureas, sulfonylurea mimetics, and any other compositions effective to block or reduce activity associated with the SUR1 channel.

[0031] The term "CNS edema" or "central nervous system edema" refers to swelling that can occur anywhere in the central nervous system, including in or near the brain or in or near the spinal cord. Thus, "spinal cord edema" and "cerebral edema" are two specific types of CNS edema, one affecting the spinal cord and the other the brain, respectively.

[0032] The phrases "CNS edema-related" or "brain edema-related" or "spinal cord-related" "injury or condition" refer to a triggering event that can cause or contribute to edema, such as CNS edema, e.g., cerebral edema or spinal cord edema. However, it should be noted that these injuries or conditions do not always result in edema in all patients. For example, stroke is a condition generally associated with CNS edema, and more specifically, cerebral edema. In certain more severe cases, stroke can result in life-threatening cerebral edema. Thus, stroke is a condition associated with CNS edema or cerebral edema, in that there is a risk of stroke-related cerebral edema. In some specific examples, injuries or conditions associated with cerebral edema may include ischemic stroke, hemorrhagic stroke, traumatic brain injury, cardiac arrest, liver failure, intracranial hemorrhage, neurosurgery, etc. Spinal cord injury, on the other hand, may be associated with spinal cord edema. Some of these injuries or conditions are not directly related to the brain or spinal cord, such as cardiac arrest or liver failure, but these injuries or conditions are known to result in CNS or cerebral edema in some cases.

[0033] "Traumatic brain injury" refers to an injury associated with mild, moderate, or severe damage that results in swelling in or around the brain and is typically direct to an area of ​​the brain (e.g., an injury affecting or near the head that can cause cerebral edema).

[0034] A "stroke" occurs when blood flow to the brain is insufficient, which can lead to cell death. As defined herein, there are essentially two known types of stroke: ischemic stroke or hemorrhagic stroke. Ischemic stroke occurs when blood flow to the brain is insufficient, while hemorrhagic stroke occurs when there is bleeding in the cranial vault or within brain tissue, and includes subarachnoid hemorrhage and intracerebral hemorrhage. Both forms can lead to cerebral edema.

[0035] As used herein, and as is well understood in the art, the terms "treating" or "treatment" refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, the alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, attenuation of the extent of the disease, stabilization of the condition (i.e., not worsening), delay or slowing of disease progression, remission or palliation of the condition, attenuation of disease recurrence, and remission (partial or complete). "Treating" and "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. In addition to being useful as a method of treatment, the methods described herein can be useful for the prevention or prophylaxis of disease.

[0036] As used herein, the term "about" is used to provide flexibility to the endpoint of a numerical range by allowing a given value to be "slightly above" or "slightly below" the endpoint. The degree of flexibility in this term may be determined by the specific variable, and it would be within the knowledge of a person skilled in the art to determine it based on experience and the relevant descriptions herein. For example, in one embodiment, the degree of flexibility may be within about ±10% of the numerical value. In another embodiment, the degree of flexibility may be within about ±5% of the numerical value. In further embodiments, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

[0037] Throughout this specification the term "or" includes "and / or".

[0038] As used herein, for convenience, multiple active agents, compounds, injuries or conditions, etc. may be presented in a common list. However, these lists should be construed as identifying each member of the list individually as a separate and unique member. Therefore, any individual member of such a list should not be construed as a de facto equivalent of any other member of the same list based on their presentation in a common group, unless otherwise indicated.

[0039] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. Such range format is used merely for convenience and brevity, and thus, not only the numerical values ​​expressly recited as limits of a range, but also all individual numerical values ​​or sub-ranges subsumed within that range, as each numerical value and sub-range is expressly set forth. It should be understood that the numerical range "about 0.01 to 2.0" should be interpreted flexibly to include not only the specifically recited value of about 0.01 to about 2.0, but also individual values ​​and subranges within the stated range. Thus, included within this numerical range are individual values ​​such as 0.5, 0.7, and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5. Furthermore, such interpretation should apply regardless of the breadth or characteristics of the range described. Furthermore, it should be noted that all percentages are by weight unless otherwise specified.

[0040] As used herein, all composition percentages are given as weight percent unless otherwise stated. When solutions of components are referred to, the percentage refers to the weight percent of the composition including the solvent (e.g., water) unless otherwise indicated.

[0041] In understanding the scope of the present disclosure, as used herein, the terms "including" or "comprising" and their derivatives are intended to be open-ended terms that specify the presence of stated properties, components, ingredients, groups, integers, and / or steps, but do not exclude the presence of other unstated properties, components, ingredients, groups, integers, and / or steps. This also applies to words of similar meaning, such as the terms "including," "having," and their derivatives. As used herein, the term "consisting" and its derivatives are intended to be closed terms that specify the presence of stated properties, components, ingredients, groups, integers, and / or steps, but exclude the presence of other unstated properties, components, ingredients, groups, integers, and / or steps. As used herein, the term "consisting essentially of" is intended to specify the presence of the stated properties, components, ingredients, groups, integers, and / or steps, as well as properties, components, ingredients, groups, integers, and / or steps that do not materially affect the basic and novel characteristic(s) of the properties, components, ingredients, groups, integers, and / or steps. Reference to any one of these transition terms (i.e., "comprising," "consisting," or "consisting essentially of") is understood to directly support substitution for any of the other transition terms not specifically used. For example, modifying the term "comprising" to "consisting essentially of" would be directly supported by this definition.

[0042] As used herein, for convenience, multiple compounds or steps may be presented in a common list. However, these lists should be construed as if each member of the list is individually identified as a separate and unique member. Therefore, any individual member of such a list should not be construed as a de facto equivalent of any other member of the same list based on their presentation in a common group, unless otherwise indicated.

[0043] Furthermore, certain compositions, injuries or conditions, steps, etc. may be discussed in the context of one specific embodiment. This is for convenience only, and it is understood that such disclosure is equally applicable to other embodiments found herein. For example, a list of active agents or drugs described in connection with a method for treating late neurological deterioration or death directly supports that embodiment, even if these drugs are not listed again in the context of an embodiment herein relating to a method for reducing midline brain shift.

[0044] In one embodiment, a method for reducing late neurological deterioration or death in a subject after injury or condition associated with CNS edema is provided.The method comprises cumulatively administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to a subject for at least about 72 hours after the start of the continuous infusion(s).It has been found that administering a SUR1-TRPM4 channel inhibitor can reduce the incidence of late neurological deterioration or death.Although this method is subject-related, typically, the occurrence of late neurological deterioration or death can be determined based on a comparison with the occurrence of late neurological deterioration in a group of patients who have not been treated with a SUR1-TRPM4 channel inhibitor."Late neurological deterioration" refers to neurological deterioration that occurs long after injury or condition associated with CNS edema. An extended period of time can include ≧24 hours, ≧48 hours, ≧72 hours, ≧84 hours, ≧96 hours, ≧108 hours, ≧120 hours, ≧132 hours, ≧148 hours, ≧160 hours, ≧172 hours, or about ≧184 hours.

