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Thiopurine prodrugs (azathioprine, AZA, and 6-mercaptopurine, 6MP) are embryotoxic to rodents and rabbits. Little is known about the developmental toxicity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine drug metabolite that is thought to mediate its liver toxicity. A limb bud assay found that 6MMPr impairs the in vitro morphogenetic differentiation of mouse limb extremities, being more potent than 6MP in the assay. This study evaluated the embryotoxicity of 6MMPr (0, 7.5, 15, 30 mg/kg bw sc) in rats after single-dose exposure in mid organogenesis (GD10). One group of pregnant rats was similarly treated with 6MP (15 mg/kg bw sc). After C-section (GD21), fetuses were weighed, and examined for external abnormalities. One third of each litter was examined for soft-tissue abnormalities while the remaining fetuses were cleared and stained for skeleton evaluation. 6MMPr caused a dose-dependent maternal weight loss followed by recovery before term pregnancy. Except for a nonsignificant increase in embryolethality and slight reduction in fetal weight at 30 mg/kg bw, no indication of embryotoxicity was noted at this dose or at lower doses of 6MMPr. In contrast, 6MP led to nearly 98 % of post-implantation losses in the presence of slight-to-mild maternal toxicity. These results are consistent with the notion that maternal treatment with 6MMPr affects embryo development, causing a nonsignificant increase in embryolethality and a slight reduction in fetal weight at 30 mg/kg bw. However, there was no increase in abnormalities at this dose, which was severely toxic to the dams, as reflected in the maternal weight gain data.

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Since the emergence of Zika virus (ZIKV) in Brazil in 2015, 48 countries and territories in the Americas have confirmed autochthonous cases of disease caused by the virus. ZIKV-associated neurological manifestations and congenital defects make the development of safe and effective antivirals against ZIKV of utmost importance. Here we evaluated the antiviral activity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine nucleoside analogue derived from the prodrug azathioprine, against the epidemic ZIKV strain circulating in Brazil. In all of the assays, an epithelial (Vero) and a human neuronal (SH-SY5Y) cell line were used to evaluate the cytotoxicity and effective concentrations of 6MMPr against ZIKV. Levels of ZIKV-RNA, viral infectious titre and the percentage of infected cells in the presence or absence of 6MMPr were used to determine antiviral efficacy. 6MMPr decreased ZIKV production by >99% in both cell lines in a dose- and time-dependent manner. Interestingly, 6MMPr was 1.6 times less toxic to SH-SY5Y cells compared with Vero cells, presenting a 50% cytotoxic concentrations (CC50) of 460.3 µM and 291 µM, respectively. The selectivity index of 6MMPr for Vero and SH-SY5Y cells was 11.9 and 22.7, respectively, highlighting the safety profile of the drug to neuronal cells. Taken together, these results identify, for the first time, the thiopurine nucleoside analogue 6MMPr as a promising antiviral candidate against ZIKV that warrants further in vivo evaluation.

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BACKGROUND: Canine distemper (CD) is a widespread infectious disease that can severely impact a variety of species in the order Carnivora, as well as non-carnivore species such as non-human primates. Despite large-scale vaccination campaigns, several fatal outbreaks have been reported in wild and domestic carnivore populations. This, in association with expansion of the disease host range and the development of vaccine-escape strains, has contributed to an increased demand for therapeutic strategies synergizing with vaccine programs for effectively controlling canine distemper. 6-methylmercaptopurine riboside (6MMPr) is a modified thiopurine nucleoside with known antiviral properties against certain RNA viruses. METHODS: We tested the inhibitory effects of 6MMPr against a wild-type CDV strain infection in cell culture. We measured infectious particle production and viral RNA levels in treated and untreated CDV-infected cells. Ribavirin (RIB) was used as a positive control. RESULTS: Here, we report for the first time the antiviral effects of 6MMPr against canine distemper virus (CDV) in vitro. 6MMPr was able to reduce viral RNA levels and to inhibit the production of infectious CDV particles. The therapeutic selectivity of 6MMPr was approximately six times higher than that of ribavirin. CONCLUSION: Our results indicate that 6MMPr has high anti-CDV potential and warrants further testing against other paramyxoviruses, as well as clinical testing of the compound against CDV.

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Se realizó un randomizado de 75 pacientes con leishmaniasis cutánea ecuatoriano con el fin de determinar el índice terapéutico de una nueva droga oral antileishmania, el ribósido de alopurinol más probenecid. Este agente fue evaluado comparándolo con controles positivos que se trataron con pentostam y con testigos no tratados. Las medidas de las lesiones disminuyeron rápidamente durante la terapia, lo que permitió determinar el porcentaje de cicatrización en los diferentes grupos. En el día 70 se realizó la evaluación de la curación de los pacientes en los diferentes grupos, obteniéndose: alopurinol (1.500 mg/6 h) más probenecid (500 mg/6 h) por 28 días, dió una curación con lesiones cicatrizadas en 10 (45,5 por ciento) de los 22 pacientes. Con pentostam (20 mg Sb/kg/día, IM por 20 días) se obtuvo una curación en 28 pacientes siendo esto de 100 por ciento de cicatrización. El grupo de no tratamiento presentó un porcentaje muy elevado de curación espontánea en 9 (75,0 por ciento) de los 12 pacientes. Todos los pacientes con tratamiento fallido o recidivas recibieron posteriormente tratamiento con pentostam. Este estudio sugiere que le ribósido de alopurinol más probenecid no es una droga con mayor eficacia contra la leishmaniasis cutánea ecuatoriana

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