Minocycline in Acute Cerebral Hemorrhage

Intracerebral hemorrhage (ICH) is perhaps the most severe neurologic catastrophe with upwards of 40% mortality and the majority of survivors left with permanent disability. In addition, to date no surgical or pharmacologic treatments have been demonstrated to improve outcome. There is a need to identify new targets and treatment strategies. The longterm goal of this candidate is to become an academic stroke neurologist specializing in vascular protection and blood-brain barrier integrity in ICH. In this proposal, the candidate will conduct an early phase, randomized clinical trial of minocycline (MC) in ICH. Under the guidance of an experienced team of mentors and collaborators, this grant will propel the candidate forward as an independent clinician scientist. Recent evidence from preclinical research has implicated blood components and their degradation products; iron, and proteases [matrix metalloproteinases (MMPs)] are directly toxic to brain tissue and promote edema. Inflammation, mediated by activated microglia/macrophages, results in further tissue injury. MC may be an ideal drug to test in ICH. It has excellent blood-brain barrier penetration and preclinical studies have shown that MC inhibits matrix metalloproteinases, chelates iron and is anti-inflammatory. As a repurposed drug, it has a long history of safety as an antibiotic. The main objective of this research project is to test the hypothesis that administration of MC significantly reduces plasma MMP-9, serum iron and plasma IL-6 in ICH patients. In addition, the pharmacokinetics of MC in ICH patients will be determined, safety of MC will be assessed and preliminary data on hemorrhage growth, perihematomal edema, and clinical outcome generated. Twenty-four patients with ICH will be randomized to MC or control within 6 hours of symptom onset. Subjects will receive 400 mg daily for a total of five doses. The first dose will be administered intravenously with subsequent doses orally or via nasogastric tube. Plasma MMP-9, iron and IL-6 will be measured prior to MC administration, and again at 24 hours, 7 (or discharge if sooner) and 90 days. Clinical assessments will be performed with the Glasgow Coma Scale and the National Institutes of Health Stroke Scale at baseline, 24 hours and 7 days or discharge, and modified Rankin Scale at 90 days. Measurement of biomarkers and clinical outcome at 90 days will be blinded to treatment arm. (AHA Program: Mentored Clinical & Population Research Program)