Found in translation: The rationale behind the early development of glibenclamide in large hemispheric infarction.

Many reasons have been put forth to explain the inability to translate neuroprotection in animal stroke models to humans. Following our determination that glibenclamide is an anti-edema drug, not a neuroprotective drug, and the revelation that the "gold standard" middle cerebral artery occlusion used for animal studies models large hemispheric infarction, a subpopulation of ischemic stroke that develops clinically relevant edema that contributes significantly to poor outcomes, we designed an innovative approach to studying the drug in patients with large hemispheric infarction. The approach included careful selection of the relevant patient population, which gave us a high degree of confidence to move forward into humans.

Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.

Background: Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction.

Methods: For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18-80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82-300 cm(3) on MRI at 18 hospitals in the USA.

Exploratory analysis of glyburide as a novel therapy for preventing brain swelling.

Background: Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm(3) treated with RP-1127 (glyburide for injection).

Pilot study of intravenous glyburide in patients with a large ischemic stroke.

Background And Purpose: Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection).

Methods: We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm3, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127≤10 hours.

Glibenclamide in cerebral ischemia and stroke.

The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death.

Validating imaging biomarkers of cerebral edema in patients with severe ischemic stroke.

Background: There is no validated neuroimaging marker for quantifying brain edema. We sought to test whether magnetic resonance imaging (MRI)-based metrics would reliably change during the early subacute period in a manner consistent with edema and whether they would correlate with relevant clinical endpoints.

Methods: Serial MRI studies from patients in the Echoplanar Imaging Thrombolytic Evaluation Trial with initial diffusion-weighted imaging (DWI) lesion volume >82 cm(3) were analyzed.

A comparative evaluation of lingual retainer failure bonded with or without liquid resin.

Objective: To prospectively evaluate and compare the effect of liquid resin on lingual retainer failure after a 2-year follow-up.

Materials And Methods: Fifty-two patients (26 males, 26 females) with a mean age of 18.3 ± 1.