RESUMEN
This review focuses on the most significant trends in the development of drugs for the treatment of malaria, African sleeping sickness and toxoplasmosis. In the case of malaria, those include new fixed-dose artemisinin combinations, antifolates and new targets in the apicoplast of Plasmodium falciparum. Targets in the treatment of trypanosomiasis are the biosynthesis of glycosylphosphatidylinositol and enzymes involved in the biosynthesis of trypanothione. Efforts to develop a vaccine against toxoplasmosis are discussed as well.
Asunto(s)
Enfermedades Parasitarias/tratamiento farmacológico , Animales , Antimaláricos/uso terapéutico , Humanos , Malaria/tratamiento farmacológico , Malaria/epidemiología , Toxoplasmosis/prevención & control , Tripanosomiasis/tratamiento farmacológico , VacunasRESUMEN
Treatment of Plasmodium falciparum with the potent inhibitor dicyclohexylamine completely arrests in vitro cell proliferation of the chloroquine-susceptible P. falciparum strain NF54 and the R strain, which shows less sensivity to chloroquine. The average inhibitory concentration (IC50) values determined for both strains revealed different inhibition profiles. The IC50 value for the chloroquine-sensitive NF54 strain was 97 microM and 501 microM for the R strain. Monitoring polyamine pools after treatment with dicyclohexylamine leads to a significant decrease in the intracellular spermidine content, which was nearly reversed by supplementation with spermidine. Since spermidine is an important precursor for the biosynthesis of hypusine and homospermidine in eukaryotes, we studied the developmental effect on both P. falciparum strains of 1,7-diaminoheptane as an inhibitor of deoxyhypusine synthase (EC 1.1.1.249) in mammalian cells, and agmatine as a moderate inhibitor of homospermidine synthase (EC 2.5.1.44). Inhibition profiles with 1,7-diaminoheptane resulted in an IC50 value of 466 microM for the NF54 strain and 319 microM for the R strain. Spermidine pools changed significantly. Inhibition with agmatine caused a strong decrease in parasitemia for the chloroquine-susceptible NF54 strain, with a determined IC50 value of 431 microM and an IC50 value of 340 microM for the less chloroquine-susceptible R strain. Spermidine was not detectable after inhibition. The uncommon triamine homospermidine occurred in both P. falciparum strains. To our knowledge this is the first evidence of homospermidine in P. falciparum. The use of specific inhibitors of spermidine metabolism might be a novel strategy for the design of new antimalarials, and suggests the occurrence of both enzymes in the parasite.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Plasmodium falciparum/efectos de los fármacos , Espermidina/biosíntesis , Agmatina/farmacología , Transferasas Alquil y Aril/antagonistas & inhibidores , Animales , Antimaláricos/farmacología , Cloroquina/farmacología , Ciclohexilaminas/farmacología , Diaminas/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Parasitemia/tratamiento farmacológico , Plasmodium falciparum/enzimología , Plasmodium falciparum/crecimiento & desarrollo , Poliaminas/análisis , Espermidina/análisis , Espermidina/farmacologíaRESUMEN
In vitro cytogenetics has been established as a valid method for evaluating the genotoxic potential of chemical agents. Armstrong et al have described a simple, quantitative approach to in vitro cytotoxicity and genotoxicity testing by using Chinese hamster ovary (CHO) cells. This approach can also be sensitive and repeatable in an inter-laboratory setting, a prerequisite for routine testing of compounds suspected of having genotoxic properties. In the present study, cytotoxicity was evaluated by the parameter of mitotic index (MI). Genotoxicity is measured by the chromosome aberration (Abs) assay as described by Armstrong et al using CHO cells. The basic analytic principles proposed were extended to include human lymphocytes. Sister chromatid exchange (SCE) analysis was used to establish an additional endpoint. Mitomycin C (MMC), an established clastogen, was used as the model compound for protocol validation. Dose response curves for MI and Abs in CHO cells were found to be consistent with those reported by Armstrong et al. Results from our extended study on lymphocytes and using SCE analysis were analogous. Our experience is that this standardized approach is indeed sensitive and reliable and can serve as a basis for an inter-laboratory testing program.