title: Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics.
abstract: Combinations of artemisinin and quinine for uncomplicated falciparum malaria were studied. A total of 268 patients were randomized to 7 days of quinine at 10 mg/kg of body weight three times a day (Q) or to artemisinin at 20 mg/kg of body weight followed by 3 (AQ3) or 5 (AQ5) days of quinine. Recrudescence rates were 16, 38, and 15% for the Q, AQ3, and AQ5 groups, respectively (P < 0.001). Recrudescence was associated with shorter parasite clearance time (PCT) and longer treatment after the blood smear had become negative (eradication time). However, classification of patients to outcome-recrudescence or radical cure-was correct in only 77% of patients. The population kinetics of the parasitemia was estimated with nonlinear mixed-effect models. Several models were tested, but the best model was a monoexponential decline of the parasitemia in which the mean parasite elimination half-life was shorter after artemisinin (5.1 h; 95% confidence interval [CI], 4.9 to 5.2 h) than after quinine (8.0 h [95% CI, 7.5 to 8.3 h]). Attempts to simulate the initial increase of the parasitemia did not result in better models with a biologically plausible interpretation. Recrudescence was associated with slower parasite clearance and a higher simulated terminal parasitemia (P(term)). The classification of patients to outcome groups based on P(term) was correct in 78% of patients. The data suggest that parasite strains with reduced sensitivity to quinine are prevalent in Vietnam, with slower parasite clearance and consequent recrudescence. A single dose of artemisinin induces rapid parasite reduction and lowers the value of P(term), but to prevent recrudescence, this should be followed by quinine for at least 3 days after parasite clearance, or 5 days in total.
authors.affiliation: Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands. p.j.devries@amc.uva.nl
authors.forename: P J
authors.initials: PJ
authors.lastname: de Vries
authors.forename: N N
authors.initials: NN
authors.lastname: Bich
authors.forename: H
authors.initials: H
authors.lastname: Van Thien
authors.forename: L N
authors.initials: LN
authors.lastname: Hung
authors.forename: T K
authors.initials: TK
authors.lastname: Anh
authors.forename: P A
authors.initials: PA
authors.lastname: Kager
authors.forename: S H
authors.initials: SH
authors.lastname: Heisterkamp
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use*; D037621:Artemisinins; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011803:Quinine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C031327:artemisinin; D011803:Quinine