Genotoxicity and maternal-fetal safety of the dried extract of leaves of Azadirachta indica A. Juss (Meliaceae) in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Azadirachta indica A. Juss (Meliaceae), popularly known as "neem", is used for the treatment of rheumatism, cancer, ulcers, diabetes, respiratory problems, among others. This species is present on six continents and contains more than 400 bioactive compounds. Practically all parts of the plant are used in the treatment of diseases. Although it is widely used, no study has evaluated the safety of this species throughout the gestational period in Wistar rats. AIM OF THE STUDY: To evaluate the genotoxicity and the effect of treatment with dried extract of leaves of Azadirachta indica on maternal toxicity and fetal development. MATERIALS AND METHODS: The dried extract of leaves of A. indica was obtained by spray drying after percolation of the plant material in 30% ethanol (w/w). The total flavonoids and rutin contents of the extract were determined by spectrophotometric method and HPLC-DAD, respectively. Pregnant Wistar rats (n = 40) were divided into four groups (n = 10/group): one control and three groups treated with dried extract of leaves of A. indica at doses of 300, 600 or 1200 mg/kg. Treatments were carried out from gestational day (GD) 0-20. During gestation, clinical signs of toxicity, weight gain, feed and water consumption of the dams were evaluated. On GD 21, rats were euthanized and cardiac blood was collected. Liver, kidneys, lung, heart, uterus, ovaries and bone marrow were collected. Reproductive performance parameters, histopathological analysis, biochemistry and genotoxicity were evaluated. Fetuses were evaluated for external morphology, skeletal and visceral changes. RESULTS: The total flavonoid content of the extract ranged from 2.64 to 3.01%, and the rutin content was 1.07%. There was no change in body mass gain, food and water consumption between the evaluated groups. There was also no difference between the groups in terms of biochemical parameters, reproductive performance, histopathological analysis of the mother's organs and genotoxicity. Supernumerary ossification sites of the sternum were observed, and other skeletal and visceral alterations were not significant. CONCLUSIONS: The treatment did not induce maternal toxicity, it was neither embryotoxic nor fetotoxic. The extract was not potentially genotoxic, and at a dose of 1200 mg/kg, it caused changes in the ossification of the sternum.

Cytotoxicity and maternal toxicity attributed to exposure to Momordica charantia L. (Cucurbitaceae) dry leaf extract.

Momordica charantia L. (Cucurbitaceae), popularly known as "bitter melon" or "bitter gourd," is a climbing plant well-adapted to tropical countries. This plant is used traditionally to treat several conditions including diabetes mellitus, inflammation, liver dysfunctions, and cancer. Given the widespread ethnopharmacological use, this study aimed to examine the cytogenetic, maternal, and developmental toxicity attributed to exposure to dry extract of M. charantia leaves using Allium cepa and Wistar rats as test models. First, phytochemical characterization of the dry extract by high performance liquid chromatography (HPLC) analyses was performed. Then, Allium cepa roots were exposed to three different concentrations of the dry extract (0.25, 0.5, or 1 mg/ml) to determine the mitotic index, frequency of chromosomal aberrations, and nuclear abnormalities. In addition, pregnant Wistar rats were administered either 500; 1,000 or 2,000 mg/kg dry extract during the gestational period (GD) days 6-15, and subsequently possible toxic effect on the dams and fetuses were recorded. HPLC analyses confirmed rutin as the main secondary metabolite present in the dry extract. In the Allium cepa test, the dry extract was cytotoxic. In Wistar rats, dry extract administration reduced water and feed intake and mean body mass gain, indicating maternal toxicity during the organogenesis period. However, the dry extract did not markedly affect reproductive outcome parameters evaluated. Regarding developmental toxicity assessment, the dry extract treatment did not significantly alter number of skeletal malformations in the offspring. Data demonstrated that the dry extract of M. charantia leaves presents cytotoxicity and low maternal toxicity, indicating indiscriminate use needs to be avoided.

