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Gametocytocidal and Sporontocidal Effects Pyrimethamine in A Bull. Org. mond. Sante 1 1968, 38, 625-632 Bull. Wid Hlth Org. Gametocytocidal and Sporontocidal Effects of Primaquine and of Sulfadiazine with Pyrimethamine in a Chloroquine-Resistant Strain of Plasmodium falciparum* KARL H. RIECKMANN,1 JAMES V. McNAMARA,2 HENRI FRISCHER,3" THOMAS A. STOCKERT,3 PAUL E. CARSON 5 & ROBIN D. POWELL ' Studies with 3 volunteers were conducted to determine the effects of a combination of sulfadiazine and pyrimethamine and the effects ofprimaquine upon mature gametocytes ofa strain ofchloroquine-resistant Plasmodium falciparum-the Malayan (Camp.) strain. One volunteer was treated with sulfadiazine and pyrimethamine; two other volunteers each received a single dose of45 mg ofprimaquine base. The combination ofsulfadiazine and pyrimethamine, although active against blood schizonts, did not exert a marked sporontocidal effect against the Malayan (Camp.) strain. In sharp contrast, primaquine, although not effective as a blood schizontocide, exerted a marked gametocytocidal and sporontocidal effect against this strain. The findings emphasize the need for further studies of the sporontocidal and gameto- cytocidal effects of drugs, particularly primaquine, against chloroquine-resistant strains of P. falciparum and suggest that primaquine may come to play an important role in preventing the transmission of such strains. With the realization that strains of Plasmodium 1964; Chin et al., 1966; Bartelloni et al., 1967; falciparum in some parts of the world are resistant Harinasuta et al., 1967), but remarkably little infor- to chloroquine, increased attention has been given mation is available concerning the sporontocidal to newer drug regimens, including the combined effects exerted by such combinations against administration of a sulfonamide and pyrimethamine. chloroquine-resistant P. falciparum. In addition, It has been known that the asexual erythrocytic relatively little information is available concerning forms of some strains of chloroquine-resistant the sporontocidal or gametocytocidal effects of pri- P. falciparum respond to certain sulfonamide- maquine against chloroquine-resistant P. falciparum. pyrimethamine combinations (DeGowin & Powell, The studies presented in this report were performed to assess the effects of a combination of sulfadiazine * These studies were supported by the Medical Research and pyrimethamine and the effects of primaquine and Development Command, Office of the Surgeon General, US Department of the Army, under Contract DA-49-193- against gametocytes of a strain of chloroquine- MD-2413 with the University of Chicago. This paper is resistant P. falciparum from Malaya (Malaysia) that contribution number 282 from the US Army Malaria Research Program. has been designated the Malayan (Camp.) strain. 1 Visiting Assistant Professor, Department of Medicine, University of Chicago, Chicago, Ill., USA. METHODS 'Major, Medical Corps, United States Army. Captain, Medical Corps, United States Army. Studies were carried out with healthy, adult, 'Assistant Professor, Department of Medicine, University male volunteers at the University of Chicago-Army of Chicago, Chicago, Ill., USA. 5Associate Professor, Department of Medicine, Uni- Medical Research Project at the Illinois State Peni- versity of Chicago, Chicago, Ill., USA. tentiary, Stateville Branch, Joliet, Ill., USA. The 2170 - 625 - 626 K. H. RIECKMANN AND OTHERS conditions ofstudy at this project have been described Volunteer 1 received concurrently 500 mg of sulfa- in detail previously (Alving et al., 1948; Powell diazine every 6 hours for 5 days and 50 mg of et al., 1964); the possibility of unintentional re- pyrimethamine daily for 3 days. The doses of infection was precluded. sulfadiazine and of pyrimethamine administered Three Caucasian volunteers (Volunteers 1, 2, and 3) were identical to those employed during previous were infected with the Malayan (Camp.) strain of studies carried out at the University of Chicago- chloroquine-resistant P. falciparum. Volunteer 1 had Army Medical Research Project to assess the blood a mosquito-induced infection and Volunteers 2 and 3 schizontocidal effects of this combination of agents had infections induced by intravenous inoculation against the Malayan (Camp.) and other strains of of small samples of blood containing approximately chloroquine-resistant P. falciparum (DeGowin & 500 000 asexual erythrocytic parasites. Asexual ery- Powell, 1964; Powell et al., 1968). Volunteers 2 throcytic forms of the Malayan (Camp.) strain had and 3 each received a single dose of 45 mg of proved resistant to all widely used synthetic anti- primaquine base. Drugs were administered orally malarial agents, including pyrimethamine adminis- and under very close supervision. Parasite counts, tered alone in a dose of 50 mg daily for 3 days for both asexual forms and gametocytes, were per- (DeGowin & Powell, 1965). A single study in which formed daily by the method of Earle & Perez (1932). 