The antimalarial properties of 2, 4-diamino-5-p-chlorophenyl-6-ethylpyrimidine, daraprim.

This study has dealt with a systematic evaluation of the antimalarial properties of Daraprim as exhibited against infections with P. cynomolgi in the rhesus monkey. The results may he summarized as follows: A. AGAINST SPOROZOITE-INDUCED INFECTIONS. 1. When administered prophylactically in daily doses of 0.075 to 20 mgm. /kgm. beginning on the day of sporozoite inoculation and continuing for eight consecutive days thereafter, Daraprim produces a striking delay in the incubation period but does not eradicate the underlying tissue stages. 2. When administered in established sporozoite-induced infections in daily doses of 0.0188 mgm. /kgm. and greater, Daraprim regularly abolishes peripheral blood parasitemia. The drug does not eradicate the underlying tissue stages, however, for relapses occur invariably even at doses as large as 1.25 to 20 mgm. /kgm. Such large doses do produce a striking prolongation of the interval between treatment and relapse. 3. Administered once weekly in a dose of 0.15 mgm. /kgm. , Daraprim effectively suppresses sporozoite-induced infections. Side-by-side comparison has demonstrated that this pyrimidine is ten to twenty times as active as chlorguanide and approximately one hundred times as active as chloroquine. 4. Daraprim, administered concurrently with primaquine, does not interfere with the ability of this 8-aminoquinoline to eradicate established sporozoite-induced infections. B. AGAINST TROPHOZOITE-INDUCED INFECTIONS. 1. Administration of Daraprim in daily doses of 0.0024 mgm. /kgm. effects a significant reduction in parasitemia in the non-immune subject. Comparison, drawn on the basis of the smallest dose required to reduce parasitemia significantly, showed that Daraprim is thirty times as effective as chlorguanide, and five hundred times as effective as chloroquine. 2. Whereas Daraprim is far more effective than chloroquine when activity is measured by minimal effects on parasitemia, the superiority of the pyrimidine is reduced greatly when the evaluation is based on the dose required to effect essentially 100 per cent cures. At this level of activity, the effectiveness of Daraprim is at most four times that of chloroquine. 3. Clearance of parasitemia and elimination of fever is a relatively slow process in infections treated with Daraprim. Over broad limits, the speed with which this pyrimidine eliminates parasitemia appears to be independent of the dosage. 4. The action of Daraprim on asexual reproduction indicates that the compound has a mode of action closely similar to that of chlorguanide and distinctly different from that of chloroquine. 5. The capacity of Daraprim to cure trophozoite-induced infections is influenced to a marked degree by the immune status of the host. The drug is far more effective against untreated infections of 30 or more days9 standing than against early infections of 5 to 10 days9 duration. 6. Single doses of Daraprim are considerably less effective than the same total amount of drug administered in seven divided daily doses. This would militate against single-dose therapy comparable to that now provided by chloroquine. 7. Development of resistance to Daraprim appears to occur with relatively great frequency and rapidity. This resistant characteristic is common to both sexual and asexual parasites, since the property survives transmission through the mosquito. 8. Infections induced by Daraprim -resistant trophozoites are equally refractory to treatment with chlorguanide but are wholly susceptible to treatment with chloroquine. These findings have been evaluated in terms of the potential usefulness of Daraprim in human malarias. It has been concluded that despite certain remarkable qualities noted above the greatest usefulness of the drug would appear to be as a routine suppressive. The flat dose-response curve of the compound, its slowness of action, and its potentiality for inducing resistance would appear to limit seriously the usefulness of the drug in the treatment of active infections.