102 期临床药讯

临床试验观察表CRF国家科技支撑计划课题哮喘（慢性持续期）临床试验观察表（Case Report Form）负责单位：江西中医学院附属医院二00八年四月《腧穴热敏化艾灸治疗哮喘（慢性持续期）的优化方案研究》多中心随机对照临床试验受试者编号：受试者姓名：汉拼缩写：联系：门诊/住院号：家庭住址：邮政编码：观察医师：观察医师职称：受试者进入研究时间：受试者结束研究时间：注：请用钢笔或签字笔填写目录病例观察表填写说明 (1)试验流程图 (2)初诊 (3)病例筛选 (4)一般资料 (6)病史特征 (7)初诊哮喘（慢性持续期）临床试验病例报告表① (6)初诊哮喘（慢性持续期）临床试验病例报告表② (7)初诊哮喘（慢性持续期）临床试验病例报告表③ (8)治疗后半个月 (10)治疗后半个月哮喘（慢性持续期）临床试验病例报告表① (29)治疗后半个月哮喘（慢性持续期）临床试验病例报告表② (29)治疗后1个月 (13)治疗后（1个月）哮喘（慢性持续期）临床试验病例报告表① (29)治疗后（1个月）哮喘（慢性持续期）治疗后2个月 (17)治疗后（2个月）哮喘（慢性持续期）临床试验病例报告表① (29)治疗后（2个月）哮喘（慢性持续期）临床试验病例报告表② (19)治疗后3个月 (20)治疗后（3个月）哮喘（慢性持续期）临床试验病例报告表① (21)治疗后（3个月）哮喘（慢性持续期）临床试验病例报告表② (22)治疗后（3个月）哮喘（慢性持续期）临床试验病例报告表③ (23)随访期 (25)治疗结束后（3个月）哮喘（慢性持续期）临床试验病例报告表① (26)治疗结束后（3个月）哮喘（慢性持续期）临床试验病例报告表② (27)随访期 (28)治疗结束后（6个月）哮喘（慢性持续期）临床试验病例报告表① (29)治疗结束后（6个月）哮喘（慢性持续治疗结束后（6个月）哮喘（慢性持续期）临床试验病例报告表③ (31)不良事件情况 (33)试验方案规定外用药记录 (34)提前中止试验/脱落登记表 (35)试验完成情况总结 (36)哮喘慢性持续期疗效判定 (37)安全性评价 (37)病例报告表（CRF）审核声明 (38)相关单据 (39)病例观察表填写说明填写CRF表前请仔细阅读以下说明1.筛选合格者根据中央随机分配系统的分配结果，填写将受试者顺序号和入组情况，再填写正式病例观察表。

◇慢性气道疾病药物治疗新进展◇摘要全球超过3亿人饱受哮喘困扰，且发病率逐年增加，作为最常见的慢性疾病之一，哮喘激发机制复杂，异质性强，是一类免疫介导的炎症疾病。

随着基于生理、病理等机制深入研究，陆续推出的治疗性小分子和激素药物已实现对大多数患者的控制和治疗，但仍有5%～10%的患者为难控制、难治疗性哮喘，即重度哮喘。

近十年来，得益于生物医药的迅猛发展，蛋白、抗体类药物凭借高有效性、高特异性、高安全性成为关键的重度哮喘治疗药物，然而由于生物制剂通常经注射给药，不可无创、快速地递送药物直接入肺迅速吸收起效，故而临床中亟需起效快、便捷、经济、安全的吸入式生物制剂。

本综述通过对哮喘发病机制的阐释，概括现行的小分子、激素类和生物类治疗药物，并总结吸入式哮喘生物制剂的研发历程，对其未来前景进行分析，旨在加深对大分子吸入药物研究方向的认知，更新该领域前沿动态，以期为更多吸入式生物制剂的开发提供参考。

关键词哮喘；给药途径；吸入给药；生物制剂中图分类号：R256.12文献标志码：A文章编号：1009-2501(2024)04-0406-08doi ：10.12092/j.issn.1009-2501.2024.04.007支气管哮喘简称哮喘，以呼吸急促、咳嗽和胸闷等多种症状为特征，与慢性气道炎症，广泛、可逆性呼气性气流阻塞和气道高反应性等症状有关［1］。

全球超过3亿人饱受哮喘困扰，且发病率逐年增加。

根据全球哮喘指南全球哮喘防治创议（global initiative for asthma ，GINA ）建议，需对患者采用阶梯式治疗方案，尤其推荐个性化治疗方案。

随着生物制剂的发展，抗体类生物制剂已成功应用至哮喘治疗，为中重度哮喘患者带来了更有效、更安全的药物选择，但其注射的给药方式，缓慢的起效速度，频繁的入院用药、高昂的用药成本在很大程度上限制了药物的推广，故而吸入式抗体药物的临床呼声日益高涨。

本综述对哮喘机制、现有治疗药物及吸入抗体药物的开发历程进行了调查研究，以期加深对哮喘发病机制及治疗药物的全面认识，同时对吸入式抗体药物的开发必要性、开发难度、研发现状进行汇总更新。

新型抗肿瘤药物临床应用指导原则（2021年版）目录第一部分新型抗肿瘤药物临床应用基本原则一、病理组织学确诊后方可使用 (01)二、靶点检测后方可使用 (02)三、严格遵循适应证用药 (06)四、体现患者治疗价值 (06)五、特殊情况下的药物合理使用……………………………………………………………六、重视药物相关性不良反应 (06)07第二部分各系统肿瘤的药物临床应用指导原则呼吸系统肿瘤用药一、吉非替尼 (08)二、厄洛替尼 (09)三、埃克替尼 (10)四、阿法替尼…………………………………………………………………………………五、达可替尼…………………………………………………………………………………六、奥希替尼…………………………………………………………………………………11 13 15七、阿美替尼…………………………………………………………………………………八、伏美替尼 (16)17九、克唑替尼…………………………………………………………………………………十、阿来替尼.............................................................................................十一、塞瑞替尼..........................................................................................十二、恩沙替尼 (17)1920 22十三、贝伐珠单抗 (23)十四、重组人血管内皮抑制素 (24)十五、安罗替尼..........................................................................................十六、依维莫司..........................................................................................十七、普拉替尼..........................................................................................十八、赛沃替尼 (25)262829十九、纳武利尤单抗…………………………………………………………………………二十、帕博利珠单抗…………………………………………………………………………二十一、度伐利尤单抗………………………………………………………………………二十二、阿替利珠单抗………………………………………………………………………二十三、卡瑞利珠单抗………………………………………………………………………二十四、替雷利珠单抗………………………………………………………………………二十五、信迪利单抗…………………………………………………………………………二十六、伊匹木单抗…………………………………………………………………………30 343738 41444546消化系统肿瘤用药一、索拉非尼…………………………………………………………………………………二、瑞戈非尼 (48)49三、仑伐替尼 (50)五、阿替利珠单抗……………………………………………………………………………六、信迪利单抗………………………………………………………………………………七、卡瑞利珠单抗……………………………………………………………………………八、替雷利珠单抗……………………………………………………………………………51 53 55 57九、帕博利珠单抗……………………………………………………………………………十、曲妥珠单抗………………………………………………………………………………59 61十一、阿帕替尼..........................................................................................十二、纳武利尤单抗 (62)63十三、维迪西妥单抗....................................................................................十四、伊马替尼 (66)67十五、舒尼替尼..........................................................................................十六、阿伐替尼..........................................................................................十七、瑞派替尼 (69)7071十八、依维莫司………………………………………………………………………………十九、索凡替尼………………………………………………………………………………72 74二十、贝伐珠单抗 (75)二十一、西妥昔单抗…………………………………………………………………………二十二、呋喹替尼……………………………………………………………………………77 79血液肿瘤用药一、伊马替尼 (80)二、达沙替尼 (82)三、尼洛替尼…………………………………………………………………………………四、吉瑞替尼 (83)84五、伊布替尼…………………………………………………………………………………六、贝林妥欧单抗……………………………………………………………………………七、维奈克拉…………………………………………………………………………………86 88 91八、利妥昔单抗………………………………………………………………………………九、维布妥昔单抗 (94)95十、西达本胺 (97)十一、硼替佐米..........................................................................................十二、信迪利单抗.......................................................................................十三、卡瑞利珠单抗....................................................................................十四、替雷利珠单抗....................................................................................十五、泽布替尼 (98)99 101 104 105十六、来那度胺………………………………………………………………………………十七、泊马度胺………………………………………………………………………………107 108十八、沙利度胺………………………………………………………………………………十九、伊沙佐米………………………………………………………………………………二十、达雷妥尤单抗…………………………………………………………………………110 111 114二十一、芦可替尼 (117)泌尿系统肿瘤用药一、依维莫司 (118)三、舒尼替尼 (120)四、阿昔替尼 (121)五、培唑帕尼…………………………………………………………………………………六、仑伐替尼…………………………………………………………………………………七、纳武利尤单抗……………………………………………………………………………八、帕博利珠单抗……………………………………………………………………………九、替雷利珠单抗……………………………………………………………………………十、特瑞普利单抗……………………………………………………………………………十一、奥拉帕利………………………………………………………………………………122 123 124 126 128 129 131乳腺癌用药一、曲妥珠单抗………………………………………………………………………………二、恩美曲妥珠单抗…………………………………………………………………………三、帕妥珠单抗………………………………………………………………………………四、伊尼妥单抗………………………………………………………………………………132 134 137 140五、拉帕替尼…………………………………………………………………………………六、吡咯替尼…………………………………………………………………………………七、奈拉替尼…………………………………………………………………………………八、哌柏西利…………………………………………………………………………………九、阿贝西利…………………………………………………………………………………十、西达本胺…………………………………………………………………………………141 143 145 146 148 150皮肤肿瘤用药一、伊马替尼 (151)二、维莫非尼…………………………………………………………………………………三、达拉非尼…………………………………………………………………………………四、曲美替尼…………………………………………………………………………………五、帕博利珠单抗……………………………………………………………………………六、特瑞普利单抗……………………………………………………………………………153 154 155 157 159骨与软组织肿瘤用药一、依维莫司 (161)二、地舒单抗 (163)三、安罗替尼 (164)头颈部肿瘤用药一、尼妥珠单抗………………………………………………………………………………二、特瑞普利单抗……………………………………………………………………………三、卡瑞利珠单抗……………………………………………………………………………四、索拉非尼…………………………………………………………………………………五、仑伐替尼…………………………………………………………………………………六、安罗替尼…………………………………………………………………………………七、纳武利尤单抗……………………………………………………………………………八、西妥昔单抗………………………………………………………………………………九、帕博利珠单抗……………………………………………………………………………171 172 173 175 176 177 179 181 183生殖系统肿瘤用药一、奥拉帕利…………………………………………………………………………………二、尼拉帕利…………………………………………………………………………………三、氟唑帕利…………………………………………………………………………………四、帕米帕利…………………………………………………………………………………附表附表1 免疫相关性不良反应和治疗调整方案……………………………………………附表2 反应性毛细血管增生症分级标准和治疗建议……………………………………185 187 190 192195 197第一部分新型抗肿瘤药物临床应用基本原则为规范新型抗肿瘤药物临床应用，提高肿瘤治疗的合理用药水平，保障医疗质量和医疗安全，维护肿瘤患者健康权益，特制定新型抗肿瘤药物临床应用指导原则。

