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.     

Evolving insights: how DNA repair pathways impact cancer evolution

Viewing cancer as a large, evolving population of heterogeneous cells is a common perspective. Because genomic instability is one of the fundamental features of cancer, this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation, development, metastasis, and relapse. With the increased mutation rate and abundant diversity of the gene pool, this heterogeneity leads to cancer evolution, which is the major obstacle in the clinical treatment of cancer. Cells rely on the integrity of DNA repair machineries to maintain genomic stability, but these machineries often do not function properly in cancer cells. The deficiency of DNA repair could contribute to the generation of cancer genomic instability, and ultimately promote cancer evolution. With the rapid advance of new technologies, such as single-cell sequencing in recent years, we have the opportunity to better understand the specific processes and mechanisms of cancer evolution, and its relationship with DNA repair. Here, we review recent findings on how DNA repair affects cancer evolution, and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.     

香药“一带一路”溯源、资源开发及功效探讨

香药是古代"丝绸之路"交流发展逐渐传入中国的传统药物,补充并丰富了我国药用资源。为积极倡导国家"一带一路"建设,推进我国外来香药资源的进一步开发和利用,服务"一带一路"沿线国家广大人民尤其是少数民族人群健康用药,通过查阅大量文献,梳理了香药的"一带一路"溯源及目前研究现状;在此基础上,从中医功效角度对其进行分类,并总结常用代表性香药的香味物质基础、功效及临床用途;并提出香药的进一步开发和利用策略,以促进其在新时代"一带一路"倡议中的快速发展,进一步增强民族医药文化自信。     

核苷类药物在乙型肝炎后肝硬化治疗中的疗效

目的分析在乙型肝炎后肝硬化治疗中采用核苷类药物的治疗价值。方法将本院在2018年1月—2019年2月期间收治的乙型肝炎后肝硬化患者68例纳入研究,以奇偶法均分为两组,对照组(34例)行常规治疗方案,观察组(34例)行核苷类药物治疗,对比两组乙型肝炎后肝硬化患者的治疗效果。结果对照组HBeAg转阴率14.71%低于观察组44.12%,P<0.05差异有统计学意义。观察组临床指标(ALT、AST、TBIL、ALB、PTA、Child-Pugh)优于对照组患者,P<0.05差异有统计学意义。观察组并发症发生率8.82%低于对照组并发症发生率为41.18%,P<0.05差异有统计学意义。结论在乙型肝炎后肝硬化治疗中采用核苷类药物可以取得显著的治疗效果,可以有效改善患者的临床症状,提升患者的转阴率,安全性较高。     

Signal Management in Pharmacovigilance: A Review of Activities and Case Studies

PurposeAfter nearly 12 decades of pharmaceutical catastrophes and the associated groundbreaking regulatory innovations, pharmacovigilance has come down to us in the present day as 3 interlocking core disciplines: case management, signal management, and benefit–risk management. This review provides a state-of-the-art introduction to the great variety of sources of safety information, both dependent on and independent of the Individual Case Safety Report (ICSR), and explains how this content undergoes management-system processes with globally accepted definitions, standards, and structures that make possible the ongoing safe use of a pharmaceutical product throughout its lifecycle. This occurs in the context of: (1) new products coming to market with new risks for drug–drug interactions, and (2) new global threats to safe manufacturing and distribution.MethodsThis narrative review, reflective of the author's experience, uses a large-frame system of signal management developed by the Council for International Organizations of Medical Sciences VIII Working Group and modified by the author to include governance. A key feature of the review is the regular inclusion of relevant case studies to provide a backdrop of the unexpected, with resulting tragic outcomes, to the ever-evolving regulatory landscape.FindingsRegarding content, beyond the commonly appreciated sources of safety information that find their way into ICSRs are non–ICSR-based sources, including preclinical data, manufacturing data, findings from subject-matter experts who participate on data-monitoring committees, outside expert panels, advocacy groups, and independent investigator studies. Regarding process, it is important to recognize that governance is crucial in the effective conduct of signal management, in that subject-matter experts are essential to the scientific and medical aspects of decision making, and business and policy executives are essential in determining the final courses of action, as these decisions have implications for the company.ImplicationsSignal management is an integral part of pharmacovigilance practices that strive to obtain all of the information necessary for maintaining the safety profiles of a company's pharmaceutical and biological products, to support favorable benefit–risk balances, and to ensure safe use by health care providers and their patients.     

COVID-19: Regulatory Landscape of Medicinal and Medical Device Products for Human Use

Against the backdrop of the COVID pandemic, the scientific and medical communities are working with all deliberate speed with state-of-the-art technologies to develop diagnostic and therapeutic products that can identify, treat, and prevent infection with SARS-CoV-2. These activities may only be legally conducted with the necessary statutes and regulations in place to facilitate the timely development, manufacturing, evaluation, and distribution of products that meet quality standards. The present regulatory landscape for medicinal and medical products for human use has been shaped by nearly 12 decades of statutory history that followed in reaction to disasters and tragedies. Five distinct, closely woven threads of statutory history have led to the regulatory infrastructure we have in place: (1) standardized processes for routine development of medicinal and medical device products for human use; (2) processes for expedited development to shorten time frames and expand patient populations; (3) mechanisms of Expanded Access to make medicinal products available to patients prior to approval of the US Food and Drug Administration; (4) Emergency Use Authorization during public health emergencies; and (5) the development of pathways for bringing generic drugs and biosimilar biologics to market. These mechanisms are being brought to bear to facilitate the defeat of infection with SARS-CoV-2.     

