How to treat injuries or conditions associated with CNS edema

Abstract

How to treat injuries or conditions associated with CNS edema [Solution] This technology relates to reducing or treating neurological swelling and related conditions with SUR1-TRPM4 channel inhibitors. In some embodiments, the method includes reducing late neurological exacerbations or preventing death, reducing midline deviation of the brain, reducing the degree of functional impairment in subjects, neutralizing blood glucose levels in subjects receiving SUR1-TRPM4 channel inhibitors, preventing cerebral swelling, treating injuries or conditions associated with CNS edema while monitoring liver enzyme activity, or treating injuries or conditions associated with CNS edema while monitoring cardiac activity.

Description

Background Art

[0001] After spinal cord injury, cardiac arrest, liver failure, intracerebral hemorrhage, neurosurgery, traumatic brain injury, stroke (ischemic and / or hemorrhagic), infection, cerebral malaria, or other similar injuries or diseases, or any form of cerebral ischemia, a subject may develop 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 and typically peaks on the second or third day.

[0002] Brain swelling can increase intracranial pressure and deprive the brain of oxygen by stopping blood flow to the brain. Brain swelling can also block the brain's drainage pathways and prevent body fluids from leaving the brain. Furthermore, as intracranial pressure increases within the skull, previously healthy brain tissue can be destroyed, and tentorial incisura herniation or uncal herniation can occur. Swelling inside and around the brain can also lead to pathological conditions 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, namely, neuronal and astrocytic cell swelling, and transcapillary influx of ions and body fluids to the site of injury. Neuronal and astrocytic cell swelling results from changes in the ionic gradient between the cell and the extracellular space. One ion channel associated with cell swelling is the NC channel, also known as the SUR1-TRPM4 channel. This channel is a non-selective Ca-activated ATP-sensitive cation channel that is activated when intracellular ATP in neuronal cells is depleted. The NC channel is thought to consist of a regulatory subunit containing sulfonylurea receptor 1 (SUR1), and a pore subunit associated with transient receptor potential cation channel subfamily M member 4 (TRPM4). 2+ It is an activated ATP-sensitive cation channel. CA-ATP The NC channel is thought to consist of a regulatory subunit containing sulfonylurea receptor 1 (SUR1), and a pore subunit associated with transient receptor potential cation channel subfamily M member 4 (TRPM4).

Summary of the Invention

[0004] Minimizing the degree of cerebral edema is a primary concern for physicians when treating subjects suffering from conditions or diseases that can cause cerebral edema. However, treating cerebral edema is particularly challenging due to the prolonged duration of swelling, the overall function of the brain, and the brain's placement within the skull. Therefore, providing treatments to reduce the degree of cerebral edema would represent an advance in this field.

[0005] With this background in mind, this disclosure relates to methods for reducing or treating CNS edema, such as cerebral edema, spinal edema, and / or related conditions.

[0006] In one embodiment, a method for reducing the incidence of late neurological deterioration (or death) in a subject following injury or condition related to CNS edema. A method is presented. This method involves administering one or more sequential 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 sequential infusions for at least 72 hours after initiation, thereby reducing late neurological exacerbations.

[0007] In another embodiment, a method is presented for reducing midline displacement of the brain in a subject after an injury or condition associated with cerebral edema. This method includes administering a SUR1-TRPM4 channel inhibitor to the subject after the subject has experienced an injury or condition associated with cerebral edema, and performing a decompressive craniotomy on the subject.

[0008] In yet another embodiment, a method is presented for improving the degree of disability in a subject suffering from an injury or condition associated with CNS edema. This method involves administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to the subject after the subject has suffered from an injury or condition associated with CNS edema. Further steps include establishing an initial degree of disability in the subject 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 has passed since the initial degree of disability was determined. In one embodiment, the first and second scoring systems or tests may be identical or different. In a specific embodiment, one scoring system is used for the first scoring system (or test).

[0009] In another embodiment, a method for counteracting the decrease in blood glucose levels in subjects receiving a SUR1-TRPM4 channel inhibitor is used. This may include administering one or more sequential infusions of a four-channel inhibitor to the subject, and co-administering a dextrose solution to the subject.

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

[0011] In another embodiment, a method for safely delivering glybrid to a subject may include administering one or more sequential infusions of glybrid to the subject and measuring liver enzyme levels while continuing glybrid administration.

[0012] In another embodiment, a method for monitoring cardiac activity when a sulfonylurea is administered to a subject may include administering one or more consecutive infusions of sulfonylurea to the subject and monitoring the subject's heart by performing an electrocardiogram.

[0013] In another embodiment, a method for delivering glybrid to a subject may include intravenous administration of glybrid to the subject, and monitoring of blood glucose, liver enzymes, and QTc during intravenous administration of glybrid to the subject.

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

[0015] In another embodiment, a method for treating a subject suffering from extensive cerebral hemispheric infarction may include administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject. The subject may 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 embodiment, a method for treating a subject suffering from extensive cerebral hemispheric infarction may include administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject. Administration may be initiated at or less than nine hours from the time of the index stroke or from the last time the subject was observed to be normal.

[0017] In another embodiment, a method for treating a subject suffering from traumatic brain injury may include administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject. Prior to treatment, the subject may exhibit radiological evidence of intracerebral blood induced by the traumatic brain injury.