药师工作总结11篇药师工作总结 1作为临床药学室的一员，除了每日深入临床了解用药情况，药剂科的工作也是我们日常工作的一部分。

1、进修回到科室后，对学习期间的相关内容以及学到的最新知识，进行总结归纳后，开展科室授课讲演。

2、每月按时点评门诊处方、急诊处方、医嘱单、查阅归档病历、Ⅰ类切口手术病历，检查用药的合理性，并及时做好相关总结工作，将所得数据总结归纳后制成表格形式，上报给医院领导。

3、开始接手本院药讯编辑工作。

每季度出版一期临床药讯，将本院用药数据以及临床上常用知识进行总结归纳，供大家参考学习。

4、每月按时计算抗菌药物临床合理应用考核评分表与药品比例评分表，为促进我院合理用药提供准确数据。

5、编写《我院非离子碘造影剂试敏相关问题的讨论》。

我院存在造影剂试敏问题的争议，主要原因一方面为既往制定的试敏方法原则与各大医院现有方法存在很大差异，另一方面原因为避免医患纠纷而进行自我保护。

本人查阅大量文献，对非离子碘造影剂市民问题进行深入讨论，从造影剂发展史、我国药典与其他国家药典编写内容，生产厂家、各大医院现状等几方面论证，结合我院实际情况给出建议。

6、参与颅内动脉瘤临床路径费用表单编写，对我院颅内动脉瘤患者的合理用药以及用药费用问题进行相关点评。

药师工作总结 2流年似水，光阴如箭，辉煌灿烂的____年弹指间就将过去，转眼又到了年终总结的时候。

回首我们营业部一年来走过的历程，有辛酸也有欢笑，有汗水更有收获……一年来，我们在公司各级领导的正确领导和大力支持下，高举中国特色社会主义伟大旗帜，以邓小平理论和“三个代表”重要思想为指导，全面学习贯彻党的xx大精神，结合工作实际，解放思想、更新观念，面对各种困难和不利因素，凭借优异的服务和辛勤的努力。

07年，我们在通信市场竞争异常激烈的不利形势下，紧紧围绕市公司“一通三畅”的战略要求和经营发展目标，积极主动开拓市场，挖掘市场潜力。

从年初开始就认真贯彻公司工作会议精神，本着立足于早、抢占市场的经营思路……在一年里，我在局领导、部门领导及同事们的关心与帮助下圆满的完成了各项工作，在思想觉悟方面有了更进一步的提高，本年度的工作总结主要有以下几项：1、思想政治表现、品德素质修养及职业道德。

