Search

The schizogony of malarial parasite is a typical cyclic phenomenon where the different stages of parasite development appear at regular time intervals. Each of the stages is specifically sensitive to different antimalarial drugs. Knowledge of the details of the cycle, drug susceptibility and the pharmacokinetics of drugs, could allow the improvement of drug action by the chronotherapeutic approach: treatment at the time of appearance of the drug sensitive stage with a drug that displays rapid pharmacokinetics. Since murine malarias serve as preferable models for in vivo drug testing, the pharmacokinetics of subcutaneously (sc) administered chloroquine (CQ) were tested in the whole blood of healthy mice and in animals slightly (1.5-3.5% parasitemia) or heavily infected (21-25% parasitemia) with Plasmodium chabaudi chabaudi. The half-time of absorption was around 5 min and almost independent of parasitemia. The apparent half-time of drug concentration decay was around 40 min in healthy animals, about 90 min at low parasitemia and about 410 min in heavy infection, indicating that the concentration of CQ is a typical spike, that is prolonged by asymptomatic disease, and considerably more by the active accumulation of CQ in infected cells. The latter is confirmed by the 3-fold higher peak blood [CQ] at the trophozoite stage and < 1.5-fold increase during schizogony. In conjunction with our previous experiments which showed that a single sc injection of 5 mg/kg CQ is sufficient to eliminate the drug susceptible mid-term trophozoite stage, the present results seem to justify to propose the chronotherapeutic approach for the treatment of malaria.

The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 days (schedule 2; one dose of 10 mg/kg followed by two doses of 5 mg/kg at 6-h intervals on the first day and two doses of 5 mg/kg at 12-h intervals on the second day) in terms of their clinical and parasitological efficacies, tolerance, and drug concentration-time curves. At 24 h schedule 2 gave higher chloroquine levels in blood, which induced a more rapid decrease in parasitemia. The time required for a 50% decrease in the initial parasitemia was shorter in patients on schedule 2 (14.3 +/- 1.6 h) than it was in patients on schedule 1 (35.5 +/- 5.4 h; P less than 0.01). Moreover, negative blood smears were obtained more rapidly with schedule 2 (50.8 +/- 3.7 h) than with schedule 1 (72 +/- 8.7 h). As predicted by the drug concentration-time curve, no high, potentially toxic peak drug concentration appeared and no adverse effects were observed with the loading dose regimen (schedule 2). These findings support the idea that a loading dose of 20 mg/kg given at intervals during the first 12 h is well tolerated and can be used to obtain a more rapid decrease in parasitemia and to shorten the treatment time of uncomplicated chloroquine-susceptible falciparum malaria in the field.

Chloroquine (Cq) and desethyl-chloroquine ( CqM ) levels were measured by HPLC in the blood, plasma, and erythrocytes of 9 healthy subjects under standard prophylactic treatment (100 mg/day for 10 days) and 8 malarial patients given a therapeutic regimen (10 or 25 mg/kg). Chloroquine levels in various fractions of the healthy subjects were as follows: whole blood: 1 265 +/- 598 nmol/l; plasma: 145 +/- 63 nmol/l of whole blood; erythrocytes: 827 +/- 460 nmol/l of whole blood. The CqM /Cq ratio in malarial patients varied from 0.4 to 0.8. These results show that Cq levels and Cq metabolization varied significantly from one individual to the next. Above all, they demonstrate the presence of Cq in other types of blood cells. This underlines the practical importance of the conditions of chloroquine assay in blood.

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 +/- 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 +/- 75 liters/kg and 2,063 +/- 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 +/- 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes (RBC) was studied in vitro before and during culture by measuring the chloroquine gradient between the cells and medium (C/M) by high-pressure liquid chromatography. The C/M values were 5.9 +/- 2.7 (n = 23) for uninfected RBC, 13 to 34 for six chloroquine-susceptible isolates (concentration required to inhibit 50% of parasite growth, less than 100 nmol/liter) in partially infected RBC (parasitemia from 0.3 to 5%) (n = 28), and 8.4 to 4.9 for four chloroquine-resistant isolates (concentration required to inhibit 50% of parasite growth, 320 to 1,500 nmol/liter) in partially infected RBC (parasitemia from 0.4 to 5%) (n = 26). Two isolates were studied before and after adaptation to continuous culture. C/M was found to decrease (34.2 to 2.1 and 19.3 to 4.9), whereas the concentration required to inhibit 50% of parasite growth increased (35 to 1,400 and 54 to 1,500 nmol/liter), thus indicating the acquisition of chloroquine resistance. These results demonstrate that chloroquine uptake decreased in RBC in which the infective strain, initially susceptible, became resistant in culture and imply that the drug is bound to ferriprotoporphyrin IX to a lesser extent or that a parasite protein competes with ferriprotoporphyrin IX to a greater extent. We suggest that genotypic modifications in the mechanism of chloroquine uptake might occur in the parasite.

Objective: The disposition of Quinimax (a Cinchona alkaloid combination of quinine, quinidine, cinchonine and cinchonidine), administered as a suppository, was evaluated in children with uncomplicated malaria. Methods: The pharmacokinetics of a single initial dose of Quinimax, administered as a suppository (20 mg/kg), were compared with those of either an intramuscular injection (8 mg/kg) in a lateral thigh muscle or a slow 4-hour intravenous injection (8 mg/kg) in 15 children with uncomplicated malaria. After the initial dose, all children received an 8 mg/kg oral dose every 8 hours for 3 days. Results: The peak plasma concentration (C) and area under the plasma concentration-time curve from 0 to 8 hours (AUC) were similar after the three routes of administration. The time to C (t) value was shorter after intrarectal (1.7 ± 0.4h) and intramuscular (1.9 ± 0.7h) than after intravenous (3.8 ± 0.2h) administration. The absolute bioavailability of intrarectal quinine from 0 to 8 hours was 43%. The treatments were well tolerated and the children were apyretic and aparasitaemic within the 7 days. Conclusions: These data confirm that administration via the intrarectal route is a possible mode of quinine delivery, but a more appropriate galenic formulation than Quinimax suppositories needs to be evaluated for the early treatment of childhood malaria in remote rural areas of Africa. [ABSTRACT FROM AUTHOR]