Comparative study of interactions between chloroquine and chlorpheniramine or promethazine in healthy volunteers: a potential combination-therapy phenomenon for resuscitating chloroquine for malaria treatment in Africa.

Although, in in-vitro and limited in-vivo studies, chlorpheniramine (CP) and promethazine (PR) have each been shown to reverse chloroquine (CQ) resistance, the pharmacokinetic basis of this reversal has not been fully elucidated. In the present study, 15 healthy volunteers were randomly allotted to receive standard doses of CQ alone or in combination with CP or PR. Blood samples were collected from each volunteer at 21 time-points, from immediately before to 168 h after the initial dose. These samples were used to follow the changes in the plasma and erythrocytic concentrations of CQ. The ratio between the mean maximum CQ concentration in the erythrocytes and that in the plasma was 4.2 for the volunteers given CQ alone, 7.3 in those given CQ-CP, and 3.2 in those given CQ-PR. CP significantly enhanced the erythrocytic accumulation of CQ, increasing the maximum CQ concentration observed in the erythrocytes by 24% (P = 0.02). The bio-availability of CQ was also significantly increased in the presence of CP, with the mean value for the area under the curve, of erythrocytic concentration v. time, increasing from 99,921 to 214,516 ng/ml.h (P=0.001). The mean half-life of CQ in the erythrocytes also increased when CP was used, from 51 to 100 h, but this change was not statistically significant (P=0.83). In contrast to CP, PR had no statistically significant effect on the disposition of CQ. As CP clearly enhances disposition of CQ, a combination of CQ with CP may be useful in the management of CQ-resistant infections. Detailed toxicological studies are required to understand the full clinical implications of CP's elevation of erythrocytic CQ concentrations.

Comparative clinical characteristics and response to oral antimalarial therapy of children with and without Plasmodium falciparum hyperparasitaemia in an endemic area.

The clinical characteristics and the responses to oral antimalarial therapy of 104 children presenting consecutively with or without Plasmodium falciparum hyperparasitaemia (HP) were investigated in an endemic area. At presentation, although the 52 children with HP were significantly younger and had significantly higher heart rates than the 52 without, there were no significant differences between the two groups in their symptoms or in any other clinical feature of their malaria. Responses to oral antimalarial drugs were similar in both groups. Analysis of the disposition kinetics of parasitaemia, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t1/2pd), volumes of blood completely cleared of parasites per unit time (CLBpd), and parasite-clearance-time:t1/2pd ratios. Three children in the HP group, all aged < 3 years, progressed to cerebral malaria within 8 h of presentation, and another HP child presented with isolated trunkal ataxia, indicative of cerebellar involvement. No child in the non-HP group had any of the features of severe malaria. Although the clinical characteristics and responses to oral therapy of children with and without HP are therefore very similar, young children with HP appear to have an increased risk of developing other features of severe malaria.