ACTIVITY OF EPIROPRIM (RO-11-8958), A DIHYDROFOLATE-REDUCTASE INHIBITOR, ALONE AND IN COMBINATION WITH DAPSONE AGAINST TOXOPLASMA-GONDII

We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate redu ctase inhibitor, alone and in combination with dapsone, against Toxopl asma gondii. In vitro, the anti-T. gondii effects of epiroprim and dap sone were observed at nanogram-per-milliliter level when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, h owever, was only parasitostatic. In a model of acute infection, mice w ere infected intraperitoneally with 10(4) parasites of the RH strain o f T. gondii and were treated for 14 days by gavage (therapy divided in to two daily dosages), starting 24 h after infection. Used alone, daps one and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0% of the mice, respectively. When these drugs were a dministered simultaneously, a 100% survival rate was observed. Pyrimet hamine-sulfadiazine (4 and 250 mg/kg/day, respectively) protected 100% of the mice. A 3-week therapy of chronically infected mice with eithe r epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine ( 15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammat ion in their brains. A combination of epiroprim and dapsone, both at 5 0 mg/kg/day, further reduced the number of brain cysts in comparison w ith the number after the corresponding monotherapies. Epiroprim may ha ve a role in the prophylaxis or therapy of human toxoplasmosis, especi ally when combined with other drugs active against T.gondii, such as d apsone.