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Two randomized, double-blind, placebo-controlled trials, in which levamisole (2.5 mg/kg) was given alone or co-administered with ivermectin (200 microg/kg) or albendazole (400 mg), were conducted. In Trial 1, safety and drug-drug interaction were explored in 42 healthy male volunteers. During Trial 2, the safety of the same treatment regimens and their efficacy against the adult worms and microfilariae of Onchocerca volvulus were investigated in 66 infected subjects of both sexes. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. The pharmacokinetic parameters for levamisole alone and the combinations were determined in Trial 1 and then compared with historical data for ivermectin and albendazole, given as single agents, to determine if drug-drug interaction had occurred. The level of efficacy against the adult worms was determined by the examination of histology sections of nodules excised 6 months posttreatment and from the changes seen in the levels of microfilaridermia within a year of treatment. Microfilaricidal efficacy was estimated from the reductions in the levels of microfilaridermia between day 0 (1 day pre-treatment) and day 30. Although the regimens were generally well tolerated, there were unexpected adverse effects in both healthy volunteers and infected subjects. Clinically significant drug-drug interactions resulted in an increase in the bio-availability of ivermectin but a reduction in that of albendazole when these drugs were co-administered with levamisole. Levamisole given alone or with albendazole had little effect on O. volvulus. The combination of levamisole with ivermectin was neither macrofilaricidal nor more effective against the microfilariae and the adult worms than ivermectin alone. The pathogenesis of the adverse events and the drug-drug interactions are discussed.