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 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.
Winstanley
P A
PA
Department of Pharmacology and Therapeutics, University of Liverpool, United Kingdom.
Mberu
E K
EK
Szwandt
I S
IS
Breckenridge
A M
AM
Watkins
W M
WM
D000818:Animals; D003622:Dapsone / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D002727:Proguanil / Q000031:analogs & derivatives / Q000494:pharmacology
D004338:Drug Combinations; D005493:Folic Acid Antagonists; C007030:chlorproguanil; D003622:Dapsone; D004094:Dihydropteroate Synthase; D002727:Proguanil