Differences in drug response of Plasmodium falciparum within an area of the Amazon region.

Clinical characteristics of patients with falciparum malaria, as well as sensitivity of Plasmodium falciparum to chloroquine and mefloquine, were investigated in 2 distinct strata within the same geographical area of the Amazon Basin. One stratum was the population living along the road, the other that living along the river, both near Rio Branco, capital of Acre State, Brazil. The clinical features did not differ between the 2 strata. Full in vitro sensitivity of P. falciparum to mefloquine was observed in both areas. However, significant differences in chloroquine sensitivity were observed between the 2 strata. EC50 values for chloroquine were 0.8484 mumol/litre for parasite isolates from the road stratum (E) and 0.4638 mumol/litre for parasite isolates from the river stratum (R). EC90 values were 2.8095 and 1.2549 mumol/litre in strata 'E' and 'R', respectively. Continuous drug pressure over years in area 'E' and relatively low drug pressure in area 'R' were presumably responsible for these differences.

In vitro drug sensitivity of Plasmodium falciparum in Acre, Brazil.

In Acre, the westernmost state of Brazil in the Amazon region, the sensitivity of Plasmodium falciparum to chloroquine, amodiaquine, mefloquine, quinine and sulfadoxine/pyrimethamine was determined in vitro by the Rieckmann microtechnique. The study was performed between January and June 1987; the in vitro parasite responses to all antimalarial drugs were determined according to the recommendations of WHO. Of 83 isolates of P. falciparum, all were sensitive to mefloquine and of 87 isolates of P. falciparum, 84 (97%) were sensitive to quinine. The EC50 for mefloquine was 0.27 mumol/l and for quinine 4.60 mumol/l. In contrast, 65 of 89 (73%) and 70 of 83 (84%) isolates were resistant to amodiaquine and chloroquine, respectively; 11 isolates even grew at 6.4 mumol chloroquine/l. The EC50 for amodiaquine was 0.34 mumol/l and for chloroquine 0.73 mumol/l. Sulfadoxine/pyrimethamine resistance was seen in 23 of 25 (92%) cases. These data clearly indicate that in the western part of the Amazon region the 4-aminoquinolines, as well as sulfadoxine/pyrimethamine, can no longer be recommended for the treatment of P. falciparum infections.

A phase II/III double-blind, dose-finding clinical trial of a combination of mefloquine, sulfadoxine, and pyrimethamine (Fansimef) in falciparum malaria.

Fansimef is a combination of 250 mg mefloquine (base), 500 mg sulfadoxine, and 25 mg pyrimethamine per tablet. One hundred and fifty adult male Brazilian patients at Belém (Pará), who had peripheral blood smears positive for Plasmodium falciparum, with or without clinical symptoms of falciparum malaria, were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. Of those receiving one tablet (48 patients), 81% were cured and 19% exhibited RI recrudescences. All the patients receiving two or three tablets of Fansimef (49 patients in each group) were cured. The rates of initial clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects included nausea, vomiting, dizziness, diarrhoea and abdominal pain, but these were mild and transient and required no specific treatment. The incidence of vomiting and nausea was highest in patients given the three-tablet dose. The results of various haematological, biochemical and urine analyses were not adversely altered by the administration of Fansimef.

Drug-resistant malaria--occurrence, control, and surveillance.

PIP: Chloroquine resistant strains of Plasmodium falciparum were initially reported during the early 1960s and are currently found in many areas of Asia and South America. The prevalence and degree of resistance are increasing in all affected areas, representing a serious setback to antimalaria programs. Alternative drugs are much more expensive and frequently more cumbersome to use. Consequently, it is essential that a concerted effort be made to arrest the spread of resistant strains by developing standardized national policies on drug use. The probable genetics and epidemiology of drug resistance are considered in this report, and attention is directed to the problems involved in its control. Antimalarial drugs interfere with important physiological functions of the parasites. Chloroquine and mepacrine apparently block acid proteases and peptidases in the phagosomes of intraerythrocytic parasites. Circumstantial evidence from "in vitro" tests suggests that strains of P. falciparum from various parts of the world, although primarily susceptible to chloroquine, exhibit, "a priori," different sensitivities. P. falciparum in the Sobat valley of Ethiopia and in central Sudan appears to be significantly less susceptible to chloroquine than the Uganda I strain. There are no indications yet of chloroquine resistance in P. vivax, P. malariae, or P. ovale. The relative prevalence of chloroquine resistant infections and the degree of resistance are still on the increase in all affected areas. The development of drug resistance in areas with previously susceptible parasites has thus far always been associated with the use of the particular medicaments. 4 main factors seem to be involved: the degree of drug pressure; the degree of host/parasite contact; the duration of drug pressure; and the type of drug used. The occurrence of chloroquine resistant falciparum malaria requires the urgent attention of the health authorities and that several operational measures be undertaken. Instructions must be provided concerning the principles of drug use in antimalaria programs in the event of the spread of drug resistance, and these instructions are reviewed. The methods for the monitoring of drug sensitivity are also reviewed. The World Health Organization (WHO) has developed global monitoring program, initially implemented in 1977 in the Southeast Asia Region. Program objectives are identified.^ieng