Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii

Abstract

We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels 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, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 104 parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0%o of the mice, respectively. When these drugs were administered simultaneously, a 100%o survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kgJday, respectively) protected 100%1v of the mice. A 3-week therapy of chronically infected mice with either 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 inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.

Combination of PS-15, epiroprim, or pyrimethamine with dapsone in prophylaxis of Toxoplasma gondii and Pneumocystis carinii dual infection in a rat model

“…There is clearly a need to develop new, effective combinations against both infections. Several experimental studies performed in vitro and in vivo have shown that PS-15, a new biguanide, and epiroprim (EPI), an analog of TMP, were effective against both P. carinii (7,8,15,26) and T. gondii (6,20) and that they might be good candidates for alternative therapy or prophylaxis. However, these results were obtained in experimental models of single infection and did not take account of the frequent association of these infections in AIDS patients.…”

Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex

“…Brodimoprim combined with dapsone was active in vitro and in vivo against some mycobacteria (5). Epiroprim combined with dapsone had promising activity in vitro and in vivo against Toxoplasma gondii (1).…”

Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone

“…The EPM-DDS combination was highly active in these models, and the drugs showed synergistic activity in vivo. The combination of EPM with DDS, which has already been demonstrated to have good in vivo activity against opportunistic infections caused by P. carinii (9,14) and Toxoplasma gondii (3,9), also shows activity against a broad range of bacteria causing respiratory tract infections. It is also likely that most atypical mycobacteria, which cause systemic infections once the CD4-cell count drops to Ͻ200/mm 3 , would be inhibited at concentrations achievable in biological fluids.…”

“…1), which is considerably more active than TMP against the DHFR from P. carinii isolates but which is not active against the human DHFR (11,12). The combination of EPM with dapsone (DDS), which is also used alone for the prophylaxis of P. carinii pneumonia (7), was highly effective against P. carinii isolates in rats (9,14) and against toxoplasmosis in mice (3,9) and in a model of mixed Pneumocystis and Toxoplasma infection (2). Since both EPM and DDS exhibit high levels of antibacterial activity, we investigated the activities of these compounds, alone and in combination, against a wide range of bacteria in comparison with those of TMP-SMZ and several other agents.…”