[0018] In another embodiment, a method for testing a treatment to address LHI may include enrolling subjects at least 18 years of age with radiologically defined LHI, treating subjects with a SUR1-TRPM4 channel inhibitor or a suitable placebo, starting 9 hours or less from the stroke or the last time observed as normal, for up to approximately 72 hours, and evaluating the mRS. The method may be considered successful if a statistically significant favorable outcome for the drug is detected in subjects 70 years or younger, or if a descriptive benefit is detected in subjects over 70 years. In certain embodiments, for example, the following items are provided: (Claim 1) A method for reducing late neurological exacerbation or death in a subject after an injury or condition associated with CNS edema, comprising the step of administering a SUR1-TRPM4 channel inhibitor to the subject after the subject has experienced an injury or condition associated with CNS edema, wherein the administration step comprises one or more sequential infusions of the SUR1-TRPM4 channel inhibitor that cumulatively continue for at least 72 hours after the commencement of one or more sequential infusions, wherein the SUR1-TRPM4 channel inhibitor reduces late neurological exacerbation. (Claim 2) The method according to claim 1, wherein the CNS edema is cerebral edema. (Claim 3) The method according to claim 2, wherein the administration step prevents the death of the subject. (Claim 4) The method according to claim 1, which reduces late neurological exacerbations or deaths when determined for a population based on the incidence of late neurological exacerbations or deaths in patients treated with the one or more consecutive infusions compared to a similar population not treated with the one or more consecutive infusions. (Claim 5) The method for reducing said late neurological worsening or death is effective when the SUR1-TRPM4 channel inhibitor is first administered within 1 hour after the subject has experienced said injury or condition associated with CNS edema, according to the method of claim 1. (Claim 6) The method for reducing the occurrence of late neurological worsening or death is effective when the SUR1-TRPM4 channel inhibitor is first administered within 4.5 hours after the subject has experienced said injury or condition associated with CNS edema, according to the method of claim 1. (Claim 7) The method for reducing the occurrence of late neurological worsening or death is effective when the SUR1-TRPM4 channel inhibitor is first administered between 4.5 hours and 10 hours after the subject has experienced said injury or condition associated with CNS edema, according to the method of claim 1. (Claim 8) The method for reducing the occurrence of late neurological worsening or death is effective when the SUR1-TRPM4 channel inhibitor is first administered between 6 hours and 12 hours after the subject has experienced said injury or condition associated with CNS edema, according to the method of claim 1. (Claim 9) The method for reducing said late neurological worsening or death is effective when the SUR1-TRPM4 channel inhibitor is first administered before about 8 hours after the subject has experienced said injury or condition associated with CNS edema, according to the method of claim 1. (Claim 10) The administration of said one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is carried out for at least 96 hours, according to the method of claim 1. (Claim 11) The administration of said one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is carried out for at least 120 hours, according to the method of claim 1. (Claim 12) The administration of said one or more continuous infusions of the SUR1-TRPM4 channel inhibitor is carried out for at least 168 hours, according to the method of claim 1. (Claim 13) The method according to claim 1, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, tracazamide, repaglinide, nateglinide, meglitinide, midaglizole, tracazamide, glyquidone, LY397364, LY389382, glisclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 14) The method according to claim 1, wherein the SUR1-TRPM4 channel inhibitor is glibide. (Claim 15) The method according to claim 1, wherein the method of treating late neurological deterioration or death is a result of hemorrhagic stroke. (Claim 16) The method according to claim 1, wherein the method of treating late neurological deterioration or death is a result of ischemic stroke. (Claim 17) The method according to claim 16, wherein the ischemic stroke occurs in the middle cerebral artery, internal carotid artery within the skull, external carotid artery outside the skull, or combinations thereof. (Claim 18) The method according to claim 1, wherein the method of treating late neurological deterioration is a result of traumatic brain injury. (Claim 19) The method according to claim 1, wherein the method of treating late neurological deterioration or death is a result of cardiac arrest, liver failure, intracerebral hemorrhage, or neurosurgery. (Claim 20) The method according to claim 1, wherein the CNS edema is spinal cord edema and the late neurological deterioration is spinal cord injury. (Claim 21) The method according to claim 1, wherein the one or more continuous infusions are initiated after a bolus dose administration. (Claim 22) The method according to claim 1, wherein the one or more continuous infusions comprise two or more continuous infusion dosages, and the first continuous infusion dosage is greater than the second continuous infusion dosage. (Claim 23) The method according to claim 1, wherein the one or more consecutive infusions are initiated after a bolus dose, and the one or more consecutive infusions comprise two or more consecutive infusion doses, the first consecutive infusion dose being greater than the second consecutive infusion dose. (Claim 24) The method according to claim 1, wherein the step of administering the SUR1-TRPM4 channel inhibitor is combined with decompressive craniotomy. (Claim 25) The method according to claim 1, wherein the step of administering the SUR1-TRPM4 channel inhibitor reduces midline displacement of the brain and cerebral edema in the subject to such an extent that the subject does not need to undergo decompressive craniotomy. (Claim 26) The steps include administering a SUR1-TRPM4 channel inhibitor to a subject after the subject has experienced an injury or condition related to cerebral edema, and The step of performing a decompressive craniotomy on the subject. A method for reducing midline deviation of the brain in a subject after an injury or condition associated with cerebral edema, including, (Claim 27) The method according to claim 26, wherein the injury or condition associated with cerebral edema is a stroke. (Claim 28) The method according to claim 26, which reduces the midline deviation of the brain in patients treated with one or more consecutive infusions, determined for a population based on the degree of midline deviation of the brain in patients treated with one or more consecutive infusions compared to a similar population not treated with one or more consecutive infusions. (Claim 29) The method according to claim 26, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibride, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, trazamide, glikidone, LY397364, LY389382, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 30) The method according to claim 26, wherein the SUR1-TRPM4 channel inhibitor is glybride. (Claim 31) The method according to claim 26, wherein the step of administering the SUR1-TRPM4 channel inhibitor comprises one or more consecutive infusions cumulatively over a period of at least 72 hours. (Claim 32) The method according to claim 26, wherein the step of administering the SUR1-TRPM4 channel inhibitor comprises one or more consecutive infusions cumulatively over a period of at least 96 hours. (Claim 33) The method according to claim 26, wherein the step of administering the SUR1-TRPM4 channel inhibitor comprises a bolus dose and one or more subsequent sequential infusions. (Claim 34) The method according to claim 26, wherein the SUR1-TRPM4 channel inhibitor treats the swelling of the lesion. (Claim 35) The method according to claim 26, wherein the SUR1-TRPM4 channel inhibitor is first administered to the subject from immediately after the injury or condition associated with cerebral edema until about 12 hours after the subject experienced the injury or condition associated with cerebral edema. (Claim 36) The method according to claim 26, wherein the SUR1-TRPM4 channel inhibitor is first administered to the subject from 4.5 hours after the injury or condition associated with cerebral edema until about 12 hours after the subject experienced the injury or condition associated with cerebral edema. (Claim 37) The method according to claim 26, wherein the administration step is performed before or during the decompressive craniotomy. (Claim 38) The method according to claim 26, wherein the administration step is performed after decompressive craniotomy. (Claim 39) The step of administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to a subject after the subject has experienced injury or condition related to CNW edema, A step of establishing the initial degree of disability of the subject after the injury or condition related to CNS edema using a first scoring system or test, and A step of determining a second degree of disability using a second scoring system or test after a certain period of time with respect to the aforementioned first degree of disability. A method for treating a subject suffering from an injury or condition associated with CNS edema, wherein the administration of the SUR1-TRPM4 channel inhibitor results in an improvement in the degree of disability. (Claim 40) The method according to claim 39, wherein the first scoring system or test and the second scoring system or test are identical. (Claim 42) The method according to claim 39, wherein the first scoring system or test and the second scoring system or test are different. (Claim 43) The method according to claim 39, wherein the administration step is performed before the establishment step. (Claim 44) The method according to claim 39, wherein the establishing step is performed before the administering step. (Claim 45) The method according to claim 39, wherein the injury or condition associated with CNS edema is a stroke. (Claim 46) The first scoring system or test, or either or both of the second scoring system or test, may be the National Institutes of Health Stroke Scale (NIHSS), Alberta Stroke Scale. The method according to claim 45, selected from the group consisting of Program Early CT Score (ASPECTS), magnetic resonance imaging (MRI), and CT scan. (Claim 47) The method according to claim 45, wherein the first scoring system or test is based on the National Institutes of Health Stroke Score System, and the second scoring system or test is based on a modified Rankin Scale or Barthel Index. (Claim 48) The steps include administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to a subject, and The step of co-administering a dextrose solution to the subject. A method for neutralizing a decrease in blood glucose levels in a subject receiving a SUR1-TRPM4 channel inhibitor, including the SUR1-TRPM4 channel inhibitor. (Claim 49) The method according to claim 48, wherein the administration step is for the treatment of injury or condition not related to CNS edema. (Claim 50) The method according to claim 48, wherein the step of administering is for the treatment of an injury or condition related to cerebral edema. (Claim 51) The method according to claim 48, wherein the dextrose solution comprises saline solution or water and about 3% to about 12% by weight of dextrose. (Claim 52) The method according to claim 48, further comprising the step of measuring the blood glucose level before or during the administration step. (Claim 53) The method according to claim 52, wherein the dextrose solution is first administered if the subject's blood glucose level is about 120 mg / dL or less. (Claim 54) The method according to claim 52, wherein the dextrose solution is first administered if the subject's blood glucose level is about 100 mg / dL or less. (Claim 55) The method according to claim 52, wherein if the blood glucose level is greater than approximately 80 mg / dL to 100 mg / dL, a 3% to 8% by weight dextrose solution is administered to the subject at a rate of approximately 50 cc / hour to approximately 120 cc / hour. (Claim 56) The method according to claim 52, wherein, when the blood glucose level is approximately 55 mg / dL to 80 mg / dL, an 8% to 12% by weight dextrose solution is administered to the subject at a rate of 50 cc / hour to 120 cc / hour. (Claim 57) The method according to claim 52, wherein if the blood glucose level is below 55 mg / dL, an 8% to 12% by weight dextrose solution is administered to the subject at a rate of 50 cc to 120 cc per hour. (Claim 58) The method according to claim 52, wherein if the blood glucose level falls below 55 mg / dL, the administration of the SUR1-TRPM4 channel inhibitor is reduced or discontinued. (Claim 59) The method according to claim 52, wherein the blood glucose level is first verified either by another measurement at the bedside or by a clinical test, and then the administration of the SUR1-TRPM4 channel inhibitor is discontinued or reduced. (Claim 60) The method according to claim 52, further comprising the step of monitoring blood glucose levels every hour for at least 12 hours. (Claim 61) The method according to claim 52, further comprising the steps of monitoring blood glucose levels every hour for 24 hours, monitoring blood glucose levels every two hours for the next 24 hours, and monitoring blood glucose levels every four hours while continuing the administration step. (Claim 62) The method according to claim 52, further comprising the step of co-administering a bolus of dextrose solution to the subject when the subject's blood glucose level falls below a predetermined level. (Claim 63) The method according to claim 52, wherein if the subject's blood glucose level is higher than approximately 80 mg / dL, the step of co-administering the dextrose solution is then stopped. (Claim 64) The method according to claim 52, wherein if the subject's blood glucose level is higher than approximately 100 mg / dL, the step of co-administering the dextrose solution is then stopped. (Claim 65) The method according to claim 52, wherein if the subject's blood glucose level is higher than approximately 120 mg / dL, the step of co-administering dextrose is then terminated. (Claim 66) The method according to claim 52, wherein if the subject's blood glucose level is higher than approximately 140 mg / dL, the step of co-administering the dextrose solution is then stopped. (Claim 67) The method according to claim 52, wherein the rate of dextrose administration is increased after there has been a tendency for blood glucose to decrease rapidly. (Claim 68) The method according to claim 67, wherein the rapid decrease in blood glucose is defined as a reduction of ≥10 mg / dL from the last measurement. (Claim 69) The method according to claim 67, wherein the rapid decrease in blood glucose is defined as a reduction of ≥30 mg / dL from the last measurement. (Claim 70) The method according to claim 48, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibride, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, trazamide, glikidone, LY397364, LY389382, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 71) The method according to claim 48, wherein the inhibitor of the SUR1-TRPM4 channel is glybride. (Claim 72) The method according to claim 50, wherein the injury or condition associated with CNS edema is a stroke. (Claim 73) The steps include determining whether a subject is at high risk of severe brain or spinal cord swelling, and, if the subject is determined to be at high risk of severe brain or spinal cord swelling, administering a SUR1-TRPM4 channel inhibitor to the subject. A method for preventing or reducing CNS edema in a subject at high risk of severe cerebral or spinal cord swelling following injury or condition associated with CNS edema, including, (Claim 74) The method according to claim 73, wherein the subject has experienced a stroke and the CNS edema is cerebral edema. (Claim 75) The method according to claim 74, wherein the subject is considered to be at high risk of severe cerebral edema if he or she exhibits at least one factor or score selected from the group consisting of at least 10 National Institutes of Health Stroke Scale (NIHSS) scores, 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 imaging (DWI) score greater than 70 cc, a CT perfusion score greater than 50 cc, poor collateral circulation as determined by CT angiography, and a CT scan showing low density of at least 33% in the middle cerebral artery region. (Claim 76) The method according to claim 75, wherein if the subject shows magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) exceeding 82 cc, the subject is considered to be at high risk of severe cerebral edema. (Claim 77) The method according to claim 75, wherein if the subject shows magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) exceeding 145 cc, the subject is considered to be at high risk of severe cerebral edema. (Claim 78) The method according to claim 75, wherein if the subject shows magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) exceeding 145 cc, the subject is considered to be at high risk of severe cerebral edema. (Claim 79) The method according to claim 75, wherein if the subject exhibits a CT perfusion score exceeding 70 cc, the subject is considered to be at high risk of severe cerebral edema. (Claim 80) The method according to claim 75, wherein if the subject shows a CT scan indicating low density of at least 50% of the middle cerebral artery region, the subject is considered to be at high risk of severe cerebral edema. (Claim 81) The method according to claim 73, wherein the administration step involves one or more consecutive infusions of a SUR1-TRPM4 channel inhibitor over a cumulative time of at least 72 hours. (Claim 82) The method according to claim 73, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibride, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, trazamide, glikidone, LY397364, LY389382, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof. (Claim 83) The method according to claim 73, wherein the SUR1-TRPM4 channel inhibitor is glybride. (Claim 84) The method according to claim 73, wherein the administration step is performed within 12 hours of the injury or condition related to the CNS edema. (Claim 85) The steps include administering one or more consecutive infusions of glybrid to the subject, and A step of measuring liver enzyme levels while continuing administration of the glybride. A method for delivering glybrid to a subject, including the glybrid. (Claim 86) The method according to claim 85, wherein the step of administering is for the treatment of an injury or condition associated with spinal edema. (Claim 87) The method according to claim 86, wherein the step of administering is for the treatment of an injury or condition related to cerebral edema. (Claim 88) The method according to claim 87, wherein the injury or condition associated with cerebral edema is a stroke. (Claim 89) The method according to claim 85, further comprising the preceding step of measuring liver enzyme levels before administering the glybride. (Claim 90) The method according to claim 85, wherein the step of measuring liver enzyme levels includes measuring the liver enzyme levels after a specific period of time since the administration step was initiated. (Claim 91) The method according to claim 90, wherein the specific period is approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 168 hours, the day the subject is discharged from the hospital, or a combination thereof. (Claim 92) The method according to claim 85, wherein the liver enzyme to be measured is aspartate aminotransferase (AST). (Claim 93) The method according to claim 85, wherein the liver enzyme to be measured is alanine aminotransferase (ALT). (Claim 94) The method according to claim 84, wherein the administration step is modified or discontinued based on the result of the measurement step. (Claim 95) The method according to claim 85, wherein the step of administering glybride is discontinued if the subject's ALT level rises to more than approximately eight times the upper limit of a normal ALT level, as determined by the administering physician. (Claim 96) The method according to claim 60, wherein the step of administering glybride is discontinued if the subject develops cholestatic jaundice or hepatitis. (Claim 97) The steps include administering one or more consecutive infusions of sulfonylurea to the subject, and A step of performing an electrocardiogram on the subject to monitor the subject's heart. A method for monitoring cardiac activity when glybride is administered to a subject, including the following: (Claim 98) The method according to claim 97, wherein the administration step is for the treatment of an injury or condition associated with spinal edema. (Claim 99) The method according to claim 97, wherein the administration step is for the treatment of injury or condition related to cerebral edema. (Claim 100) The method according to claim 97, wherein the injury or condition associated with cerebral edema is a stroke. (Claim 101) The method according to claim 97, wherein the step of performing the electrocardiogram includes a preceding step of performing the electrocardiogram on the subject before the step of administering the sulfonylurea. (Claim 102) The method according to claim 97, wherein the step of performing the electrocardiogram includes a step of performing an electrocardiogram on the subject after a specific period of time has elapsed since the administration step was started. (Claim 103) The method according to claim 97, wherein the specific period is approximately 4 to 6 hours, approximately 24 hours, approximately 48 hours, approximately 60 to 72 hours, approximately 168 hours, the day the subject is discharged, or a combination thereof. (Claim 104) The method according to claim 97, wherein the step of administering sulfonylurea is discontinued if the QTc of the electrocardiogram exceeds approximately 550 ms. (Claim 105) The method according to claim 97, wherein the injury or condition associated with cerebral edema is a stroke. (Claim 106) The steps include administering glybride intravenously to the subject, and Steps to monitor blood glucose, liver enzymes, and QTc during the step of intravenously administering the glybride to the subject. A method for delivering glybrid to a subject, including the glybrid. (Claim 107) The method according to claim 106, further comprising the step of administering dextrose to the subject. (Claim 108) A method for treating a subject suffering from extensive cerebral hemispheric infarction, comprising the step of administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject, wherein the subject is under 71 years of age and the treatment improves a functional outcome as measured by one or more outcome scales. (Claim 109) A method for treating a subject suffering from extensive cerebral hemispheric infarction, comprising the step of administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject, 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 for treating a subject suffering from extensive cerebral hemispheric infarction, comprising the step of administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor, wherein the administration step is initiated 9 hours or less from the time of stroke confirmation or from the last time the subject was observed to be normal. (Claim 111) A method for treating a subject suffering from traumatic brain injury, comprising the step of administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel agent to the subject, wherein the subject exhibits radiological evidence of intracerebral blood induced by the traumatic brain injury prior to the treatment. (Claim 112) The step of registering subjects who are at least 18 years old and defined as radiologically LHI, A step of treating the subject with a SUR1-TRPM4 channel inhibitor or a suitable placebo, starting 9 hours or less from the time of stroke or the last time observed to be normal, for up to approximately 72 hours. Steps to evaluate mRS, A method for testing a treatment for widespread cerebral hemispheric infarction, including, the method being considered successful if a statistically significant favorable outcome for the drug is detected in subjects aged 70 years or younger, or if a descriptive benefit is detected in subjects aged 70 years or older.

