In vitro and in vivo reversal of chloroquine resistance in Plasmodium falciparum with promethazine.

Abstract

The effect of combining promethazine with chloroquine was examined against Plasmodium falciparum in vitro in the Aotus-P. falciparum model and in bioassays from volunteers given promethazine. The combination of chloroquine plus promethazine (1 ϫ 10 Ϫ6 M) reversed chloroquine resistance in standard P. falciparum clones and patient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentrations (IC 50 s) for chloroquine against resistant parasites by 32-92%. Coadministration of promethazine with chloroquine also demonstrated a dose-dependent effect in Aotus monkeys infected with chloroquine-resistant P. falciparum. Monkeys were given a chloroquine dose (20 mg/kg of body weight for seven days), which normally has no effect on parasitemia, plus 10, 20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowest promethazine dose, but re-treatment with 20 mg/kg resulted in clearance of parasitemia. Initial treatment with chloroquine and 20 or 40 mg/kg of promethazine cleared parasitemia in some animals followed by recrudescence. Retreatment 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/l of blood) and subsequently cleared without re-treatment. An in vitro bioassay model was developed to examine the effects of clinically achievable 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 IC 50 values for chloroquine by 20-58% with the most significant reductions occurring in plasma obtained from volunteers 3-4 hr after ingestion. Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no effect on chloroquine susceptibility, suggesting that study of the pharmacokinetic disposition and potential interaction is warranted to optimize the dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or prevention of chloroquine-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 chloroquine resistance. Clinical evaluation of therapeutic regimens is required to validate clinical efficacy of this promising combination for treatment of uncomplicated chloroquine-resistant malaria.

Repeated infection of Aotus monkeys with Plasmodium falciparum induces protection against subsequent challenge with homologous and heterologous strains of parasite.

“…[7][8][9][10][11] A small number of heterologous challenges have been performed in the past using P. falciparum strains in Aotus monkeys. These studies, performed in other species of Aotus, also showed that previous infection provided protection from subsequent challenge with the same strain.…”

Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

“…6 For more than 40 years, the Panamanian Aotus ( Aotus lemurinus. lemurinus ) has been used to adapt new strains of malaria [7][8][9] study its biology, [10][11][12] pathogenesis of its infection, [13][14][15] and to test the efficacy and pharmacokinetics of antimalarial compounds [16][17][18][19][20][21][22][23][24][25][26][27] against these new strains. More recently, this model has also been used to test the efficacy and immunogenicity of antimalarial vaccines through the use of repeated challenge, 28 plasmid DNA vaccines, [29][30][31][32] temperature-sensitive mutants, 33 synthetic peptides, 34 recombinant proteins, [35][36][37] and even to test the immunogenicity of hepatitis B DNA vaccines.…”

Nonylphenolethoxylates as Malarial Chloroquine Resistance Reversal Agents

“…The degree of chloroquine resistance is calculated as the IC 50 observed in the presence of various concentrations of NP30 divided by the control (no NPE added) chloroquine IC 50 (274 Ϯ 56 nM). Values greater than 1 indicate that the particular NPE rendered the P. falciparum parasites less sensitive to chloroquine, while values less than 1 indicate that the particular NPE sensitized P. falciparum to chloroquine (17). Nonlinear analysis of the chloroquine IC 50 at known NP30 concentrations indicated that a concentration of approximately 1 M (0.0002% on a weight/volume basis) resulted in a 50% decrease in the degree of chloroquine resistance of the parasites.…”

“…The initial observation that drug resistance in P. falciparum could be modulated by verapamil (16) has led to reports that antipsychotics (e.g., chlorpromazine [1]), histamine (H-1) receptor antagonists (e.g., promethazine [17] and chlorpheniramine [2]), and other agents can reverse chloroquine resistance in vitro and in animal models (3). While these observations suggest that chloroquine combined with a second agent can be used to treat malaria, these agents have the disadvantage of being pharmacologically active compounds with multisystemic effects that may result in a variety of side effects.…”