Angiotensin II receptor antagonist telmisartan in isolated systolic hypertension(ARAMIS)study:efficacy and safety of telmisartan20,40or80mg versus hydrochlorothiazide12.5mg or placeboAthanasios J.Manolis a,John L.Reid b,Dick de Zeeuw c,Michael B.Murphy d, Elke Seewaldt-Becker e and Ju¨rgen Ko¨ster f on behalf of the ARAMIS Study GroupObjective To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide(HCTZ)12.5mg,and are well tolerated,in lowering systolic blood pressure(SBP)in patients with isolated systolic hypertension(ISH).Patients and methods A2–4-week single-blind placebo run-in was followed by randomization of1039patients (age36–84years)with ISH[seated SBP150–179mmHg and seated diastolic blood pressure(DBP)<90mmHg]to once-daily double-blind treatment with telmisartan20,40 or80mg,HCTZ12.5mg,or placebo.The change in seated trough SBP after6weeks compared with baseline was the primary end point.Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP.Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation.Results Baseline demographics in telmisartan20mg(n206),40mg(n210),80mg(n207),HCTZ12.5mg (n205)and placebo(n211)treatment groups were comparable:(mean6SD)age,63.0610.9years;SBP, 162.968.1mmHg;and DBP83.465.0mmHg.No previous antihypertensive therapy had been received by 66%of the patients.Mean reductions in seated trough SBP (adjusted for baseline and country)were:telmisartan20mg,15.6mmHg(n204);40mg,17.9mmHg(n209); and80mg,16.9mmHg(n205),compared with placebo, 11.4mmHg(n208),and HCTZ12.5mg,15.7mmHg(n204).The target fall in seated trough SBP(<140mmHg or reduction by>20mmHg)was achieved in46.6%(telmisartan20mg),51.7%(telmisartan40mg), 53.9%(telmisartan80mg),27.4%(placebo)and42.7% (HCTZ12.5mg);the response rate was significantly higher for telmisartan80mg than for HCTZ12.5mg(P0.03).All-causality adverse events occurred in19.9,17.6and20.3% receiving telmisartan20,40and80mg,respectively;20.9% receiving placebo and22.0%receiving HCTZ12.5mg.No drug-related serious adverse events occurred.Conclusions All doses of telmisartan(20–80mg)were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ12.5mg.Tolerability of telmisartan was similar to that of placebo.J Hypertens22:1033–1037&2004Lippincott Williams&Wilkins.Journal of Hypertension2004,22:1033–1037Keywords:telmisartan,angiotensin receptor blocker,isolated systolic hypertension,hydrochlorothiazide,efficacya Tzanio General Hospital,Piraeus,Greece,b Department of Medicine and Therapeutics,University of Glasgow,Glasgow,UK,c Department of Clinical Pharmacology,University of Groningen,Groningen,The Netherlands,d Department of Pharmacology and Therapeutics,University College,Cork, Ireland,e Clinical Research Department,Boehringer Ingelheim Pharma KG, Biberach,Germany andf Medical Data Services/Biostatistics,Boehringer Ingelheim Pharma KG,Ingelheim,Germany.Sponsorship:This study was funded by Boehringer Ingelheim. Correspondence and requests for reprints to Professor A.G.Manolis,Tzanio General Hospital,Piraeus,Greece.Tel:+303014592184;e-mail:ajmanol@otenet.grReceived25October2002Revised13January2004Accepted13January2004IntroductionUntil recently,isolated systolic hypertension(ISH)was considered a physiological feature of ageing and of little clinical significance.Now,it is regarded as being a more important determinant of cardiovascular risk in the elderly than elevated diastolic blood pressure (DBP)[1].Also,ISH plays an important role in stroke [2].Defining ISH as a systolic blood pressure (SBP).140mmHg and a DBP,90mmHg,15%of people.60years have ISH[3]and,among subjects between50and59years of age,ISH accounts for87% of cases of uncontrolled hypertension[4].Presented as a poster at the11th European Meeting on Hypertension,Milan,Italy,15–18June2001.Original article1033 0263-6352&2004Lippincott Williams&Wilkins DOI:10.1097/01.hjh.0000098301.94994.d5The Systolic Hypertension in the Elderly Program showed that a low-dose diuretic,with or without aâ-blocker,reduced the incidence of stroke and other cardiovascular events[5]and the Systolic Hypertension in Europe trial[6]revealed the benefits of combining antihypertensive agents from different classes in redu-cing stroke in patients>60years with ISH.Thiazide diuretics,such as hydrochlorothiazide(HCTZ),have been used asfirst-line treatment of ISH in the elderly [7].However,some physicians are hesitant to prescribe them because of the possible negative impact of side-effects[7].Electrolyte imbalance,glucose intolerance, cardiac arrhythmias and gout may also restrict their use in the elderly[8].The