In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs

The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture...

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Vydané v:Antimicrobial agents and chemotherapy Ročník 39; číslo 4; s. 948
Hlavní autori: Winstanley, P A, Mberu, E K, Szwandt, I S, Breckenridge, A M, Watkins, W M
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.04.1995
Predmet:
Animals
Dapsone - pharmacology
Dihydropteroate Synthase - antagonists & inhibitors
Drug Combinations
Drug Synergism
Folic Acid Antagonists - pharmacology
Granulocytes - drug effects
Hematopoietic Stem Cells - drug effects
Humans
Plasmodium falciparum - drug effects
Proguanil - analogs & derivatives
Proguanil - pharmacology
ISSN:0066-4804
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Shrnutí:The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethamine-sulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.
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ISSN:0066-4804
DOI:10.1128/aac.39.4.948