This safety study is a crucial prelude to testing the effectiveness of the combination in patients. In previous studies in rats, the size of brain damage was reduced up to 80 percent when a combination of caffeine and ethanol, called caffeinol, was administered within three hours after an artery supplying blood to the brain was blocked (ischemic stroke).
Those studies "demonstrated that the combination of caffeine and ethanol may reduce the amount of damage after stroke. Neither caffeine or alcohol offered protection alone, but the combination was protective," says senior author James C. Grotta, M.D., professor of neurology and director of the stroke program, University of Texas-Houston Medical School, Houston, Texas.
In this study, Grotta and colleagues sought to determine the safety and tolerability of caffeinol in humans.
Researchers administered the combination to 23 stroke patients (16 women, average age 71). The patients represented a diverse racial mix: nine white, nine black, four Hispanic and one Asian.
"Our goal was to see if we could safely achieve the same blood levels of caffeinol that we achieved in our animal studies," he says. "We discovered that we could use even lower doses than we used in the animal studies and achieve the blood levels that were neuroprotective in animals."
Moreover caffeinol, which is given by infusion, can be safely administered to patients who are also receiving clot-busting treatment with tissue plasminogen activator (tPA). Eight patients received both caffeinol and tPA. One patient with a very severe stroke who received caffeinol and tPA suffered an intracerebral hemorrhage (bleeding within the brain), but Grotta says an independent safety officer concluded it was not related to caffeinol.
The first set of four patients were given low-dose caffeinol (caffeine 6 milligrams per kilogram plus ethanol 0.2 grams per kilogram). That dose did not achieve the target blood level, so the dose was increased (8 mg/kg caffeine and 0.4 g/kg ethanol) in the next group of 19 patients. That achieved target blood levels, he says. However, Grotta cautioned that the ethanol level may need further adjustment because a patient with a history of heart disease developed reversible heart failure at that dose level. It is unclear how caffeinol works to protect the brain, but it is being studied.
A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination. In addition, Grotta plans a study that will combine caffeinol with thermo-cooling of stroke patients. Other studies have suggested that cooling the brain can limit stroke damage, and Grotta says that combining cooling and caffeinol may extend that protection.
Co-authors are Paisith Piriyawat, M.D.; W. Scott Burgin, M.D.; Lise A. Labiche, M.D.; and Jaroslaw A. Aronowski, Ph.D.
The research was funded in part by the National Institutes for Neurological Disorders and Stroke. Editor's note: For more information on stroke, visit the American Stroke Association Web site: strokeassociation.org
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