[0045] SUR1-TRPM4 channel inhibitors may include any active agent effective in blocking SUR1-TRPM4, and some examples may include glyburide (also known as glibenclamide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, or glimepiride, metabolites that interact with SUR1, or combinations thereof. Some compounds that act on non-selective channels that may be associated with SUR include, for example, pincolant, flufenamic acid, mefenamic acid, niflumic acid, rimonabant, and SKF963. In one embodiment, the SUR1-TRMP4 channel inhibitor is glyburide. In another embodiment, the SUR1-TRMP4 channel inhibitor is tobutamide. In yet another embodiment, the SUR1-TRMP4 channel inhibitor is glycazide. is.

[0046] The SUR1-TRPM4 channel inhibitor can be administered as a bolus injection, continuous infusion, or a combination thereof. In some cases, administration can include multiple bolus injections or multiple continuous infusions. In other embodiments, administration can include one or more continuous infusions after a bolus injection. For example, a bolus injection can be followed by a first continuous infusion, and then a second continuous infusion with a slower infusion rate than the first infusion. In another embodiment, a bolus injection is followed by a continuous infusion. In another embodiment, a bolus injection is followed by a first continuous infusion, and then a second continuous infusion. In yet another embodiment, the first continuous infusion is followed by a second continuous infusion and a third continuous infusion.

[0047] The administration provided herein can be carried out over a long period of time. Administration can be carried out over a period of ≥12 hours, ≥24 hours, ≥48 hours, ≥72 hours, ≥76 hours, ≥80 hours, ≥84 hours, ≥88 hours, ≥92 hours, ≥96 hours, ≥100 hours, ≥104 hours, ≥108 hours, ≥112 hours, ≥116 hours, ≥120 hours, ≥124 hours, ≥128 hours, ≥132 hours, ≥136 hours, ≥140 hours, ≥144 hours, ≥148 hours, ≥152 hours, ≥156 hours, ≥160 hours, ≥164 hours, ≥168 hours, or ≥172 hours. In one embodiment, administration comprises one or more continuous infusions for a cumulative duration of at least 72 hours. In another embodiment, administration comprises one or more continuous infusions for at least 96 hours. In yet another embodiment, the administration comprises one or more continuous infusions for at least 120 hours. In alternative examples, the administration of one or more continuous infusions can occur over a period of ≦72 hours, ≦48 hours, or ≦24 hours.

[0048] The exact dosage will vary based on the underlying condition, the degree of swelling, the subject's weight, and / or the SUR1-TRMP4 channel inhibitor administered. The bolus injection is expected to be administered at about 100 μg to about 200 μg. In one embodiment, the bolus injection is about 110 μg to about 140 μg, or about 125 μg. In another embodiment, the bolus injection is about 140 μg to about 160 μg, or about 150 μg. In yet another embodiment, the bolus injection is about 160 μg to about 190 μg, or about 175 μg. The continuous infusion is expected to be administered at an infusion rate of about 100 μg / hour to about 300 μg / hour. In one embodiment, the infusion rate is about 110 μg / hour to about 140 μg / hour, or about 125 μg / hour. In another embodiment, the infusion rate is about 140 μg / hour to about 160 μg / hour, or about 150 μg / hour. In yet another embodiment, the infusion rate is about 160 μg / hour to about 190 μg / hour, or about 175 μg / hour. In a further embodiment, the infusion rate is about 190 μg / hour to about 225 μg / hour, or about 200 μg / hour. Further embodiments include infusion rates of about 225 μg / hour to about 300 μg / hour, or about 250 μg / hour.

[0049] Unlike clot busters, which are typically administered to subjects with ischemic stroke, SUR1-TRPM4 channel inhibitors do not cause bleeding. Therefore, SUR1-TRPM4 channel inhibitors can be effective both when first administered immediately after the injury or condition, or when first administered at a period after the injury or condition associated with cerebral edema occurs. In one embodiment, the first administration of the SUR1-TRPM4 channel inhibitor can be within the first hour, the first two hours, the first three hours, the first four hours, the first six hours, the first eight hours, or the first ten hours after the onset of the injury or condition. In another embodiment, the first administration of the SUR1-TRPM4 channel inhibitor can be at least 4 hours, at least 4.5 hours (a period during which clot busters may be ineffective or even dangerous), at least 6 hours, at least 8 hours, or at least 10 hours after the injury or condition associated with cerebral edema occurs. In another example, the first administration of the SUR1-TRPM4 channel inhibitor can be within 6 hours after the injury or condition occurs. In a further embodiment, the first administration of the SUR1-TRPM4 channel inhibitor may be within 6 hours after the injury or condition occurs. In another embodiment, the first administration may be within 8 hours after the injury or condition occurs. In a further embodiment, the first administration of the SUR1-TRPM4 channel inhibitor may be within 10 hours after the injury or condition occurs.

[0050] The underlying injury or condition that leads to late neurological deterioration, death, or other conditions discussed herein is not particularly limited. This may include any disease or condition that leads to brain swelling. In one embodiment, the underlying condition is traumatic brain injury. In another embodiment, the underlying condition is stroke. If the underlying condition is stroke, the stroke can be ischemic or hemorrhagic stroke. In another embodiment, the stroke can be ischemic stroke, occurring in the middle cerebral artery or carotid artery (intracranial or extracranial) or any other location related to ischemic stroke. If the stroke is hemorrhagic stroke, it can occur or originate from any known location related to hemorrhagic stroke, including both or either subarachnoid hemorrhage or intracerebral hemorrhage.

[0051] Also provided herein is a method for reducing brain midline shift in a subject after traumatic brain injury or stroke.Cerebral midline shift can be caused by changes in lesion volume or lesion swelling.The method can include administering a SUR1-TRPM4 channel inhibitor to the subject after the subject has experienced an injury or condition related to cerebral edema, and performing decompressive craniectomy on the subject.Midline shift can be measured by CT scan or MRI scan, or by using transcranial Doppler.The reduction of midline shift can be determined by comparing the amount of midline shift in stroke or TBI patients who have not been treated with a SUR1-TRPM4 channel inhibitor or decompressive craniectomy. The reduction in brain midline shift is greater than about 5%, greater than about 8%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, less than about 40%, The reduction in brain midline shift may be greater than 5% or greater than about 50%. In some embodiments, the reduction in brain midline shift is greater than the reduction achieved when a SUR1-TRPM4 channel inhibitor is administered or when decompressive craniectomy is performed. In other embodiments, the reduction is greater than the additive effect of either treatment administered individually. In one embodiment, the SUR1-TRPM4 channel inhibitor reduced both lesion volume and lesion swelling. In another embodiment, the SUR1-TRPM4 channel inhibitor not only reduces brain midline shift but also treats lesion swelling. In some examples, the method may further include administering tissue plasminogen activator (TPA) or a clot buster activator before or together with the SUR1-TRPM4 channel inhibitor. This may be particularly effective when TPA or a clot buster activator is administered, but is still considered safe, for example, within the first 4.5 hours of an injury or condition associated with cerebral edema. Examples of TPA or clot buster activators that can be co-administered include activase, tenectoplase, urokinase, streptokinase, and / or desmoteplase. Furthermore, clots can be removed by devices, i.e., mechanical thrombectomy. Administration of TPA or clot buster activators is typically by intravenous infusion, but oral and subcutaneous administration are also included as administration routes. The SUR1-TRPM4 channel inhibitor, dosage form, dosage rate, dosage time frame, dosage duration for initial administration, underlying condition, and other details can be as discussed above.

