The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.
Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. Methods The pharmacokinetic properties of oral artesunate and artemether (4 mg kg x1 ) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. Results Despite a 29% lower molar dose, oral artesunate administration resulted in signi®cantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (Pj0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40±76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the ®rst day of treatment, 31 (17±100)%, compared to the second day, 72 (44±118)% (P=0.018). In vivo parasite clearance and time above the in vitro IC 90 were similar for the two drugs, despite considerable differences in C max and AUC. Conclusions The oral antimalarial bioavailability following artemether was signi®cantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.
SUMMARYMacrophage activation during acute falciparum malaria in 71 Thai aduils was investigated by measuring urinary neopterin and serum interferon-gamma (IFN--;). Neopterin. a product of IFN-yactivated macrophages. was elevated in 94"'l, of patients upon admission (day 0, prior to treatment) and in all at some time during the period of study. Neopterin levels tended to rise further (days 1-5) before failing back towards the normal range as patients recovered following effective chemotherapy (days 6-8). IFN--; was measured in 32 patients and found to be directly related to neopterin concentration. Both neopterin and IFN-)' values were highest in patients experiencing a lirst malaria infection. Among those with histories of prior malaria, neopterin and IFN-y levels were inversely related to the number of previous infections. Morbidity, as assessed by degree and duration of fever, was direclly related to neopterin concentration. This longitudinal study quantitatively describes the extent and duration of macrophage activation in falciparum malaria, Thedala also suggest that wiih repeated malaria infection and antigen exposure, there is a progressive decrease or possibly suppression of the T cell macrophage interaction mediated by IFN--;.
The pharmacokinetics and tolerance of a 4.5 gm 7-day halofantrine loading dose regimen were evaluated in 10 Thai patients with malaria and in 10 noninfected volunteers. Halofantrine peak plasma concentrations and bioavailability on the first day of treatment were significantly lower in patients with malaria than in healthy volunteers. Halofantrine elimination half-life was significantly shorter in patients with malaria than healthy control subjects (9.5 versus 15.8 days). These data show a distinct effect of acute malaria on the absorption and elimination of the drug. In addition, marked intersubject and intrasubject variability in peak and trough halofantrine levels was observed, indicating variable drug absorption. This dosing regimen was effective and well tolerated, with mild transient diarrhea during the first few days of treatment in both groups. To produce consistently effective drug levels, the currently recommended dosing regimens may be suboptimal. Slow halofantrine elimination raises concern for induction of parasite resistance when the drug is used in endemic areas of the world.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.