Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer, Actelion Pharmaceuticals), an oral ETA/ETB receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

Bosentan

Bosentan (Tracleer), an orally administered dual endothelin (ET)(A) and ET(B) receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH).The efficacy of oral bosentan 125 mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.     

Perspectives on the use of data mining in pharmaco-vigilance.

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmaco-vigilance. In 2003, a group of statisticians, pharmaco-epidemiologists and pharmaco-vigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmaco-vigilance methods. Perspectives from both the FDA and the industry are provided.Data mining is a potentially useful adjunct to traditional pharmaco-vigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.     

Postmarketing survey on the clinical use of cefotiam

We performed a survey of clinical experience of cefotiam (CTM: Pansporin) as postmarketing surveillance (PMS), and evaluated the efficacy and safety of CTM in 10,499 cases of data which were collected during the first 2 years after approval. The following results were obtained. The efficacy rate of CTM in the treatment of various infections was 83.2%, which was equal or superior to the clinical results obtained before approval. A total of 472 adverse drug reactions was reported by 10,499 patients (4.50%). The commonest adverse drug reactions was liver function abnormality (230 cases), followed by dermal symptoms (103 cases), gastrointestinal symptoms (53 cases) and renal function abnormality (20 cases) in the order mentioned. All of these adverse drug reactions had already been known for cephem antibiotics, and no remarkable adverse drug reactions specific to CTM was found. The above PMS results indicate the same efficacy of CTM that obtained from premarketing studies. As regards safety, there was no remarkable unexpected adverse drug reaction and their profile was also the same as that found in premarketing studies. Thus, the utility of CTM was confirmed.     

磷酸氯喹治疗新型冠状病毒肺炎的药品不良反应/事件分析及风险管理建议

目的通过分析磷酸氯喹治疗新型冠状病毒肺炎(简称新冠肺炎)出现的药品不良反应/事件(ADR/AE)报告,为新冠肺炎临床用药安全提供参考。方法对深圳市2020年1月1日至3月6日期间上报的磷酸氯喹治疗新冠肺炎不良反应病例报告进行统计分析。结果根据追踪获知共有32位患者使用了磷酸氯喹治疗新冠肺炎,对收到的21例怀疑药品为磷酸氯喹的新冠肺炎ADR/AE进行了统计分析:其ADR/AE发生率为65.62%,男女比例1∶1.1;30~39岁及50~59岁年龄段发生的ADR/AE比例较高,分别为38.10%、23.81%;发生率较高依次为:消化系统、循环系统(含心脏)、神经肌肉系统、眼睛损害;心律失常是磷酸氯喹可致命的ADR/AE类型;肝损周期较短,平均3.5天;联合有潜在肝损伤的中药汤剂时可能增加肝损伤风险;ADR/AE最短当天发生,最长用药后9天发生,多发生在用药后2~7天。结论临床在使用磷酸氯喹治疗新冠肺炎的过程中,应避免联用禁忌的药物,尽量减少不必要的联合用药,密切观察ADR/AE,一旦发现应积极处理,从而保障患者的用药安全。     

我院聚集性药品不良反应/事件病例分析

通过对我院2011年度聚集性药品不良反应/事件(ADR/ADE)病例进行统计分析,并对产生聚集性不良反应/事件的原因进行分析,提出相应的方法,尽可能减少药品不良反应/事件带来的危害,并对相关科室和用量较大药物进行重点监测,保障患者用药安全.     

Correlation of antituberculosis drug-related liver injury and liver function monitoring: A 12-year experience of the Taiwan Drug Relief Foundation

Antituberculosis drug-related liver injury (ATLI) is the most prevalent hepatotoxicity in many countries. Whether monitoring liver tests is beneficial to prevent this potentially grave adverse drug reaction (ADR) is open to debate. The Taiwan Drug Relief Foundation (TDRF) was established by the Taiwan Food and Drug Administration to collect severe cases of ADR and carry out drug injury relief tasks. Our intention was to explore the role of monitoring liver tests in the susceptibility and severity of ATLI from the database of this foundation. All cases of suspected ATLI collected by the TDRF from 1999 to 2012 were reviewed. The basic demographic data, clinical course, and laboratory data of these patients were analyzed. A total of 57 cases with severe ATLI were verified and enrolled into this study. There was a high mortality (71.9%) in this cohort. Twenty-four cases (42.1%) were chronic viral hepatitis B carriers, who had higher baseline serum aminotransferase level than noncarriers. The patients without monitoring liver tests had higher peak serum alanine aminotransferase, bilirubin levels, and mortality (adjusted odds ratio, 8.87; 95% confidence interval = 1.32–59.41; p = 0.024) than those with monitoring liver tests. In conclusion, patients with severe ATLI whose records were collected by the TDRF have a high mortality. Patients without follow-up monitoring liver tests had more severe liver injuries and higher mortality than those with monitoring live tests. To alleviate this potentially grave ADR, checking of liver biochemical tests prior to antituberculosis treatment and periodic monitoring of these tests thereafter are highly suggested.     

