Induction of labor at term with vaginal misoprostol or a prostaglandin E2 pessary: a noninferiority randomized controlled trial.

BACKGROUND: Induction of labor is among the most common procedures for pregnant women. Only a few randomized clinical trials with relatively small samples have compared misoprostol with dinoprostone. Although their efficacy seems similar, their safety profiles have not been adequately evaluated, and economic data are sparse. OBJECTIVE: This study aimed to test the noninferiority of vaginal misoprostol (prostaglandin E1) (25 µg) to a slow-release dinoprostone (prostaglandin E2) pessary (10 µg) for induction of labor with an unfavorable cervix at term. STUDY DESIGN: This was an open-label multicenter randomized noninferiority trial at 4 university hospitals of the Research Group in Obstetrics and Gynecology between 2012 and 2015. We recruited women who underwent induction of labor for medical reasons, those with a Bishop score of ≤5 at ≥36 weeks' gestation, and those with a cephalic-presenting singleton pregnancy with no previous cesarean delivery. Women were randomly allocated to receive either vaginal misoprostol at 4-hour intervals (25 µg) or a 10-mg slow-release dinoprostone pessary. The primary outcome was the total cesarean delivery rate. Noninferiority was defined as a difference in the cesarean delivery rates between the groups of no more than 5%. Secondary outcomes included neonatal and maternal morbidity, vaginal delivery at <24 hours after starting the induction of labor process, and maternal satisfaction. RESULTS: The study included 1674 randomized women. The per-protocol analysis included 790 women in each group. The total cesarean delivery rates were 22.1% (n=175) in the misoprostol group and 19.9% (n=157) in the dinoprostone group, a difference of 2.2% (with an upper-bound 95% confidence limit of 5.6%) (P=.092). Results in the intention-to-treat analysis were similar. Neonatal and maternal morbidity rates were similar between groups. Vaginal delivery within 24 hours was significantly higher in the misoprostol group (59.3% vs 45.7%; P<.001) as was maternal satisfaction, assessed in the postpartum period by a visual analog scale (mean score, 7.1±2.4 vs 5.8±3.1; P<.001). CONCLUSION: The noninferiority of a 25-µg dose of vaginal misoprostol every 4 hours to the dinoprostone pessary for cesarean delivery rates after induction of labor at term could not be demonstrated, although the confidence limit of the difference barely exceeded the noninferiority margin. Nonetheless, given the small difference between these cesarean delivery rates and the similarity of neonatal and maternal morbidity rates in this large study, the clinical risk-to-benefit ratio justifies the use of both drugs.

Antiproliferative activity and phenotypic modification induced by selected Peruvian medicinal plants on human hepatocellular carcinoma Hep3B cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The high incidence of human hepatocellular carcinoma (HCC) in Peru and the wide use of medicinal plants in this country led us to study the activity against HCC cells in vitro of somes species used locally against liver and digestive disorders. MATERIALS AND METHODS: Ethnopharmacological survey: Medicinal plant species with a strong convergence of use for liver and digestive diseases were collected fresh in the wild or on markets, in two places of Peru: Chiclayo (Lambayeque department, Chiclayo province) and Huaraz (Ancash department, Huaraz province). Altogether 51 species were collected and 61 ethanol extracts were prepared to be tested. Biological assessment: All extracts were first assessed against the HCC cell line Hep3B according a 3-step multi-parametric phenotypic assay. It included 1) the evaluation of phenotypic changes on cells by light microscopy, 2) the measurement of the antiproliferative activity and 3) the analysis of the cytoskeleton and mitosis by immunofluorescence. Best extracts were further assessed against other HCC cell lines HepG2, PLC/PRF/5 and SNU-182 and their toxicity measured in vitro on primary human hepatocytes. RESULTS: Ethnopharmacological survey: Some of the species collected had a high reputation spreading over the surveyed locations for treating liver problems, i.e. Baccharis genistelloides, Bejaria aestuans, Centaurium pulchellum, Desmodium molliculum, Dipsacus fullonum, Equisetum bogotense, Gentianella spp., Krameria lapacea, Otholobium spp., Schkuhria pinnata, Taraxacum officinale. Hep3B evaluation: Fourteen extracts from 13 species (Achyrocline alata, Ambrosia arborescens, Baccharis latifolia, Hypericum laricifolium, Krameria lappacea, Niphidium crassifolium, Ophryosporus chilca, Orthrosanthus chimboracensis, Otholobium pubescens, Passiflora ligularis, Perezia coerulescens, Perezia multiflora and Schkuhria pinnata) showed a significant antiproliferative activity against Hep3B cells (IC50≤ 50µg/mL). This was associated with a lack of toxicity on primary human hepatocytes in vitro. Immunofluorescence experiments on Hep3B cells showed that crude extracts of Schkuhria pinnata and Orthrosanthus chimboracensis could block Hep3B cells in mitosis with an original phenotype. Crude extracts of Perezia coerulescens, Perezia multiflora, Achyrocline alata, Ophryosporus chilca, Otholobium pubescens and Hypericum laricifolium could modify the overall microtubule cytoskeletal dynamics of Hep3B cells in interphase by an original mechanism. CONCLUSIONS: Our method allowed us to select 9 extracts which displayed antiproliferative activities associated with original cellular phenotypes on Hep3B cells, regarding known microtubule-targeting drugs. Both chemical and cellular studies are ongoing in order to elucidate natural compounds and cellular mechanisms responsible of the activities described.