Proguanil Plus Sulfamethoxazole is not Causally Prophylactic in the Macaca mulatta—Plasmodium cynomolgi Model

Abstract

Abstract.New drugs for causal prophylaxis of malaria are needed. A proguan il/sulfamethoxazole combination was investigated using a rhesus monkey model (Macaca mulaiia infected with Plasmodium cynomolgi) to determine whether causal prophylaxis could be achieved. When a five-day regimen of proguanil (40 mg/kg/day) combined with sulfamethoxazole (100 mg/kg/day) was used, infection of all animals (6 of 6) was observed, with an extended prepatent period (median 40 days). Two control animals became infected on days 9 and 23 following sporozoite inoculation. Plasma concentrations indicated that proguanil and sulfamethoxazole were adequately absorbed and metabolized to cycloguanil and N4-acetylsulfamethoxazole, respectively. Analysis of liver biopsy specimens demon strated that the drugs were present two days following sporozoite inoculation but were not detectable one week later. Proguanil plus sulfamethoxazole does not eliminate exoerythro cytic-stage parasites in the rhesus monkeyâ€"P. cynomolgi model.

HIV Treatments Reduce Malaria Liver Stage Burden in a Non-Human Primate Model of Malaria Infection at Clinically Relevant Concentrations In Vivo

“…Also, these data are consistent with our previous report that TMP-SMX delays liver stage parasite development in rodent malarias and in P. falciparum in vitro [2], [4], and other antifolates have such activity against P. falciparum in vivo [20], [21]. Delayed development of Plasmodium liver stages in vitro and in vivo has been observed with other antifolates, specifically, with P. knowlesi and P.cynomolgi [18], [22], [23], a Plasmodium which is studied experimentally in rhesus macaques also. It is likely that transmission intensity, as well as antifolate resistance, may contribute to the degree to which TMP-SMX reduces liver stage malaria burden in the field.…”

Neither the HIV Protease Inhibitor Lopinavir-Ritonavir nor the Antimicrobial Trimethoprim-Sulfamethoxazole Prevent Malaria Relapse in Plasmodium cynomolgi-Infected Non-Human Primates

“…If hypnozoites are spared, however, which they have been shown to be with pyrimethamine and proguanil with P. cynomolgi in vivo , primary parasitemia itself could be delayed and relapses still occur. These antifolates have also been shown to kill the exoerythrocytic stages of P. cynomolgi and P. knowlesi in vitro [40] , [44] – [48] , all consistent with what we observed. Trimethoprim alone, and at a much higher dose (50 mg/kg BID compared to the 4 mg/kg BID we used) has been shown to have no anti-hypnozoite effect, nor an effect on delaying primary parasitemia, when used in combination with sub-therapeutic doses of primaquine [48] .…”

“…An increase in the time to detection of parasites in the presumed first and second relapses as detected by smear were each used to deduce liver stage reductions, and appearance of parasites after treatment with quinine and quinidine were considered relapses, as previously described [20] , [23] . Study outcomes are presented as Kaplan-Meier survival curves, and statistics are descriptive [40] .…”

Oxidative activation of proguanil and dapsone acetylation in Thai soldiers.

“…Proguanil (PROG) and cycloguanil (CYC) were measured by ion-paired high-performance liquid chromatography (h.p.l.c.) [9]. The inter-and intraassay coefficients of variation for both PROG and CYC at 10 ng ml-' were less than 10% (n = 6).…”