50 mg of pyrimethamine had been administered Different groups of 2- to 3-day-old mosquitos daily for 3 days to a partially immune volunteer (A. stephensi) were allowed to bite Volunteers 1, 2, infected with the Malayan (Camp.) strain had and 3 before administration of medication and at revealed that, in this volunteer, pyrimethamine intervals thereafter. Each of these groups of mos- administered alone exerted no appreciable sporon- quitos was allowed to bite one of these volunteers tocidal effect against this strain; different groups of on only one occasion. Mosquitos were then kept mosquitos (Anopheles stephensi) were allowed to under insectary conditions (temperature, 28°C-30°C; bite this partially immune volunteer before, during, relative humidity, 80%-90%). Randomly-selected and after administration of pyrimethamine and no mosquitos from -each group were examined for alteration in the development of oocysts or of sporo- oocysts and for sporozoites; at least 10 mosquitos zoites in these mosquitos was evident (Powell et al., from each group were examined for oocysts begin- unpublished observations). Studies presented in this ning on the 6th day after they had bitten a particular report were intentionally carried out with partially volunteer, and, with one exception (when only immune volunteers to minimize the likelihood that the 7 mosquitos were available for examination), at least symptoms would necessitate concomitant adminis- 10 other mosquitos from each group were examined tration of other agents, such as quinine, that might for sporozoites beginning on the 10th day after complicate the studies. Volunteers 1 and 3 had been they had bitten a particular volunteer. Larger num- treated previously with subcurative doses of quinine bers of mosquitos were examined when available. to relieve symptoms and to suppress asexual para- During studies with Volunteers 1 and 3, mos- sitaemia temporarily; Volunteer 2 had acquired quitos from certain groups that had been allowed partial immunity during a previous infection with to bite one of these volunteers 12-14 days previously this strain. Studies were initiated (1) when it were allowed to bite other volunteers to determine appeared clinically that these volunteers had ac- conclusively whether or not mosquitos in these quired a sufficient degree of immunity to make it particular groups were infective. Seven additional, unlikely that additional medication with, for instance, healthy, Caucasian volunteers (Volunteers 4-10), quinine, would be necessary during the period of all non-immune and all previously uninfected, par- study, and (2) when both continuing asexual parasi- ticipated in the latter phases of the investigations. taemia and significant gametocytaemia were evident. Mosquitos that bit Volunteers 4-10 were examined Before initiation of these studies, parasites of the immediately after they had obtained a blood meal. Malayan (Camp.) strain had been exposed to blood The number of sporozoites in the salivary glands of schizontocides such as chloroquine and quinine, each of these mosquitos was graded as follows: but the parasites of this strain that were employed 1-9 sporozoites, +; 10-99 sporozoites, + +; to infect Volunteers 1, 2, and 3 had not been previ- 100-999 sporozoites, + + +; 1000 or more sporo- ously exposed to sulfonamides or sulfones or to zoites, + + + +. The total number of + signs primaquine. recorded for the mosquitos that bit a particular On the 38th day after onset of patent infection volunteer was referred to as the " infectivity ". PRIMAQUINE AND SULFADIAZINE-PYRIMETHAMINE IN FALCIPARUM MALARIA 627 RESULTS in preventing the development and normal matura- tion of oocysts. Among different groups of mos- Studies with Volunteer I quitos that were allowed to bite this volunteer Volunteer 1 was treated with a combination of before, during, or after treatment, the proportion sulfadiazine and pyrimethamine commencing on the of those examined that contained oocysts and the 38th day after the onset of a patent infection with average number of oocysts (20.8) per infected mos- the Malayan (Camp.) strain (Fig. 1). This volunteer quito remained relatively high (Fig. 1); the oocysts had last received small doses of quinine on the detected appeared morphologically normal on exam- 29th day after the onset of patency; it is therefore ination by light microscopy. The proportion of unlikely that quinine influenced the results of these mosquitos examined that contained sporozoites in studies. Treatment with sulfadiazine and pyrime- the salivary glands after biting this volunteer during
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