[0052] Furthermore, the present disclosure relates to a method for improving the degree of disability in a subject suffering from an injury or condition associated with CNS edema. The method includes administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to the subject after the subject suffers from an injury or condition associated with CNS edema. A further step includes establishing the subject's initial degree of disability based on a first scoring system or test, and determining a second degree of disability using a second scoring system or test after a certain period of time has passed since the initial degree of disability was determined. In one embodiment, the first and second scoring systems or tests can be the same or different. In this embodiment, the improvement in the subject is determined, e.g., quantified, by the scoring system(s). In one embodiment of this method, as a result of administering the SUR1-TRPM4 channel inhibitor, an improvement in the difference in the degree of disability is achieved based on the scoring system(s). For example, an improvement in the difference in the degree of disability of at least about 10% based on a stroke scoring system can be achieved. In other embodiments, the reduction in the degree of disability may be at least about 15%, at least about 20%, at least about 25%, or at least about 30%. Scoring systems may be based on the National Institutes of Health Stroke Scoring System (NIHSS), the modified Rankin Scale, the Barthel Index, or the size of the lesion measured by CT and / or MRI, particularly if the injury or condition associated with CNS edema is stroke. In one example, a first scoring system or test may be based on the NIHSS, and a second scoring system or test may be based on the modified Rankin Scale or the Barthel Index or the NIHSS. Imaging and / or other scoring systems may be used for other injuries or conditions associated with CNS edema.

[0053] In another example, a method for treating a subject suffering from a large hemispheric infarction can include administering a therapeutically effective amount of an intravenous SUR1-TRPM4 channel inhibitor to the subject. In one example, the subject can be under 71 years old, and treatment can improve functional outcomes as measured by one or more outcome scales. In another example, the subject can have a lesion volume of at least about 100 cc, or an ASPECTS score of less than or equal to 5, or both. In another example, administration can begin 9 hours or less from the time of stroke confirmation or from the time the subject was last observed normal. In yet another example, the subject can exhibit radiological evidence of intracerebral blood induced by traumatic brain injury prior to treatment. Radiological evidence can be obtained using MRI or CT. The intracerebral blood can result from a focal contusion, for example, having a minimum volume of at least about 0.5 mL or at least about 1 mL.

[0054] In another example, a method for testing a treatment for large hemispheric infarction may include enrolling subjects at least 18 years of age with radiologically defined LHI, treating the subjects with a SUR1-TRPM4 channel inhibitor or a matching placebo for up to about 72 hours, starting 9 hours or less from the stroke or from the last observed normal time point, and assessing the mRS. The method may be considered successful if a statistically significant result in favor of the drug is detected in subjects 70 years of age or younger, or if a descriptive benefit is detected in subjects over 70 years of age.

[0055] The SUR1-TRPM4 channel inhibitor, dosage form, dosage rate, dosage time frame, dosage period for initial dosing, underlying condition, other details, etc. may be as discussed above and elsewhere herein.

[0056] In another embodiment, a method for counteracting a decrease in blood glucose levels in a subject receiving a SUR1-TRPM4 channel inhibitor can include administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to the subject and co-administering a dextrose solution to the subject. A further step can include measuring blood glucose levels before or during such administration. In one example, administration can be after or as a result of an injury or condition associated with CNS edema. In another example, such a method can also be for administering a SUR1-TRPM4 channel inhibitor for indications other than those associated with CNS edema. In any case, this can be done to protect the kidney, liver, intestine, or heart.

[0057] In one embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 100 mg / dL or less. In another embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 95 mg / dL or less. In yet another embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 90 mg / dL or less. In yet another embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 80 mg / dL or less. In a further embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 110 mg / dL or less. In a further embodiment, the dextrose solution is administered first if the subject's blood glucose level is about 120 mg / dL or less. In yet another embodiment, the dextrose solution is administered if the subject's blood glucose level is trending rapidly downward. In general, dextrose supplementation should not typically be administered if blood glucose is above about 140 mg / dL. A rapid decline is defined by the clinician but may include a decrease of ≥ 10 mg / dL, ≥ 20 mg / dL, ≥ 30 mg / dL, ≥ 40 mg / dL, ≥ 50 mg / dL, ≥ 60 mg / dL, ≥ 70 mg / dL, ≥ 80 mg / dL, ≥ 90 mg / dL, or ≥ 100 mg / dL from the last measurement.

[0058] Dextrose solutions can contain dextrose in saline or water. The weight percent of dextrose in a dextrose solution is typically 1% to 25% by weight, although concentrations outside this range, such as 2% to 20% by weight, 3% to 15% by weight, 3% to 12% by weight, 3% to 8% by weight, and 8% to 12% by weight, can also be used. In other words, the weight percent of dextrose in a dextrose solution can vary and be administered to a subject based on certain variables, including the subject's blood glucose level. Exemplary dextrose solutions, such as commonly used dextrose solutions, can include 5% dextrose by weight in normal saline (D5NS) and 10% dextrose by weight in normal saline (D10NS), although such solutions can also be in water or partial normal saline (e.g., 1 / 2 normal saline) rather than in normal saline. In one embodiment, if a subject's blood glucose level is greater than about 80 mg / dL to 100 mg / dL, a 3% to 8% by weight dextrose solution may be administered to the subject at about 50 cc / hour to about 120 cc / hour. In another embodiment, if a subject's blood glucose level is between about 55 mg / dL and 80 mg / dL, a 8% to 12% by weight dextrose solution may be administered to the subject at 50 cc / hour to 120 cc / hour. In yet another embodiment, if a subject's blood glucose level is <55 mg / dL, a 8% to 12% by weight dextrose solution may be administered to the subject at 50 cc / hour to 120 cc / hour. In a further embodiment, if a subject's blood glucose level falls below 55 mg / dL, administration of glyburide or other SUR1-TRPM4 channel inhibitor is reduced or even stopped entirely. In some embodiments, if the subject's blood glucose level falls below a certain level, such as 70 ml / dL, the method further includes administering a bolus of dextrose solution to the subject. In one embodiment, the bolus can be a 5% to 60% by weight dextrose solution in water or saline, specifically 50% dextrose in water (D50W), ½ normal saline, or normal saline.

[0059] When determining the amount of dextrose to be delivered, the physician may consider the total fluid appropriately delivered to the subject (which may include maintenance fluid and fluid containing a SUR1-TRPM4 channel inhibitor). In one example, the total fluid volume may be, for example, 50 cc / hour to 200 cc / hour, or 70 cc / hour to 150 cc / hour, or 80 cc / hour to 130 cc / hour. The exact volume may depend on clinical judgment and should take into account any history of pulmonary edema. Using the Holliday-Segar nomogram, a typical total fluid rate for a 70 kg individual is 100 cc / hour, and for a 100 kg individual, it is 130 cc / hour.

[0060] In some embodiments, the method further comprises monitoring the subject's blood glucose level. Monitoring can be performed every hour, every 2 hours, every 4 hours, every 8 hours, every 12 hours, every 24 hours, or a combination thereof. In a specific embodiment, monitoring can be performed every hour for the first 24 hours that the SUR1-TRPM4 channel inhibitor is administered, then every 2 hours for the next 24 hours, for example, between the 25th and 48th hours that the SUR1-TRPM4 channel inhibitor is administered, and then every 4 hours for the remainder of the R1-TRPM4 channel inhibitor infusion. Once the subject's blood glucose level falls below 70 mg / dL, monitoring can be performed, for example, every 15 minutes until the subject's blood glucose level rises to ≥ 80 mg / dL for three consecutive readings without exogenous bolus glucose administration.

