Carboxylic ionophores in malaria chemotherapy: The effects of monensin and nigericin on Plasmodium falciparum in vitro and Plasmodium vinckei petteri in vivo

被引:45
作者
Adovelande, J
Schrevel, J
机构
[1] Lab. de Biol. Parasitaire/C., ERS 156 CNRS, Mus. National d'Histoire Naturelle, 75231 Paris Cédex 05
[2] Mus. National d'Histoire Naturelle, Lab. de Biol. Parasitaire/C., 75231 Paris Cédex 05, 61, rue Buffon
关键词
Plasmodium falciparum; Plasmodium vinckei petteri; carboxylic; ionophores; monensin; nigericin; chloroquine;
D O I
10.1016/S0024-3205(96)00514-0
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Chloroquine is widely used in malaria chemotherapy. Due to its weak base properties, this drug accumulates in the parasite food vacuole where it acts initially by raising the pH of this organelle, thereby reducing the digestion of hemoglobin by the parasite and preventing its growth. Nevertheless, alkalinization of the food vacuole and inhibition of lysosomal protein degradation could also be achieved by means of carboxylic ionophores such as monensin and nigericin. These drugs intercalate into intracellular organelle membranes and exchange protons for K+ or Na+. In the present study, we show that monensin and nigericin exhibit in vitro intrinsic antimalarial activities at nanomolar and picomolar range, respectively, on P.falciparum and thereby appear 25 fold and 30,000 fold more potent than chloroquine. The very low IC50 values exhibited by these two ionophores prompted us to test their antimalarial activities in vivo on Plasmodium vinckei petteri. We found that the ED(50) and ED(90) values were respectively 1.1mg/kg and 3.5mg/kg for monensin; 1.8mg/kg and 4.6mg/kg for nigericin. In addition, when treated with monensin at 10mg/kg, 100% of the infected mice were cured. Interestingly, nigericin can be combined with monensin and we show that this combination is synergic. Thus, this finding would allow the use of lower doses of these ionophores and prevent occurrence of drug resistance. Carboxylic ionophores can be viewed as a new strategy in malaria chemotherapy.
引用
收藏
页码:PL309 / PL315
页数:7
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