Abstract
BackgroundMirincamycin is a close analog of the drug clindamycin used to treat Plasmodium falciparum blood stages. The clinical need to treat Plasmodium vivax dormant liver stages and prevent relapse with a drug other than primaquine led to the evaluation of mirinicamycin against liver stages in animals.Methodscis-mirinicamycin and trans-mirinicamycin were evaluated as prophylaxis against early liver stages of Plasmodium berghei in mice and as antirelapse hypnozoiticides against Plasmodium cynomolgi in the Rhesus monkey (Macaca mulatta).ResultsMirincamycin was very effective against early liver stages of P. berghei in mice: both cis and trans enantiomers were 90-100% causally prophylactic at 3.3 mg/kg/day for 3 days orally. Both cis and trans mirincamycin, however, failed to kill dormant liver stages (hypnozoites) in the P. cynomolgi infected Rhesus monkey, the only preclinical hypnozoite model. Mirincamycin enantiomers at 80 mg/kg/day for 7 days orally, a dose that generated exposures comparable to that seen clinically, did not prevent relapse in any of four monkeys.ConclusionsAlthough efficacy against early liver stages of P. berghei was thought to correlate with anti-hypnozoite activity in primates, for mirincamycin, at least, there was no correlation. The negative P. cynomolgi hypnozoite data from Rhesus monkeys indicates that mirincamycin is unlikely to have potential as a clinical anti-relapse agent.
Highlights
Mirincamycin is a close analog of the drug clindamycin used to treat Plasmodium falciparum blood stages
Clindamycin is a lincosamide antibiotic which in combination with quinine is recommended for the treatment of P. falciparum blood stages [2]
When P. falciparum blood stages in Aotus monkeys were treated for seven days, mirincamycin 10 mg/kg/day was curative, clindamycin 15 mg/kg/day cured only one of three monkeys, and chloroquine 20 mg/kg/day was not curative [5]
Summary
Mirincamycin is a close analog of the drug clindamycin used to treat Plasmodium falciparum blood stages. The clinical need to treat Plasmodium vivax dormant liver stages and prevent relapse with a drug other than primaquine led to the evaluation of mirinicamycin against liver stages in animals. Treatment of P. vivax requires elimination of the blood stages, the cause of clinical disease, with standard blood schizonticides, and elimination of the dormant hypnozoite stages in the liver to prevent relapse of blood infection. Clindamycin is a lincosamide antibiotic which in combination with quinine is recommended for the treatment of P. falciparum blood stages [2]. When P. falciparum blood stages in Aotus monkeys were treated for seven days, mirincamycin 10 mg/kg/day was curative, clindamycin 15 mg/kg/day cured only one of three monkeys, and chloroquine 20 mg/kg/day was not curative [5]. The superior efficacy of mirincamycin vs clindamycin for treatment of P. falciparum was reiterated recently when
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