关于药品不良反应与药害事件的思考

目的:正确区分药品不良反应(ADR)及与药品相关的药害事件。方法:从"齐二药"、"欣弗"事件入手,对ADR、药品安全性、药品质量事故、错误用药事故、输液反应的内涵进行概念及性质辨析,介绍判定ADR及有效减少ADR的方法。结果与结论:药源性危害不可避免,临床实践中应准确判断并积极预防,以减少药物对患者的损害;政府相关部门应尽快建立ADR伤害救济制度。     

Adverse drug reactions in liver cirrhosis

Summary Impaired liver function may increase susceptibility to drug toxicity. In a prospective drug surveillance study of 1280 patients the frequency of adverse drug reactions (ADR) was higher in 333 patients with clinical and/or histopathological evidence of liver cirrhosis than in 188 with other liver diseases (p<0.01) and than in 759 without liver disease (p<0.0001). The 128 cirrhotics had 339 events considered definitely or probably related to drug therapy by consensus of the monitoring team and the attending physicians. ADR were 93.8% dose-related, 11.2% were severe but only one was fatal. ADR were most commonly associated with diuretics (32.6% of patients administered the drugs), potassium salts (6.5%), antimicrobials (3.9%) and sedatives (3.5%). Most common manifestations were metabolic (62.6%), gastrointestinal (13.2%) and neurologic (11.9%). The frequency of ADR was higher in females (p<0.05), patients receiving more drugs (p<0.001), those with longer hospital stay (p<0.001) and those with ascites (p<0.0001), portal hypertension (p<0.0001), prior hepatic encephalopathy (p<0.02) or prolonged prothrombin time (p<0.0001). Adverse reactions were more common for drugs biotransformed greater than 50% by the liver (p<0.005). These findings show that ADR are more frequent in severe hepatic dysfunction.     

基于美国FAERS数据库的卡格列净不良反应信号挖掘

目的：利用大样本数据对卡格列净的不良反应（adverse drug reactions,ADR）信号进行挖掘分析,为临床合理安全用药提供参考。方法：收集美国FDA不良事件报告系统中2015年第一季度至2021年第二季度共26季度的卡格列净的ADR报告,采用报告比值比（reporting odds ratio,ROR）法和比例报告（proportional reporting ratio,PRR）法对其进行数据挖掘。利用国际医学用语词典（Medical Dictionary for Drug Regulatory Activities,MedDRA）分析药物不良事件安全信号。结果：共提取到卡格列净相关ADR报告14 039份,除去信息未知的情况,其中女性5 439例（38.7%）,男性5 824例（41.5%）;年龄主要分布在45~64岁（3 779例,占26.92%）。挖掘到该药相关ADR信号主要表现为截肢、酮症酸中毒、泌尿生殖系统感染等事件,且截肢好发于男性及高龄患者;泌尿生殖系统感染好发于女性。将信号进行规整比对,还挖掘出骨髓炎、特发性阴囊坏死、胰腺炎、排尿障碍等药品说明书中尚未提及的ADR。结论：利用FAERS数据库可较全面深入地分析卡格列净的ADR,为临床安全合理用药提供参考。     

依达拉奉不良反应的文献分析

目的了解依达拉奉的安全性,为临床更安全有效地使用该药提供有价值的信息。方法通过《中国期刊网全文数据库》(CHKD),检索2007-2008年发表的有关依达拉奉的临床研究文献。筛选用药中进行不良反应监测的文献,进行汇总分析。结果共获得符合条件的病例报道77篇,涉及病例3096例。发生ADR的病例185例次,占全部病例的5.96%。依达拉奉的ADR以转氨酶升高以及皮肤损害、肾功能损害发生率较高,分别为42.70%、19.46%和12.43%。结论依达拉奉主要的不良反应是转氨酶升高、皮疹和肾功能损害,临床安全性较好。     

