IN-VITRO AND IN-VIVO REVERSAL OF CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM WITH PROMETHAZINE

The effect of combining promethazine with chloroquine was examined aga inst Plasmodium falciparum in vitro in the Aotus-P. falciparum model a nd in bioassays from volunteers given promethazine. The combination of chloroquine plus promethazine (1 x 10(-6) M) reversed chloroquine res istance in standard P. falciparum clones and patient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentratio ns (IC(50)s) for chloroquine against resistant parasites by 32-92%, Co administration of promethazine with chloroquine also demonstrated a do se-dependent effect in Aotus monkeys infected with chloroquine-resista nt P. falciparum. Monkeys were given a chloroquine dose (20 mg/kg of b ody weight for seven days), which normally has no effect on parasitemi a, plus 10, 20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowest promethazine dose, b ut re-treatment with 20 mg/kg resulted in clearance of parasitemia. In itial treatment with chloroquine and 20 or 40 mg/kg of promethazine cl eared parasitemia in some animals followed by recrudescence. Retreatme nt at higher doses cured one monkey and resulted in initial clearance and delayed recrudescence 28 or 63 days after treatment in two monkeys . Recrudescent parasitemia in the two monkeys was low (10 parasites/mu l of blood) and subsequently cleared without re-treatment. An in vitr o bioassay model was developed to examine the effects of clinically ac hievable doses of promethazine on parasites susceptibilities in vitro. Plasma samples taken at hourly intervals from patients given a single oral dose of 25 mg of promethazine decreased the IC50 values for chlo roquine by 20-58% with the most significant reductions occurring in pl asma obtained from volunteers 3-4 hr after ingestion. Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no e ffect on chloroquine susceptibility, suggesting that study of the phar macokinetic disposition and potential interaction is warranted to opti mize the dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or prevention of chloroquin e-associated pruritus or as an antiemetic suggest that the combination is safe and effective when used at standard dosages. The results from this study demonstrate that promethazine is a potent modulator of chl oroquine resistance. Clinical evaluation of therapeutic regimens is re quired to validate clinical efficacy of this promising combination for treatment of uncomplicated chloroquine-resistant malaria.