[0061] In some cases, a decision may be made to stop administering the dextrose solution if the blood glucose level is high. In this example, the dextrose solution may be stopped when the subject's blood glucose level is ≧150 mg / dL, about ≧140 mg / dL, about ≧130 mg / dL, or about ≧120 mg / dL. In one example, a whole blood glucose of <70 mg / dL may be verified before stopping or reducing administration of the drug, either by performing another measurement at the bedside or by clinical testing.

[0062] In one embodiment, a subject treated with a SUR1-TRPM4 inhibitor can be monitored for blood glucose, in one example as follows: Every hour (±30 minutes) for the first 24 hours or so, Every 2 hours (±30 minutes) from approximately 25 hours to approximately 48 hours, and Then every 4 hours (± 60 minutes).

[0063] Once blood glucose falls to below about 70 mg / dL, the monitoring frequency can be increased to every 15 minutes (±10 minutes) until blood glucose is greater than or equal to about 80 for about three consecutive readings without exogenous glucose supplementation.

[0064] When the drug is discontinued and restarted, blood glucose can be measured hourly for approximately 3 hours (±30 minutes).

[0065] If glucose is no longer needed, monitoring can be returned to the previous protocol frequency, eg, 1, 2, or 4 hours in this example.

[0066] In another embodiment, blood glucose may be controlled in a subject treated with a SUR1-TRPM4 inhibitor, for example, as follows: If baseline blood glucose is less than about 100 mg / dL, the initial maintenance fluid may be about 5% dextrose in normal saline (D5NS) at a rate of about 70 to about 100 cc / hour. - If blood glucose falls below about 100 mg / dL, D5NS may be initiated at about 70 to about 100 cc / hour. Increased or decreased IV fluid rate titration may be required. It can be used to maintain blood glucose above about 80 mg / dL. If blood glucose is below about 80 mg / dL, D5NS can be initiated, or if already receiving D5NS, the subject can be switched to about 10% dextrose in normal saline (D10NS). - If blood glucose tends to fall rapidly or continuously, D5NS can be initiated, or if D5NS is already being administered, the subject can be switched to D10NS. In the event that blood glucose is higher than about 140 mg / dL, D5NS or D10NS cannot be administered. Any confirmed blood glucose below about 70 mg / dL can be treated with a 50 mL ampoule of about 50% dextrose in water (D50W). If D50W is not available, another concentration of dextrose fluid can be used in sufficient volume to achieve an equivalent amount of dextrose.

[0067] The SUR1-TRPM4 channel inhibitor, dosage form, dosage rate, dosage time frame, dosage period for initial administration, underlying condition, other details, etc. may be as discussed above and elsewhere herein, or may be modified, for example, according to a clinical decision made by the treating medical professional. For example, different dosages and timing may be implemented, or different routes of administration may also be implemented.

[0068] In another example, a method for preventing brain swelling in a subject at high risk for severe brain swelling may include determining whether the subject is at high risk for severe brain swelling, and administering one or more continuous infusions of a SUR1-TRMP4 channel inhibitor to the subject once determined to be at high risk for severe brain swelling.

[0069] Taking stroke as an example of where this method would be beneficial, it is generally accepted that life-threatening swelling can occur in up to 8% of hospitalized ischemic stroke patients and up to 15% of all middle cerebral artery (MCA) strokes. Patients who progress to such swelling typically exhibit a National Institute of Heath Stroke Score (NIHSS) of greater than 20 when the dominant hemisphere is involved, and greater than 15 when the non-dominant hemisphere is involved. In another example, most cases (probably greater than 99%) that progress to developing significant swelling have an NIHSS of ≥ 10. Patients with an NIHSS score below 10 are not prone to developing life-threatening swelling. Therefore, patients at high risk of developing such swelling can be identified using imaging or scoring techniques. Thus, subjects with stroke or other injuries or conditions associated with cerebral edema should have a National Institute of Heath Stroke Score (NIHSS) of at least 10. Alberta Stroke Program Early CT Score (ASPECTS) of 4 or less. Early CT Score (ASPECTS), magnetic resonance imaging (MRI) diffusion weighted image (DWI) over 70cc, magnetic resonance imaging (MRI) diffusion weighted image (DWI) over 82cc, magnetic resonance imaging (MRI) diffusion weighted image (DWI) over 145cc, CT perfusion core over 50cc, 70 A subject may be considered at high risk for severe brain swelling if they exhibit at least one factor selected from the group consisting of a CT perfusion core of more than 1000 cc, poor collateral circulation as determined by CT angiography (or other means), a CT scan showing hypodensity over at least 33% of the middle cerebral artery territory, and / or a CT scan showing hypodensity over at least 50% of the middle cerebral artery territory. In some embodiments, a subject is first assessed as having an NIHSS score of 10 or greater, and then evaluated by one of the other methods outlined above. In some embodiments, a subject may be considered at high risk if their ASPECTS score is ≦5, ≦4, ≦3, or ≦2. In some embodiments, a subject may be considered at high risk if their MRI DWI is greater than 82 cc.

[0070] In particular, patients with extensive hemispheric infarction (LHI) are at particular risk for swelling. These subjects typically have a stroke in the middle cerebral artery territory, which can be further identified radiologically using MRI, DWI, or CT perfusion of at least about 70 cc, at least about 80 cc, at least about 90 cc, or at least about 100 cc, or may exhibit an ASPECTS score of ≦5, ≦4, ≦3, or ≦2. In the methods contemplated herein for treating subjects with LHI, in one example, the subject may be younger than about 76 years old or younger than about 71 years old. Furthermore, subjects with a National Institutes of Health Stroke Scale (NIHSS) of at least 10 may have acceptable results if the drug is administered 10 hours or less after the time of stroke confirmation or the last known incident. Administration times of 9 hours or less may also produce acceptable results. These methods may result in improvements in one or more clinically meaningful endpoints, including survival / mortality, modified Rankin Scale (as a fully ordinal scale and / or dichotomized), Barthel Index, and / or EuroQol. These improvements may be evident at one or more time points, including about 90 days (or about 3 months), about 180 days (or about 6 months), and / or about 12 months (or 1 year) after stroke.

[0071] In connection with the method for treating LHI, a method for testing drugs for treating LHI is also contemplated. According to these methods, LHI patients aged 18 years or older can be radiologically selected and enrolled. The subjects tested typically have an NIHSS score of 10 or higher and can be treated with a SUR1-TRPM4 channel inhibitor or a matching placebo, starting within 10 hours or less (or even 9 hours or less) of the time of the stroke or last known incident, with treatment lasting up to about 72 hours. These methods can result in improvements in the drug group versus the placebo group for one or more clinically meaningful endpoints, including survival / mortality, modified Rankin Scale (as a completely ordinal scale and / or dichotomized), Barthel Index, and / or EuroQol. These assessments can be performed at one or more time points, including about 90 days (or about 3 months), about 180 days (or about 6 months), and / or about 12 months (or 1 year) after the stroke.

