Certain of the processes thought to contribute to the pathogenesis of falciparum malaria may be disrupted by pentoxifylline, a drug which was developed to improve blood flow in patients with peripheral and cerebral vascular disease, and with sickle cell anemia. Pentoxifylline (PTX) can decrease TNF production (which may in turn decrease nitric oxide production and impair the cytoadherence of parasitized red cells to capillary endothelial cells), increase red cell deformability, and disrupt rosettes (unparasitized red cells adhering to parasitized red cells). All of these may be contributing to the pathogenesis of severe malaria, particularly cerebral malaria. Pentoxifylline is a safe drug, and is well-tolerated, even if taken for long periods of time. It has been used as adjunct therapy in severe malaria. In two single case reports, the patients improved dramatically within hours of starting PTX. In a study involving 56 Burundian children with severe malaria, all of whom received quinine, there were no deaths among the 36 PTX recipients, but 5 of the 30 control patients died (p = 0.055). Studies of adults in Germany and Thailand failed to corroborate these findings, which is not surprising, given the major differences between severe malaria in adults and children. We propose to begin with a dose4inding study (randomized, double-blind, placebo controlled) during which we will collected pharmacokinetic data along with detailed measures of efficacy (cerebral blood flow, cerebral blood volume, serial measures of cytokines, rosette formation). This study will be carried out at the Kenya SMAC site; they are most experienced with the required hemodynamic measurements. Data from this study will inform our choice for the larger therapeutic trial, which will involve all SMAC sites. If necessary, more detailed studies will continue in Kilifi. Approximately 500 children with cerebral malaria will be enrolled annually into the proposed placebo-controlled, double-blind, mortality- based study. All children will receive parenteral quinine; half will receive a continuous infusion of PTX, and the control group will receive a placebo infusion. A 5% decrease in mortality could be detected with a total enrollment of around 2,000 patients (four year' effort for the network). Given the magnitude of malaria mortality across the continent, even a relatively small decrease like this ill translate into many lives saved. Pentoxifylline is a potential intervention in a serious pediatric disease. This network creates an unprecedented opportunity to test it quickly, carefully and thoroughly.
