4 research outputs found
Uterotonic agents for preventing postpartum haemorrhage:a network meta-analysis (Protocol)
Brathys e Trigynobrathys (88 e 59 representantes, respectivamente) são as duas maiores seções do gênero Hypericum que são distribuídos principalmente na América Central e América do Sul. Das mais de 100 espécies sul-americanas de Hypericum quase 65 são endêmicas dos Páramos, ecossistemas de alta altitude, caracterizados por uma vegetação composta principalmente de plantas de roseta gigantes, arbustos e gramíneas, nos quais Hypericum é um componente importante. Tendo em vista o escasso conhecimento da fitoquímica destas espécies de Hypericum, o presente estudo teve como objetivo estudar a composição fitoquímica e algumas bioatividades de seis espécies de Hypericum nativas do Peru (H. aciculare, H. andinum, H. brevistylum, H. decandrum, H. laricifolium e H. silenoides). O material vegetal, seco ao ar, das seis espécies (partes aéreas, caules, folhas e flores), e material vegetal subterrâneo de H. andinum (raízes e caules), foram moídas e extraídas por maceração à temperatura ambiente com n-hexano. Além disso, foram obtidos extrato etanólicos a partir de quatro espécies (H. andinum, H. brevistylum, H. laricifolium e H. silenoides). Os extratos n-hexano foram fracionados e as frações foram sometidas a processos cromatográficos obtendo-se cinco derivados de floroglucinol diméricos conhecidos, uliginosina A, uliginosina B, isouliginosina B, hiperbrasilol B e isohiperbrasilol B. Além disso, foram identificadas duas estruturas monoméricas e duas diméricas inéditas em H. andinum (raízes) e em H. laricifolium, andinina A, hiperlaricifolina A, laricifolina A e laricifolina B. Andinina A mostrou potencial atividade antidepressiva no teste de natação forçada. Do mesmo modo, a atividade antidepressiva dos extratos etanólicos foi avaliada. Estes quatro extratos apresentaram potencial atividade antidepressiva. As análises fitoquímicas por TLC, HPLC-DAD e UPLC-DAD/Q-TOF-MS revelaram que estes extratos são ricos em flavonoides, principalmente hiperosídeo. Os extratos n-hexano foram também analisados por um novo método de HPLC-DAD associado a LC-MS e UPLC-Q-TOF-MS . A presença de homólogos superiores M + 14 e regioisómeros foi determinada. A ocorrência natural destes cinco floroglucinois homólogos superiores M + 14 é descrita e a presença de outros compostos identificados pelo padrão de fragmentação MS é apresentada. Estes extratos e o seu principal componente foram capazes de inibir potencialmente a quimiotaxia induzida por LPS. Estes resultados sugerem que os extratos de espécies de Hypericum das seções Brathys e Trigynobrathys são fontes potenciais de novos anti-inflamatórios e antidepressivos.Brathys and Trigynobrathys (88 and 59 representatives, respectively) are the two largest sections of the genus Hypericum that are principally distributed in Central and South America. Of the more than 100 South American species of Hypericum almost 65 are endemic to the Páramos, high-altitude grassland ecosystems characterized by vegetation composed mainly of giant rosette plants, shrubs and grasses, in which Hypericum is a prominent component. In view of the scare knowledge on the phytochemistry of these Hypericum species, the present research aimed to study the phytochemical composition and some bioactivities of six Peruvian Hypericum species (H. aciculare, H. andinum, H. brevistylum, H. decandrum, H. laricifolium and H. silenoides). The air-dried aerial plant material of those six species (stems, leaves and flowers), and underground plant material of H. andinum (roots and stems), were ground and extracted by maceration at room temperature with n-hexane. Additionally crude ethanolic extracts were obtained from four species (H. andinum, H. brevistylum, H. laricifolium and H. silenoides). The n-hexane extracts were fractionated, and fractions were further processed by chromatographic procedures to yield five known dimeric acylphloroglucinol derivatives uliginosin A, uliginosin B, isouliginosin B, hyperbrasilol B and isohyperbrasilol B. In addition, two monomeric and two dimeric acylphloroglucinol structures were identified in H. andinum (roots extract) and H. laricifolium for the first time, andinin A, hyperlaricifolin A, laricifolin A and laricifolin B. Andinin A showed potential antidepressant-like activity in the forced swimming test. Similarly, the antidepressant-like activity of the crude ethanolic extracts was assessed. These four extracts possessed a potential antidepressant-like activity. The phytochemical analyses by TLC, HPLC-DAD and UPLCDAD/Q-TOF-MS revealed that the extracts were rich in flavonoids, principally hyperoside. The n-hexane extracts were also analyzed by a new HPLC-DAD fingerprint method associated with LC-MS and UPLC-Q-TOF-MS. The presence of M + 14 higher homologues and regioisomers could be distinguished. The natural occurrence of these five M + 14 higher homologues is described and the presence of other compounds identified by their MS fragmentation pattern is presented. These extracts and their main dimeric acylphloroglucinol component were able to potently inhibit the LPS-induced chemotaxis on rat PMN. These results suggest that extracts of Hypericum species from sections Brathys and Trigynobrathys are potential sources of new anti-inflammatory and antidepressant molecules