[0072] Table 1 below shows an exemplary dosing schedule. References to mass are for the SUR1-TRPM4 channel inhibitor in drug only (note there is no placebo). [Table 1]

[0073] In assessing outcomes, subjects may be divided into two age groups: ≤70 years and >70 years. Statistical significance is assessed only in the ≤70 year cohort on the mRS using analyses that preserve the ordinal scale, such as the Mann-Whitney test (and similar tests), which is an ordinal logistic regression under the proportional odds assumption, providing a sliding dichotomy. Success is defined in terms of a two-sided p-value of <0.05 or an odds ratio with a 90% confidence interval that does not cross 1. The >70 cohort is analyzed descriptively only, which may involve describing a point estimate of a common odds ratio derived using ordinal logistic regression or one or more odds ratios based on individual points of the mRS dichotomy (e.g., 0-4 vs. 5-6, 0-3 vs. 4-6, or 0-2 vs. 3-6). Survival / mortality is also assessed. Such odds ratios should favor drug treatment but may be accompanied by a 90% confidence interval that crosses 1. Similar point estimates can be used in populations of ≤70 to elucidate the direction and magnitude of any treatment effect demonstrated by a Mann-Whitney test (or similar test). The calculated odds ratios favoring the drug are greater than about 1.1, greater than about 1.2, and even more preferably greater than 1.3.

[0074] The SUR1-TRPM4 channel inhibitor, dosage form, dosage rate, dosage time frame, dosage period for initial dosing, underlying condition, other details, etc. may be as discussed above and elsewhere herein.

[0075] Furthermore, a method for safely delivering glyburide to a subject can include administering one or more continuous infusions of glyburide to the subject and measuring liver enzyme levels while continuing to administer the glyburide. In one example, administration can be after or as a result of an injury or condition associated with CNS edema. In another example, such a method can also be for administering glyburide for indications other than those associated with CNS edema. In either case, this can be done to protect the kidneys, liver, intestines, or heart. According to the package insert for oral glyburide, glyburide can temporarily elevate aminotransferases.

[0076] In some cases, the method further includes the preceding step of measuring the subject's liver enzyme levels before administering glyburide. This may be performed to establish a baseline liver enzyme level. The method may also include measuring the liver enzyme levels a specific period after the administration step begins. In some embodiments, the subject's liver enzyme levels may be monitored at 4-hour intervals, 6-hour intervals, 8-hour intervals, 12-hour intervals, 24-hour intervals, etc. Alternatively, the levels may be tested at about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 154 hours, about 168 hours, the day the subject is discharged from the hospital, or a combination thereof.

[0077] Monitoring may include measuring various enzymes. In one embodiment, the liver enzyme measured is aspartate aminotransferase (AST). In another embodiment, the liver enzyme measured is alanine aminotransferase (ALT). In another embodiment, the liver enzyme measured is indirect bilirubin and / or direct bilirubin and / or total bilirubin. Monitoring may also involve measuring a subject's AST and ALT levels, or ALT and bilirubin, or ALT, AST, and bilirubin. In one embodiment, administration of glyburide is discontinued if a subject's ALT or AST levels rise above about 8 times the upper limit of normal ALT or AST levels. In one embodiment, administration of a SUR1-TRPM4 channel inhibitor may be discontinued if a subject's ALT or AST levels rise above about 6 times the upper limit of normal ALT or AST levels, as determined by the administering physician. In yet another embodiment, glyburide administration is discontinued if the subject's ALT or AST levels rise above about four times the upper limit of normal ALT or AST levels, as determined by the administering physician. In a further embodiment, glyburide administration may be discontinued if the subject develops cholestatic jaundice or hepatitis. What these exact levels are and what constitutes an unsafe risk of continued treatment may be determined by the physician based on existing enzyme levels, levels considered safe, the trade-off between enzyme levels and treating CNS edema, and the like. In one embodiment, glyburide administration may be discontinued if the subject's total bilirubin levels rise above about two times the upper limit of normal.

[0078] The dosage form, dosage rate, dosage time frame, dosage period for initial dosing, underlying condition, other details, etc. may be as discussed above and elsewhere herein.

[0079] In another example, a method for monitoring cardiac activity when administering a sulfonylurea to a subject can include administering one or more continuous infusions of glyburide to the subject and performing an electrocardiogram on the subject to monitor the subject's heart. In one example, administration can be after or as a result of an injury or condition associated with CNS edema. In another example, such a method can also be for administration of glyburide for indications other than those associated with CNS edema. In either case, this can be done to protect the kidney, liver, intestine, or heart. Sulfonylureas, including glyburide, carry a black box warning for cardiac mortality. Furthermore, studies of oral glyburide have shown that it can cause QTc prolongation.

[0080] In one embodiment, the method may further include performing an electrocardiogram on the subject before administering glyburide or another sulfonylurea. In yet another embodiment, the step of performing an electrocardiogram includes performing an electrocardiogram on the subject a specific period of time after the administering step has begun. The specific period for performing an electrocardiogram may be about 2 to 8 hours apart, about 4 to 6 hours apart, about 4-6 hours (after the start of the infusion), about 24 hours, about 48 hours, about 60-72 hours, about 168 hours, the day the subject is discharged from the hospital, or a combination thereof. The method may include discontinuing glyburide administration if the subject's QTc is ≥ about 550 ms, ≥ about 600 ms, ≥ about 500 ms, ≥ about 475 ms, or ≥ about 450 ms, for example, for a period of at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes. If necessary, leads may be repositioned to ensure accurate readings.

[0081] The dosage form, dosage rate, dosage time frame, dosage period for initial dosing, underlying condition, other details, etc. may be as discussed above and elsewhere herein.

[0082] In another example, a method of delivering glyburide to a subject may include intravenously administering glyburide to the subject and monitoring blood glucose, liver enzymes, and QTc while intravenously administering glyburide to the subject. Any of the embodiments described herein, along with the accompanying details, may be applicable to this example.

[0083] As noted with respect to the various methods discussed herein, these methods are applicable to various injuries or conditions associated with CNS edema. However, not all of these injuries or conditions necessarily result in CNS edema, and therefore may be "associated with" or alternatively be "at risk" for developing CNS edema. One example of this is stroke. For example, space-occupying cerebral edema secondary to a cerebral hemisphere ischemic stroke (affecting the entire middle cerebral artery territory or beyond) can lead to intracranial hypertension and eventual brain herniation, resulting in significant morbidity and mortality. This condition usually manifests itself between the second and fifth day after the onset of the ischemic stroke, with swelling peaking two to three days after the incident. This can further lead to destruction of previously healthy brain tissue and widespread brain tissue displacement, resulting in transtentorial or uncal herniation and brain death; therefore, such complications may account for the rapid neurological deterioration seen in such patients. For example, life-threatening swelling can occur in up to 8% of hospitalized ischemic stroke patients and up to 15% of all middle cerebral artery (MCA) strokes. Thus, whether it is from a stroke or other injury or condition associated with CNS edema, the methods of the present disclosure may be beneficial for many of these subjects experiencing or at risk of experiencing CNS edema.

