Effect of pentoxifylline on cytokine patterns in the therapy of complicated Plasmodium falciparum malaria.

The effect of pentoxifylline (PTX) was tested for its capacity to modulate cytokine responses during therapy of severe Plasmodium falciparum malaria in a placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand. The patients received standard antimalarial treatment with artesunate (120 mg intravenously given immediately, then 60 mg every 12 hr for a total dose of 600 mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the first three days of antimalarial treatment. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were markedly elevated in all patients prior to treatment. After 6 hr of high-dose PTX treatment, TNF and IL-6 levels significantly decreased while an increase in TNF and IL-6 levels was seen after 6 hr of low-dose PTX or placebo treatment (P < 0.01). After 12 and 24 hr of high-dose PTX infusion, TNF-receptor plasma concentrations were lower than in low-dose PTX- or placebo-treated patients (P < 0.01), whereas no differences between the groups with regard to IL-6 receptor levels were observed. We conclude that 40 mg/kg/day of PTX reduces plasma levels of TNF, IL-6, and TNF-receptor in patients with severe malaria. Whether this reduction improves clinical outcome remains to be determined.

Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand.

Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria. Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose pentoxifylline (1.67 mg/kg/hr). All 45 patients had one or more manifestations of severe malaria such as cerebral malaria (n = 18), renal failure requiring hemodialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). The overall severity was comparable in the three groups. Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients. In addition, a number of subsidiary outcome variables were examined in specific subgroups, including the recovery time from coma for patients with cerebral malaria, the duration of intubation in patients with respiratory distress, the number of hemodialysis treatments needed for patients with acute renal failure, and the number of units of blood administered to patients requiring transfusion. Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment. No significant differences among the three treatment groups were found for any of the outcome variables examined. We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit.

PIP: Pentoxifylline, an inhibitor of tumor necrosis factor, was evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria admitted to the Bangkok (Thailand) Hospital for Tropical Diseases, in a 5-month period in 1994. All patients had 1 or more clinical manifestations of severe malaria, including cerebral malaria (n = 18), renal failure requiring dialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). Patients were randomly assigned to receive treatment for 72 hours with a combination of intravenously administered artesunate and either placebo (n = 15), low-dose (0.83 mg/kg/hour) pentoxifylline (n = 15), or high-dose (1.67 mg/kg/hour) pentoxifylline (n = 15). Overall severity was comparable in all 3 groups. Concentrations of tumor necrosis factor were reduced in all 3 groups 48 hours after treatment. There were no significant differences between groups in terms of parasite and fever clearance time, recovery time from coma in patients with cerebral malaria, duration of intubation in patients with respiratory distress, number of hemodialysis treatments required for patients with acute renal failure, or number of units of blood administered to patients in need of transfusion. These findings suggest that the addition of pentoxifylline to artesunate therapy for severe malaria produces no evident clinical benefit.