An old intravenous antibiotic may have new life as a stroke treatment, researchers say. Minocycline appears to reduce stroke damage in multiple ways - inhibiting white blood cells and enzymes that, at least acutely, can destroy brain tissue and blood vessels, respectively, says Dr. David Hess, chair of the Department of Neurology in the Medical College of Georgia School of Medicine.
The broad-spectrum antibiotic also seems to reduce cell suicide in the minutes and hours following a stroke, enabling more cells to recover.
He and other researchers leading a clinical trial that will study the drug in 60 stroke patients in Georgia, Kentucky and Oregon say they believe the antibiotic will be a safe, effective adjunct therapy for tPA, the only FDA-approved drug therapy for strokes.
"It's a safe drug that is easy to give and tolerate, that gets into the brain well, and may reduce bleeding, the primary side effect of tPA," says Dr. Hess, principal investigator on the $1.8 million National Institute of Neurological Disorders and Stroke-funded clinical trial. "We think it will make strokes smaller and patient outcomes better."
Their animal studies have shown the drug, given within six hours of a stroke, then every 12 hours for up to three days - the peak time of inflammation - reduces stroke damage by up to 40 percent.
"We know it's safe in humans and we know the concentrations we need to see improvement in the brains of rats can be achieved safely in humans," says Dr. Susan C. Fagan, professor of pharmacy at the University of Georgia, assistant dean for the MCG program of the UGA College of Pharmacy and study co-investigator. "That's an important consideration."
The drug's safety and optimal stroke dose are the primary focus of the phase-one clinical trial in stroke patients who arrive at MCG, University of Kentucky or Oregon Health & Science University within six hours of symptom onset and with measurable neurological symptoms. Every study patient will get one of four doses, starting with 200 milligrams, the most common dose already used, and increasing incrementally up to 700 milligrams. They'll get half their first dose at subsequent 12-hour intervals for a three-day period then be followed for 90 days.
"We are going to be drawing samples from patients to make sure we achieve the concentrations that we want in the blood, plus we want to define the half-life in stroke patients to see if it's different than in the younger patients who take it for other reasons,' says Dr. Fagan. Newer intravenous antibiotics have replaced minocycline in the United States, but an oral version is used to treat conditions such as acne and rheumatoid arthritis. "If the half-life is longer, we can give it less frequently. We are really fine-tuning the dose," she says. They'll do this by looking in the blood for biomarkers, indicators of inflammation, to see if inflammatory factors go up after three days. "It may give us a clue we should treat patients longer," says Dr. Fagan, a co-investigator on the studies leading to minocycline's use in rheumatoid arthritis.
One way minocycline fights inflammation is by inhibiting microglial cells, white blood cells activated by a stroke, says Dr. Hess. "When they get activated, they get angry and produce materials that damage the brain. The inflammatory cascade is bad and good. Early on it's bad, later on it may actually do some good things," he says. Typically these microglial cells are sentinel immune cells for the brain, helping eliminate infections and secreting factors that support neurons. However, acutely in a stroke, brain tissue can become their target. "They are basically cleaning house at first, then later, they are supportive, releasing growth factors and promoting the growth of new blood vessels," adds Dr. Fagan.