[0019] Here, illustrative embodiments are shown, and specific terminology is used herein to describe those embodiments. However, it should be understood that these drawings are merely illustrative and should not be considered to limit the scope. [Brief explanation of the drawing]

[0020] [Figure 1] Figure 1 shows the incidence rate of mortality in individuals suffering from injuries or conditions associated with cerebral edema, based on clinical studies conducted and presented herein. [Figure 2] Figure 2 shows the incidence of deaths in individuals who suffered cerebral edema-related injury or condition and were treated with either decompressive craniotomy and either the research drug or placebo in clinical studies conducted and presented herein. [Figure 3] Figure 3 shows the distribution of individual mRS scores in clinical studies. [Figure 4] Figure 4 shows the median 90-day Barthel Index score of individuals in clinical studies conducted and presented herein. [Figure 5] Figure 5 shows the average percentage reduction in midline deviation of the brains of the study participants. [Figure 6] Figure 6 shows the individual FLAIR ratios in clinical studies conducted and presented herein. [Figure 7] Figure 7 shows disruption of the blood-brain barrier in an individual during a clinical study conducted and presented herein. [Figure 8] Figure 8 shows an analysis of mRS outcomes according to lesion size in extensive cerebral hemisphere infarction. [Modes for carrying out the invention]

[0021] Before disclosing and describing specific embodiments of the present invention, it should be understood that the present invention is not limited to the specific processes and materials disclosed herein and are therefore subject to some degree of variation. Furthermore, it should be understood that the scope of the present invention is defined solely by the appended claims and their equivalents, and that the terminology used herein is intended to describe only specific embodiments and is not intended to limit them.