angiotensin-converting enzyme (ACE)inhibitors are an alternative treatment because of their ability to lower morbidity and mortality[9]. Angiotensin receptor blockers(ARBs),which like ACE inhibitors act on the renin–angiotensin system,should also prove effective.Two small-scale,double-blind studies have evaluated ARBs in patients with ISH: losartan was compared with atenolol,and valsartan with placebo[10,11].Another larger-scale,open-label,un-controlled study assessed the efficacy of candesartan cilexetil[12].Telmisartan is a highly lipophilic ARB that binds insurmountably to the AT1receptor[13]and has a terminal elimination half-life of about24h[14].Clinical studies using ambulatory blood pressure show that telmisartan provides blood pressure control at the end of the once-daily dosing interval[15].Also,telmisartan significantly reduces pulse velocity by the carotid artery route[16].This study was performed to identify telmisartan doses that are more effective than placebo and not inferior to HCTZ in lowering SBP in patients with ISH,and that are well tolerated.Patients and methodsStudy designThe multicentre,double-blind,parallel-group,rando-mized study received prior approval by local institu-tional review boards.During the initial single-blind run-in,patients received placebo for2weeks if not in receipt of antihypertensive therapy or for4weeks if treated at the time of enrolment(visit1).At visit2,the patients were randomized to6weeks’double-blind treatment with telmisartan20,40or80mg,HCTZ 12.5mg,or placebo.The patients were monitored at visits3(2weeks’double-blind treatment)and4(end of treatment).Patients were instructed not to take their trial medication on the days of clinic visits,which were always in the morning at approximately the same time and within23–26h of the most recent intake of study medication.This ensured measurement of trough blood pressures.Seated cuff SBP and DBP,heart rate,use of concomitant medication and spontaneously reported adverse events were pliance with medi-cation(determined by counting returned tablets)was evaluated at visits2and4.A physical examination and laboratory tests(haematology,clinical chemistry,urina-lysis)were performed at visits1and4,and a12-lead ECG was obtained at visits1,2and4.PatientsPatients were between35and84years old,with a mean seated cuff SBP/DBP of150–179/,90mmHg at randomization.Patients receiving antihypertensive therapy immediately before the study were only eligi-ble if withdrawal of the medication and possible admin-istration of placebo for10weeks would not jeopardize their health.Patients with secondary hypertension, hepatic and/or renal dysfunction,clinically relevant electrolyte imbalance,symptomatic cardiovascular or cerebrovascular disease,or inadequately controlled or recently stabilized diabetes mellitus,or gout were excluded.Pregnant or nursing women or of childbear-ing potential were excluded.Patient evaluationBlood pressure was measured using a manual cuff sphygmomanometer.The primary efficacy end point was the change from visit2in seated trough SBP(i.e. 24h post-dose)after6weeks’double-blind treatment (visit4).Secondary end points were percentage of patients with mean seated trough SBP<140mmHg and/or>20mmHg SBP reduction,and the change from baseline in seated trough DBP.Safety was eval-uated by physical examination,laboratory parameters, 12-lead electrocardiogram and adverse events. Statistical analysisNon-inferiority of telmisartan was defined as a SBP reduction that was<5mmHg of that achieved with HCTZ.Previous studies suggest that the standard deviation of the change from baseline in seated trough SBP may be<16mmHg.Thus,151patients per treatment group would have a90%power to detect a 6.0mmHg difference between telmisartan and placebo. At80%power,and using a standard deviation of 16mmHg,161patients would be required to establish bining the two calculations,and assuming a dropout rate of about10%,180patients should be randomized to each treatment group.The primary analysis was performed on the intent-to-treat population:all patients who took at least one dose of double-blind medication,and with baseline SBP and at least one SBP measurement during double-blind treatment.Analysis of covariance was performed with data adjusted for baseline and country,utilizing visit2 as the covariate.Telmisartan was compared with place-bo using a superiority hypothesis,and with HCTZ1034Journal of Hypertension2004,Vol22No5using a non-inferiority hypothesis for the mean reduc-tions from visit 2in mean seated trough SBP.All