[0084] Embodiments of the present disclosure will be described with reference to the following examples, which are provided for illustrative purposes only and should not be used to limit the scope of or interpret the present invention. [Example]

[0085] Example 1 Randomized, double-blind, placebo-controlled study in large hemispheric infarction A randomized, double-blind, placebo-controlled clinical study was conducted to determine the efficacy of SUR1-TRPM4 channel inhibitors in reducing or treating neurological conditions associated with cellular swelling and CNS or cerebral edema. In this study, 83 subjects with clinician-estimated brain lesions of 82cc to 300cc were treated with either a glyburide test drug solution or a placebo solution within approximately 10 hours of the injury or condition associated with cerebral edema. In the "per-protocol" group, 77 patients were centrally identified as having brain lesions of 82cc to 300cc. Forty-one subjects received the test drug, and 36 subjects received a placebo. The test drug was administered as follows: a 0.13 mg bolus of the SUR1-TRPM4 channel inhibitor was administered over approximately 2 minutes, followed by a 0.16 mg / hour continuous infusion for 6 hours, followed by a 0.11 mg / hour continuous infusion for 66 hours, for a total dosing period of 72 hours. The total daily doses of study drug on days 1, 2, and 3 were 3.12 mg, 2.67 mg, and 2.67 mg, respectively.

[0086] Mortality data The incidence of mortality was recorded at both 30 and 90 days after treatment. The reduction in mortality resulting from administration of SUR1-TRPM4 channel inhibitors is shown in Table 2 below and graphed in Figure 1. [Table 2-1] [Table 2-2]

[0087] As can be seen in the table above, subjects in the test drug group had approximately a half lower percentage of deaths.

[0088] Decompressive craniectomy (DC) data Additional mortality data was collected as mortality data related to drug and placebo treatment with and without decompressive craniectomy (DC). Essentially, the occurrence of deaths was recorded for study participants who died after DC before the end of the study period. The occurrence of deaths with DC compared to without DC is shown below in Table 3 and graphed in Figure 2. [Table 3]

[0089] As seen in Table 3, in this particular study, the best results were achieved in the test drug group that also underwent the DC procedure, but these results were only slightly better than those in the test drug group that did not undergo the DC procedure. More specifically, in the placebo group, the DC procedure was beneficial compared with no DC procedure, but both outcomes were inferior to those seen in the test drug groups (with or without decompressive craniotomy). Figure 2 shows the raw data values ​​seen in Table 3 in terms of percentages. Note that the average time before decompression is not explained in these numbers because they can vary widely based on the judgment and, to some extent, the schedule of the attending physician making these types of decisions. Also note that two late decompressive surgeries were performed due to late neurological deterioration. These surgeries could have been avoided if patients had been treated with the SUR1-TRPM4 channel inhibitor for a longer period, e.g., 5 or 7 days.

[0090] mRS score Subjects in this study were also tested using the modified Rankin Scale (mRS). One way to assess outcomes in a wide range of strokes, such as those studied, is to determine the percentage of patients in each group with an mRS of 0 to 4 90 days after stroke. The results of the 90-day mRS study are shown in Table 4 below and graphed in Figure 3. [Table 4]

[0091] As can be seen in Table 4, the proportion of mRS scores of 0–4 in subjects receiving SUR1-TRPM4 channel inhibitors was, on average, 14.6% higher than the mRS scores of individuals who did not receive the study drug. Furthermore, the median mRS in the treatment group was 4, compared to a median of 5 for placebo.

[0092] Barthel Index The Barthel Index is another functional outcome that can be used to evaluate the outcome of stroke patients. The subjects in this study were also scored using the Barthel Index initially and again at approximately 90 days. The degree of improvement in the Barthel Index score is shown in Table 5 below and graphed in Figure 4. [Table 5]

[0093] As can be seen in Table 5, Barthel Index scores were better in the test drug group than in the placebo group.

[0094] Midline deviation data Subjects in this study also underwent MRI scans at 72-96 hours to obtain images and observe the extent of reduction in midline shift. The mean percent reduction is shown below in Table 6 and graphed in Figure 5. [Table 6]

[0095] Based on MRI scans, the percent reduction in midline shift (or greater reduction in midline shift) was, on average, more favorable for individuals in the test drug group than for those in the placebo group. The percent reduction was determined by comparing the median midline shift for each group at 72 to 96 hours.

[0096] FLAIR ratio A FLAIR ratio (MRI measure of blood-brain barrier disruption) study was also performed in which study subjects were evaluated to determine reduction in vasogenic edema, if possible. The FLAIR ratio results are shown in Table 7 below and graphed in Figure 6. [Table 7]

[0097] Based on this study, the test drug group performed, on average, better than the placebo group. A lower FLAIR ratio is an indication of less disruption of the blood-brain barrier.

[0098] Disruption of MMPs Additionally, MMP-9 values ​​based on blood samples were obtained for study participants at 24 and 72 hours and then averaged. MMP-9 levels are known to be elevated after stroke and are thought to represent blood-brain barrier dysfunction. The average MMP-9 values ​​are shown in Table 8 below and graphed in Figure 7. [Table 8]

[0099] Based on this study, the test drug group performed, on average, better than the placebo group.

[0100] Blood glucose monitoring and correction a) During a double-blind, placebo-controlled study, one patient receiving a 10% by weight dextrose solution had a documented, laboratory-confirmed decrease in blood glucose level to 51 mg / dL. In this example, the glyburide infusion rate was reduced by 30%, and the patient's blood glucose level stabilized. b) During a double-blind, placebo-controlled study, one of the patients had a blood glucose level of 57 mg / dL at the time of care, with a laboratory retest of 67 mg / dL. In this case, the patient was given normal saline and then changed to 5% dextrose by weight, where the patient's blood glucose stabilized.

[0101] Results in subjects ≤70 years old In an attempt to identify the population most likely to benefit from treatment, different age groups were analyzed, and despite the fact that ischemic stroke is understood to be a condition of older adults, it was surprisingly found that efficacy was more pronounced in the ≤70 year old population, and this was consistent across multiple endpoints including survival / mortality, mRS, Barthel Index, and EuroQol-5D.

[0102] Improved survival In the entire per-protocol population, odds ratios (ORs) ranged from 2.54 to 2.74 at various time points. These results just exceeded statistical significance at 90 days or later (an odds ratio of 1 indicated no effect), thus generally indicating an overall improvement. However, in the per-protocol population of ≤70, results were statistically significant at all time points, with a more substantial range of ORs, ranging from 3.41 to 3.79. The data are shown in Table 9 below. [Table 9-1] [Table 9-2]

[0103] Mortality may be multifactorial and depend on factors such as pre-existing comorbidities and risk factors. To further understand the effects of glyburide, we elucidated the survival benefit attributable to our hypothesized mechanism of action. Specifically, cause of death was determined by three reviewers blinded to the study drug group. Imaging and clinical data were used to determine cause of death among other outcomes. The determined mortality rate attributable to edema in the per-protocol group was 2.44% (1 / 41) vs. 22.22% (8 / 36), p=0.01 (Fisher's exact test, two-tailed p). Consistent with our proposed mechanism of action, mortality attributable to edema was the underlying factor behind the reduction in overall mortality.

[0104] Improvement in mRS The mRS assesses global disability after stroke, and when assessed at 90 days, it is the most widely used primary outcome measure commonly used in acute stroke trials. It provides an ordinal hierarchical scale for assessing disability, ranging from 0 (asymptomatic) to 6 (death). While the mRS is often analyzed as a dichotomous outcome, this approach often weakens the power to detect effects and has been shown to obscure both positive and negative effects. Conversely, ordinal analyses can preserve the full power of the mRS and better reflect health status by pricing each transition.