[0022] In describing and claiming this invention, the following terminology shall be used.

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

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

[0025] As used herein, the terms “extreme hemispheric infarction” or “LHI” mean adjacent (for example) 、 This refers to ischemic stroke affecting all or subtotal areas of the middle cerebral artery (MCA), with or without involvement of the anterior cerebral artery (ACA) and / or posterior cerebral artery (PCA).

[0026] As used herein, “late neurological exacerbation” refers to a neurological exacerbation that occurs after an injury or condition resulting in neurological swelling. The exacerbation may begin after the injury or condition occurs, but may occur at a maximum of 72, 96, 120, 144, 168 hours, or longer, after the underlying injury or condition.

[0027] The term "lesion" refers to an abnormality in brain tissue. In some cases, a lesion may be a space-occupying lesion that has a recognizable volume and can affect nearby tissues 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 (by weight) of the SUR1-TRPM4 channel inhibitor is replaced by an equal amount (by weight) of another inactive ingredient, such as water. Furthermore, "placebo" may have typical slight formulation differences due to the absence of the 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 sulfonylurea, sulfonylurea mimetic, and any other composition effective in blocking or reducing the channel-related activity of SUR1.

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

[0032] The phrases “CNS edema-related,” “cerebral edema-related,” or “spinal cord-related,” “injury or condition” refer to triggering events that can cause or contribute to edema, such as cerebral edema or spinal cord edema. However, it should be noted that these injuries or conditions do not always cause edema in all patients. For example, stroke is generally a condition associated with CNS edema, and more specifically, cerebral edema. In certain more severe cases, stroke can result in life-threatening cerebral edema. Therefore, stroke is a condition associated with CNS edema or cerebral edema in that it carries 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, intraventricular hemorrhage, and neurosurgery. Spinal cord injury, on the other hand, may be associated with spinal cord edema. While some of these injuries or conditions are not directly related to the brain or spinal cord, such as cardiac arrest or liver failure, it is known that these injuries or conditions can, in some cases, result in CNS edema or cerebral edema.

[0033] "Traumatic brain injury" refers to injuries that result in swelling within or around the brain and are typically direct to a region of the brain (for example, affecting injuries to the head or near the head that can cause cerebral edema), and are associated with mild, moderate, or severe injuries.

[0034] A stroke occurs when there is insufficient blood flow to the brain and can lead to cell death. As defined herein, there are essentially two known types of stroke: ischemic stroke and hemorrhagic stroke. An ischemic stroke occurs when there is insufficient blood flow to the brain, while a 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 result in cerebral edema.

[0035] As used herein and as well understood in the art, the terms “treating” or “treatment” mean an approach to obtain a favorable or desired outcome, including clinical outcomes. Favorable or desired clinical outcomes may include, but are not limited to, reduction or remission of one or more symptoms or conditions, whether detectable or undetectable; attenuation of disease severity; stabilization of disease (i.e., no worsening); delay or slowing of disease progression; remission or mitigation of disease; attenuation of disease relapses; and remission (partial or complete), whether detectable or undetectable. “Treatment” and “treatment” may also mean extending survival compared to the survival expected without treatment. In addition to being useful as methods of treatment, the methods described herein may be useful for the prevention or prevention of disease.

[0036] As used herein, the term “about” is used to impose flexibility on an endpoint by indicating that a given value may be “slightly above” or “slightly below” an endpoint of a numerical range. The degree of flexibility in this term may be defined by certain variables, which will be within the knowledge of those skilled in the art to determine 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] In this specification, multiple activators, compounds, damages, or conditions may be represented in common lists for convenience. However, these lists should be interpreted as each member of the list being individually identified as a distinct and unique member. Therefore, no individual member of such a list should be interpreted, unless otherwise indicated, as a de facto equivalent of any other member of the same list based on their presentation in a common group.

[0039] Concentration, quantity, and other numerical data may be expressed or presented in range format as herein. Such range format is used solely for convenience and conciseness, and therefore, not only the numerical values ​​explicitly cited as limits to the range, but also all individual numerical values ​​or sub-ranges contained within that range, as well as each numerical value and sub-range explicitly cited It should be understood that the range should be interpreted flexibly, including what is used as if it were. For example, the numerical range "approximately 0.01 to 2.0" should be interpreted to include not only the explicitly cited value of approximately 0.01 to approximately 2.0, but also the individual values ​​and subranges within the indicated range. Therefore, what is included in 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 width or characteristics of the range described. In addition, please note that all percentages are weights unless otherwise specified.

[0040] In this specification, all composition percentages are given as weight percentages unless otherwise specified. Where a solution of a component is mentioned, the percentage refers to the weight percentage of the composition including the solvent (e.g., water) unless otherwise indicated.

[0041] In order to understand the scope of this disclosure, the terms “including” or “comprising” and their derivatives, as used herein, are intended to be open-ended terms that identify the existence of mentioned characteristics, components, elements, groups, integers, and / or steps, but do not exclude the existence of other unmentioned characteristics, components, elements, groups, integers, and / or steps. This also applies to similar terms such as “including,” “having,” and their derivatives. The terms “consisting” and their derivatives, as used herein, are intended to be closed terms that identify the existence of mentioned characteristics, components, elements, groups, integers, and / or steps, but exclude the existence of other unmentioned characteristics, components, elements, groups, integers, and / or steps. As used herein, the term “consisting essentially of” is intended to identify the presence of a property, component, element, group, integer, and / or step mentioned, as well as properties, components, elements, groups, integers, and / or steps that do not significantly affect the fundamental and novel characteristics of the property, component, element, group, integer, and / or step. A reference to any one of these transition terms (i.e., “comprising,” “consisting,” or “consisting essentially”) is understood to directly support the substitution of any of the other transition terms not specifically used. For example, modifying a term from “comprising” to “consisting essentially of” would be directly supported by this definition.

[0042] In this specification, multiple compounds or steps may be represented in a common list for convenience. However, these lists should be interpreted as each member of the list being individually identified as a distinct and unique member. Therefore, no individual member of such a list should be interpreted, on its own, 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 disclosures are equally applicable to other embodiments found herein. For example, a list of activators or drugs described in relation to a method for treating late neurological exacerbations or death would serve as direct support for that embodiment, even if these drugs are not listed again in the context of embodiments relating to methods for reducing midline deviation of the brain.

[0044] In one embodiment, a method is presented for reducing late neurological exacerbations or death in subjects following injury or condition associated with CNS edema. This method involves administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to the subject cumulatively over at least approximately 72 hours from the start of the sequential infusions. It has been found that administration of SUR1-TRPM4 channel inhibitors can reduce the incident of late neurological exacerbations or death. While this method is subject-dependent, the occurrence of late neurological exacerbations or death can typically be determined based on a comparison with the occurrence of late neurological exacerbations in a group of patients not treated with SUR1-TRPM4 channel inhibitors. “Late neurological exacerbations” refers to neurological exacerbations that occur long after injury or condition associated with CNS edema. Longer periods may include ≥24 hours, ≥48 hours, ≥72 hours, ≥84 hours, ≥96 hours, ≥108 hours, ≥120 hours, ≥132 hours, ≥148 hours, ≥160 hours, ≥172 hours, or approximately ≥184 hours.

[0045] SUR1-TRPM4 channel inhibitors may include any activator effective in blocking SUR1-TRPM4, some examples of which may include glibride (also known as glibenclamide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tobutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, trazamide, glikidone, LY397364, LY389382, glyclazide, 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, mefanamic acid, niflumic acid, limonaban, and SKF963. 5 is included. In one embodiment, the SUR1-TRMP4 channel inhibitor is glybrid. In another embodiment, the SUR1-TRMP4 channel inhibitor is tobutamide. In yet another embodiment, the SUR1-TRMP4 channel inhibitor is glycazide. That is the case.

[0046] SUR1-TRPM4 channel inhibitors may be administered as a bolus injection, a series of infusions, or a combination thereof. In some cases, administration may involve multiple bolus injections or multiple series of infusions. In other embodiments, administration may involve one or more series of infusions following a bolus injection. For example, a first series of infusions may be given after a bolus injection, followed by a second series of infusions at a slower infusion rate compared to the first infusion. In yet another embodiment, a series of infusions may be given after a bolus injection. In yet another embodiment, a bolus injection may be given after a first series of infusions, followed by a second series of infusions. In yet another embodiment, a second series of infusions and a third series of infusions may be given after a first series of infusions.

