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Glibenclamide for the treatment of acute CNS injury.

ABSTRACT: First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis-all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

SUBMITTER: Kurland DB

PROVIDER: S-EPMC3817601 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Glibenclamide for the treatment of acute CNS injury.

Kurland David B DB Tosun Cigdem C Pampori Adam A Karimy Jason K JK Caffes Nicholas M NM Gerzanich Volodymyr V Simard J Marc JM

Pharmaceuticals (Basel, Switzerland) 20131011 10

First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (for ...[more]

PMID: 24275850

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Project description:BackgroundRecent research has established that acute kidney injury (AKI) is a common problem in severe paediatric malaria. Limited access to kidney diagnostic studies in the low resources settings where malaria is common has constrained research on this important problem.MethodsEnrolment data from an ongoing clinical trial of antipyretics in children with central nervous system (CNS) malaria, CNS malaria being malaria with seizures or coma, was used to identify risk factors for AKI at presentation. Children 2-11 years old with CNS malaria underwent screening and enrollment assessments which included demographic and anthropomorphic data, clinical details regarding the acute illness, and laboratory studies including creatinine (Cr), quantitative parasite count (qPC), quantitative histidine rich protein 2 (HRP2), lactate, and bilirubin levels. Children with a screening Cr > 106 µmol/l were excluded from the study due to the potential nephrotoxic effects of the study drug. To identify risk factors for AKI at the time of admission, children who were enrolled in the study were categorized as having AKI using estimates of their baseline (i.e. before this acute illness) kidney function and creatinine at enrollment applying the Kidney Disease: Improving Global Outcome (KDIGO) 2012 guidelines. Logistic regressions and a multivariate model were used to identify clinical and demographic risk factors for AKI at presentation among those children enrolled in the study.Results465 children were screened, 377 were age-appropriate with CNS malaria, 22 (5.8%) were excluded due to Cr > 106 µmol/l, and 209 were enrolled. Among the 209, AKI using KDIGO criteria was observed in 134 (64.1%). One child required dialysis during recovery. Risk factors for AKI in both the logistic regression and multivariate models included: hyperpyrexia (OR 3.36; 95% CI 1.39-8.12) and age with older children being less likely to have AKI (OR 0.72; 95% CI 0.62-0.84).ConclusionAKI is extremely common among children presenting with CNS malaria. Hyperpyrexia with associated dehydration may contribute to the AKI or may simply be a marker for a more inflammatory systemic response that is also affecting the kidney. Appropriate fluid management in children with CNS malaria and AKI may be challenging since generous hydration to support kidney recovery could worsen malaria-induced cerebral oedema in this critically ill population. Trial registration https://clinicaltrials.gov/ct2/show/NCT03399318.

Dataset Information

Glibenclamide for the treatment of acute CNS injury.

Publications

Glibenclamide for the treatment of acute CNS injury.

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