treatment comparisons were performed at a one-sided Ƽ0.025.Pairwise tests between selected treatment groups for percentages of patients achieving the target response were performed using Fisher exact tests.Analysis of covariance was carried out on adjusted mean changes in DBP.Safety and tolerability of telmisartan and HCTZ were determined in all patients receiving at least one dose of double-blind treatment and were presented descriptively.ResultsDemographicsIn total,1039patients entered,were randomized at 100centres in 17countries in Europe,Australia and South Africa,and received at least one dose of study drug.Baseline characteristics in the treatment groups were comparable (Table 1).Previous antihypertensive treat-ment had been received by 34%of patients;drugs used were ACE inhibitors (10.5%),calcium antagonists (9.3%),â-blockers (7.9%),diuretics (6.4%),ARBs (4.5%),other monotherapies (3.2%)or combination therapy (2.7%).Clinical efficacyAt baseline,SBP was comparable in the five groups (Table 1).During double-blind treatment,compliance was 98–99%.After 6weeks’placebo,the mean reduc-tion in seated trough SBP was 11.4mmHg (adjusted for baseline and country,Fig.1).Adjusted mean SBP reductions with telmisartan 20,40and 80mg were 15.6,17.9and 16.9mmHg,respectively.The SBP reductions with telmisartan were all significantly greater compared with placebo:20mg, 4.2mmHg (P ¼0.0042);40mg,6.5mmHg (P ¼0.0001)and 80mg, 5.6mmHg (P ¼0.0002).The mean adjusted SBP reduction with HCTZ was 15.7mmHg,which was superior to that achieved with placebo (4.3mmHg,P ¼0.0038).Statistical analy-sis showed that telmisartan was not inferior to HCTZ.Subgroup analysis was performed on patients according to age (,65years and >65years).With patients aged ,65years,baseline SBP in the five treatment groupswas in the range 161–162mmHg.Placebo produced an adjusted mean reduction in SBP of 12.0mmHg.The adjusted reductions achieved with telmisartan 20,40and 80mg of 17.1,19.3and 18.8mmHg,respectively,compared with baseline,were significantly greater than those achieved with placebo (P ¼0.0141,0.0001and 0.0002,respectively).The adjusted reduction of SBP with HCTZ of 14.5mmHg was not superior to that of placebo (P ¼0.1750).In the subjects aged >65years,baseline SBP was in the range 163–165mmHg.In placebo-treated patients,the adjusted reduction in SBP after 6weeks’treatment was 7.9mmHg.Adjusted mean reductions with telmi-sartan 20,40and 80mg,compared with baseline,were 14.2,17.7and 16.5mmHg;all doses of telmisartan were significantly superior to placebo (P ¼0.0314,0.0005and 0.0003,respectively)in reducing SBP.In the HCTZ group,the adjusted reduction in SBP of 15.7mmHg was significantly superior compared with that of placebo-treated patients (P ¼0.0001).Table 1Demographic and baseline characteristicsCharacteristicPlacebo (n ¼211)Telmisartan 20mg(n ¼206)Telmisartan 40mg(n ¼210)Telmisartan 80mg(n ¼207)HCTZ 12.5mg (n ¼205)Total (n ¼1039)Male (%)90(42.7)87(42.2)87(41.4)91(44.0)94(45.9)449(43.2)Age (years)Mean (SD)63.6(10.2)63.0(11.5)62.7(10.8)62.5(10.9)63.3(11.2)63.0(10.9)>65years (%)46.952.450.047.351.749.7Duration of hypertension (years),mean (SD) 5.4(7.0) 5.1(6.3) 5.0(6.5) 4.8(7.1) 4.8(7.2) 5.0(6.8)SBP a (mmHg),mean (SD)163.3(7.8)163.5(8.0)162.7(8.2)162.4(8.2)162.5(8.1)162.9(8.1)DBP a (mmHg),mean (SD)83.5(5.1)83.7(5.2)83.4(4.6)83.2(5.1)83.5(5.0)83.4(5.0)Pulse (bpm),mean (SD)72.2(9.9)72.4(10.0)72.1(9.9)72.4(9.9)72.7(9.8)72.4(9.9)aCuff measurements.SD,standard deviation;SBP,systolic blood pressure;DBP,diastolic bloodpressure.Placebo (n ϭ 208)n ϭ 204)ϭ 209)Telmisartan 80 mg (n ϭ 205)n ϭ 204)ϪϪϪϪϪM e a n c h a n g e i n t r o u g h c u f f S B P (m m H g )Fig.1Adjusted mean changes in trough seated systolic blood pressure.HCTZ,hydrochlorothiazide;**P ,0.01;***P ,0.001.Isolated systolic hypertension Manolis et al .1035Mean seated trough SBP of<140mmHg and/or SBP reduction of>20mmHg was achieved in27.4%with placebo,in46.6,51.7and53.7%,respectively,with telmisartan20,40and80mg(P,0.0001)and in42.0% with HCTZ(P,0.0001).Telmisartan80mg produceda significantly higher response rate than HCTZ(P¼0.03).Adjusted seated trough DBP was not reduced by placebo.Telmisartan20,40and80mg,and HCTZ produced small reductions in DBP compared with placebo,of 2.4(P¼0.0002), 3.3(P¼0.0001), 3.0 (P¼0.0001)and1.9mmHg(P¼0.0145),respectively. SafetyIncidences of all-causality adverse events were19.9, 17.6and20.3%,respectively,for telmisartan20,40and 80mg,20.9%for placebo and22.0%for HCTZ.Treat-ment-related events were experienced by37(3.6%) patients,with