Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

Effects of the flood regime on the body condition of fish of different trophic guilds in the Upper Paraná River floodplain, Brazil

In this study, we evaluated the influence of various hydrological cycles on the feeding body condition of fish species of different trophic guilds in the Paraná River floodplain, as well as the impacts of upstream impoundments on fish conditions. Attributes of the river floods (duration, time of year, intensity, and variability in a given year) and the body condition, measured by the mean residuals of length-weight ratios, of the detritivorous, herbivorous, insectivorous, invertivores, omnivorous, piscivorous, and planktivorous species were evaluated. Fish were sampled during a period before (1986-1994) and after (2000-2004) the completion of filling of the Porto Primavera Reservoir, which is located upstream from the floodplain area under study. Three sub-basins in the floodplain were sampled: the Ivinheima River, which has no dams; the Paraná River, which has several dams; and the Baia River, which is influenced by the Paraná. A two-way ANOVA identified significant variations in mean body conditions for localities and for the hydrological cycles, and the interactions were also significant. The findings revealed that before the Porto Primavera Reservoir was filled, the body condition of the feeding guilds varied similarly in the three sub basins, but this pattern was not observed after filling was completed. However, in years with minor or no floods, the body condition was high, especially in the sub-basins influenced by Porto Primavera (Paraná and Baía). Pearson's and Spearman's correlations showed that most effects of the floods were unfavorable to the body condition of the guilds, except for the annual variation in water level, which aids herbivores in accessing allochthonous food resources. Detritivores were negatively affected by all flood attributes. A correlation between the relative stomach weight (mean residual of the ratio of total and stomach weights) and the body condition demonstrated the poor relationship between the amount of food intake and weight gain; insectivores were the exception, showing a significant negative correlation. Therefore, for this guild, there is evidence that their food sources during floods have low nutritional value. It is hypothesized that dry years lead to improvement in the nutritional quality of food resources, and that the water released from the upstream dam dilutes and removes these resources without providing new food inputs. This exacerbates the effects of floods on body conditions