[0047] The administrations presented herein may be carried out over a long period of time. Administrations may be carried out over periods 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, the administration includes one or more consecutive infusions with an accumulated time length of at least 72 hours. In another embodiment, the administration includes one or more consecutive infusions with an accumulated time length of at least 96 hours. In yet another embodiment, administration includes one or more consecutive infusions over at least 120 hours. In an alternative embodiment, the administration of one or more consecutive infusions may be carried out over ≤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 body weight, and / or the SUR1-TRMP4 channel inhibitor being administered. Bolus injections are expected to be administered in doses of approximately 100 μg to 200 μg. In one embodiment, the bolus injection is approximately 110 μg to 140 μg, or 125 μg. In another embodiment, the bolus injection is approximately 140 μg to 160 μg, or 150 μg. In yet another embodiment, the bolus injection is approximately 160 μg to 190 μg, or 175 μg. Continuous infusions are expected to be administered at infusion rates of approximately 100 μg / hour to 300 μg / hour. In one embodiment, the infusion rate is approximately 110 μg / hour to 140 μg / hour, or 125 μg / hour. In another embodiment, the injection rate is approximately 140 μg / hour to approximately 160 μg / hour, or approximately 150 μg / hour. In yet another embodiment, the injection rate is approximately 160 μg / hour to approximately 190 μg / hour, or approximately 175 μg / hour. In yet another embodiment, the injection rate is approximately 190 μg / hour to approximately 225 μg / hour, or approximately 200 μg / hour. Further embodiments include injection rates of approximately 225 μg / hour to approximately 300 μg / hour, or approximately 250 μg / hour.

[0049] Unlike clotbusters, which are typically administered to subjects with ischemic stroke, SUR1-TRPM4 channel inhibitors do not induce bleeding. Therefore, SUR1-TRPM4 channel inhibitors may be effective both when administered for the first time immediately after the injury or condition, or when administered for the first time some time after the injury or condition associated with cerebral edema occurs. In one embodiment, the first dose of a SUR1-TRPM4 channel inhibitor may be within the first 1 hour, first 2 hours, first 3 hours, first 4 hours, first 6 hours, first 8 hours, or first 10 hours after the injury or condition occurs. In another embodiment, the first dose of a SUR1-TRPM4 channel inhibitor may be within a certain period after the injury or condition associated with cerebral edema occurs, at least 4 hours, at least 4.5 hours (a period during which clotbusters may be ineffective or even dangerous), at least 6 hours, at least 8 hours, or at least 10 hours. In yet another embodiment, the first dose of a SUR1-TRPM4 channel inhibitor may be within 6 hours after the injury or condition occurs. In a further embodiment, the first dose of the SUR1-TRPM4 channel inhibitor may be administered within 6 hours of the onset of injury or condition. In another embodiment, the first dose may be administered within 8 hours of the onset of injury or condition. In yet another embodiment, the first dose of the SUR1-TRPM4 channel inhibitor may be administered within 10 hours of the onset of injury or condition.

[0050] The underlying injury or condition resulting in late neurological exacerbation, death, or other conditions discussed herein is not particularly limited. This may include any disease or condition resulting in cerebral edema. 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 may be ischemic or hemorrhagic stroke. In another embodiment, the stroke may be ischemic stroke and occur in the middle cerebral artery or carotid artery (intracranial or extracranial) or any other site associated with ischemic stroke. If the stroke is hemorrhagic stroke, it may occur or originate from any known site associated with hemorrhagic stroke, including both or either subarachnoid hemorrhage or intracerebral hemorrhage.

[0051] Similarly presented herein are methods for reducing midline displacement of the brain in subjects following traumatic brain injury or stroke. Midline displacement of the brain can be caused by changes in lesion volume or swelling of the lesion. The methods may include 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 craniotomy on the subject. Midline displacement may be measured by CT scan or MRI scan, or using transcranial Doppler. Reduction of midline displacement may be determined by comparing it to the amount of midline displacement in TBI patients who have not been treated with stroke or SUR1-TRPM4 channel inhibitor or decompressive craniotomy. Reduction in midline deviation of the brain was greater than 5%, greater than 8%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, and less than 40%. The reduction may be greater than 5%, or even greater than approximately 50%. In some embodiments, the reduction in midline displacement of the brain is greater than the reduction achieved when either a SUR1-TRPM4 channel inhibitor is administered or a decompressive craniotomy is performed. In other embodiments, the reduction is greater than the additive effect of either of the individually performed procedures. In one embodiment, the SUR1-TRPM4 channel inhibitor reduced both the lesion volume and the swelling of the lesion. In another embodiment, the SUR1-TRPM4 channel inhibitor not only reduces midline displacement of the brain but also treats the swelling of the lesion. In some embodiments, the method may further include administering tissue plasminogen activator (TPA) or a clotbuster activator before or with the SUR1-TRPM4 channel inhibitor. This may be particularly effective when a TPA or clotbuster activator is administered, but is still considered safe, for example, within the first 4.5 hours when the injury or condition associated with cerebral edema occurs. Examples of TPA or clotbuster activators that may be co-administered include activase, tenectoplase, eurokinase, streptokinase, and / or desmoteplase. Furthermore, clots can be removed by devices, i.e., mechanical thrombectomy. Administration of TPA or clotbuster activators is typically by intravenous infusion, but oral and subcutaneous administration are also included as routes of administration. SUR1-TRPM4 channel inhibitors, dosage forms, administration rates, administration timeframes, duration of administration for initial doses, underlying conditions, and other details may be as discussed above.

[0052] Furthermore, this 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 comprises administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to a subject after the subject has suffered from an injury or condition associated with CNS edema. Further steps include establishing an initial degree of disability in the subject 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 following the determination of the initial degree of disability. In one embodiment, the first and second scoring systems or tests may be identical or different. In this embodiment, the improvement in the subject is determined, for example, quantified, by the scoring system(s). In one embodiment of this method, as a result of the administration of the SUR1-TRPM4 channel inhibitor, an improvement in the difference in the degree of disability is achieved based on the scoring system(s) or (single or more). For example, an improvement in the difference in the degree of disability may be achieved, which is at least about 10% based on a stroke scoring system. 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%. The scoring system may be based on the National Institutes of Health Stroke Score System (NIHSS), a 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 embodiment, the first scoring system or test may be based on the NIHSS, and the second scoring system or test may be based on a 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 embodiment, a method for treating a subject suffering from extensive cerebral hemispheric infarction may involve administering a therapeutically effective dose of an intravenous SUR1-TRPM4 channel inhibitor to the subject. In one embodiment, the subject may be under 71 years of age, and treatment may improve a functional outcome as measured by one or more outcome scales. In another embodiment, the subject may have a lesion volume of at least about 100 cc, or an ASPECTS score of less than or equal to 5, or both. In yet another embodiment, administration may be initiated 9 hours or less from the time of stroke confirmation, or from the last time the subject was observed to be normal. In yet another embodiment, the subject may show radiological evidence of intracerebral blood induced by traumatic brain injury prior to treatment. Radiological evidence may be obtained using MRI or CT. Intracerebral blood may result from a localized contusion having a minimum volume of, for example, at least about 0.5 mL or at least about 1 mL.

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

[0055] SUR1-TRPM4 channel inhibitors, dosage forms, administration rates, administration timeframes, duration of administration for initial dosing, underlying conditions, and other details may be as discussed above and throughout this specification.

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

[0057] In one embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 100 mg / dL or less. In another embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 95 mg / dL or less. In yet another embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 90 mg / dL or less. In yet another embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 80 mg / dL or less. In yet another embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 110 mg / dL or less. In yet another embodiment, the dextrose solution is initially administered if the subject's blood glucose level is approximately 120 mg / dL or less. In yet another embodiment, the dextrose solution is administered if the subject's blood glucose level tends to decrease rapidly. Generally, dextrose supplementation should not be typically performed if blood glucose levels are higher than approximately 140 mg / dL. A tendency for 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 may contain dextrose in saline or water. The weight percentage of dextrose in a dextrose solution is typically between 1% and 25% by weight, but 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, may also be used. In other words, the weight percentage 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. Examples of commonly used dextrose solutions may include 5% dextrose in normal saline (D5NS) and 10% dextrose in normal saline (D10NS), although such solutions may also be in water or partially in normal saline (e.g., 1 / 2 normal saline) rather than in normal saline. In one embodiment, if the subject's blood glucose level is greater than approximately 80 mg / dL to 100 mg / dL, a 3% to 8% by weight dextrose solution may be administered to the subject at approximately 50 cc / hour to approximately 120 cc / hour. In another embodiment, if the subject's blood glucose level is approximately 55 mg / dL to 80 mg / dL, an 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 the subject's blood glucose level is <55 mg / dL, an 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 the subject's blood glucose level is below 55 mg / dL, the administration of glybride or other SUR1-TRPM4 channel inhibitors is reduced or even discontinued. 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 may be a 5% to 60% by weight dextrose solution in water or saline, specifically water (D50W), 1 / 2 normal saline, or 50% dextrose in normal saline.

