Pharmacology of absorption and distribution: optimal use of antimalarial drugs in the treatment of severe falciparum malaria in Kenya

Since 1989; a project at the KEMRI CRC Unit at Kilifi has focused on the design of appropriate and praticable regimens for the treatment of severe falciparum malaria. Initially; there was no data describing the absorption; distribution and elimination of quinine in Kenyan children; who constitute the great majority of patients. Pharmacokinetic studies were conducted to define these variables; which formed the basis for the design of appropriate and praticable treatment regimens. Even with optimal clinical management; the majority is high in cases of severe malaria treated with quinine at Kilifi. Alternative drugs have been studied in a search for a therapeutic regimen which will further reduce mortality

Selection of drug-resistant P.falciparum parasites as a consequence of the use of long half-life antimalarial drugs

The pharmacokinetic characteristics of individual drugs may influence the epidemiology of drug resistance in malaria. Pyrimethamine-sulfadoxine (PSD); an effective malaria treatment in Kenya; has long elimination half-life. Although the initial; disease-producing parasite population may be eradicated by treatment; in theory; parasites which re-infect the host may be subjected to selection by residual drug. From in vitro chemosensitivity data; and a knowledge of the pharmacokinetic parameters for the two drugs; a Regsistance Selection Period (RSP) was defined for PSD. In a field trial at Kilifi; reinfection of study subjects during the RSP by pyrimethamine-resistant parasites was more frequent tahn by sensitive parasites. At times after treatment beyond RSP; the frequency of resistant parasites was not significantly different to the frequency before treatment. These results are discussed in terms of the increasing use of PSD to treat falciparum malaria in Africa; and the feneral relationship between elimination half-life and resistance selection

Daily low dose chlorproguanil is an effective alternative to daily proguanil in the prevention of P. falciparum malaria in Kenya

156 coastal schoolchildren participated in a placebo controlled trial. All the children were treated with chloroquine 25mg/kg over 3 days plus single dose pyrimethamine-sulfadoxine and then randomised to receive one of four regimens:- A:7.5 mg chlorproguanil daily; B: 50 mg chlorproguanil weekly; C: 100mg proguanil daily; D: 100 mg Calcium lactate weekly. The children were followed up daily for 169 days for P.falciparum parasitaemia. Each 'terminal' event for the construction of life table; was treated with single dose pyrimethamine-sulfadoxine and the child removed from the trial. At the end of the study; 34/37 children had suffered a terminal event in the placebo group compared to 12/39 in the daily proguanil 100 mg group; 15/39 in the daily chlorproguanil 7.5 mg group and 22/40 in the weekly chlorproguanil 50 mg group. Life table analysis found a significant reduction (P is greater than 0.001) in the risk of malaria in all the chemoprophylactic groups compared to the placebo group. Daily proguanil also gave greater protection than weekly chloroproguanil (P greater than 0.05); but there was no difference between daily proguanil and daily chlorproguanil (P less than 0.1). Daily chlorproguanil 7.5 mg; has a lower cumulative dose; greater in vitro activity and increased intracellular concentration of the metabolite. Compared to proguanil and increased intracellular concentration of the metabolite. Therefore; daily proguanil has significant potential as another chealp; effective; nontoxic chemoprophylactic addition to vector avoidance measures