Journal
STROKE
Volume 41, Issue 10, Pages 2283-2287Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.110.582601
Keywords
dose-finding; ischemic stroke; minocycline; neuroprotection; pharmacokinetics
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Funding
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS055728]
- Pfizer, Inc
- VA Merit Review, National Institute of Neurological Disorders and Stroke [RO1 NS063965]
- VA Merit Review [EIA0740002N]
- Actelion and the National Institute of Neurological Disorders and Stroke
- National Institutes of Health [RO1DK074385]
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Background and Purpose-Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. Methods-Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results-Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65 +/- 13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5 +/- 5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. Conclusions-Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator. (Stroke. 2010;41:2283-2287.)
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