comparable incidences in the different treatment groups.Most events were mild or moderate in intensity;severe events occurred in three patients treated with telmisartan20mg,three treated with telmisartan40mg,two treated with telmisartan80mg, two treated with HCTZ and two patients in receipt of placebo.In total,15serious adverse events occurred in 13patients;none occurring during active treatment were thought to be related to treatment.Treatment was discontinued due to an adverse event infive placebo-treated patients;four,four and three patients, respectively,receiving telmisartan20,40and80mg; and four patients receiving HCTZ.No relevant changes from baseline in median laboratory values,pulse rate or ECG were detected.DiscussionThis large-scale,double-blind study showed that telmi-sartan20,40or80mg is superior to placebo in controlling ISH,and produces clinically significant reductions in seated trough SBP after6weeks’treat-ment.In this study,placebo produced a relatively large reduction in SBP,which was comparable to that ob-served in other large-scale studies[5,6].Thefindings of the present study are consistent with two previous smaller-scale studies conducted in patients with ISH, which found that the ARBs valsartan and candesartan are effective in reducing SBP[11,12].The study comprised patients between the ages of36 and84years,but the mean age of subjects in all groups was approximately63years,with approximately equal proportions,65years and>65years old.Subgroup analysis of the data suggests that the more elderly patients might benefit more from telmisartan treatment, with reductions compared with placebo of5.9,9.1and 9.2mmHg with doses of20,40and80mg,respectively,as opposed to reductions of 5.1,8.4and 6.9mmHg, respectively,in those aged,65years.One explanation may be that the placebo effect was greater in the younger patients.Another possibility is that the base-line values were higher in the elderly subgroup.This may lead to smaller room for improvement in younger patients.A general practitioner questionnaire revealed that most only treat ISH in patients with a median SBP of 180mmHg[17].The reluctance to treat is confirmed in this study;the majority of patients had not received antihypertensives previously.Physicians’concerns about side-effects[7]are unjustified,as telmisartan was not associated with any higher incidence of side-effects than placebo.This is consistent with other studies evaluating the use of telmisartan in hypertensive pa-tients of all ages[18].This short-term study showed that low-dose HCTZ was also well tolerated.In long-term use,higher doses are often employed which may increase the incidence of adverse effects and laboratory abnormalities,especially in the elderly[7].In the past,there has been concern that treating patients with ISH may result in a reduction in both SBP and DBP.In patients with coronary heart disease, a decline in DBP to,80–85mmHg may reduce coronary bloodflow–the so-called‘J-curve phenomen-on’[19].In patients with coronary artery disease,this may lead to ischaemia.However,the results of the Hypertension Optimal Treatment(HOT)trial suggest that the J-curve phenomenon is not a problem[20]. The present study found that the DBP reductions in patients treated with telmisartan or HCTZ were small, although statistically significant,compared with place-bo.In conclusion,this large-scale,double-blind study in patients with ISH showed that once-daily telmisartan 20–80mg produced significantly greater reductions in SBP than placebo,and was not inferior to HCTZ 12.5mg.Telmisartan was well tolerated,with a side-effect profile no different to that of placebo. 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临床药学㊀基金项目:山东省医学会临床药学应用研究项目(Ｎｏ.ＹＸＨ２０１９ＺＸ００９)ꎻ山东省第一批药品临床综合评价项目(Ｎｏ.２０２１ＹＺ０１２)作者简介:栾亚丽ꎬ女ꎬ主管药师ꎬ研究方向:医院药事管理与药学服务ꎬＥ－ｍａｉｌ:ｓｌｙｙｌｙｌ１２０９＠１６３.ｃｏｍ通信作者:王晓君ꎬ女ꎬ主管药师ꎬ研究方向:医院药品管理ꎬＴｅｌ:０５３１－６８７７９０８０ꎬＥ－ｍａｉｌ:ｗａｎｇｘｉａｏｊｕｎ＿９＠１６３.ｃｏｍ基于真实世界数据的西妥昔单抗临床综合评价栾亚丽１ꎬ王元明２ꎬ高田田１ꎬ王晓君１(１.山东第一医科大学附属省立医院药学部ꎬ山东济南２５００１２ꎻ２.山东省药师协会ꎬ山东济南２５０１０１)摘要:目的㊀基于真实世界数据对西妥昔单抗开展临床综合评价ꎬ拟为临床合理使用及药品相关决策提供依据ꎮ方法㊀参考药品临床综合评价相关指南ꎬ基于真实世界数据ꎬ从安全性㊁有效性㊁经济性㊁创新性㊁适宜性㊁可及性６个维度对西妥昔单抗进行评价ꎮ结果㊀安全性ꎬ西妥昔单抗的多数不良反应与贝伐珠单抗㊁传统化疗方案无显著性差异ꎬ但皮疹发生率显著高于其他两种方案ꎻ有效性ꎬ西妥昔单抗与贝伐珠单抗无显著性差异ꎬ但５％的缓解率远低于临床试验结果ꎻ经济性ꎬ进行倾向值得分匹配后ꎬ应用西妥昔单抗与应用贝伐珠单抗方案的总费用无显著性差异ꎬ但显著高于传统化疗方案总费用ꎻ创新性ꎬ西妥昔单抗可用于头颈部鳞癌ꎬ填补了该领域临床治疗空白ꎬ满足了临床需求ꎬ具有一定的创新性ꎻ适宜性ꎬ非劣性ꎻ可及性ꎬ当前在山东地区的可获得性和可负担性相对较差ꎮ结论㊀与贝伐珠单抗相比较ꎬ西妥昔单抗在安全性㊁有效性㊁经济性㊁适宜性无显著性差异ꎬ创新性有优势ꎬ可及性略差ꎮ关键词:药品临床综合评价ꎻ结直肠癌ꎻ西妥昔单抗ꎻ真实世界数据中图分类号:Ｒ９５㊀文献标志码:Ａ㊀文章编号:２０９５－５３７５(２０２４)０４－０３９６－０６ｄｏｉ:１０.１３５０６/ｊ.ｃｎｋｉ.ｊｐｒ.２０２４.０４.