The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug

We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, re...

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Vydáno v:The American journal of tropical medicine and hygiene Ročník 60; číslo 6; s. 943
Hlavní autoři: Kinyanjui, S M, Mberu, E K, Winstanley, P A, Jacobus, D P, Watkins, W M
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.06.1999
Témata:
Animals
Antidotes - pharmacology
Antimalarials - pharmacology
Antimalarials - therapeutic use
Asia, Southeastern
Dose-Response Relationship, Drug
Drug Resistance
Folic Acid - pharmacology
Folic Acid Antagonists - pharmacology
Folic Acid Antagonists - therapeutic use
Hematinics - pharmacology
Humans
Inhibitory Concentration 50
Kenya
Leucovorin - pharmacology
Malaria, Falciparum - drug therapy
Plasmodium falciparum - drug effects
Plasmodium falciparum - growth & development
Prodrugs - pharmacology
Prodrugs - therapeutic use
Proguanil - analogs & derivatives
Proguanil - pharmacology
Proguanil - therapeutic use
Triazines - pharmacology
Triazines - therapeutic use
Asia, Southeastern
Kenya
ISSN:0002-9637
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Shrnutí:We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10(-5) mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.
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ISSN:0002-9637
DOI:10.4269/ajtmh.1999.60.943