The chemotherapy of rodent malaria, XXIII Causal prophylaxis, part II: Practical experience with Plasmodium yoelii nigeriensis in drug screening.

Data are presented on the causal prophylactic action of about 100 compounds of various types against Plasmodium yoelii nigeriensis N67 in mice. Examples are given to show how action against pre-erythrocytic schizonts may be differentiated from action on emerging erythrocytic stages. In a series of 35 8-aminoquinolines, all but 10 showed definite causal prophylactic activity at tolerated doses. The data permit the compounds to be ranked in order of activity, and many are shown to be more active in this test system than primaquine. Marked causal prophylactic activity is displayed by a variety of quinone structures, several of which show a significant residual action on blood stages. A high level of activity is found in dihydrofolate reductase inhibitors within several chemical classes. Rorguanil is more effective as a causal prophylactic than a blood schizontocide in the mouse as in man. Sulphonamides and sulphones are also effective in this system. The active levels are influenced by the content of PABA in the diet of the hosts. Causal prophylactic action has been detected in a number of experimental compounds including some antibiotics (such as tetracycline and clindamycin). The pyrocatechol RC 12 shows only slight activity at the maximum tolerated dose. Chloroquine, mepacrine, quinine, quinolinemethanols and phenanthrenemethanols are inactive as causal prophylactics. It is concluded that a rodent malaria-mouse model does provide a relatively simple model for the screening of drugs for causal prophylaxis, and the data so obtained are of relevance to the detection of causal prophylactics against human malaria.