[0059] When determining the amount of dextrose to be delivered, the physician may consider the total fluid to be adequately delivered to the subject (this may include maintenance fluid and fluid containing a SUR1-TRPM4 channel inhibitor). In one embodiment, 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 any history of pulmonary edema should be considered. Using a 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 includes monitoring the subject's blood glucose level. Monitoring may be performed every hour, every two hours, every four hours, every eight hours, every twelve hours, every twenty-four hours, or a combination thereof. In one specific embodiment, monitoring may be performed every hour for the first 24 hours of administration of the SUR1-TRPM4 channel inhibitor, then every two hours for the next 24 hours, for example, between the 25th and 48th hours of administration of the SUR1-TRPM4 channel inhibitor, and then every four hours for the remaining R1-TRPM4 channel inhibitor infusions. If the subject's blood glucose level falls below 70 mg / dL, monitoring may be performed every 15 minutes, for example, until the subject's blood glucose level rises to ≥80 mg / dL in three consecutive readings without exogenous bolus glucose administration.

[0061] In some cases, if blood glucose levels are high, a decision may be made to discontinue the administration of dextrose solution. In this embodiment, the dextrose solution may be discontinued if the subject's blood glucose level is ≥150 mg / dL, approximately ≥140 mg / dL, approximately ≥130 mg / dL, or approximately ≥120 mg / dL. In one example, whole blood glucose <70 mg / dL may be verified before discontinuing or reducing drug administration, either by performing another measurement at the bedside or by clinical laboratory testing.

[0062] In one embodiment, subjects treated with a SUR1-TRPM4 inhibitor may be monitored for blood glucose as follows: For the first approximately 24 hours, every hour (±30 minutes), From approximately the 25th hour to approximately the 48th hour, every 2 hours (±30 minutes), Then every 4 hours (±60 minutes).

[0063] When blood glucose levels fall to below approximately 70 mg / dL, monitoring frequency may be increased to every 15 minutes (±10 minutes) until blood glucose levels are greater than or equal to approximately 80 in approximately three consecutive readings without exogenous glucose supplementation.

[0064] If the medication is interrupted and then resumed, blood glucose levels may be measured hourly for approximately 3 hours (±30 minutes).

[0065] If glucose is not required, monitoring can be reverted to the frequency of the previous protocol, for example, 1, 2, or 4 hours in this embodiment.

[0066] In another embodiment, blood glucose can be controlled in subjects treated with a SUR1-TRPM4 inhibitor, for example, as follows: - If baseline blood glucose is less than approximately 100 mg / dL, the initial maintenance fluid may be approximately 5% dextrose (D5NS) in normal saline at a rate of approximately 70 to 100 cc / hour. - If blood glucose is below approximately 100 mg / dL, D5NS can be started at approximately 70 to 100 cc / hour. Dose setting (titration) of increasing or decreasing IV fluid rate. Using this, it is possible to maintain blood glucose levels above approximately 80 mg / dL. - If blood glucose levels are below approximately 80 mg / dL, D5NS may be initiated, or if D5NS is already being administered, the subject may be switched to approximately 10% dextrose in a normal serum line (D10NS). - If blood glucose levels tend to decline rapidly or continuously, D5NS may be initiated, or if D5NS is already being administered, the subject may be switched to D10NS. - In cases where blood glucose levels are higher than approximately 140 mg / dL, D5NS or D10NS cannot be administered. - Any confirmed blood glucose levels below approximately 70 mg / dL can be treated with a 50 mL ampoule of approximately 50% dextrose in water (D50W). If D50W is unavailable, a dextrose fluid of another concentration can be used in sufficient volume to achieve the same amount of dextrose.

[0067] SUR1-TRPM4 channel inhibitors, dosage forms, administration rates, administration timeframes, duration of administration for initial dosing, underlying conditions, and other details may be as discussed above and throughout this specification, or may be modified according to clinical decisions made, for example, by the healthcare professional administering the treatment. For example, different dosages and timings may be administered, or different routes of administration may also be used.

[0068] In another embodiment, a method for preventing cerebral edema in subjects at high risk of severe cerebral edema may include determining whether a subject is at high risk of severe cerebral edema, and administering one or more sequential infusions of a SUR1-TRMP4 channel inhibitor to subjects who have been determined to be at high risk of severe cerebral edema.

[0069] In describing stroke as an example where this method may 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 have a National Institute of Heath Stroke Score (NIHSS) of ≥20 when the dominant hemisphere is involved, and ≥15 when the non-dominant hemisphere is involved. In other instances, the vast majority (perhaps over 99%) of cases 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 be identified using at least 10 National Institutes of Health Stroke Scale (NIHSS) score, 7 or less; Alberta Stroke Program Early CT Score (ASPECTS), 4 or less; Alberta Stroke Program Early CT Score (ASPECTS), Magnetic Resonance Imaging (MRI) Diffusion-Weighted Imaging (DWI) exceeding 70cc, Magnetic Resonance Imaging (MRI) Diffusion-Weighted Imaging (DWI) exceeding 82cc, Magnetic Resonance Imaging (MRI) Diffusion-Weighted Imaging (DWI) exceeding 145cc, CT Perfusion Core exceeding 50cc, 70 A subject may be considered at high risk of severe cerebral edema if they exhibit at least one factor selected from the group consisting of a CT perfusion core exceeding cc, poor collateral circulation as determined by CT angiography (or other means), a CT scan showing low density of at least 33% of the middle cerebral artery region, and / or a CT scan showing low density of at least 50% of the middle cerebral artery region. In some embodiments, a subject is first assessed for having an NIHSS of 10 or greater, and then assessed 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 82cc.

[0070] In particular, patients with extensive hemispheric infarction (LHI) are at especially high risk of swelling. These subjects typically have a stroke in the middle cerebral artery region and can be further identified radiologically using MRI, DWI, or CT perfusion of at least approximately 70cc, at least approximately 80cc, at least approximately 90cc, or at least approximately 100cc, or may exhibit ASPECTS scores of ≤5, ≤4, ≤3, or ≤2. In one embodiment, in the method intended herein for treating subjects with LHI, the subjects may be less than approximately 76 years of age or less than approximately 71 years of age. Furthermore, subjects with at least 10 on the National Institutes of Health Stroke Scale (NIHSS) may have acceptable outcomes if the drug is administered 10 hours or less from the time of stroke confirmation or the last known incident. Administration times of 9 hours or less may also yield acceptable outcomes. These methods may result in improvements in one or more clinically meaningful endpoints, including survival / mortality, modified Rankin Scale (as a complete ordinal scale and / or bipartite), Barthel Index, and / or EuroQol. These improvements may be evident at one or more time points, including approximately 90 days (or 3 months), 180 days (or 6 months), and / or 12 months (or 1 year) after stroke.

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

[0072] Table 1 below shows an exemplary medication schedule. Note that the references to mass refer only to the drug-only SUR1-TRPM4 channel inhibitor (placebo is not included). [Table 1]

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

[0074] SUR1-TRPM4 channel inhibitors, dosage forms, administration rates, administration timeframes, duration of administration for initial dosing, underlying conditions, and other details may be as discussed above and throughout this specification.

[0075] Furthermore, methods for safely delivering glybrid to a subject may include administering one or more sequential infusions of glybrid to the subject and measuring liver enzyme levels while continuing glybrid administration. In one embodiment, administration may be after or as a result of an injury or condition associated with CNS edema. In another embodiment, such methods may also be for the administration of glybrid for indications other than those associated with CNS edema. In any case, this may be done to protect the kidneys, liver, intestines, or heart. According to the oral glybrid package insert, glybrid may transiently increase aminotransferases.

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

[0077] Monitoring may involve 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 yet another embodiment, the liver enzymes are indirect bilirubin and / or direct bilirubin and / or total bilirubin. Monitoring may similarly involve measuring both AST and ALT levels of the subject, or ALT and bilirubin, or ALT, AST, and bilirubin. In one embodiment, administration of glybride is discontinued if the subject's ALT or AST level rises to about eight times the upper limit of normal ALT or AST levels. In one embodiment, administration of a SUR1-TRPM4 channel inhibitor may be discontinued if the subject's ALT or AST level rises to about six times the upper limit of normal ALT or AST levels, as determined by the administering physician. In yet another embodiment, administration of glybrid may be discontinued if, as determined by the administering physician, the subject's ALT or AST levels rise to about four times the upper limit of normal ALT or AST levels. In yet another embodiment, administration of glybrid 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, a trade-off assessment between enzyme levels and treating CNS edema, etc. In one embodiment, administration of glybrid may be discontinued if the subject's total bilirubin levels rise to about twice the upper limit of normal.

