Rhesus monkeys (Macaca mulatta) were infected with Plasmodium cynomolgi by sporozoite inoculation and the effects of pyrimethamine, sulfamethazine, primaquine, and quinocide (WIN-10,448) given per os, and chloroquine given intramuscularly, were studied by microscopic examination of the tissue (liver) stages obtained at biopsy.
When administration of drug was begun the day before infection and continued for a total of 8 doses, results were as follows:
Pyrimethamine at 2.5 mg/kg/day. No exoerythrocytic parasites could be found in the sections, although blood parasites developed in each of the monkeys 37 and 50 days, respectively, after infection. Exoerythrocytic stages developed normally in the controls.
Primaquine at 3.0 mg/kg/day. No exoerythrocytic parasites could be found in the sections and parasitemia did not develop during the period of observation. Exoerythrocytic stages developed normally in the controls.
When administration of drug was begun on the 6th day after infection and continued for 3, 5 or 10 doses, results were as follows:
Pyrimethamine at 1 mg/kg/day, for 3 or 4 days. Alteration of the parasites was noticeable after 24 hours and morpho-pathological changes continued until disintegration was practically complete at 120 hours. Each of the treated animals developed a delayed parasitemia 33, 40, and 41 days, respectively, after infection.
Pyrimethamine at 1.0 mg/kg/day, plus sulfamethazine at 100 mg/kg/day for 5 days. The curative effect of pyrimethamine was not enhanced and each of the animals showed blood parasites 28 and 29 days respectively, after infection. Exoerythrocytic stages were normal in the controls.
Primaquine at 0.5 mg/kg/day, for 10 days. Before 96 hours, development of the exoerythrocytic stages appeared to have been arrested. At 96 and 120 hours the parasites were shrunken and distorted, and at 144 hours parasites were difficult to find. None were found at 168 and 192 hours. One animal never developed a parasitemia, but each of the others did; one during the treatment regimen and the other on the 26th day after infection. Exoerythrocytic stages were normal in the controls.
Quinocide at 0.5 and at 1.0 mg/kg/day, for 10 days. No alterations of the exoerythrocytic stages were seen at 48 hours. At 120 hours, changes were similar to those produced by primaquine, but less marked although the quinocide dosage was double the primaquine dosage. Blood parasites became patient in each of the monkeys on day 8 after infection. Exoerythrocytic stages in the controls were normal.
Chloroquine given intramuscularly at 25 mg/kg/day, for 3 days. The drug had no effect on the exoerythrocytic stages.
These studies show that it is experimentally feasible to assess the curative effects of drugs by observing the exoerythrocytic parasites directly.
Far East Research Unit, USAMRU, IMR, Kuala Lumpur, Malaya