[0105] The magnitude of the difference between the placebo arm and the treatment arm on the ordinal mRS is often measured using the Mann-Whitney test, and a common odds ratio (OR) can be derived using proportional odds methodology to examine effect sizes. According to this, a common OR of 1.2 represents a clinically meaningful difference. The OR for an effect size of ≤70 patients in the per-protocol population was 2.49, which represents a substantial clinical effect. [Table 10]

[0106] Although not statistically significant, the effect sizes for dichotomizations of 0–3 and 0–4 in patients ≤70 in the per-protocol population were 14% and 22%, respectively, which significantly exceeded the minimum clinically meaningful effect size and demonstrated a substantial clinical benefit on the mRS.

[0107] BI Improvements The Barthel Index (BI) is a measure of activities of daily living. It is widely used and approved in stroke trials and is one of the more commonly used scales for acute stroke. In one example, the minimum clinically important change beyond measurement error is approximately 20 points on a 100-point scale, which was used as the reference value in this study. The median delta or difference between drug and placebo at 90 days, 6 months, and 12 months in the per-protocol population of ≤70 was 35, 27.5, and 45, respectively, all of which exceeded the acceptable threshold. The general interpretation of the BI is that a score of ≤40 is considered a clearly poor outcome, while a score of ≥60 is a clearly good outcome. In this trial, the median BI scores in the placebo group were ≤40 at 90 days, 6 months, and 12 months (25, 32.5, and 30, respectively), while in the glyburide group, scores were ≥60 at all time points (60, 60, and 75, respectively). These results at 12 months were also statistically significant (p=0.03). [Table 11]

[0108] Improvement in EQ-5D The EuroQol-5D (EQ-5D) is a comprehensive instrument used to assess quality of life in a variety of conditions, including stroke. It is the most commonly used instrument to gather cost-effectiveness information in calculating quality-adjusted life years (QALYs), which supports pricing and reimbursement discussions. It is one of the most widely used health-related quality of life instruments used in clinical research. The minimal clinically important difference in stroke has been reported to be 0.08–0.12 units (Kim et al., 2015). The overall per-protocol population and ≤70 per-protocol In both populations, the median difference between drug and placebo was greater than 0.12 at all time points. At 6 and 12 months, the difference was statistically significant in the 70 population. [Table 12]

[0109] Timing of treatment Unlike thrombolytic therapy in ischemic stroke, which relies on clot removal and tissue reperfusion before tissue death, anti-edema therapy should have a broader time window because edema development is part of a secondary response to the original injury. The ultimate effect of this process, brain herniation, actually peaks 2-3 days after injury. Based on a mechanism of action based on an effect on edema rather than tissue sparing via reperfusion, there is no reason to a priori expect that time-criticality would be evident within the first few hours after stroke confirmation. Surprisingly, however, the inventors observed such an effect.

[0110] Ordinal logistic regression was used to compare the distribution of mRS in the entire per-protocol population with the population receiving the drug 9 hours or less (from stroke confirmation or from the last time the subject was seen to be normal), and an enhanced treatment effect was observed, manifested as an enhanced odds ratio (an odds ratio of 1 indicates no effect). The effect on mortality (survival) was similarly enhanced in analyses using logistic regression. Thus, drug treatment at 9 hours or less appears to be superior, surprisingly, despite the fact that there is no expectation of time significance at this point in the natural history of the condition. [Table 13]

[0111] Specificity for widespread hemispheric infarction Although edema is involved in many different conditions, most commonly ischemic stroke, the clinical benefit of edema treatment in ischemic stroke may be minimized to zero for infarct volumes of some magnitude. Using the data from this study, we were able to determine a threshold lesion size below which outcomes are unaffected by drug treatment. More specifically, this analysis assessed the "shift" in the mRS as a function of increasing lesion size. A modified intent-to-treat population was utilized to include the widest distribution of lesion sizes. Baseline DWI Each 10 cc increase in lesion size (median determined) was associated with an OR of 0.88 in the placebo group (p = 0.026), confirming previous findings that lesion size is a negative prognostic variable for outcome. The interaction between treatment and lesion size yielded an OR of 1.09 (p = 0.244), indicating that the treatment effect was greater with larger lesion extent; e.g., each 10 cc increase in DWI size resulted in a 1.09-fold increase in mRS "shift." By extrapolating a lesion extent of approximately 100 cc for "zero effect," drugs would not be expected to function significantly in patients with smaller lesions, consistent with the fact that these patients are less likely to develop clinically meaningful edema in the first place. Larger lesions with greater edema may have more dramatic results. This concept is visually represented in Figure 8, where a "zero effect" is indicated by an OR for mRS shift of 1. In this case, there was no shift below approximately 100 cc. More specifically, in patients with baseline lesions ≦100 cc, the OR was calculated to be 1.00 (p=0.99), e.g., the drug had minimal to no effect in lesions less than 100 cc, which supported the findings of the interaction analysis.

[0112] Example 2 Randomized, double-blind, placebo-controlled study in traumatic brain injury To evaluate the effect of glyburide, a representative SUR1-TRPM4 channel inhibitor, on edema in TBI, a double-blind, placebo-controlled study was conducted at three clinical sites in 29 subjects with moderate or severe TBI (Glasgow Coma Scale score 4-12) or mild TBI (GCS 13-14) with hemorrhage on CT scans. Study drug administration was as follows: a 0.13 mg bolus of the SUR1-TRPM4 channel inhibitor was administered over approximately 2 minutes, followed by a 6-hour continuous infusion at 0.16 mg / hour, followed by a 66-hour continuous infusion at 0.11 mg / hour, for a total dosing time of 72 hours. The total daily doses of study drug on days 1, 2, and 3 were 3.12 mg, 2.67 mg, and 2.67 mg, respectively. All subjects were evaluated by MRI scans at baseline and 72 hours.

[0113] Fourteen subjects (seven drug and seven placebo) identified at baseline as having evidence of lesional blood (i.e., blood associated with the contusion) and who underwent MRI scans at both baseline and 72 hours were evaluated for edema using MIM software version 5.6. A blinded reader used T2 images to determine x, y, and z measurements of the total apparent contusion, unless missed; in that case, DTI images were used. Only contusions that could be reliably measured (measuring at least approximately 1 cc) were measured. The reader also used SWI images to determine volumetric measurements of hemorrhage in a similar manner. Linear measurements were captured in centimeters (cm), and all volumes were captured in cubic centimeters (cc). Volumes were calculated using the ABC / 2 standard. The volume of apparent edema was calculated as the difference between the total apparent contusion volume and the hemorrhage volume. For analysis, if there were multiple lesions, the volumes of all lesions meeting the threshold were combined.

[0114] At baseline, the drug group had a larger mean edema volume (8.72 ml vs. 2.12 ml for placebo, a four-fold difference), worse clinical characteristics as measured by the mean motor and ocular domains of the Glasgow Coma Scale (GCS, 6.14 vs. 7.67 for placebo), and an intubation rate (3 of 7 vs. 5 of 7 for placebo). Despite this, the drug group showed less edema evolution from baseline to 72 hours (10.28-fold growth vs. 2.14-fold growth for placebo) and no difference in mean Expanded Glasgow Coma Scale score (GOSE, 6 vs. 6.17 for placebo) at 180 days. From these data, we can conclude that despite a more severe clinical profile and four-fold higher edema than placebo at baseline, the drug substantially reduced edema growth and resulted in clinical outcomes identical to those of the placebo group. No drug-related effects were detected in non-lesioned subjects or in non-lesioned brain areas, indicating that the drug effect was surprisingly not edema-specific, but specific to lesion-associated edema.