[0078] The dosage form, administration rate, administration time frame, duration of administration for the initial dose, underlying condition, and other details may be as discussed above and throughout this specification.

[0079] In another embodiment, a method for monitoring cardiac activity when a sulfonylurea is administered to a subject may include administering one or more consecutive infusions of glibride to the subject and performing an electrocardiogram on the subject to monitor the subject's heart. In one embodiment, the administration may be after or as a result of an injury or condition associated with CNS edema. In another embodiment, such a method may also be for the administration of glibride for indications other than those associated with CNS edema. In any case, this may be done to protect the kidneys, liver, intestines, or heart. Sulfonylureas, including glibride, have a black-bordered warning regarding cardiac mortality. Furthermore, studies of oral glibride have shown that it may cause QTc prolongation.

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

[0081] The dosage form, administration rate, administration time frame, duration of administration for the initial dose, underlying condition, and other details may be as discussed above and throughout this specification.

[0082] In another embodiment, the method for delivering glybrid to a subject may include intravenous administration of glybrid to the subject, and monitoring of blood glucose, liver enzymes, and QTc during intravenous administration of glybrid to the subject. Any of the embodiments described herein, along with their associated details, may be applicable to these embodiments.

[0083] As mentioned with respect to the various methods discussed herein, these methods are applicable to a variety of injuries or conditions associated with CNS edema. However, not all of these injuries or conditions always result in CNS edema; rather, they can be said to "be associated with" or "risk" CNS edema. One example is stroke. For instance, spatially occupying cerebral edema secondary to ischemic stroke of the cerebral hemisphere (affecting the entire middle cerebral artery territory or beyond) can lead to intracranial hypertension and eventual brain herniation, resulting in significant pathological conditions and mortality. This condition usually manifests itself between 2 and 5 days after the onset of ischemic stroke, with swelling peaking 2 to 3 days after the incident. This can further lead to destruction of previously healthy brain tissue, as well as extensive brain tissue displacement resulting in tentoricular notch or uncinate gyrus herniation and brain death; therefore, such complications can be the cause of the rapid neurological exacerbation seen in such patients. For example, life-threatening swelling can occur in up to 8% of ischemic stroke patients during hospitalization and up to 15% of all middle cerebral artery (MCA) strokes. Therefore, whether it originates from a stroke or from other injuries or conditions associated with CNS edema, the methods of this disclosure may be beneficial to many such subjects who are experiencing or at risk of experiencing CNS edema.

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

[0085] (Example 1) A randomized, double-blind, placebo-controlled study of widespread cerebral hemispheric infarction. A randomized, double-blind, placebo-controlled clinical study was conducted to determine the efficacy of a SUR1-TRPM4 channel inhibitor in reducing or treating neurological conditions associated with cell swelling and CNS edema or cerebral edema. In this study, 83 subjects, estimated by clinicians to have brain lesions ranging from 82cc to 300cc, were treated with either a study drug solution of glybride or a placebo solution within approximately 10 hours of the injury or condition associated with cerebral edema. Of the “per protocol” group, 77 patients were centrally confirmed to have brain lesions ranging from 82cc to 300cc. Forty-one subjects received the study drug, and 36 subjects received placebo. The study drug was administered as follows: a bolus of 0.13 mg of the SUR1-TRPM4 channel inhibitor was administered over approximately 2 minutes, followed by a continuous infusion of 0.16 mg / hour for 6 hours, and then a continuous infusion of 0.11 mg / hour for 66 hours, for a total treatment period of 72 hours. The total daily doses of the 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 the 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, the percentage of deaths among subjects in the test drug group was approximately half as low.

[0088] Decompressive craniotomy (DC) data Since mortality data were associated with drug and placebo treatments with and without decompressive craniotomy (DC), further mortality data were collected. Essentially, the occurrence of deaths was recorded for study participants who died after DC before the end of the study period. Table 3 below shows the incidence of deaths with and without DC, and this is graphed in Figure 2. [Table 3]

[0089] As seen in Table 3, in this particular study, the best results were achieved in the study drug group that also underwent a DC procedure, but these results were only slightly better than those in the study drug group that did not undergo a DC procedure. More specifically, in the placebo group, having a DC procedure was beneficial compared to not having one, but both were inferior to the outcomes seen in the study drug group (with or without decompressive craniotomy). Figure 2 shows the raw data values ​​seen in Table 3 in terms of percentages. Note that the mean time before decompression does not account for these numbers, as they can vary considerably based on the judgment of the physician making these types of decisions and, to some extent, the schedule. Note also that two delayed decompressive surgeries were performed due to late neurological exacerbations. These surgeries might have been avoidable if the patients had been treated with SUR1-TRPM4 channel inhibitors for a longer period, e.g., 5 or 7 days.

[0090] mRS score Participants in this study were also tested using a 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 who had an mRS of 0–4 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 shown in Table 4, the proportion of subjects receiving the SUR1-TRPM4 channel inhibitor with an mRS score of 0-4 was, on average, 14.6% higher than that of individuals who did not receive the study drug. Furthermore, the median mRS score in the treatment group was 4, compared to 5 in the placebo group.

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

[0093] As can be seen in Table 5, the Barthel Index score was superior in the study drug group compared to the placebo group.

[0094] Midline deviation data In this study, subjects underwent MRI scans between 72 and 96 hours to obtain images and observe the degree of reduction in midline deviation. The average percentage reduction is shown in Table 6 below and graphed in Figure 5. [Table 6]

[0095] Based on MRI scan images, the percentage reduction in midline deviation (or greater reduction in midline deviation) was, on average, more favorable in individuals in the test drug group than in the placebo group. The percentage reduction was determined by comparing the median midline deviations in each group at 72–96 hours.

[0096] FLAIR ratio A FLAIR ratio study (an MRI measure of blood-brain barrier interference) was also conducted, where study subjects were evaluated to determine, where possible, the reduction of vasogenic edema. 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 better on average than the placebo group. A low FLAIR ratio indicates less interference with the blood-brain barrier.

[0098] Destruction of MMP Furthermore, MMP-9 levels based on blood samples were obtained for study participants at 24 and 72 hours, and then averaged. MMP-9 levels are known to rise after stroke and are thought to indicate impaired blood-brain barrier function. The average MMP-9 levels are shown in Table 8 below and graphed in Figure 7. [Table 8]

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

[0100] Monitoring and correction of blood glucose levels a) During a double-blind, placebo-controlled study, one patient who received a 10% by weight dextrose solution recorded a decrease in blood glucose level to 51 mg / dL, which was confirmed in the laboratory. In this example, the dose of glybride infusion was reduced by 30%, and the patient's blood glucose level stabilized. b) During a double-blind, placebo-controlled study, one patient had a blood glucose level of 57 mg / dL at the time of care, which was 67 mg / dL on a laboratory retest. In this case, the patient was given normal saline, which was then switched to 5% by weight dextrose, where the patient's blood glucose stabilized.

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

[0102] Improvement of survival Across the entire perprotocol population, the odds ratios (ORs) ranged from 2.54 to 2.74 at various time points. These results were just above statistical significance at day 90 or beyond (an odds ratio of 1 indicated no effect), and therefore generally represent overall improvement. However, in the perprotocol population ≤70, the results were statistically significant at all time points and had a more substantial OR range of 3.41 to 3.79. The data are shown in Table 9 below. [Table 9-1] [Table 9-2]

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

[0104] Improvement of mRS The mRS, which assesses overall disability after stroke and is assessed at 90 days, is the most widely used primary outcome measure commonly used in acute stroke trials. This scale provides an ordinal hierarchical scale for assessing disability, ranging from 0 (no symptoms) to 6 (death). While the mRS is often analyzed as a binary outcome, this approach often weakens its ability to detect effects and has been shown to obscure both positive and negative effects. Conversely, ordinal analysis can retain the full capacity of the mRS and better reflects health status by assigning value to each transition.