０１５Ｃｌｉｎｉｃａｌａｐｐｌｉｃａｔｉｏｎｅｖａｌｕａｔｉｏｎｏｆｃｅｔｕｘｉｍａｂｂａｓｅｄｏｎｒｅａｌ－ｗｏｒｌｄｄａｔａＬＵＡＮＹａｌｉ１ꎬＷＡＮＧＹｕａｎｍｉｎｇ２ꎬＧＡＯＴｉａｎｔｉａｎ１ꎬＷＡＮＧＸｉａｏｊｕｎ１(１.ＤｅｐａｒｔｍｅｎｔｏｆＰｈａｒｍａｃｙꎬＳｈａｎｄｏｎｇＰｒｏｖｉｎｃｉａｌＨｏｓｐｉｔａｌＡｆｆｉｌｉａｔｅｄｔｏＳｈａｎｄｏｎｇＦｉｒｓｔＭｅｄｉｃａｌＵｎｉｖｅｒｓｉｔｙꎬＪｉｎａｎ２５００１２ꎬＣｈｉｎａꎻ２.ＳｈａｎｄｏｎｇＰｈａｒｍａｃｉｓｔｓＡｓｓｏｃｉａｔｉｏｎꎬＪｉｎａｎ２５０１０１ꎬＣｈｉｎａ)Ａｂｓｔｒａｃｔ:Ｏｂｊｅｃｔｉｖｅ㊀Ｔｏｃｏｎｄｕｃｔａｃｌｉｎｉｃａｌａｐｐｌｉｃａｔｉｏｎｅｖａｌｕａｔｉｏｎｏｆｃｅｔｕｘｉｍａｂｂａｓｅｄｏｎｒｅａｌ－ｗｏｒｌｄｄａｔａꎬｅｘｐｌｏｒｅｔｈｅｃｏｎｔｅｎｔａｎｄｍｅｔｈｏｄｓｏｆｔｈｅｃｌｉｎｉｃａｌｃｏｍｐｒｅｈｅｎｓｉｖｅｅｖａｌｕａｔｉｏｎｏｆａｎｔｉｔｕｍｏｒｄｒｕｇｓꎬａｎｄｐｒｏｖｉｄｅａｂａｓｉｓｆｏｒｒａｔｉｏｎａｌｃｌｉｎｉｃａｌｕｓｅａｎｄｄｒｕｇ－ｒｅｌａｔｅｄｄｅｃｉｓｉｏｎ－ｍａｋｉｎｇ.Ｍｅｔｈｏｄｓ㊀Ａｃｃｏｒｄｉｎｇｔｏｔｈｅｇｕｉｄｅｌｉｎｅｓｏｆｃｌｉｎｉｃａｌａｐｐｌｉｃａｔｉｏｎｅｖａｌｕａｔｉｏｎꎬｃｅｔｕｘｉｍａｂｗａｓｅｖａｌｕａｔｅｄｉｎｓｉｘｄｉｍｅｎｓｉｏｎｓｂａｓｅｄｏｎｒｅａｌ－ｗｏｒｌｄｄａｔａ.Ｒｅｓｕｌｔｓ㊀Ｔｈｅｅｖａｌｕａｔｉｏｎｒｅｓｕｌｔｓｏｆｖａｒｉｏｕｓｄｉｍｅｎｓｉｏｎｓｓｈｏｗｅｄｔｈａｔｍｏｓｔａｄｖｅｒｓｅｒｅａｃｔｉｏｎｓｏｆｃｅｔｕｘｉｍａｂｗｅｒｅｎｏｔｓｉｇｎｉｆｉｃａｎｔｌｙｄｉｆｆｅｒｅｎｔｆｒｏｍｂｅｖａｃｉｚｕｍａｂａｎｄｃｏｍｍｏｎｃｈｅｍｏｔｈｅｒａｐｙｒｅｇｉｍｅｎｓꎬｂｕｔｔｈｅｉｎｃｉｄｅｎｃｅｏｆｒａｓｈｗａｓｓｉｇｎｉｆｉｃａｎｔｌｙｈｉｇｈｅｒｔｈａｎｔｈｅｏｔｈｅｒｓ.Ｉｎｔｅｒｍｓｏｆｅｆｆｉｃａｃｙꎬｔｈｅｒｅｉｓｎｏｓｉｇｎｉｆｉｃａｎｔｄｉｆｆｅｒｅｎｃｅｂｅ￣ｔｗｅｅｎｃｅｔｕｘｉｍａｂａｎｄｂｅｖａｃｉｚｕｍａｂꎬｂｕｔｔｈｅｒｅｍｉｓｓｉｏｎｒａｔｅｏｆ５％ｉｓｍｕｃｈｌｏｗｅｒｔｈａｎｔｈｅｃｌｉｎｉｃａｌｔｒｉａｌｒｅｓｕｌｔｓ.Ａｆｔｅｒｐｒｏｐｅｎｓｉｔｙｓｃｏｒｅｍａｔｃｈｉｎｇꎬｔｈｅｒｅｗａｓｎｏｓｉｇｎｉｆｉｃａｎｔｄｉｆｆｅｒｅｎｃｅｉｎｔｈｅｔｏｔａｌｃｏｓｔｏｆｔｈｅｂｅｖａｃｉｚｕｍａｂｒｅｇｉｍｅｎꎬｂｕｔｉｔｗａｓｓｉｇｎｉｆｉｃａｎｔｌｙｈｉｇｈ￣ｅｒｔｈａｎｔｈｅｔｏｔａｌｃｏｓｔｏｆｔｈｅｃｏｍｍｏｎｃｈｅｍｏｔｈｅｒａｐｙｒｅｇｉｍｅｎ.Ｃｅｔｕｘｉｍａｂｃａｎｂｅｕｓｅｄｆｏｒｈｅａｄａｎｄｎｅｃｋｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉ￣ｎｏｍａｗｈｉｃｈｃａｎｆｉｌｌｔｈｅｃｌｉｎｉｃａｌｔｒｅａｔｍｅｎｔｇａｐａｎｄｍｅｅｔｔｈｅｃｌｉｎｉｃａｌｒｅｑｕｉｒｅｍｅｎｔｓ.Ｉｔｉｓａｎａｌｏｇｏｕｓｔｏｏｔｈｅｒｓｉｍｉｌａｒａｎｔｉ－ｔｕｍｏｒｄｒｕｇｓａｎｄｈａｓｎｏｏｂｖｉｏｕｓａｄｖａｎｔａｇｅｓｏｖｅｒｔｈｅｃｕｒｒｅｎｔｓｕｉｔａｂｉｌｉｔｙꎬｂｕｔａｖａｉｌａｂｉｌｉｔｙａｎｄａｆｆｏｒｄａｂｉｌｉｔｙｏｆｃｅｔｕｘｉｍａｂｉｎＳｈａｎｄｏｎｇｉｓｒｅｌａｔｉｖｅｌｙｐｏｏｒ.Ｃｏｎｃｌｕｓｉｏｎ㊀Ｃｏｍｐａｒｅｄｗｉｔｈｂｅｖａｃｉｚｕｍａｂꎬｃｅｔｕｘｉｍａｂｈａｓｎｏｓｉｇｎｉｆｉｃａｎｔｄｉｆｆｅｒｅｎｃｅｉｎｓａｆｅｔｙꎬｅｆｆｉｃａｃｙꎬｅ￣ｃｏｎｏｍｙꎬａｎｄｓｕｉｔａｂｉｌｉｔｙꎬａｎｄｈａｓａｄｖａｎｔａｇｅｓｉｎｉｎｎｏｖａｔｉｏｎａｎｄｓｌｉｇｈｔｌｙｐｏｏｒａｃｃｅｓｓｉｂｉｌｉｔｙ.Ｋｅｙｗｏｒｄｓ:ＣｌｉｎｉｃａｌａｐｐｌｉｃａｔｉｏｎｅｖａｌｕａｔｉｏｎꎻＣｏｌｏｒｅｃｔａｌｃａｎｃｅｒꎻＣｅｔｕｘｉｍａｂꎻＲｅａｌ－ｗｏｒｌｄｄａｔａ㊀㊀国家卫生健康委«关于规范开展药品临床综合评价工作的通知»和«抗肿瘤药物临床综合评价技术指南(２０２２年版试行)»(以下简称 技术指南 )为抗肿瘤药品临床综合评价工作的开展指明了具体方法和思路[１－２]ꎮ结直肠癌是最常见的消化道肿瘤之一ꎬ发病率及死亡率均高[３－４]ꎬ近年来分子靶向药物已成为结直肠癌治疗领域研究与应用的焦点[５]ꎮ头颈部鳞状细胞癌是世界第六大常见癌症ꎬ治疗手段十分有限ꎬ总生存时间往往不足１年ꎮ西妥昔单抗一直是治疗结直肠癌的重要药物ꎬ近期又获批了头颈部鳞癌的适应证ꎬ目前我国药品临床综合评价工作结合医院患者实际使用开展评价案例较少[６－８]ꎬ尚未有研究对西妥昔单抗进行临床综合评价ꎮ本研究拟以西妥昔单抗为例ꎬ基于真实世界数据开展临床综合评价ꎬ为临床合理使用及相关决策制定提供依据ꎬ并为其他药品临床综合评价工作的开展提供借鉴ꎮ１㊀资料与方法１.１㊀数据来源㊀选择山东省三级综合性医院和肿瘤专科医院各１家ꎬ分别抽取２０１９年１月１日至２０２０年８月３１日期间应用西妥昔单抗的患者病例１０９份和１０７份ꎮ同时从综合性医院抽取了同期７９份应用贝伐珠单抗㊁以及１００份应用传统化疗方案治疗结直肠癌患者的病例ꎬ作为对照组ꎮ提取山东省药品集中采购平台２０１９年１月１日至２０１９年１２月３１日的采购配备数据ꎮ１.２㊀研究方法㊀根据«药品临床综合评价管理指南(２０２１年版试行)»(以下简称 管理指南 )ꎬ从安全性㊁有效性㊁经济性㊁创新性㊁适宜性㊁可及性６个维度开展科学规范的整合分析与综合研判ꎮ对于年龄㊁住院天数㊁住院次数等定量指标ꎬ以均值ʃ标准差描述ꎻ对于性别㊁疾病分类等计数资料用频数和百分比表示ꎮ对于安全性和有效性的指标ꎬ采用卡方检验或者Ｆｉｓｈｅｒ精确概率法进行药物间的差异性比较ꎮ采用最小成本法进行经济性评价ꎬ并利用倾向性得分匹配对年龄㊁住院时间㊁住院次数等协变量进行调整ꎮ配备率数据来源于山东省药品集中采购平台ꎬ２０１９年全国和山东省居民人均可支配收入来自国家统计局和山东省统计局公布的数据ꎮ使用ＩＢＭＳＰＳＳＳｔａｔｉｓｔｉｃｓ２６.０软件和ＳｔａｔａＭＰ１４软件进行统计分析ꎬ双侧检验水准α＝０.０５ꎬＰ<０.０５认为具有显著性差异ꎮ２㊀结果２.１㊀基于真实世界数据的临床综合评价指标体系构建情况㊀本研究根据 管理指南 建立西妥昔单抗临床综合评价指标体系ꎬ包括安全性㊁有效性㊁经济性㊁创新性㊁适宜性和可及性６个一级指标ꎬ对应的二级指标见表１ꎮ表１㊀西妥昔单抗临床综合评价指标体系一级指标二级指标安全性不良反应发生率有效性疗效评价情况分析经济性日均住院总费用创新性填补临床治疗空白ꎬ未满足的临床需求适宜性适应证㊁贮存条件和给药方式可及性配备率㊁可负担性２.２㊀基线特征㊀本研究对于安全性评价基于来自两家医院的３９５份病例的各类不良反应发生频率ꎬ患者基本信息情况见表２ꎮ两家医院患者男性数量均高于女性ꎬ平均年龄相近ꎮ平均住院天数和平均住院次数两家医院差异较大ꎬ肿瘤专科医院均远高于综合医院ꎮ表２㊀抽取的３９５份患者病历基本信息变量西妥昔单抗(ｎ＝２１６)贝伐珠单抗(ｎ＝７９)传统化疗方案(ｎ＝１００)某综合医院(ｎ＝１０９)某肿瘤专科医院(ｎ＝１０７)某综合医院某综合医院男性８１(７４.３１％)７２(６７.２９％)３９(４９.３７％)６１(６１.００％)女性２８(２５.６９％)３５(３２.７１％)４０(５０.６３％)３９(３９.００％)年龄５８.５０ʃ９.７２５９.０４ʃ１１.８４５７.９７ʃ１２.２８５８.５ʃ１０.９１住院天数３.８７ʃ２.８５１０.２０ʃ１２.２２４.００ʃ２.７５３.４２ʃ２.４６住院次数５.８３ʃ４.８１１１.９７ʃ９.０２６.６２ʃ４.３１５.２５ʃ３.２８结直肠癌１０５(９６.３３％)９８(９１.５９％)７９(１００％)１００(１００％)头颈部鳞癌４(３.６７％)９(８.４１％)０(０％)０(０％)２.３㊀安全性㊀接受３种治疗方案的３９５名患者真实世界数据中出现的不良反应分布见表３ꎮ发生率较高的不良反应有消化道反应㊁骨髓抑制㊁发热等ꎬ３组间无显著性差异ꎮ但西妥昔单抗的皮疹发生率(１０.６５％)远高于其他两种方案(０％)ꎬ具有显著性差异(Ｐ<０.０５)ꎮ２.４㊀有效性㊀考虑到采用阳性对照(头对头试验)得到的有效性结果更具说服力ꎬ目前西妥昔单抗治疗头颈部鳞癌的病例数量较少ꎬ因此有效性的分析基于同一家综合医院的１８４份结直肠癌患者数据ꎬ包括１０５名应用西妥昔单抗(未纳入４份头颈部鳞癌患者病历)和７９名应用贝伐珠单抗的患者ꎮ根据 技术指南 要求进行归类:①完全缓解ꎻ②部分缓解ꎻ③疾病稳定ꎻ④疾病进展ꎻ⑤因肿瘤致早期死亡ꎻ⑥因治疗毒性致早期死亡ꎻ⑦其他原因致早期死亡ꎻ⑧无法分类(不能评价或资料不完整)ꎮ归入４~８类的患者视为治疗无效ꎮ表３㊀３种用药方案的不良反应发生情况不良反应西妥昔单抗(ｎ＝２１６)贝伐珠单抗(ｎ＝７９)传统化疗方案(ｎ＝１００)例数发生率(％)例数发生率(％)例数发生率(％)Ｐ值消化道反应３４１５.７４１７２１.５２９９.０００.０６５骨髓抑制２９１３.４３１１１３.９２１５１５.０００.９３２发热２０９.２６１０１２.６６９９.０００.６４９皮疹２３１０.６５００.００００.００<０.００１腹泻８３.７０４５.０６００.０００.０６４胸闷２０.９３１１.２７００.０００.７７２乏力４１.８５２２.５３１１.０００.７７３失声００.００００.００１１.０００.４５３头痛３１.３９００.００１１.０００.８１６转氨酶轻度升高００.００００.００１１.０００.４５３四肢麻木１０.４６１１.２７２２.０００.３１６㊀㊀化疗周期在５~６个周期之间ꎬ疗效评价结果见表４ꎮ基于贝伐珠单抗的方案整体有效率(６８.３５％)略高于西妥昔单抗(６６.６７％)ꎬ卡方检验无统计学差异ꎮ表４㊀１８４名结直肠癌患者疗效评价分析疗效西妥昔单抗(ｎ＝１０５)贝伐珠单抗(ｎ＝７９)例数占比平均化疗周期例数占比平均化疗周期完全缓解００.０００００.０００部分缓解５４.５９４.２５５６.３３１０.００疾病稳定６５５９.６３５.２７４９６２.０３５.３９疾病进展３５３２.１１４.９２２３２９.１１５.８７因肿瘤致早期死亡００.０００１１.２７１２.００因治疗毒性致早期死亡００.０００００.０００其他原因致早期死亡００.０００００.０００无法分类００.０００１１.２７９.００有效数合计(占比)７０(６６.６７％)５４(６８.３５％)卡方统计量０.０５８Ｐ值０.４６８２.