Efficacy of epiroprim (Ro11-8958), a new dihydrofolate reductase inhibitor, in the treatment of acute Toxoplasma infection in mice.

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Efficacy of epiroprim (Ro11-8958), a new dihydrofolate reductase inhibitor, in the treatment of acute Toxoplasma infection in mice.

Am J Trop Med Hyg. 1996 Mar;54(3):249-52. Unique Identifier : AIDSLINE MED/96183672
Martinez A; Allegra CJ; Kovacs JA; Critical Care Medicine Department, Clinical Center, National; Institutes of Health, Bethesda, Maryland, USA.

Abstract: Toxoplasma gondii is a major cause of focal encephalitis in patients with acquired immunodeficiency syndrome. Epiroprim, an inhibitor of dihydrofolate reductase, was evaluated in vitro and in a mouse model of acute infection for activity against T. gondii. The 50% inhibitory concentration (IC50) of epiroprim for T. gondii dihydrofolate reductase was 0.9 micromole, similar to that of pyrimethamine, but epiroprim was 650-fold more selective than pyrimethamine for T. gondii compared with human dihydrofolate reductase. While intraperitoneally administered epiroprim (300 mg/kg/day for 14 days) alone was ineffective in mice acutely infected with the RH strain of T. gondii, 100% survival was seen when it was combined with orally administered sulfadiazine (375 mg/kg/day), which alone was also ineffective. Increases in survival were seen in combination with doses of sulfadiazine as low as 0.375 mg/kg/day. Orally administered epiroprim combined with dapsone also prolonged survival. Thus epiroprim is an active and potentially less toxic alternative pyrimethamine for the treatment of toxoplasmosis.

Keywords: Acute Disease Administration, Oral Animal Anti-Infective Agents/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/ THERAPEUTIC USE Antiprotozoal Agents/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/ *THERAPEUTIC USE Dapsone/ADMINISTRATION & DOSAGE/THERAPEUTIC USE Drug Therapy, Combination Folic Acid Antagonists/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/ *THERAPEUTIC USE Half-Life Human Injections, Intraperitoneal Injections, Subcutaneous Mice Mice, Inbred BALB C Sulfadiazine/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/THERAPEUTIC USE Toxoplasmosis, Animal/*DRUG THERAPY Trimethoprim/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/ PHARMACOKINETICS/THERAPEUTIC USE JOURNAL ARTICLE
960730
M9670483

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