Assessing the safety of using the dry extract of Justicia pectoralis Jacq. (Acanthaceae) during pregnancy of Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Justicia pectoralis Jacq. (Acanthaceae), popularly known as tilo, chambá and anador, is widely used in folk medicine in Latin American countries as a sedative, anti-anxiety, reducing menopause symptoms and in the treatment of pathologies of the respiratory tract. Although J. pectoralis is widely used by the female population, there are no studies on the safety of using this species during pregnancy. AIM OF THIS STUDY: To evaluate the effects of prenatal treatment with dry extract from the aerial parts of J. pectoralis on maternal and developmental toxicity in Wistar rats. MATERIAL AND METHODS: Pregnant Wistar rats (n = 10/group) were treated from gestational day (GD) 0-20 with the vehicle (control group) or with the dry extract of J. pectoralis at doses of 300, 600 or 1200 mg/kg. During pregnancy, clinical signs of toxicity, maternal weight, feed and water intake were evaluated. On GD 21, rats were anesthetized and intracardiac blood was collected to evaluate biochemical parameters. During cesarean section, reproductive performance parameters were recorded. The liver, kidneys, uterus and ovaries were removed for histopathological analysis. Fetuses were examined for possible malformations and/or skeletal and visceral variations. RESULTS: Treatment with dry extract of J. pectoralis did not alter weight gain, feed intake or biochemical and maternal reproductive performance parameters There were also no significant histopathological changes in the maternal organs, as well as external, skeletal and visceral malformations in the fetuses. CONCLUSION: Oral administration of J. pectoralis dry extract during pregnancy did not induce maternal toxicity or embryotoxic and teratogenic effects.

[The use of phytotherapy during pregnancy: a global overview]. / O uso da fitoterapia durante a gestação: um panorama global.

The scope of this study is to present an integrative review of the prevalence of the use of phytotherapy during pregnancy. A review of the topic was made by research in the Scielo, Medline and Science Direct databases using the following key words: "herbs and pregnancy," "plant and gestation," with their respective terms in Portuguese. Forty-six articles published between 2000 and 2015 met the study's inclusion and exclusion criteria and were included in this review. Of these, 11 were carried out in Europe, 10 in Asia, 5 in Africa, 3 in Oceania, 16 in America and only one of which was a multinational study. In most of these (67.39%), the interview method was used. A substantial variability in the prevalence of phytotherapy use was reported in the articles. In addition, camomile, ginger, garlic, mint and echinacea were the species most used by pregnant women. Despite the socioeconomic and ethnic-cultural variables among women worldwide, phytotherapy use during gestation is a widespread practice.

Este artigo tem como objetivo realizar uma revisão integrativa da literatura sobre a prevalência do uso da fitoterapia durante a gestação. Foi realizado um levantamento nas bases de dados SciELO, Medline e Science Direct com os descritores "herbal and pregnancy", "plant and gestation" e seus correspondentes em português: "planta e gestação"; "erva e gravidez". Dentre os artigos publicados entre 2000 e 2015, 46 estudos clínicos preencheram os critérios de inclusão e exclusão e foram selecionados para esta revisão. Destes, 11 foram realizados na Europa, 10 na Ásia, 5 na África, 3 na Oceania, 16 na América e, apenas um, foi de caráter multinacional. Na maioria dos estudos (67,39%) o método utilizado foi o de entrevista. A prevalência do uso da fitoterapia descrita nas publicações foi muito variável. Ademais, a camomila, o gengibre, o alho, a menta e a equinácea foram as espécies mais utilizadas pelas gestantes. Os dados mostram que o uso da fitoterapia durante a gestação é uma prática disseminada entre mulheres de todo o mundo, independentemente das variáveis socioeconômicas e étnico-culturais que eventualmente possam distingui-las.

O uso da fitoterapia durante a gestação: um panorama global / The use of phytotherapy during pregnancy: a global overview

Resumo Este artigo tem como objetivo realizar uma revisão integrativa da literatura sobre a prevalência do uso da fitoterapia durante a gestação. Foi realizado um levantamento nas bases de dados SciELO, Medline e Science Direct com os descritores "herbal and pregnancy", "plant and gestation" e seus correspondentes em português: "planta e gestação"; "erva e gravidez". Dentre os artigos publicados entre 2000 e 2015, 46 estudos clínicos preencheram os critérios de inclusão e exclusão e foram selecionados para esta revisão. Destes, 11 foram realizados na Europa, 10 na Ásia, 5 na África, 3 na Oceania, 16 na América e, apenas um, foi de caráter multinacional. Na maioria dos estudos (67,39%) o método utilizado foi o de entrevista. A prevalência do uso da fitoterapia descrita nas publicações foi muito variável. Ademais, a camomila, o gengibre, o alho, a menta e a equinácea foram as espécies mais utilizadas pelas gestantes. Os dados mostram que o uso da fitoterapia durante a gestação é uma prática disseminada entre mulheres de todo o mundo, independentemente das variáveis socioeconômicas e étnico-culturais que eventualmente possam distingui-las.

