The primary objective of antimalarial treatment is to cure the infection, but an important secondary objective is to prevent transmission. Primaquine has unique multiple-stage activity against malaria parasites. In 1951, primaquine was selected as the most active and least toxic hypnozoitocidal drug among the 8-aminoquinoline series (5
). The causal prophylactic and gametocytocidal effects of primaquine in P. falciparum
were characterized later (6
). Since then primaquine has been recommended and used as a transmission-blocking agent in falciparum malaria, albeit with little evidence that this policy has a significant effect on the incidence of malaria at the community level. Primaquine is considered to have insignificant activity against asexual stages of P. falciparum
), although there have been uncertainties as to whether or not this results from resistance. Primaquine does have significant activity against asexual blood stages in P. vivax
malaria, but the activity is weaker than those of other major antimalarial drugs (15
). A new long-acting 8-aminoquinoline, tafenoquine (19
), has been shown in vitro to be more effective than primaquine against asexual stages of malaria parasites and is still under investigation for the treatment and prophylaxis of falciparum malaria infection.
In the present study, primaquine in combination with quinine or artesunate had no additional significant effects on the activity of either drug against asexual blood stages as assessed by FCT and PCT. This confirms earlier in vivo studies indicating a lack of activity against blood stages in falciparum malaria (1
). Only the quinine-tetracycline regimen gave a 100% cure rate, which is significantly better than those of the other quinine-containing regimens. In areas where malaria is endemic, mixed infection with P. falciparum
and P. vivax
is common, and mixed infection is found in over 30% of patients coming from the border areas of Thailand where malaria transmission is high (8
). However, 7-day regimens of primaquine as used here are probably not sufficient to eradicate the hypnozoites of P. vivax
Artemisinin derivatives are the most active of the antimalarial drugs against the asexual blood stages of malaria parasites. They also reduce gametocyte carriage in P. falciparum
). In recent field studies in Thailand, this effect has been greater than that with primaquine (21
). In the present study, artesunate with or without primaquine was more rapidly acting than the quinine regimens as assessed by PCTs, although recrudescence rates and rates of cryptic vivax infections in the artesunate groups were not significantly different from those in the quinine groups. Patients treated with artesunate alone had significantly lower gametocyte carrier rates (44%) than those treated with the other nonprimaquine regimens (57% for quinine and 77% for quinine-tetracycline). Artesunate effectively prevented the appearance of gametocytemia. The average GCT with artesunate alone (median = 138 h) was also shorter than that with quinine or quinine-tetracycline (216 and 288 h, respectively), but there was considerable variation and these differences were not statistically significant. The mechanism whereby artemisinins reduce P. falciparum
gametocytemia in vivo (4
) and in vitro (7
) has not been fully elucidated. The artemisinin derivatives could act in three linked ways: they may possess gametocytocidal effects against more mature sexual stages, as in the case of primaquine; they may directly inhibit gametocyte development by preventing development of the younger sequestered stages (stages I to III); or they may simply prevent gametocytogenesis through rapid elimination of the asexual stages. These results confirm that artesunate is more effective than quinine in the prevention of gametocyte development.
Primaquine at all studied doses showed significant gametocytocidal effects, in that gametocyte clearance was accelerated, but primaquine did not prevent gametocyte development, and there was no evidence of synergy with quinine or artesunate against asexual stages of P. falciparum. The incidences of gametocytemia in patients treated with combined primaquine regimens were not significantly different from those for the nonprimaquine regimens in either the quinine or artesunate groups, but combinations including primaquine shortened the duration of gametocyte carriage two- to sixfold compared to the corresponding regimens without primaquine (P ≤ 0.038). This corresponds with earlier studies and indicates that primaquine is a potent gametocytocidal drug. In the present study, the overall GCTs did not correlate with PCTs, supporting the unrelated activities of primaquine against asexual and mature gametocyte stages of P. falciparum. In summary, the results of the present study indicate that artesunate is a potent inhibitor of gametocytogenesis but is inferior to primaquine in terms of gametocyte clearance. In reducing transmission potential, primaquine had a greater effect when added to quinine than to artesunate. Of all the studied regimens, the artesunate-primaquine combination gave the lowest rate of gametocyte detection and the shortest duration of gametocytemia.