The changing in vitro susceptibility pattern to pyrimethamine/sulfadoxine in Plasmodium falciparum field isolates from Kilifi, Kenya.

Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987-1988 and 1993-1995 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and tested as described elsewhere. In both studies, PM and SD susceptibility tests were done separately. There was a highly significant decrease (P < 0.01) in the in vitro sensitivity of P. falciparum isolates to PM and SD between the two trials. In the first trial, the isolates were either sensitive to both PM and SD or resistant to PM and sensitive to SD. During the second trial, isolates were either resistant to PM and sensitive to SD or resistant to both drugs. These results are important in estimating the useful therapeutic life (UTL) of PM/SD in this area and in identifying alternative antifolate drugs.

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

To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.

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