Abstract The scope of this study is to present an integrative review of the prevalence of the use of phytotherapy during pregnancy. A review of the topic was made by research in the Scielo, Medline and Science Direct databases using the following key words: "herbs and pregnancy," "plant and gestation," with their respective terms in Portuguese. Forty-six articles published between 2000 and 2015 met the study's inclusion and exclusion criteria and were included in this review. Of these, 11 were carried out in Europe, 10 in Asia, 5 in Africa, 3 in Oceania, 16 in America and only one of which was a multinational study. In most of these (67.39%), the interview method was used. A substantial variability in the prevalence of phytotherapy use was reported in the articles. In addition, camomile, ginger, garlic, mint and echinacea were the species most used by pregnant women. Despite the socioeconomic and ethnic-cultural variables among women worldwide, phytotherapy use during gestation is a widespread practice.

Developmental toxicity evaluation of Pimenta pseudocaryophyllus (Gomes) Landrum, (E)-methyl isoeugenol chemotype, in Wistar rats.

BACKGROUND: Pimenta pseudocaryophyllus (Gomes) Landrum (Myrtaceae) has been traditionally used in Brazilian folk medicine. Studies have established the botanical characterization, phytochemistry profile, and pharmacological potential of this species, including antibiotic, anxiolytic, antidepressant, antioxidant, antinociceptive, and anti-inflammatory properties. Despite its widespread use, no previous study has been conducted regarding its toxicological profile, especially during pregnancy. Thus, this study investigated the developmental toxicity of the dry leaf extract of the P. pseudocaryophyllus, (E)-methyl isoeugenol chemotype, in rats. METHODS: First, the dry leaf extract was prepared by a spray-drying technique. Then, pregnant Wistar rats were orally treated with dry extract at doses of 0, 2000, 2500, or 3000 mg/kg from gestational day 6 through 15 (organogenesis period). On gestational day 21, the rats underwent cesarean sections and the reproductive outcomes and biochemistry parameters related to hepatic and renal markers were evaluated. Additionally, the fetuses were examined for external and skeletal variations and malformations. RESULTS: The spray-drying technique preserved the phytocomplex components and showed a satisfactory yield. No relevant differences were seen in the food consumption, reproductive performances, and hepatic and renal biochemical parameters between groups. However, there was a decrease in body weight gain of the dams during the organogenesis period and an increase of minor skeletal variations in the offspring (increased fetal incidences only of delayed ossification of the metacarpals, metatarsals, phalanges, sternebra, and rudimentary ribs) treated with the dry extract. CONCLUSION: The extract of P. pseudocaryophyllus, (E)-methyl isoeugenol chemotype, showed low maternal toxicity and induced minor skeletal variations in the offspring. Birth Defects Research 109:1292-1300, 2017. © 2017 Wiley Periodicals, Inc.

Prednisone reduces ketoconazole-induced skeletal defects in rat fetuses.

Ketoconazole (KT) is a broad-spectrum antifungal agent whose pharmacological activity is based on the capability to interfere with steroid biosynthesis through an interaction with fungal cytochrome P-450 enzymes and thereby avoiding the formation of fungal walls. As the inhibition of fungal cytochrome P-450 by KT is not specific, the mammalian cytochrome P-450 species, which play an important role in the biosynthesis of steroidogenesis, are also affected. The reproductive and developmental toxicity of KT have been assessed. This antimycotic agent has been reported as embryotoxic and teratogenic when administered in high doses (80 mg/kg) to pregnant rats. The mechanisms by which KT exert teratogenic effects remains to be elucidated. When considering the potential inhibitory effect of KT on mammalian steroid biosynthesis as a possible responsible for the skeletal anomalies induced by this drug, this study aimed at determining whether steroid maternal supplementation may prevent the skeletal anomalies induced by KT. To test this hypothesis, maternal supplementation with prednisone (PRED) (0.1, 0.2 or 0.4 mg/kg) and 80 mg/kg of KT were administered to pregnant Wistar rats (n = 10) during organogenesis period. On gestational day 21, the dams were euthanized and examined for standard parameters of reproductive outcome. In summary, the results showed that PRED supplementation therapy may cause reductions in the incidence of KT-induced cranial and appendicular skeletal anomalies as well as cleft palate in the rat, being these results more consistent with 0.4 mg/kg of this drug. These results suggest an important role for glucocorticoids in KT-induced teratogenesis.