2014~2018年湖北省对乙酰氨基酚不良反应报告回顾性分析

目的:探究对乙酰氨基酚(APAP)所致不良反应(ADR)的特点,为临床安全用药提供参考依据。方法:采用回顾性研究方法,对2014~2018年湖北省药品(医疗器械)不良反应监测中心收集的179份APAP所致ADR报告的上报单位、ADR类型与关联性评价、患者性别年龄、ADR发生时间、ADR累及系统-器官及所涉及的临床症状和转归、药物剂型与联合用药情况等进行统计分析。结果:179份ADR主要来自药品经营企业和医疗机构上报,关联性评价为"可能"的报告比例最高。一般的ADR有156例(87.15%),严重的ADR有13例(7.26%),新的ADR有10例(5.59%),新的严重的ADR有1例(0.56%)。患者男女比例为1.43∶1,年龄主要分布在0~10岁(35.20%);ADR多在用药1~2 d发生(87.15%),累及多个系统-器官,主要为皮肤及附件损害、胃肠系统损害、中枢及外周神经系统损害、全身性系统损害等;导致ADR的APAP剂型以片剂(62.01%)和栓剂(22.35%)为主。174例ADR患者经停药或积极对症处理后治愈或好转。结论:APAP所致ADR主要以皮肤及附件损害和胃肠系统损害为主,长期或者过量使用可产生严重皮肤反应和肝肾功能损害,临床应密切监测患者用药情况,给予相应处理措施,保证患者用药安全。     

Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists

Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.     

Post-marketing drug safety measures for the attainment of safer and more effective use of drug

In contrast with the 20th century's dramatic improvements in the direct and/or hazardous toxicity of drugs, indirect toxicity and/or long-term safety concerns such as relation of cancer risk and TNF-alpha receptor blockers have caused significant complexity in post-marketing surveillance (PMS) scenery. The post-marketing phase of drugs and their safety measures now appear to be much more complicated and heavier than decades ago. The spontaneous adverse drug reaction (ADR) reporting system which has been one of the main pillars of PMS measures for almost 50 years may have to be reviewed in terms of its effectiveness, and may need augmentation from medical data bases. Only a pharmaco-epidemiological analysis and integration of the output with a conventional spontaneous reporting approach offers a chance to satisfy the current complex safety issues. Today's tendency toward practical saturation at medical/pharmaceutical frontiers, by regulatory authorities and safety divisions of pharmaceutical companies with ever-increasing day-to-day safety information can also be pointed out. Such phenomena may actually reduce the productivity of safety measures and also jeopardize the maintenance of an acceptable risk/benefit drug ratio. To alleviate these potential negative implications, establishment of a consortium to act as a sentinel that would gather up-to-date and essential safety information, including epidemiological data, from all sources and provide it plus recommendations to all stakeholders can be suggested. Through such activities, we could expect significant improvement of drug safety measures in post-marketing phase which would effectively cover not only new drugs but also generic and bio-simulated drugs.     

我院2012年144例药品不良反应报告分析

目的了解本院药品不良反应（ADR）发生的特点及规律,为临床用药提供参考。方法选择本院2012年收集的144例ADR报告,分别从患者年龄、性别、给药剂型、ADR涉及药品种类、涉及器官或系统以及具体临床表现等方面进行分析。结果本院144例ADR中,抗菌药物引起的ADR最为多见,占43.1%,其次为心血管系统用药,占20.8%;给药剂型以注射剂最为常见,占84.0%;临床表现以皮肤损伤为主,占47.9%。结论应重视ADR报告,加强合理用药,减少不良反应事件发生,保证患者用药安全。     

药品不良反应信息监管的思考

目的完善药品不良反应信息监管制度。方法以药品不良反应案例为切入点,分析药品不良反应信息监管中存在的问题并提出建议。结果与结论完善多级药品不良反应监测体系、完善两级信息发布制度、完善突发药品不良事件的监管机制,为政府监管和公众安全用药提供有效的信息。     

药物警戒视角下黄体酮注射液致注射部位不良反应/事件原因分析及对策建议

目的 探讨药物警戒视角下黄体酮注射液致用药部位出现药品不良反应/事件（ADR/ADE）的原因，提出安全用药和风险管理建议。方法 对国家药品不良反应监测系统（https://www.adrs.org.cn）中涉及河南省行政区域的不良反应报告进行检索，检索时间2010年1月—2022年12月（按药品不良反应发生时间计），怀疑药品为黄体酮注射液，报告单位类别为医疗机构，筛选黄体酮注射液相关的ADR/ADE。在中国学术期刊全文数据库（CNKI）、维普生物医学数据库（VIP）和万方数据库（Wanfang Data）中，以“黄体酮注射液”“致”“不良反应”“不良事件”“风险”等为关键词进行组合检索，检索周期2000年1月—2022年12月，剔除非安全性文献和重复文献，检索黄体酮注射液ADR/ADE。基于黄体酮注射液ADR/ADE发生特点，分析黄体酮注射液致ADR/ADE的风险来源，进而探讨控制措施并提出建议。结果 通过国家药品不良反应监测系统检索河南省报告药品不良反应结果发现黄体酮注射液 ADR/ADE 个例报告 263例，涉及 ADR/ADE 表现 454例次，ADR/ADE例次数较多的损害表现为注射部位红肿、硬结、疼痛、脂膜炎、红斑、皮疹等。文献检索得到黄体酮注射液相关安全性文献 23篇，共提取出个例 ADR/ADE报告 125例，涉及 ADR/ADE表现 147例次，ADR/ADE例次数较多的依次为注射部位脂膜炎、硬结、疼痛、皮疹等。黄体酮注射液致用药部位损害的原因可能与不合理用药因素、辅料因素、说明书缺陷因素等有关。结论 建议提升黄体酮注射液质量标准、提高合理用药水平、修订完善药品说明书，最终保护患者用药安全。     

Sitaxsentan in the management of pulmonary arterial hypertension.

