The inhibitory effect of a drug combination on the development of mefloquine resistance inPlasmodium berghei

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Abstract
Lines of Plasmodium berghei were exposed to drug selection pressure in successive passages in mice. The compounds used were chloroquine, mefloquine, a 2:1 mixture of sulphadoxine with pyrimethamine (S-P), and a variable mixture of mefloquine with S-P. Resistance developed to all lines. Resistance to the S-P combination developed significantly more slowly than did resistance to chloroquine or mefloquine. The development of resistance to the mixture of mefloquine and S-P was greatly inhibited. The joint blood schizontocidal action of mefloquine with the S-P combination was shown to be additive, not potentiating. Resistance to all the compounds used under these experimental conditions was shown to be unstable on withdrawal of the drug selection pressure. The mefloquine-resistant line remained sensitive to chloroquine but was cross-resistant to quinine and to a synthetic quinine analogue. The line which was resistant (at a low level) to mefloquine plus S-P was sensitive to chloroquine, but was resistant to pyrimethamine or sulphadoxine if these were used alone, and even, to a lesser degree, to the S-P combination. The significance of these observations is discussed in relation to drug resistance in P. falciparum. It is considered that mefloquine resistance is a possibility against which precautions should be taken, and a rationale is developed for the field trial of a mixture of mefloquine plus a combination of sulphadoxine with pyrimethamine (Fansidar ®).