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

[0106] Although not statistically significant, the effect sizes for the 0-3 and 0-4 dichotomies in patients ≤70 in the perprotocol population were 14% and 22%, respectively. These figures significantly exceed the minimum clinically meaningful effect size, demonstrating a considerable clinical effect 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 prevalent scales used in acute stroke. In one example, the smallest clinically significant change beyond the error of measurement was approximately 20 points on a 100-point scale, which was used as the reference value in this study. In the perprotocol population with ≤70, the median deltas or differences observed between the drug and placebo at 90 days, 6 months, and 12 months were 35, 27.5, and 45, respectively, all of which were above the acceptable threshold. In the general interpretation of the BI, a score of ≤40 is considered a clearly poor outcome, while a score of ≥60 is considered 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 glybride 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] Improvements to EQ-5D EuroQol-5D (EQ-5D) is a comprehensive assessment tool used to evaluate quality of life in a variety of conditions, including stroke. It is the most commonly used assessment tool (instrument) for gathering cost-effectiveness information in the calculation of adjusted quality of life years (QALYs) to support pricing and reimbursement discussions. It is one of the most widely used health-related quality of life assessment tools in clinical research. The smallest clinically significant difference in stroke has been reported to be 0.08–0.12 units (Kim et al., 2015). Perprotocols are applied to the entire population and perprotocols ≤70. 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 populations where ≤70. [Table 12]

[0109] Timing of treatment Unlike thrombolytic therapy in ischemic stroke, which relies on the removal of blood clots and reperfusion of tissue before tissue death, anti-edema therapy should have a broader timeframe because the progression of edema is part of the secondary response to the original injury. Brain herniation, the final consequence of this process, actually peaks 2-3 days after injury. Based on the mechanism of action, which is based on the effect on edema rather than tissue preservation via reperfusion, there is no reason to deductively predict that the importance of time will become apparent in the first few hours after stroke confirmation. Surprisingly, however, the inventors observed such an effect.

[0110] Using ordinal logistic regression, the mRS distribution across the entire perprotocol population was compared to the population that received the drug 9 hours or less (from stroke confirmation or the last time the subject was seen as normal), and an enhancement of the treatment effect was observed in the form of 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. Therefore, drug treatment 9 hours or less appears to be superior, surprisingly, despite the fact that there is no expectation of time importance at this point in the natural course of the condition. [Table 13]

[0111] Specificity for widespread cerebral hemisphere infarction Edema is involved in several different conditions, most commonly in ischemic stroke, although the clinical effect of edema management in ischemic stroke can be minimized to zero for a certain volume of infarct. Using the data from this study, we were able to determine a threshold lesion size under which the outcome is unaffected by drug treatment. More specifically, in this analysis, we evaluated the mRS "shift" as a function of increasing lesion size. A modified intent-to-treat population was used to include the broadest lesion size distribution. Baseline DWI Each 10cc increase in lesion size (centrally determined) was associated with an OR of 0.88 in the placebo group (p=0.026), supporting the previous finding 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 larger the lesion extent, the greater the treatment effect; for example, each 10cc increase in DWI size resulted in a 1.09-fold increase in the mRS "shift." By extrapolating to a lesion extent of approximately 100cc with "zero effect," it could not be predicted that the drug would function significantly in patients with smaller lesions, which is consistent with the fact that these patients are less likely to develop clinically significant edema in the first place. Larger lesions with greater edema may yield more dramatic results. This concept is visually represented in Figure 8, where "zero effect" is indicated by an OR of mRS shift of 1. In this case, there was no shift below approximately 100cc. More specifically, in patients with baseline lesions of ≤100cc, the OR was calculated to be 1.00 (p=0.99), meaning that, for example, the drug effect in lesions of less than 100cc ranged from minimal to no effect, which supported the findings of the interaction analysis.

[0112] (Example 2) A randomized, double-blind, placebo-controlled study in traumatic brain injury. To evaluate the efficacy of glybride as a representative SUR1-TRPM4 channel inhibitor for edema in TBI, a double-blind, placebo-controlled study was conducted at three clinical sites with 29 subjects having moderate or severe TBI (Glasgow Coma Scale score 4–12) or mild TBI (GCS 13–14) with bleeding on CT scans. The study drug was administered as follows: a bolus of 0.13 mg of the SUR1-TRPM4 channel inhibitor was administered over approximately 2 minutes, followed by a continuous infusion of 0.16 mg / hour for 6 hours, and then a continuous infusion of 0.11 mg / hour for 66 hours, for a total administration time of 72 hours. The total daily doses of the 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 at 72 hours.

[0113] Fourteen subjects (7 drug-treated and 7 placebo-treated) identified as having evidence of lesional blood (i.e., blood associated with the contusion) at baseline and who underwent MRI scans at both baseline and 72 hours were assessed for edema using MIM software version 5.6. Blinded readers used T2 images to elucidate x, y, and z measurements of the entire apparent contusion, where possible, and used DTI images in cases where T2 images were missed. Only contusions that could be reliably measured (at least approximately 1 cc measured) were measured. Readers also used SWI images to elucidate volumetric measurements of bleeding 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 bleeding volume. In the analysis, if there were multiple lesions, the volumes of all lesions that met the threshold were combined.

[0114] At baseline, the drug group had a larger mean edema volume (8.72 ml compared to 2.12 ml in placebo, a four-fold difference), worse clinical features as measured by the mean motor and ocular domains of the Glasgow Coma Scale (GCS, 6.14 compared to 7.67 in placebo), and a higher intubation rate (5 out of 7 compared to 3 out of 7 in placebo). Despite this, the drug group showed less edema progression from baseline to 72 hours (2.14 times growth compared to 10.28 times growth in placebo), and there was no difference in the mean expanded Glasgow Coma Scale score (GOSE, 6 compared to 6.17 in placebo) at day 180. From these data, it can be concluded that despite a more severe clinical profile and four times higher edema at baseline, the drug substantially reduced edema proliferation or growth compared to placebo, resulting in identical clinical outcomes to the placebo group. No drug-related effects were detected in subjects without lesions or in brain regions without lesions. This suggests, surprisingly, that the drug's effect is not edema-specific, but is specific to lesion-related edema.

[0115] Therefore, in studies 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 are balanced with respect to baseline clinical features such as GCS or its individual components (motor, ocular, or linguistic), it can be expected that the drug group may yield improved clinical outcomes on a scale such as a GOSE with a minimum effect size of at least 4% or an odds ratio of at least 1.2, which is more favorable to the drug than placebo.

[0116] (Example 3) Control of blood glucose Subjects treated with an intravenous SUR1-TRPM4 inhibitor according to the protocol described herein may be monitored and glucose controlled. Monitoring and treatment may be carried out in one embodiment as follows: For the first 24 hours, every hour (±30 minutes), From the 25th to the 48th hour, every 2 hours (±30 minutes), Then every 4 hours (±60 minutes).

[0117] When blood glucose levels fall to below approximately 70 mg / dL, monitoring frequency is increased to every 15 minutes (±10 minutes) until blood glucose levels reach 80 or higher in three consecutive readings without exogenous glucose supplementation.

[0118] If the medication is interrupted and then restarted, blood glucose levels are measured hourly for approximately 3 hours (±30 minutes). If glucose is no longer needed, monitoring is returned to its previous frequency (e.g., approximately every 1, 2, or 4 hours).

[0119] Blood glucose can be further controlled in subjects treated with intravenous SUR1-TRPM4 inhibitors as follows: - If baseline blood glucose is less than 100 mg / dL, an initial maintenance solution consisting of approximately 5 wt% dextrose (D5NS) in normal saline may be administered at a rate of 70 to 100 cc / hour. - If blood glucose falls below approximately 100 mg / dL, D5NS is initiated at a rate of 70 to 100 cc / hour. Blood glucose can be maintained above approximately 80 mg / dL by using dose settings that increase or decrease the IV fluid rate. - If blood glucose is less than 80 mg / dL, D5NS may be initiated, or if D5NS is already being administered, the subject may be switched to approximately 10 wt% dextrose in a normal serum line (D10NS). - If there is a tendency for blood glucose to decrease rapidly or continuously, D5NS may be initiated, or if D5NS is already being administered, the subject may be switched to D10NS. - In cases where blood glucose levels are higher than approximately 140 mg / dL, D5NS or D10NS will not be administered. - Any confirmed blood glucose levels below approximately 70 mg / dL can be treated with approximately 50 mL ampoules of 50 wt% dextrose in water (D50W). If D50W is unavailable, a dextrose fluid of another concentration can be used in sufficient volume to achieve the same amount of dextrose.

[0120] The above protocol or any similar variation may be described in various documents related to the drug. These documents may include, but are not limited to, protocols, statistical analysis plans, investigational drug brochures, clinical guidelines, drug guides, risk assessment and mediation programs, prescribing information, and other documents that may be related to the drug. Such documents are specifically intended to be physically packaged as a kit with the SUR1-TRPM4 channel inhibitor drug, to be beneficial or as required by regulatory authorities.

[0121] While this disclosure has been described in relation to a particular embodiment, those skilled in the art will understand that various modifications, changes, omissions, and substitutions can be made without departing from the spirit of this disclosure. Accordingly, this disclosure is intended to be limited only by the following claims.

Claims

[Claim 1] The invention as shown in the drawings.

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