Gastrointestinal safety of coxibs: systematic review and meta‐analysis of observational studies on selective inhibitors of cyclo‐oxygenase 2

Prior meta‐analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case‐control, nested case‐control and case‐crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty‐eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44–1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64–8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56–2.61)] and celecoxib [RR 1.53 (95% CI 1.19–1.97)]. Gastrointestinal risk was also high for the subgroups aged <65 years and low‐dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low‐dose coxibs and <65‐year‐old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.     

Quantification and validation of nine nonsteroidal anti‐inflammatory drugs in equine urine using gas chromatography–mass spectrometry for doping control

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used in therapeutic doses in human and veterinary medicine for the treatment of inflammation, pain, and fever. A method for the simultaneous determination of nine NSAIDs, known as therapeutic prohibited substances, in equine urine was developed and fully validated according to the European Commission Decision 2002/657/EC and Association of Official Racing Chemists criteria. The validation was performed for naproxen, flunixin, ketoprofen, diclofenac, eltenac, meclofenamic acid, phenylbutazone, vedaprofen, and carprofen in equine urine in accordance with the International Screening Limits (ISL) regulated by International Federation of Horseracing Authorities. After basic hydrolysis, samples were extracted with a C18 cartridge using automated solid‐phase extraction. Several derivatization reagents were investigated, and trimethylphenylammonium hydroxide/methanol (20/80, v/v) was selected. Analyses were carried out using gas chromatography–mass spectrometry with selected ion monitoring mode, but the method can be applied to a large number of analytes. The within‐laboratory reproducibility was not more than 12.8% (≤15%), and mean relative recoveries ranged from 91.1% to 104.1% for inter‐day and intra‐day precision. The decision limits (CCα) and detection capabilities (CCβ) were evaluated at concentrations near the ISL for each therapeutic substance. The validation results demonstrated that the method is highly reproducible, easily applicable, and suitable for the analysis of some NSAIDs in equine urine that have not been previously published. Finally, the method was also applied to known positive samples.     

基于网络药理学的黄芪抗心力衰竭作用机制

目的 基于网络药理学研究黄芪抗心力衰竭的作用机制。方法 采用活性成分筛选与靶点预测技术,结合生物信息学手段,预测黄芪抗心力衰竭的潜在作用靶点,并进行信号通路分析,从而探讨其治疗心力衰竭的分子机制。结果 在TCMSP数据中搜索筛选得到20个相应黄芪化学成分,同时利用靶点预测技术共筛选出相关靶点121个。同时在疾病基因数据库检索得到10 962个与心力衰竭发生、发展有关的已知靶点基因,利用string数据库和Cytoscape软件中的网络拓扑分析共筛选获取关键靶点8个。GO富集分析显示,黄芪可通过参与细胞能量代谢、血管内环境变化、神经活性配受体作用、激素活性等10个生物功能的PI3K/AKT、p38丝裂原活化蛋白激酶(p38MAPK)和MAPK/NF-κB等10条关键信号通路发挥抗心力衰竭的作用。结论 中药黄芪抗心力衰竭的作用具有多成分、多靶点、协同作用的特点。     

Multiparametric MRI as an early biomarker of individual therapy effects during concomitant treatment of brain tumours

The aim of this study was to determine the ability of multiparametric MRI to identify the early effects of individual treatment, during combined chemo‐radiotherapy on brain tumours. Eighty male rats bearing 9L gliosarcomas were randomized into four groups: untreated, anti‐angiogenic therapy (SORA group), microbeam radiation therapy (MRT group) and both treatments (MRT+SORA group). Multiparametric MRI (tumour volume, diffusion‐weighted MR imaging (ADC), blood volume fraction (BVf), microvessel index (VSI), vessel wall integrity (AUC_P846) and tissue oxygen saturation (StO₂)) was performed 1 day before and 2, 5 and 8 days after treatment initiation. Unpaired t‐tests and one‐way ANOVA were used for statistical analyses. Each MR parameter measured in our protocol was revealed to be sensitive to tumour changes induced by any of the therapies used (individually or combined). When compared with untreated tumours, SORA induced a decrease in BVf, VSI, StO₂ and AUC_P846, MRT generated an increase in ADC and AUC_P846 and combined therapies yielded mixed effects: an increase in ADC and AUC_P846 and a decrease in BVf, StO₂ and AUC_P846. MRT and MRT+SORA significantly slowed tumour growth. Despite these two groups presenting with similar tumour sizes, the information yielded from MR multiparameter assessment indicated that, when used concomitantly, each therapy induced distinguishable and appreciable physiological changes in the tumour. Our results suggest that multiparametric MRI can monitor the effects of individual treatments, used concomitantly, on brain tumours. Such monitoring would be useful for the detection of tumour resistance to drug/radiotherapy in patients undergoing concomitant therapies. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of corticosteroids on articular cartilage: have animal studies said everything?

Intra‐articular (IA) corticosteroids (CS) have been used in the treatment of osteoarthritis for many years, although their effects on articular cartilage are not fully understood. To identify whether previous animal studies have provided enough evidence about the effects of CS, we undertook a systematic review that identified 35 relevant in vivo animal experimental studies between 1965 and 2014 assessing the effects of CS on either normal cartilage, or in either induced osteoarthritis (OA) or synovitis. The quality of the methodology was assessed. Deleterious effects, both structural and biochemical, have mainly been reported in rabbits and are associated with frequent administration of CS, sometimes at high dose and with systemic side effects. In dogs, four identified studies concluded that there were beneficial effects with methylprednisolone acetate (MPA) and triamcinolone hexacetonide therapy. In horses, MPA was mostly deleterious, while triamcinolone acetonide had positive effects in one study highly rated at quality assessment. However, many methodological weaknesses have been identified, such as the lack of pharmacokinetic and pharmocodynamics data and the large variation in doses between studies, the limited selection criteria at baseline, the absence of blinding, and the lack of statistics or appropriate controls for testing the effects of the vehicle of the drug. Those methodological weaknesses weaken the conclusions of numerous studies that assess beneficial or deleterious effects of CS on articular cartilage. Animal studies have not yet provided definitive data, and further research is required into the role of CS in articular pathobiology.