In vitro and in vivo susceptibility of Plasmodium falciparum isolates from Liberia to pyrimethamine, cycloguanil and chlorcycloguanil

Abstract

In vivo susceptibility of Plasmodium falciparum to chlorproguanil and in vitro susceptibility to pyrimethamine, cycloguanil and chlorcycloguanil were studied in 38 children from two Liberian villages. Children in one village (Lagbala) had received monthly chemosuppression with chlorproguanil from 1976–1985, and children in the other village (JDF) had received fortnightly chlorproguanil from 1981–1985.

The highest and lowest IC₁₀₀ for pyrimethamine differed by a factor of 10⁵, but they differed only by a factor of 10³ for chlorcycloguanil. The mean IC₁₀₀ for chlorcycloguanil was significantly lower (P<0·0001) than the mean IC₁₀₀ for pyrimethamine and cycloguanil, and the IC_l00 for the samples most resistant to chlorcycloguanil (10⁻⁸M) was still well below peak blood concentrations after chlorproguanil administration.

Resistance could be defined as IC₁₀₀ ⩾ 10⁻⁶ M for pyrimethamine and IC₁₀₀ ⩾ 10⁻⁸ M for chlorcycloguanil. The isolates most resistant or most sensitive to pyrimethamine were also the most resistant or most sensitive to chlorcycloguanil, indicating partial cross-resistance between the two drugs.

The in vivo response to chlorproguanil 1·5 mg kg⁻¹ in Lagbala was equal to the response in 1983. Chlorproguanil 1·5 mg kg⁻¹ resulted in lower parasite rates on day 3 and 7, but did not prevent 60% of the children requiring treatment with chloroquine during the four weeks' follow-up after chlorproguanil administration.