title: Efficacy of epiroprim (Ro11-8958), a new dihydrofolate reductase inhibitor, in the treatment of acute Toxoplasma infection in mice.
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.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: J A
authors.initials: JA
authors.lastname: Kovacs
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003622:Dapsone / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D013411:Sulfadiazine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014124:Toxoplasmosis, Animal / Q000188:drug therapy*; D014295:Trimethoprim / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000890:Anti-Infective Agents; D000981:Antiprotozoal Agents; D005493:Folic Acid Antagonists; D013411:Sulfadiazine; D003622:Dapsone; C082896:epiroprim; D014295:Trimethoprim