Minocycline May Improve Stroke Outcomes Out to 24 Hours

Susan Jeffrey
Medscape Medical News 2007. © 2007 Medscape
October 1, 2007 — Results of a randomized open-label trial suggest that the use of minocycline 6 to 24 hours after an acute ischemic stroke is associated with significantly improved clinical outcomes.
"The improvement was already apparent within a week of the stroke," said study author Yair Lampl, MD, from the Edith Wolfson Medical Center and Tel Aviv University, Israel, in a statement from the American Academy of Neurology. "This is exciting because many people who have had stroke cannot be treated if they don't get to the hospital within 3 hours after symptoms start, which is the time frame for current available treatments."
However, he added, "while these are promising results, a much larger, closed-label study is needed to confirm our findings."
Their report appears in the October 2 issue of Neurology.
Neuroprotective Effects of Minocycline
Minocycline is a semisynthetic, second-generation derivative of tetracycline, and has been shown to have a "clear beneficial protective effect," in animal models of multiple sclerosis, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as in stroke models, the authors write.
The proposed mechanism of benefit is thought to relate not to its antibiotic action but to its anti-inflammatory effects, a reduction in microglial activation, matrix metalloproteinase reduction, nitric oxide production, or inhibition of apoptotic cell death, they note.
To look more closely at the potential benefit of minocycline in stroke, the researchers carried out a randomized, open-label, evaluator-blinded study comparing 200 mg of minocycline given orally for 5 days with placebo. The therapeutic window was from 6 to 24 hours after the onset of stroke.
The primary outcome was change from baseline to day 90 on the National Institutes of Health Stroke Scale (NIHSS) with minocycline treatment vs placebo; secondary outcomes were a comparison of NIHSS scores on day 7 and day 30, and the modified Rankin Scale (mRS) and Barthel Index (BI) scores on days 7, 30, and 90.
Of 152 patients randomized, 74 received minocycline and 77 placebo. NIHSS scores at admission were similar between groups.
The pattern of benefit was apparent by days 7 and 30, they note. Deaths, myocardial infarction, recurrent strokes, and hemorrhagic transformations did not differ by treatment group.
Because there were some baseline differences between the groups, they repeated the primary analysis of NIHSS score at 90 days using an analysis of covariance with patient age, peptic ulcer disease, use of ACE inhibitors, sulfonylureas, and baseline NIHSS score as covariates. "The difference between groups remained significant and, in fact, the difference in means increased slightly after adjustment for the effect of these covariates," they write.
Confirmation of their results in a larger double-blind trial is needed, they conclude, as well as further research to refine the dose of minocycline; it was given in this study at a dosage with proven safety, but it is not known if this is an optimal dose, they note. Minocycline was given orally in this trial, but intravenous treatment might be more effective, the authors speculate. Finally, the time window for treatment was 6 to 24 hours, but earlier treatment may have different efficacy, they write.
Finding a Neuroprotectant That Works
Asked for comment by Medscape Neurology and Neurosurgery, Philip Gorelick, MD, from the University of Illinois College of Medicine at Chicago, said this study by Lampl et al "provides an exciting possibility for neuroprotection" and that "minocycline [is] a multipotential neuroprotectant in acute ischemic stroke. These early-phase study results suggest that this agent may be beneficial."
"It is too early to conclude, however, that the agent is efficacious in acute ischemic stroke; a large-scale study will be needed to prove the point," he adds. "As everyone knows, all prior studies have failed to definitively prove that neuroprotection in acute ischemic stroke is safe and effective. We look forward to the results of further testing of this agent in the hopes of finally finding a neuroprotectant that works."
The authors report no conflict of interest.
Neurology. 2007; 69:1404-1410.