How is safety of dermatology drugs assessed: trials,registries, and spontaneous reporting

ABSTRACT

Introduction: Skin conditions are common and highly varied in their etiology; therefore, a diverse array of therapeutics are utilized. Drug safety studies in dermatology can be challenging as there are over 3000 diagnoses to consider. As a result, dermatologists rely on data from multiple sources including clinical trials and real-world evidence.

Areas covered: In this review, we cover the main sources of safety data available, their strengths and weaknesses and how dermatologists should utilize such data. We use real-world examples of the different types of adverse events reported and how they are best captured by either randomized controlled trials or post-marketing pharmacovigilance methods. With multiple new therapies in dermatology, such as dupilumab for atopic dermatitis and janus-kinase inhibitors for alopecia areata the specialty is awash with evolving high-level evidence for their use. It is important to understand the optimal way to assess safety from trials but also appreciate the need for ongoing capture of safety data in clinical practice.

Expert opinion: In dermatology, there is a plethora of conditions to treat and clinical trials, post-marketing surveillance, such as drug registries and spontaneous reporting, all enable dermatologists to gain a more comprehensive understanding of the safety profiles of drugs being used.     

益气化瘀解毒方对MRP、GST-π和Topo Ⅱ基因在Sorafenib获得性耐药人肝癌QGY7702细胞表达的干预研究

目的探讨益气化瘀解毒方干预后对Sorafenib获得性耐药人肝癌QGY7702细胞(QGY7702/Sora)增殖及MRP、GST-π和Topo Ⅱ基因表达的影响。方法培养QGY7702/Sora细胞和QGY7702细胞,利用Cell Counting Kit-8(CCK-8)法检测Sorafenib对细胞的半数抑制率浓度(IC50值),计算耐药指数RI;观察益气化瘀解毒方对耐药细胞的增殖影响;采用荧光定量PCR检测药物干预前后2种细胞中MRP、GST-π和Topo Ⅱ基因表达水平。结果亲本细胞和耐药细胞Sorafenib的IC50值分别为(7.993±0.522)μmol/L和(19.651±1.216)μmol/L,RI约为2.5。益气化瘀解毒方可抑制耐药细胞的增殖活性。2种细胞的MRP、GST-π、Topo Ⅱ表达量无明显差异(P>0.05)。Sorafenib组可促进耐药细胞MRP 、GST-π基因的过表达(P<0.05),益气化瘀解毒方组可抑制GST-π基因的过表达(P<0.01),且联合Sorafenib可显著提高Topo Ⅱ基因的表达量(P<0.01)。结论 QGY7702/Sora细胞MRP、GST-π和Topo Ⅱ的表达水平与亲本细胞无显著差异。耐药细胞对Sorafenib敏感性降低与MRP、GST-π过表达相关,而益气化瘀解毒方拮抗Sorafenib耐药与抑制GST-π过表达相关。     

含功能性油的水飞蓟宾超饱和自纳米乳的制备与体外评价

目的制备含功能性油的水飞蓟宾超饱和自纳米乳(SLB-S-SNEDDS),并对其进行表征及体外评价研究,以提高难溶性药物水飞蓟宾的生物利用度。方法铁氢化钾还原力与1,1-二苯基-2-苦肼基(DPPH)自由基清除实验筛选功能性油脂;伪三元相图考察乳化剂乳化能力;测定粒径、多分散指数(PDI)、Zeta电位等考察混合油相比例与载药量;相容性与溶出度实验筛选促过饱和物质并考察其质量浓度;从外观、粒径分布、自乳化效率、形态学等方面表征SLB-S-SNEDDS,并进行溶出度、抗氧化能力、细胞毒性等体外评价。结果所得SLB-S-SNEDDS处方为(1)小麦胚芽油/Capryol 90-Cremophor ELP-Transcutol HP与(2)沙棘籽油/Capryol 90-Cremophor ELP-Transcutol HP,1 g基质(包含0.043 g小麦胚芽油或沙棘籽油、0.387 g Capryol 90、0.380 g Cremophor ELP、0.190 g Transcutol HP),水飞蓟宾的添加量为各组分平衡溶解度之和的20%,Soluplus的添加量为上述总质量的0.1%。小麦胚芽油、沙棘籽油体系分别为淡黄色、亮黄色透明状均一液体,2种体系自乳化分散后均呈近球形白色扁平乳滴,粒径约为50 nm,乳化时间均为65 s。与药物原料及SLB-SNEDDS相比,SLB-S-SNEDDS中水飞蓟宾的累积溶出率8h内均维持在85%～110%,表明该体系能够显著提高药物的溶出度。SLB-S-SNEDDS与铁氰化钾反应后的吸光度(A值0.452～0.782,0.488～0.765)以及DPPH自由基清除率(39.09%～96.02%,30.54%～89.20%)均高于相应质量浓度下水飞蓟宾原料的A值与清除率(0.411～0.760,22.89%～63.21%),表明2种处方体系均能提高水飞蓟宾的抗氧化能力。细胞毒性实验结果显示,在5、10μmol/L药物浓度下,水飞蓟宾原料组、水飞蓟宾S-SNEDDS组及其相应的空白S-SNEDDS组细胞生存率均90%,说明SLB-S-SNEDDS及其所用辅料对人克隆结肠腺癌细胞(Caco-2)毒性较小、安全性较好。结论制备的含功能性油SLB-S-SNEDDS在提高水飞蓟宾累积溶出率的同时,增强了其抗氧化能力,为将超饱和自纳米乳(S-SNEDDS)用于改善难溶性药物水溶性及其生物活性提供有益参考。     

Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.