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Background: Both malnutrition and malaria affect drug disposition and are frequent among children in the tropics. We assessed their respective influence on quinine distribution., Methods: Forty children were divided into 4 groups: children with normal nutritional status without (group 1) or with (group 2) cerebral malaria, and malnourished children without (group 3) or with (group 4) cerebral malaria. All children received an infusion of 8 mg/kg of a combination solution of cinchona alkaloids that contained 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (corresponding to 4.7 mg/kg quinine base). The children with malaria then received repeated infusions every 8 hours for 3 days. Pharmacokinetic profiles of plasma and erythrocyte quinine were determined during the first 8 hours, together with quinine protein binding. Additional measurements of plasma quinine concentrations were used to simulate quinine concentrations profiles in children with malaria with and without malnutrition. Clinical recovery and parasitemia clearance times were determined in the children with malaria., Results: Compared with control children, malaria and malnutrition increased plasma concentrations of quinine and reduced both the volume of distribution and the total plasma clearance. Simultaneously, alglycoprotein plasma concentrations and protein-bound fraction of the drug were increased. Erythrocyte quinine concentrations correlated strongly with free plasma quinine but not with the extent of parasitemia. Similar effective and nontoxic quinine concentration profiles were obtained in malaria with and without malnutrition., Conclusions: Severe global malnutrition and cerebral malaria have a similar effect on quinine pharmacokinetics in children. Moderate malnutrition does not potentiate cerebral malaria-mediated modifications of quinine disposition. These results suggest that current parenteral quinine regimens can be used, unmodified, to treat children with both malaria and malnutrition.

1. Three groups of seven children aged 2-14 years with acute uncomplicated Plasmodium falciparum malaria received 12.8 mg kg-1 quinine gluconate by the intrarectal route (new cream formulation) or 8 mg kg-1 Quinimax (a Cinchona alkaloid alkaloid combination) by the intramuscular or intravenous (4 h infusion) route every 8 h for 3 days. Clinical and parasitological status was similar in the three groups at enrolment. 2. At 36 h, body temperature of all children of the three groups was returned to normal and remained so until day 7. 3. The decrease in parasitaemia did not differ between the three groups and the time required for a 50% fall in parasitaemia relative to baseline was 12.3 +/- 5.4, 18.2 +/- 6.1 and 14.5 +/- 4.2 h in the intrarectal, intramuscular and intravenous treatment groups, respectively. Parasitaemia expressed as a percentage of initial values was not significantly different in the three groups after 48 h of treatment (7.4 +/- 16.0, 4.1 +/- 4.2 and 2.2 +/- 3.8% in the intrarectal, intramuscular and intravenous treatment groups, respectively). All the patients were aparasitaemic by day 7. 4. The tolerability of the three treatments was good; in particular, no rectal irritation was reported with the cream formulation. 5. The tmax occurred later after intrarectal (4.1 +/- 2.4 h) and intravenous infusion (3.8 +/- 0.5 h) than after intramuscular injection (1.6 +/- 1.3 h) (P = 0.02). Cmax was lower with the intrarectal (3.0 +/- 1.0 mg 1(-1)) and intramuscular routes (3.2 +/- 0.7 mg 1(-1)) than with the intravenous route (5.1 +/- 1.4 mg 1(-1)) (P = 0.003). Areas under the curve (AUC(0, 8 h)) were smaller with intrarectal (17.0 +/- 7 mg 1(-1) h) and intramuscular routes (19.4 +/- 4.8 mg 1(-1)) than with the intravenous route (27.8 +/- 8.2 mg 1(-1) h) (P = 0.02). The approximate bioavailability of intrarectal quinine from 0 to 8 h was 36% vs intravenous quinine and 51% vs intramuscular quinine. 6. The good tolerability and efficacy of this new intrarectal quinine formulation outweigh its low approximate bioavailability. This new approach might thus be a safe and effective alternative to intramuscular quinine injection for the treatment of children with acute uncomplicated Plasmodium falciparum malaria in the field.

In order to avoid the frequent side effects with injections of quinine in african children, empirical intrarectal administration of quinine (Quinimax, Sanofi Winthrop) has already been used successfully in Madagascar and Niger. In an attempt to optimise its use, a pharmacokinetic study was carried out with 66 children, 2 to 15 years old, admitted in pediatric unit for acute uncomplicated Plasmodium falciparum malaria, but warranting parenteral therapy. Children received Quinimax intrarectally (20 mg/kg/12h), intravenously (12,5 mg/kg in a slow infusion over 4 hours/12h) or intramusculary (12,5 mg/kg/12h). Plasma quinine concentrations were determined by HPLC. In this study, temperature and parasite clearance were similar in the 3 groups. A second randomized study was performed with 3 different dosages of intrarectal Quinimax: 8 and 13 mg/kg/8h and 20 mg/kg/12h. Temperature fell stably to normal at 36 hours with all regimens. Total clearance of parasitaemia was only obtained at 48 h with 30 mg/kg/12h regimen. Pharmacokinetic stimulation allowed to propose that intrarectal administration of Quinimax 20 mg/kg/8h would be a safe and effective regimen. A third approach studied the efficacy and pharmacokinetics of a new rectal quinine formulation (12,8 mg/kg/8h quinine gluconate) compared to IM and IV (8 mg/kg/8h) : at 36h, body temperature of all children was returned to normal and remained so until day 7. Parasitaemia expressed as a percentage of initial values was not different in the 3 groups after 48 h. At day 7, all the patients were aparasitaemics. The good tolerability and efficacy of this new intrarectal quinine formulation might allow to propose this route as an alternative to intramuscular route for the treatment of childhood malaria in Africa.