Maternal and fetal outcome of pregnancy in Swiss mice infected with Plasmodium berghei ANKAGFP.

Malaria in pregnant women is associated with risk of maternal and perinatal morbidity and mortality, and there are few antimalarial drugs considered safe to treat them, so it is necessary to develop safer antimalarial medicines. The goal of this study was to develop an animal model for human malaria during pregnancy by characterizing the maternal and fetal outcomes in malaria infected Swiss mice. For that, in the present study, we evaluated the outcome of pregnancy in Swiss mice infected with Plasmodium berghei ANKAGFP. We observed a reduction of fetal body weight and signs of skeletal ossification retardation in the offspring of mice infected on GD 12. The group of mice infected with malaria presented premature deliveries and histopathology changes consistent with placental malaria. Our study suggests that Swiss Webster mice infected with P. berghei ANKAGFP on GD 12 might be a valuable model to investigate the safety and the efficacy of new antimalarial drugs indicated to pregnant women.

Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor.

Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 µM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.

Clinical and non-clinical safety of artemisinin derivatives in pregnancy.

Malaria in pregnancy is a clinically wasting infectious disease, where drug therapy has to be promptly initiated. Currently, the treatment of this infection depends on the use of artemisinin derivatives. The World Health Organization does not recommend the use of these drugs in the first trimester of pregnancy due to non-clinical findings that have shown embryolethality and teratogenic effects. Nevertheless, until now, this toxicity has not been proved in humans. Artemisinin derivatives mechanisms of embryotoxicity are related to depletion of circulating embryonic primitive erythroblasts. Species differences in this sensitive period for toxicity and the presence of malaria infection, which could reduce drug distribution to the fetus, are significant to the risk assessment of artemisinin derivatives treatment to pregnant women. In this review we aimed to assess the results of non-clinical and clinical studies with artemisinin derivatives, their mechanisms of embryotoxicity and discuss the safety of their use during pregnancy.

Effects of Angiotensin-Converting Enzyme Inhibitor Derived from Tropaeolum majus L. in Rat Preimplantation Embryos: Evidence for the Dehydroepiandrosterone and Estradiol Role.

Although several studies have shown the inhibitory effects of Tropaeolum majus extracts (HETM) on angiotensin-converting enzyme (ACE) activity, no studies have been carried out during the beginning of pregnancy, when humoral and hormonal imbalance may affect zygote and early embryo transport. This study investigates whether HETM can affect embryonic development when administered during the one-cell-blastocyst period. Pregnant Wistar rats received orally the HETM (3, 30, and 300 mg/kg/day) from the 1st to the 7th gestational day. Rats were killed on the 8th day of pregnancy and the following parameters were evaluated: clinical symptoms of toxicity (including organ weights), number of corpora lutea, implants per group, preimplantation losses ratio, and the serum levels of dehydroepiandrosterone (DHEA), estradiol, and progesterone. No clinical symptoms of maternal toxicity were evidenced. On the 8th day of pregnancy, the levels of DHEA and estradiol were increased and significant preimplantation losses were observed at all doses used. The present study reveals that the HETM can raise levels of DHEA and estradiol and induce difficulty in the embryo implantation in the early stages of pregnancy. The data contributes significantly to the safety aspects of using this natural product when trying to get pregnant or during pregnancy.

Study on the developmental toxicity of combined artesunate and mefloquine antimalarial drugs on rats.

Antimalarial drug combinations containing artemisinins (ACTs) have become first choice therapies for Plasmodium falciparum malaria. Data on safety of ACTs in pregnancy are limited and no previous study has been conducted on the developmental toxicity of artesunate-mefloquine combinations on the first trimester of gestation. To evaluate the developmental toxicity of an artesunate/mefloquine combination, pregnant rats were treated orally with artesunate (15 and 40 mg/kg bwt/day), mefloquine (30 and 80 mg/kg bwt/day) and artesunate/mefloquine (15/30 and 40/80 mg/kg bwt/day) on gestation days 9-11. Dams were C-sectioned on day 20, and their uteri and fetuses removed and examined for soft tissue and skeleton abnormalities. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Mefloquine (80 mg/kg bwt/day) was maternally toxic and enhanced fetal variations. Combination of artesunate and mefloquine did not enhance their toxicity compared to the toxicity observed after its separate administration. Embryotoxicity of artesunate was apparently attenuated when it is co-administered with mefloquine.

Sodium fluoride does not alter sperm production or sperm morphology in rats

The aim of the present study was to evaluate the effects of sodium fluoride (NaF) on the male reproductive system. Adult male rats were exposed to NaF in drinking water for 30 days at three concentrations: 1.54 (control, tap water), 50 and 100 ppm. Body and organ weights, daily sperm production, sperm number and morphology were investigated. No difference was observed on the sperm number and morphology among the groups, as well as body weight and organ absolute and relative weights. Overall, despite the presence of a mild degree of dental fluorosis in the higher dose group, the results indicated that exposure to NaF at the doses used in the present study did not adversely affect sperm production and morphology of male rats.

Screening for in vivo (anti)estrogenic and (anti)androgenic activities of Tropaeolum majus L. and its effect on uterine contractility.

ETHNOPHARMACOLOGICAL RELEVANCE: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility. MATERIALS AND METHODS: Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg. RESULTS: In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid. CONCLUSIONS: HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats.

Vitamin C and resveratrol supplementation to rat dams treated with di(2-ethylhexyl)phthalate: impact on reproductive and oxidative stress end points in male offspring.

This study was carried out to assess the influence of di(2-ethylhexyl)phthalate (DEHP) alone or associated with antioxidants on the male reproductive system in newborn rats, emphasizing the implications of oxidative stress and hormonal balance during prenatal and early postnatal periods. Wistar females were exposed by oral route to DEHP alone or associated with antioxidants from gestational day 7 to lactational day 2 according to the following treatment regimens: (C) vehicle control (canola oil + 1% Tween-80); (V) vitamin C (200 mg/kg) + canola oil; (R) resveratrol (10 mg/kg) + canola oil; (D) DEHP (500 mg/kg) + 1% Tween-80; (DV) DEHP (500 mg/kg) + vitamin C (200 mg/kg); and (DR) DEHP (500 mg/kg) + resveratrol (10 mg/kg). Two male pups per litter were randomly selected and necropsied on postnatal day 2. The brain and liver were removed and weighed and anogenital distance (AGD) was measured. Additionally, the testes were removed for assessment of intratesticular testosterone levels and histopathology; the liver was used to measure biomarkers of oxidative stress. Vitamin C and resveratrol alone did not affect the reproductive end points and did not induce oxidative stress. Exposure of dams to DEHP alone and associated with antioxidants resulted in hepatomegaly in offspring and significantly increased the incidence of multinucleated gonocytes in seminiferous cords. Testosterone and AGD presented a trend to decrease in DEHP-exposed groups. Catalase activity increased only in groups exposed to DEHP associated with antioxidants, although GST (gluthatione-S-transferase) activity decreased in all DEHP-exposed groups. The levels of hydroperoxides increased only in group exposed to DEHP associated with vitamin C. These results indicate that the association of DEHP with antioxidants was unable to ameliorate DEHP-induced reproductive changes, and the coadministration of DEHP and these antioxidants might even contribute to an overall increase in oxidative stress.