DEVELOPMENT OF RESISTANCE TO CHLORGUANIDE (PALUDRINE) DURING TREATMENT OF INFECTIONS WITH PLASMODIUM CYNOMOLGI

¹ The Christ Hospital Institute of Medical Research, Cincinnati, Ohio

Preliminary observations suggested that resistance to chlorguanide could develop when infections with the trophozoites of Plasmodium cynomolgi were treated with subcurative doses of the above drug. The present report deals with systematic investigations of this possibility and closely related problems.

Experiments have shown that a high degree of chlorguanide resistance was developed when infections with Plasmodium cynomolgi were treated with successively increasing doses of the biguanide. Such a procedure led to at least a two thousandfold change in the response of infections to the drug. Thus, in monkeys inoculated with the parent strain, chlorguanide in daily doses of 0.0188 mgm. per kgm. regularly controlled the infection. In contrast to this, in monkeys infected with the resulting resistant strain, daily administration of 40 mgm. per kgm. of chlorguanide, the maximum tolerated dose, was without effect on the course of the infection. This resistant characteristic seems to be a well established property of the parasite, since it persisted for a period of at least 5 months during which time trophozoites were passed through 6 untreated monkeys.

Transfer of the resistant characteristic through the sexual and extrinsic cycles of the parasite was also studied. The result showed that the characteristic of chlorguanide resistance, which had been developed during asexual activity, was also a property of the sexual forms of the parasite and could be transmitted without loss through the mosquito.

Studies were also made of the response of infections produced by the chlorguanide resistant strain to treatment with other antimalarial drugs. This work showed that infections induced by trophozoites of the resistant and parent strains were equally susceptible to treatment with such drugs as chloroquine and quinacrine. Likewise, infections with sporozoites of the resistant and parent strains were equally susceptible to treatment with pentaquine.

The practical and theoretical significance of these findings is discussed.