title: Potent antipneumocystis and antitoxoplasma activities of piritrexim, a lipid-soluble antifolate.
abstract: Piritrexim, a lipid-soluble antifolate, was evaluated for its activity against Pneumocystis carinii and Toxoplasma gondii. The concentration of piritrexim needed to inhibit 50% of the catalytic activity of P. carinii dihydrofolate reductase (DHFR) was 19.3 nM, and that for T. gondii DHFR was 17.0 nM, concentrations that were 40- to over 1,000-fold less than those needed for the inhibition of activity by trimethoprim and pyrimethamine, the antifolates conventionally used in treating these organisms. Piritrexim was able to inhibit replication of T. gondii in a mouse peritoneal macrophage model at concentrations of 0.1 to 1.0 microM. Leucovorin, a reduced folate that can bypass the inhibition of DHFR by antifols in mammalian cells but not in protozoa, did not affect the ability of piritrexim to inhibit T. gondii replication. The addition of sulfadiazine, which alone was ineffective, to piritrexim allowed inhibition of T. gondii replication at lower concentrations of piritrexim than when piritrexim was used alone. These results suggest that piritrexim, alone or combined with a sulfonamide, may be a highly potent antitoxoplasma and antipneumocystis agent that could provide major pharmacologic and clinical advantages over available agents.
authors.affiliation: Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: J A
authors.initials: JA
authors.lastname: Kovacs
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: J C
authors.initials: JC
authors.lastname: Swan
authors.forename: J C
authors.initials: JC
authors.lastname: Drake
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
authors.forename: B A
authors.initials: BA
authors.lastname: Chabner
authors.forename: H
authors.initials: H
authors.lastname: Masur
mesh_terms: D000818:Animals; D005493:Folic Acid Antagonists; D051379:Mice; D008807:Mice, Inbred BALB C; D011010:Pneumocystis / Q000187:drug effects* / Q000201:enzymology; D011739:Pyrimethamine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology; D016597:Trimetrexate
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011799:Quinazolines; C024530:piritrexim; D016597:Trimetrexate; D011739:Pyrimethamine