[0115] Thus, in a study consisting only of subjects identified at baseline as having radiologically defined (e.g., CT or MRI) lesions that can be reliably measured (approximately 0.5 cc or larger) and that can be balanced with respect to baseline clinical characteristics such as GCS or its individual components (motor, ocular, speech), it can be expected that a drug group may result in improved clinical outcomes on a scale such as the GOSE with a minimum effect size of at least 4% in favor of the drug over placebo or an odds ratio of at least 1.2.

[0116] Example 3 Blood glucose control Subjects treated with intravenous SUR1-TRPM4 inhibitors according to the protocols described herein can be monitored and glucose controlled. In one example, monitoring and treatment can be performed as follows: Every hour (±30 minutes) for the first 24 hours, Every 2 hours (±30 minutes) from the 25th hour to the 48th hour, and Then every 4 hours (± 60 minutes).

[0117] Once blood glucose falls below approximately 70 mg / dL, monitoring frequency is increased to every 15 minutes (±10 minutes) until blood glucose is 80 or greater for three consecutive readings without exogenous glucose supplementation.

[0118] When the drug is discontinued and restarted, blood glucose is measured hourly for approximately 3 hours (± 30 minutes). If glucose is no longer needed, monitoring is returned to the previous frequency (e.g., about every 1, 2, or 4 hours).

[0119] Blood glucose may further be controlled in subjects treated with intravenous SUR1-TRPM4 inhibitors as follows: - If baseline blood glucose is less than 100 mg / dL, an initial maintenance fluid of approximately 5% by weight dextrose in normal saline (D5NS) at a rate of 70 to 100 cc / hour may be administered. - If blood glucose falls below approximately 100 mg / dL, D5NS is initiated at a rate of 70 to 100 cc / hour. Titration of increased or decreased IV fluid rates can be used to maintain blood glucose above approximately 80 mg / dL. If blood glucose is less than 80 mg / dL, D5NS can be initiated, or if already receiving D5NS, the subject can be switched to approximately 10% dextrose by weight in normal saline (D10NS). - If blood glucose tends to fall rapidly or continuously, D5NS is initiated, or if D5NS is already being administered, the subject can be switched to D10NS. - In the event that blood glucose is higher than about 140 mg / dL, D5NS or D10NS will not be administered. Any confirmed blood glucose below about 70 mg / dL can be treated with about a 50 mL ampoule of 50% by weight dextrose in water (D50W). If D50W is not available, another concentration of dextrose fluid can be used in a volume sufficient to achieve the same amount of dextrose.

[0120] Any of the above protocols or similar variations thereof may be described in various documents related to pharmaceutical products. These documents may include, but are not limited to, protocols, statistical analysis plans, investigator's brochures, clinical guidelines, medication guides, risk assessment and intervention programs, prescribing information, and other documents that may be related to pharmaceutical products. It is specifically contemplated that such documents may be physically packaged with the SUR1-TRPM4 channel inhibitor pharmaceutical product, as a kit, as needed, or as required by regulatory authorities.

[0121] While the present disclosure has been described with respect to certain specific embodiments, those skilled in the art will appreciate that various modifications, changes, omissions, and substitutions may be made therein without departing from the spirit of the present disclosure. Accordingly, it is intended that the present disclosure be limited only by the scope of the following claims.

Claims

1. 1. A pharmaceutical composition for reducing late neurological deterioration or mortality in a subject following a cerebral hemispheric infarction, comprising: the subject has a brain lesion volume of more than 100 cc, the pharmaceutical composition comprises a SUR1-TRPM4 channel inhibitor, and the SUR1-TRPM4 channel inhibitor is a sulfonylurea; The pharmaceutical composition is administered to the subject after the subject has experienced a cerebral hemispheric infarction, reducing late neurological deterioration or mortality.

2. 10. The pharmaceutical composition of claim 1, (i) when determined for a population based on the occurrence of late neurological deterioration or death in patients treated with the one or more first consecutive infusions, is said late neurological deterioration or death reduced compared to a similar population not treated with said one or more first consecutive infusions; (ii) the administration of the SUR1-TRPM4 channel inhibitor is combined with decompressive craniectomy; or (iii) administration of the SUR1-TRPM4 channel inhibitor reduces midline brain shift and cerebral edema in the subject sufficiently to obviate the need for the subject to undergo decompressive craniectomy; Pharmaceutical compositions.

3. 3. The pharmaceutical composition of claim 1 or claim 2, comprising a first therapeutic dose of the SUR1-TRPM4 channel inhibitor for one or more first continuous infusions and a second therapeutic dose of the SUR1-TRPM4 channel inhibitor for one or more second continuous infusions of the SUR1-TRPM4 channel inhibitor, wherein the first therapeutic dose and the second therapeutic dose continue cumulatively for at least 72 hours after the initiation of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor.

4. 3. The pharmaceutical composition of claim 1 or claim 2, wherein the first administration of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor is initiated within one hour after the subject experiences the cerebral hemispheric infarction.

5. 3. The pharmaceutical composition of claim 1 or claim 2, wherein the first administration of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor is initiated within 4.5 hours after the subject experiences the cerebral hemispheric infarction.

6. 3. The pharmaceutical composition of claim 1, wherein the first administration of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor is initiated no earlier than 8 hours after the subject experiences the cerebral hemispheric infarction.

7. 4. The pharmaceutical composition of claim 3, wherein the first therapeutic dose and the second therapeutic dose continue cumulatively for at least 96 hours after the initiation of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor.

8. 4. The pharmaceutical composition of claim 3, wherein the first therapeutic dose and the second therapeutic dose continue cumulatively for at least 120 hours after the initiation of the first therapeutic dose of the SUR1-TRPM4 channel inhibitor.

9. 4. The pharmaceutical composition of claim 3, wherein the one or more first continuous infusions are initiated after the bolus dose administration.

10. 4. The pharmaceutical composition of claim 3, wherein the one or more first continuous infusions comprises two or more continuous infusion dosages, and the first therapeutic dose is greater than the second therapeutic dose.

11. 3. The pharmaceutical composition of claim 1 or claim 2, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after the subject has experienced the cerebral hemispheric infarction, before, during, or after the subject has undergone decompressive craniotomy.

12. 3. The pharmaceutical composition of claim 1 or claim 2, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after or during measuring the subject's blood glucose level.

13. 13. The pharmaceutical composition of claim 12, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after or during detection of a blood glucose level of 120 mg / dL or 100 mg / dL or less in the subject, and a dextrose solution is administered to the subject.

14. 13. The pharmaceutical composition of claim 12, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after or during detection of a blood glucose level of greater than 80 mg / dL to 100 mg / dL in the subject, and a 3% to 8% by weight dextrose solution is administered to the subject at 50 cc / hour to 120 cc / hour.

15. 13. The pharmaceutical composition of claim 12, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after or during detection of a blood glucose level of 55 mg / dL to 80 mg / dL in the subject, and an 8% to 12% by weight dextrose solution is administered to the subject at 50 cc / hour to 120 cc / hour.

16. 13. The pharmaceutical composition of claim 12, wherein the SUR1-TRPM4 channel inhibitor is administered to the subject after or during detection of a blood glucose level of less than 55 mg / dL in the subject, and an 8% to 12% by weight dextrose solution is administered to the subject at 50 cc / hour to 120 cc / hour.

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