Inhibitors of NCCa-ATP channels for therapy
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Publication Number
US-8557867-B2
Publication Date
2013-10-15
Expiration Date
2028-06-20
Abstract
Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NCca-ATP channel and include, for example, inhibitors of SUR1 and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.
Core Innovation
The invention provides methods and compositions for treatment and prevention of intraventricular hemorrhage (IVH) and progressive hemorrhagic necrosis (PHN), particularly after spinal cord injury (SCI). The core of the innovation is the identification and inhibition of the NCCa-ATP channel, a unique non-selective cation channel activated by intracellular calcium and inhibited by intracellular ATP. The NCCa-ATP channel consists of a regulatory subunit, sulfonylurea receptor 1 (SUR1), and a pore-forming subunit closely resembling transient receptor potential melastatin 4 (TRPM4). Inhibitors of SUR1 and TRPM4, including known antagonists like glibenclamide, can effectively block or modulate this channel to treat or prevent pathologies associated with IVH, PHN, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury.
The problem addressed is the lack of effective therapy for secondary injury mechanisms such as PHN in spinal cord injury and for intraventricular hemorrhage in premature infants, which cause significant morbidity and mortality. PHN is characterized by progressive capillary fragmentation, hemorrhage, and necrosis that exacerbate the initial injury, leading to loss of vital spinal cord tissue. IVH arises from bleeding in fragile brain vessels of premature infants and results in severe neurological consequences. Existing therapies, including corticosteroids and other pharmacological interventions, have not been effective in preventing these conditions.
The invention solves the problem by elucidating the role of the SUR1-regulated NCCa-ATP channel in endothelial cells and neurons, linking its activation to cellular depolarization, cytotoxic edema, oncotic cell death, capillary breakdown, and hemorrhage. By providing antagonists or inhibitors that target SUR1 and/or TRPM4, the activity of this channel can be suppressed, thereby preventing cell swelling, vascular integrity loss, and reducing lesion size, edema, hemorrhage, and neurological dysfunction. This molecular targeting offers a novel and effective therapy for preventing or treating secondary hemorrhagic necrosis and intraventricular hemorrhage.
Claims Coverage
The patent contains one independent claim focusing on a method of treating or preventing intraventricular hemorrhage in infants via administration of SUR1-regulated NCCa-ATP channel inhibitors.
Method of preventing intraventricular hemorrhage using SUR1-regulated NCCa-ATP channel inhibition
Administering an effective amount of an NCCa-ATP channel inhibitor, specifically glibenclamide, to the mother prior to birth of an infant at risk of intraventricular hemorrhage to prevent or treat the condition.
Administration prior to 37 weeks gestation
Providing the SUR1-regulated NCCa-ATP channel inhibitor to the mother before 37 weeks of gestation to reduce risk.
Treatment of mothers at risk for premature labor
Providing the inhibitor to mothers identified as at risk for premature labor to prevent intraventricular hemorrhage in infants.
Treatment in pregnancies less than 37 weeks with labor symptoms
Administering the inhibitor to mothers with pregnancies less than 37 weeks gestation who exhibit symptoms of labor.
Multiple routes of inhibitor administration
Administering the NCCa-ATP channel inhibitor via intravenous, subcutaneous, intramuscular, intracutaneous, or intragastric routes.
Combination with MgADP administration
Further comprising administration of MgADP to the individual in combination with the inhibitor.
The claims cover a method of preventing or treating intraventricular hemorrhage in infants by administering inhibitors of the NCCa-ATP channel, specifically glibenclamide, to the mother prior to birth with multiple administration routes and possible combination therapy with MgADP.
Stated Advantages
Inhibition of the NCCa-ATP channel reduces progressive hemorrhagic necrosis and edema following spinal cord injury and decreases lesion size and neurological dysfunction.
SUR1 antagonists such as glibenclamide are associated with improved stroke outcomes in humans with diabetes mellitus.
Blockade of SUR1-regulated channels prevents capillary fragmentation and progressive secondary hemorrhage, reducing morbidity and mortality.
Co-administration of glucose with channel antagonists allows higher doses and greater protection without hypoglycemia.
Documented Applications
Treatment and prevention of progressive hemorrhagic necrosis following spinal cord injury.
Treatment and prevention of intraventricular hemorrhage in premature infants, including administration to the infant postnatally or to the mother prenatally.
Treatment and prevention of intraventricular hemorrhage in infants at risk, including those born before 37 weeks gestation or with low birthweight.
Treatment and prevention of traumatic brain injury and its secondary effects, including progressive secondary hemorrhage and edema.
Treatment and prevention of subarachnoid hemorrhage related to hypoxic or ischemic injury.
Use in diagnostic and therapeutic protocols for insurance claim processing related to these medical conditions.
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