Safety assessment of MEFAS: an innovative hybrid salt of mefloquine and artesunate for malaria treatment.

Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high prevalence and mortality of the disease, new and less toxic therapeutic agents need to be developed, such as MEFAS, a low-cost hybrid salt that consists of artesunate and mefloquine. However, the efficacy of MEFAS has been systematically demonstrated, its safety requires further investigation. This study investigated the acute toxicity of MEFAS and its precursors, artesunate, and mefloquine. A total of 42 female Swiss mice were divided into seven groups (n = 6/group) that were treated orally by gavage with vehicle (filtered water, negative control), MEFAS (50, 500, and 1000 mg/kg), and 1:1 concentrations of artesunate + mefloquine (50, 500, and 1000 mg/kg). Clinical signs of toxicity were observed for 14 d after treatment. On day 15, the animals were weighed, deeply anesthetized with isoflurane, and euthanized for subsequent collection of the liver, spleen, and kidneys. The relative organ weights were determined, followed by histopathological analysis. Artesunate + mefloquine produced toxic effects compared with the negative control group, reflected by changes in clinical signs, relative organ weights, and histopathological alterations. In MEFAS-treated animals, no changes were observed compared with the negative control group. These findings demonstrate that MEFAS is safer than artesunate + mefloquine after acute administration in mice.

90-Day Oral Toxicity Assessment of Tropaeolum majus L. in Rodents and Lagomorphs.

Tropaeolum majus L., popularly known as nasturtium, is a species widely used in the form of infusions and salads. In the last years, the antihypertensive, diuretic, and calcium and potassium sparing activities of T. majus preparations were shown. Moreover, no preclinical 90-day oral toxicity studies were conducted. Thus, this study evaluated the toxicity of the hydroethanolic extract obtained from T. majus (HETM) leaves in female and male mice, rats, and rabbits. Swiss mice and Wistar rats were treated with HETM (75, 375, and 750 mg/kg). The doses of rabbits (30, 150, and 300 mg/kg) were calculated by allometric extrapolation. The control groups received vehicle. The animals were orally treated, daily, for 90 days. At the end, the animals were anesthetized, and body weight gain, relative weight of liver, kidney, and spleen, and histopathological changes were evaluated. Serum hematological and biochemical parameters were also analyzed. No alterations were found in body and organ weights or in histopathological and biochemical evaluation. Hematological analyses revealed small changes in lymphocytes and neutrophil counts in rats after administration of 750 mg/kg of HETM. These results showed that 90-day use of T. majus is safe in rodents and lagomorphs.

Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice.

Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but the resistance of Toxoplasma gondii appears as a relevant public health problem. In order to identify new drugs to toxoplasmosis treatment, we performed a molecular docking of raltitrexed to T. gondii thymidylate synthase-dihydrofolate reductase (TS-DHFR) and also evaluated its efficacy in infected mice. Initially, raltitrexed was docked on the crystallographic structures of TS-DHFR from T. gondii and Mus musculus. Then, 48 h after infection with the T. gondii RH strain, different groups of mice received an oral dose of raltitrexed (0.15, 0.75, and 1.5 mg kg-1). Two days after treatments, raltitrexed was able to prevent mortality and reduce the number of tachyzoites in the peritoneal fluid and liver imprints from infected mice. The results showed that raltitrexed has important protective activities against the T. gondii RH strain. Molecular docking still suggests that the effects against the parasite may be dependent on the inhibition of T. gondii thymidylate synthase. This study opens new perspectives for the use of raltitrexed in patients infected with T. gondii, especially when conventional treatments do not exhibit the expected efficacy.