Uterotonic agents for preventing postpartum haemorrhage:A network meta-analysis
BackgroundPostpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best.ObjectivesTo identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile.Search methodsWe searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies.Selection criteriaAll randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review.Data collection and analysisAt least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions.Main resultsThis network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH ≥ 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate-quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate-quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of ≥ 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH ≥ 500 mL.The outcomes and rankings for the outcome of PPH ≥ 1000 mL were similar to those of PPH ≥ 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% versus 0.6%) and hypertension [RR 1.77 (95% CI 0.55 to 5.66), low-quality evidence; 1.2% versus 0.7%), while the misoprostol plus oxytocin combination had the higher risk for fever (RR 3.18 (95% CI 2.22 to 4.55), moderate-quality evidence; 11.4% versus 3.6%) when compared with oxytocin. Carbetocin had similar risk for side-effects compared with oxytocin although the quality evidence was very low for vomiting and for fever, and was low for hypertension.Authors' conclusionsErgometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were more effective for preventing PPH ≥ 500 mL than the current standard oxytocin. Ergometrine plus oxytocin combination was more effective for preventing PPH ≥ 1000 mL than oxytocin. Misoprostol plus oxytocin combination evidence is less consistent and may relate to different routes and doses of misoprostol used in the studies. Carbetocin had the most favourable side-effect profile amongst the top three options; however, most carbetocin trials were small and at high risk of bias.Amongst the 11 ongoing studies listed in this review there are two key studies that will inform a future update of this review. The first is a WHO-led multi-centre study comparing the effectiveness of a room temperature stable carbetocin versus oxytocin (administered intramuscularly) for preventing PPH in women having a vaginal birth. The trial includes around 30,000 women from 10 countries. The other is a UK-based trial recruiting more than 6000 women to a three-arm trial comparing carbetocin, oxytocin and ergometrine plus oxytocin combination. Both trials are expected to report in 2018.Consultation with our consumer group demonstrated the need for more research into PPH outcomes identified as priorities for women and their families, such as women's views regarding the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge. To date, trials have rarely investigated these outcomes. Consumers also considered the side-effects of uterotonic drugs to be important but these were often not reported. A forthcoming set of core outcomes relating to PPH will identify outcomes to prioritise in trial reporting and will inform futures updates of this review. We urge all trialists to consider measuring these outcomes for each drug in all future randomised trials. Lastly, future evidence synthesis research could compare the effects of different dosages and routes of administration for the most effective drugs
Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis
Background: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective. Objectives: To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. Methods: The Cochrane Pregnancy and Childbirth’s Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (Cytotec®; Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon®; Novartis International AG, Basel, Switzerland), carbetocin (Pabal®; Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin (Syntometrine®; Alliance Pharma plc, Chippenham, UK), oxytocin, and a placebo or no treatment]. Primary outcomes were stratified according to the mode of birth, prior risk of PPH, health-care setting, drug dosage, regimen and route of drug administration. Sensitivity analyses were performed according to study quality and funding source, among others. A model-based economic evaluation compared the relative cost-effectiveness separately for vaginal births and caesareans with or without including side effects. Results: From 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data. Limitations: There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out. Conclusions: Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data. Study registration: This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO–Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13–1414 (University of Birmingham, Birmingham, UK). Funding: Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report