Plasma Concentrations Of Quinine Research Articles

Quinine disposition in globally malnourished children with cerebral malaria.

Both malnutrition and malaria affect drug disposition and are frequent among children in the tropics. We assessed their respective influence on quinine distribution. 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. 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. 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.

Pharmacokinetics of quinine and 3-hydroxyquinine in severe falciparum malaria with acute renal failure

The plasma concentrations of quinine and its main metabolite, 3-hydroxyquinine (3OHQn), were measured in 5 adult Thai patients with severe Plasmodium falciparum malaria and acute renal failure. Two patients required peritoneal dialysis but all survived. During acute renal failure plasma concentrations of 3OHQn rose to reach up to 45% of the levels of the parent compound. The estimated median (range) quinine clearance was 0·83 mL/kg/min (0·58-1·16), and 3OHQn clearance/fraction of quinine converted was 3·40 mL/kg/min (2·58-4.47). The estimated 3OHQn terminal elimination half-life was 21 h (16·5–32·5). These data suggest that 3OHQn contributes about 12% of the antimalarial activity of the parent compound in patients with falciparum malaria and acute renal failure. It is also likely that 3OHQn contributes to adverse effects, although this metabolite is not quantitated routinely by current highperformance liquid chromatography quinine assays.

A simple method for assessing quinine pre-treatment in acute malaria

Administration of a loading dose of quinine in severe malaria may be dangerous if therapeutic blood concentrations are already present because of previous treatment. To assess the reliability of the history of pretreatment we conducted a prospective study of 379 adult patients with acute falciparum malaria admitted to a hospital in western Thailand. Admission plasma concentrations of quinine were measured by high performance liquid chromatography (HPLC), and compared with the patients' history of previous quinine treatment. The sensitivity of the history was 59% (95% confidence interval [CI] 49–69%), the specificity was 79% (95% CI 74–84%), the positive predictive value was 53%, and the negative predictive value 82%. A rapid (10 min) semi-quantitative estimate of plasma quinine concentrations, based on a simple ‘dipstick’ method using a quinine-specific monoclonal antibody, proved considerably more sensitive and specific. The correlation between the dipstick estimate and the subsequent HPLC measurement of plasma quinine concentration was 0.85 ( n = 404; P < 0.0001). In 404 admission samples, the negative predictive value of the dipstick estimate for plasma quinine concentrations >1 μg/mL was 100%. In Thailand the history of previous quinine treatment given by the patients or their relatives was unreliable but the quinine dipstick provided a simple and rapid means of assessment of quinine pre-treatment in acute falciparum malaria.

The reproducibility of quinine bioavailability.

Plasma concentrations of quinine were measured in six healthy volunteers after a duplicate administration of 15 mg kg-1 of quinine hydrochloride orally and the administration of 15 mg kg-1 of quinine dihydrochloride as an infusion over 6 h. Quinine absorption rate devised by deconvolution was shown to be complete in less than 2 h. The mean (+/- s.d.) fraction available (F) was 0.76 (0.11) after both oral doses and maximum plasma drug concentrations occurred at 1.90 (0.83) h and 2.00 (0.30) h, respectively. The reproducibility of absorption was high, with a within-subject coefficient of variation of less than 10% for Cmax, AUC and F. Thus, quinine absorption is extensive, fast and reproducible in healthy volunteers.

Fatal Plasmodium falciparum Malaria after an Inadequate Response to Quinine Treatment

A 24-year-old man with severe Plasmodium falciparum malaria died after 77 h of treatment with full parenteral doses of quinine. His peripheral parasitemia at death exceeded the level on admission. Plasma concentrations of quinine were abnormally low throughout. This case emphasizes the importance of pharmacokinetic factors in determining the therapeutic response in severe P. falciparum malaria.

Quinine disposition kinetics.

Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1.