ABSTRACT
Abstract Malaria represents a major health problem worldwide, affecting around 198 million people in 2016 according to WHO database. For decades, anti-malarial drug therapy has been used in the battle against this disease and its uncontrolled usage in endemic areas has developed the appearance of the drug resistance. Thus, it has emerged the necessity of finding new treatments that could be used as an alternative cure to malaria infection. The aim of this work was the evaluation of two photo-excitable compounds: Compound 1, which is (2E)-3-(4-dimethylamino-phenyl)-1-(4-imidazol-1-yl-phenyl)prop-2-en-1-one) and Compound 2, (1E,4E)1-[4-(dimethylamino)phenyl]-5-(4-methoxyphenyl)-1,4-pentadiene-3-one) as possible anti-malaria drugs with Plasmodium berghei ANKA strain in BALB/c mice as murine model. Cytotoxicity effect was evaluated by a cell proliferation by colorimetry assay (MTS); and the drug incorporation into the parasite was assessed in vitro with Indirect Immunofluorescence Assay (IFA) to determine the localization of the drugs into the parasitized red blood cells (RBCs). Finally, the curative effect of compounds no-radiation (fundamental state) and ration drugs were evaluated by oral drug administration of this drugs in BALB/c mice and chloroquine was used as positive control. This curative effect was determined daily by the parasitemia percentage. The results showed that both compounds were cytotoxic in fundamental state. Furthermore, cytotoxic effect was increased after radiation into the Solar Simulator, and compound 2 was more cytotoxic than compound 1. Curative assays showed that both compounds in fundamental state were non effective as anti-malarial drug. However, in the curative assays in the mice treated with compound 2, when this was ration showed a survival rate of 33 % and a parasitemia percentage decrease in compare to compound 1. Although the compounds did not show a similar or better anti-malarial effect than Chloroquine, Compound 2 presented certain anti-malarial effect after solar radiation. Rev. Biol. Trop. 66(2): 880-891. Epub 2018 June 01.
Resumen La malaria representa un importante problema de salud en todo el mundo, afectando a alrededor de 198 millones de personas en 2016 según la base de datos de la OMS. Durante décadas, se ha utilizado la terapia con fármacos anti-malpricos en la lucha contra esta enfermedad y su uso incontrolado en las zonas endémicas ha desarrollado la aparición de resistencia a los fármacos. Por lo tanto, se ha surgido la necesidad de encontrar nuevos tratamientos que podrían ser utilizados como una cura alternativa para la infección por el paludismo. El objetivo de este trabajo fue evaluar dos compuestos foto-excitables: El compuesto 1, que es (2E) -3- (4-dimetilamino-fenil) -1- (4-imidazol-1-ilfenil) prop-2 1-ona) y el Compuesto 2, (1E, 4E) -1- [4- (dimetilamino) fenil] -5- (4-metoxifenil) -1,4-pentadieno-3-ona) como posibles drogas antimaláricas con la cepa ANKA de Plasmodium berghei en ratones BALB / c como modelo murino. El efecto de la citotoxicidad se evaluó mediante una proliferación celular con el ensayo de colorimetría (MTS); y la incorporación del fármaco en el parásito se evaluó in vitro con Ensayo de Inmunofluorescencia Indirecta (IFA) para determinar la localización de los fármacos en los glóbulos rojos parasitados (RBCs). Finalmente, se evaluó el efecto curativo de los compuestos sin radiación (estado fundamental) y los fármacos irradiados mediante la administración oral de los fármacos en los ratones BALB / c, y se usó cloroquina como control positivo de cura. Este efecto curativo se determinó diariamente por el porcentaje de parasitemia. Los resultados mostraron que ambos compuestos eran citotóxicos en estado fundamental. Además, el efecto citotóxico se incrementó después de la radiación en el Simulador Solar, y el compuesto 2 fue más citotóxico que el compuesto 1. Los ensayos curativos mostraron que ambos compuestos en estado fundamental no eran eficaces como fármacos antimaláricos. Sin embargo, en los ensayos curativos en los ratones tratados con el compuesto 2, cuando fue irradiado, se observó una tasa de supervivencia del 33 % y una disminución del porcentaje de parasitemia en comparación con el compuesto 1. Aunque los compuestos no mostraron un efecto similar o mejor antimalárico que la cloroquina, el compuesto 2 presentó cierto efecto antimalárico después de la radiación solar.
Subject(s)
Animals , Plasmodium/drug effects , Dimethylamines/pharmacology , Imidazoles/therapeutic use , Malaria/drug therapy , Solar RadiationABSTRACT
It has been claimed that the activity of Na+/H+ exchanger (NHE) is altered in spontaneously hypertensive rats (SHR) suggesting a possible role for it in the pathophysiology of hypertension. The purpose of this study has been to investigate the effect of blockade of NHE on the noradrenaline (NA) and 26K+ induced tone and on the recovery of tone from acid induced contractions in the portan vein of spontaneously hypertensive rats (SHR) as compared to their controls of Wistar Kyoto rats (WKY). Blockade of NHE by 10(-4) dimethylamiloride (DMA) raised the tone of NA and 26K+ activated preparation of both strains, the contractions being higher with NA activation. Total blockade of NHE by replacement of Na in solution with N-methy-D-Glucamine (NMDG) raised the tone of the NA activated preparations by 45+/-10%, n=8, P<0.01 and 33+/-4%, n=12, P < 0.01 in SHR and WKY respectively. The time for 50% relaxation from NH4Cl washout contraction was significantly prolonged by 10(-5) and 10(-4) M DMA in both strains under NA or 26K+ activation. DMA effect was greater on NA than on 26K+ activated preparations, and was not significantly different when comparing SHR to WKY results. In conclusion the results reported in this study indicate that NHE has similar activity in WKY and SHR portal veins and that its blockade contracts both preparations. Therefore, it is unlikely that increased NHE activity, acting directly on vascular smooth muscle tone, could be a primary cause for hypertension.