PURPOSE: The pharmacology, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosing and administration of the endothelin receptor antagonist, sitaxsentan, and its role in the treatment of pulmonary arterial hypertension (PAH) are reviewed. SUMMARY: PAH is a serious and potentially devastating chronic disorder of the pulmonary circulation. Bosentan is the first and only approved endothelin receptor antagonist for the treatment of PAH. Endothelin-1, a potent endogenous vasoconstrictor and smooth-muscle mitogen, has been shown to be overexpressed in the plasma and lung tissue of patients with PAH; the reduction or blockade of entothelin-1 may aid in disease symptomatology and progression. Activation of ET(A) leads to vasoconstriction and vascular smooth-muscle-cell proliferation. Sitaxsentan is an orally active, organic nonpeptide that binds competitively to the ET(A) receptor. Sitaxsentan, unlike bosentan, has a high affinity for the ET(A) receptor. In one trial, sitaxsentan was compared with placebo, and the results suggested that sitaxsentan was more effective than placebo. A 12-week, open-label trial demonstrated the safety and efficacy of sitaxsentan in 20 patients. The Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) trial randomized patients to receive placebo, sitaxsentan 100 mg orally once daily, or sitaxsentan 300 mg orally once daily. Significant improvements in exercise capacity and cardiopulmonary hemodynamics were demonstrated. The results of STRIDE-2, the second randomized sitaxsentan trial, demonstrated the efficacy and safety of 100 mg sitaxsentan and the unacceptable safety profile of 300 mg sitaxsentan. CONCLUSION: Sitaxsentan is an orally administered endothelin receptor blocker that offers the effective and safe treatment of patients with mild to moderate PAH.     

欧美国家与我国利用社交媒体收集药物不良反应的应用现状对比及启示

目的:比较欧美国家与我国利用社交媒体收集药物不良反应(ADR)的应用现状,为我国相应工作的完善提供借鉴。方法:通过检索中国知网、Web of Science、Elsevier ScienceDirect、SpringerLink等数据库的相关文献,查阅国际人用药品注册技术协调会(ICH)官网的相关资料,介绍欧美国家(组织)如美国、欧盟、英国、法国等利用社交媒体(或相关移动应用程序)收集ADR的现状,并与我国相应工作进行比较,分析利用社交媒体收集ADR的优点以及可能存在的问题,同时对我国利用社交媒体收集ADR的工作提出建议。结果与结论:2013年以来,欧美许多国家陆续开始利用社交媒体(如Twitter、Facebook等)收集ADR,例如美国药物研究与制造商协会(PhRMA)发布的关于社交媒体上涉及药物安全问题的草案,欧盟组织的创新药物计划(IMI)网络识别药物不良反应事件(WEB-RADR)项目等都包含了利用社交媒体收集ADR的内容。通过这一途径可以更方便患者报告ADR,有助于药物警戒部门及时收集ADR信息,并可作为传统药物安全信息报告的重要补充;另一方面,其也存在患者自发报告的健康词汇与医学专业词汇不匹配,平衡公众健康维护和患者隐私权保护的关系面临挑战,各种偏差影响了利用社交媒体收集ADR的报告率及质量等不足。我国在利用社交媒体(如微信、微博、QQ等社交媒体或工具以及应用程序、小程序等)收集ADR信息时,应确保报告ADR应用程序的易用性与安全性,完善应用程序的设计以符合ICH个例安全报告电子传输执行指导原则E2B(R3)数据要素和信息规范;同时,还要充分发挥监管部门的监督作用并考虑非监管因素,并采取隐私保护措施以使其符合伦理道德。     

某三甲医院近5年药品不良反应分析

目的 促进临床安全用药,并加强医疗机构药品不良反应(ADR)的报告工作.方法 检索国家药品不良反应监测系统中某三甲医院2015年至2019年上报并完成评价的ADR报告,回顾性分析ADR的类型、患者年龄、性别、给药途径、药品类别、累及系统/器官、转归、报告人职业等.结果 共检索到ADR报告1127例.ADR发生最多的类型...