５㊀经济性㊀根据以上研究ꎬ西妥昔单抗和贝伐珠单抗治疗结直肠癌患者的疗效无统计学差异ꎬ因此采用最小成本法进行经济学评价ꎮ由于综合医院和专科医院的平均住院日差距较大ꎬ经济性分析仅基于来自综合医院的结直肠癌患者的数据ꎬ包括１０５份使用西妥昔单抗㊁７９份贝伐珠单抗和１００份未应用任何靶向药物的传统化疗患者病例ꎮ采用有放回的倾向性得分匹配法对年龄㊁住院天数㊁住院次数等变量进行调整ꎬ对各方案的费用进行比较ꎮ应用西妥昔单抗与贝伐珠单抗进行匹配分析前后结果ꎬ具体见表５㊁图１ꎻ应用西妥昔单抗与传统化疗方案进行匹配分析前后结果ꎬ具体见表６㊁图２ꎮ综合来看ꎬ无论是否对混杂因素进行匹配ꎬ西妥昔单抗对比贝伐珠单抗的费用无统计学差异ꎬ但与全身系统化疗方案相比有统计学差异ꎮ表５㊀匹配前后西妥昔单抗对比贝伐珠单抗的费用差异(单位:元)匹配前后西妥昔单抗贝伐珠单抗差异标准差Ｔ值匹配前２０６８６.４８１９３２４.６６１３６１.８３１９７５.０７０.６９匹配后２０４８５.５８２０５２１.７７－３６.２０２００１.１２－０.０２图１㊀西妥昔单抗与贝伐珠单抗倾向性得分匹配表６㊀匹配前后西妥昔单抗对比传统化疗方案的费用差异(单位:元)匹配前后西妥昔单抗传统化疗方案差异标准差Ｔ值匹配前２０６８６.４８１０６３４.９３１００５１.５５１７３３.３４５.８匹配后１９０３１.１１１１１５１.０５７８８０.０６１４２２.１５５.５４图２㊀西妥昔单抗与传统化疗方案倾向性得分匹配２.６㊀创新性㊀通过基因检测等手段找到敏感而特异的预后标志物ꎬ实现个体化治疗是临床治疗结直肠癌的一大趋势ꎬ西妥昔单抗在ＲＡＳ基因野生型患者中的优势明显ꎬ对于更加精确适应证人群的靶向治疗具有一定的创新性ꎮ此外ꎬ２０１９年４月ꎬ默克公司向国家药品监督管理局提交西妥昔单抗联合铂类化疗作为复发和/或转移性头颈部鳞癌一线治疗的注册申请ꎬ并于２０１９年８月因 具有明显治疗优势创新药 纳入优先审评程序ꎮ通过优先审评㊁审批的通道上市ꎬ体现了其创新性ꎮ头颈部鳞癌作为西妥昔单抗的新适应证ꎬ２０２０年３月在中国获批ꎬ打破了中国复发和/或转移性头颈部鳞癌患者３０年来铂类化疗效果不佳的困局ꎬ并扩大了在肿瘤人群中的应用范围ꎮ西妥昔单抗联合化疗展现出了对复发和/或转移头颈部鳞癌显著的效果[９]ꎬ填补临床治疗空白ꎬ体现出其具有一定的创新性ꎮ２.７㊀适宜性㊀通过查阅药品说明书㊁诊疗指南等资料以及访谈医护人员发现ꎬ西妥昔单抗疗效确切ꎬ适应证明确ꎬ药代动力学参数完整ꎬ用于不同适应证治疗方案的治疗剂量是统一的ꎬ便于临床医生记忆掌握ꎬ给药剂量㊁频次适宜ꎬ依从性良好ꎬ技术特点适宜性较好ꎮ从贮存条件和给药方式上来看ꎬ西妥昔单抗作为抗肿瘤注射剂ꎬ在贮存和使用方面有着较为严格的要求ꎬ其适宜性不劣于同类药品ꎮ２.８㊀可及性㊀对２０１９年的配送数据进行分析ꎬ从医院等级来看ꎬ配备西妥昔单抗的医院共６４家ꎬ其中三级医院４２家㊁二级医院２１家㊁基层医院１家ꎬ各级医院数量均普遍低于贝伐珠单抗ꎮ通过计算山东省配备该药品医院的数量与肿瘤专科医院及有肿瘤科的医院数量的占比ꎬ获得不同级别医院的西妥昔单抗和贝伐珠单抗的配备率ꎬ情况见表７ꎮ表７㊀山东省不同等级医院西妥昔单抗与贝伐珠单抗配备率医院等级西妥昔单抗贝伐珠单抗医院数量配备率(％)医院数量配备率(％)山东省的肿瘤专科医院及有肿瘤科的医院数量Ｐ值三级４２３２.０６５３４０.４６１３１０.０９９二级２１８.４７５９２３.７９２４８<０.００１基层医院１４.７６４１９.０５２１０.３４３未定级ＮＡＮＡＮＡＮＡ２２－合计６４１５.１７１１６２７.４９４２２㊀㊀由于肿瘤患者的治疗多集中在二㊁三级医院ꎬ所以西妥昔单抗㊁贝伐珠单抗的配备也主要集中在二㊁三级医院ꎬ２０１９年西妥昔单抗在二㊁三级医院的配备率分别为８.４７％和３２.０６％ꎬ均低于贝伐珠单抗(２３.７９％和４０.４６％)ꎮ各地市配备率均低于５０％ꎬ普遍低于贝伐珠单抗ꎬ可获得率相对较低ꎮ㊀㊀参照管理指南ꎬ可负担性指标建议采用人均年治疗费用占城乡居民家庭年人均可支配收入比重ꎮ由于本研究抽取的西妥昔单抗使用时间为２０１９年１月１日至２０２０年８月３１日ꎬ主要的数据分布于２０１９年ꎬ经查询ꎬ国家统计局公布的２０１９年全国和山东省居民人均可支配收入分别为３０７３３元和３１５９７元ꎮ根据文献研究结果[１０]ꎬ结直肠癌的治疗疗程平均为４.８个月(首月用药１８支ꎬ后续月份１６支)ꎬ年用量为１８支＋３.８月ˑ１６支＝７８.８支ꎮ西妥昔单抗人均年用药治疗费用＝７８.８支ˑ１２０４.３５元/支＝９４９０２.７８元ꎬ是全国居民人均可支配收入的３.０９倍ꎬ是山东省人均可支配收入的３.００倍ꎬ可负担性较差ꎮ由于各个省份的报销政策不尽相同ꎬ不同医保类型患者的报销比例也有所差别ꎬ按照综合报销比例为６５％进行粗略估计ꎬ西妥昔单抗人均年用药治疗自付费用为３３２１５.９７元ꎬ分别是全国和山东省居民人均可支配收入的１.０８倍和１.０５倍ꎮ从计算结果来看ꎬ患者的西妥昔单抗治疗可负担性一般ꎬ说明肿瘤患者的治疗负担仍相对较重ꎮ３㊀讨论本研究发现在真实世界应用中ꎬ西妥昔单抗常见的不良反应为消化道反应㊁骨髓抑制㊁发热等ꎻ既往的临床试验中[９ꎬ１１－１４]ꎬ西妥昔单抗最常见的不良反应为中性粒细胞减少症㊁腹泻㊁皮疹和甲沟炎等ꎬ真实世界数据与临床试验结果相似ꎮ另外考虑本研究为回顾性研究ꎬ症状轻微㊁没有对症治疗等病历中未记录不良反应的无法统计到ꎬ因此安全性评价方面ꎬ不良反应发生率可能会低于实际情况ꎮ既往多项临床实验证明了西妥昔单抗的有效性[９ꎬ１１－１５]ꎬ特别是在ＲＡＳ基因野生型的优势明显ꎬＴＡＩＬＯＲ研究早期的数据显示ꎬ西妥昔单抗联合ＦＯＬ￣ＦＯＸ－４ꎬ能够显著提高中国ＲＡＳ野生型ｍＣＲＣ患者的无进展生存期(９.２个月对比７.４个月)和总生存期(２０.８个月对比１６.５个月)ꎬ显著提高左半ｍＣＲＣ患者的总生存期(２２.０个月对比１８.３个月)ꎬ得到了各大权威指南的推荐[１６－１９]ꎬ是结直肠癌治疗中疗效最为显著的靶向药物ꎬ能够有效缩瘤ꎮ然而在真实世界研究中ꎬ有效性指标却很难从医院的数据库中直接获得ꎬ通过划分８个大类对有效性进行界定ꎬ获得的有效性结果约６７％ꎮ但如果仅从缓解率结果来看ꎬ完全缓解加上部分缓解约为５％ꎬ这与临床试验中６０％左右的客观缓解率结果相差较大ꎬ说明进一步开展基于真实世界的疗效性研究具有一定的必要性ꎮ管理指南对于经济性方面的评价ꎬ建议选择成本－效果分析(ＣＥＡ)等一系列卫生技术评估的方法ꎮ但从真实世界数据出发ꎬ由于效果指标不易获得ꎬ构建经济学评价模型存在一定技术上的难度ꎮ考虑到有效性无统计学差异ꎬ本研究仅对费用进行了分析ꎬ可以为后续结直肠癌领域相关经济学评价的开展提供成本数据的参考ꎬ助力药品临床综合评价的开展ꎮ从可及性来看ꎬ本研究采用医疗卫生机构药品配备率进行评价ꎬ由于该类药品必须在有抗肿瘤药物使用经验的医师指导下使用ꎬ用药过程需密切监测患者状况ꎬ分母选择了山东省的肿瘤专科医院及有肿瘤科的医院数量ꎮ然而从可获得性方面来看ꎬ西妥昔单抗在二㊁三级医院与各地市的配备率均低于５０％ꎮ当前国际上对药品可获得率没有严格统一的标准ꎬ一般认为配备率<５０％为可获得率较低ꎬ５０％~８０％为可获得率较好ꎬ>８０％为可获得率很好ꎮ从创新性和适宜性的评价来看ꎬ缺乏量化的相关指标ꎬ评价较为主观ꎮ４㊀局限性本研究存在着一定的不足和局限性ꎮ由于当前的数据可获得性有限ꎬ本研究基于山东省两家医院的真实世界数据ꎬ回顾性分析西妥昔单抗在临床实际应用情况ꎬ由于头颈部鳞癌的适应证获批时间较短ꎬ真实世界使用西妥昔单抗治疗的头颈部鳞癌患者病例数非常少ꎬ所以未纳入头颈部鳞癌患者进行有效性㊁经济性评价ꎻ仅从综合医院获取应用贝伐珠单抗以及应用传统化疗方案治疗结直肠癌患者的病例作为对照组ꎬ本研究纳入的使用西妥昔单抗治疗的结直肠癌患者ꎬ均为基因检测结果ＲＡＳ野生型ꎬ使用贝伐单抗和传统化疗的患者大多数未进行基因检测ꎬ所以未对ＲＡＳ基因型这一变量进行分析ꎬ存在一定的选择偏倚ꎻ另外ꎬ部分指标存在着主观性强㊁无法量化的问题ꎮ因此有必要继续探索开展多维度综合评价ꎬ通过专家咨询等方法对各个方面的证据进行整合后的综合评价ꎬ进一步提升评价结果的科学性和可推广性ꎮ５㊀结论本研究通过开展基于真实世界数据的西妥昔单抗临床综合评价ꎬ从安全性㊁有效性㊁经济性㊁创新性㊁适宜性㊁可及性等多个维度对西妥昔单抗进行综合评价ꎬ作为治疗结直肠癌一线药物ꎬ西妥昔单抗在安全性㊁有效性㊁经济性㊁适宜性与贝伐珠单抗整体无显著性差异ꎬ仅皮疹发生率明显高于贝伐珠单抗ꎬ对于ＲＡＳ基因野生型患者疗效优势明显ꎻ作为治疗头颈部鳞癌药物ꎬ对复发和/或转移头颈部鳞癌提供了新的治疗选择ꎬ具有一定创新性ꎻ在山东地区的可获得性和可负担性相对较差ꎮ参考文献:[１]㊀国家卫生健康委办公厅.关于规范开展药品临床综合评价工作的通知[ＥＢ/ＯＬ].(２０２１－０７－２１)[２０２３－０７－２８].ｈｔｔｐ://ｗｗｗ.ｎｈｃ.ｇｏｖ.ｃｎ/ｙａｏｚｓ/ｓ２９０８/２０２１０７/５３２ｅ２０８００ａ４７４１５ｄ８４ａｄｆ３７９７ｂ０ｆ４８６９.ｓｈｔｍｌ.[２]国家药物和卫生技术综合评估中心关于发布心血管病㊁抗肿瘤㊁儿童药品临床综合评价技术指南的通知[ＥＢ/ＯＬ].(２０２２－０６－２９)[２０２３－０７－２８].ｈｔｔｐ://ｗｗｗ.０ｎｈｅｉ.ｃｎ/ｎｈｅｉ/ｚｎｆｂ/２０２２０６/ｃ０１ｄ８７ａ２９０６６４ｂ０１ｂｆ４２ａ９ｄａｄ７６９ｄ６９ｆ.ｓｈｔｍｌ.[３]ＳＵＮＧＨꎬＦＥＲＬＡＹＪꎬＳＩＥＧＥＬＲＬꎬｅｔａｌ.ＧｌｏｂａｌＣａｎｃｅｒＳｔａｔｉｓｔｉｃｓ２０２０:ＧＬＯＢＯＣＡＮＥｓｔｉｍａｔｅｓｏｆＩｎｃｉｄｅｎｃｅａｎｄＭｏｒｔａｌｉｔｙＷｏｒｌｄｗｉｄｅｆｏｒ３６Ｃａｎｃｅｒｓｉｎ１８５Ｃｏｕｎｔｒｉｅｓ[Ｊ].ＣＡＣａｎｃｅｒＪＣｌｉｎꎬ２０２１ꎬ７１(３):２０９－２４９.[４]陈万青ꎬ孙可欣ꎬ郑荣寿ꎬ等.２０１４年中国分地区恶性肿瘤发病和死亡分析[Ｊ].中国肿瘤ꎬ２０１８ꎬ２７(１):１－１４.[５]高嘉敏ꎬ冯群ꎬ许晓燕ꎬ等.结直肠癌抗代谢药物及其代谢靶点研究进展[Ｊ].中国新药与临床杂志ꎬ２０２０ꎬ３９(３):１３４－１４０.[６]覃肖潇ꎬ金春林ꎬ王美凤ꎬ等.含钆对比剂的临床综合评价[Ｊ].临床药物治疗杂志ꎬ２０２１ꎬ１９(９):３４－４０. [７]符雨嫣ꎬ金春林ꎬ孙辉ꎬ等.晚期肝癌一线系统治疗药品的临床综合评价[Ｊ].临床药物治疗杂志ꎬ２０２１ꎬ１９(１０):６６－７０.[８]程文迪ꎬ金春林ꎬ罗雅双ꎬ等.眼科抗血管内皮生长因子药品的临床综合评价[Ｊ].临床药物治疗杂志ꎬ２０２１ꎬ１９(１０):５２－５９.[９]ＧＵＯＹꎬＬＵＹꎬＨＡＮＧＱꎬｅｔａｌ.ＬＢＡ６－Ｆｉｒｓｔ－ｉｎｅｃｅｔｕｘｉｍａｂｐｌｕｓｃｉｓｐｌａｔｉｎａｎｄｆｌｕｏｒｏｕｒａｃｉｌｓｃｉｓｐｌａｔｉｎａｎｄｆｌｕｏｒｏｕｒａｃｉｌｉｎＣｈｉｎｅｓｅｐａｔｉｅｎｔｓｗｉｔｈｒｅｃｕｒｒｅｎｔａｎｄ/ｏｒｍｅｔａｓｔａｔｉｃｓｑｕａ￣ｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａｏｆｔｈｅｈｅａｄａｎｄｎｅｃｋ:Ｔｈｅｒａｎｄｏｍ￣ｉｚｅｄꎬｐｈａｓｅＩｌｌＣＨＡＮＧＥ－２ｔｒｉａｌ[Ｃ].ＣＳＣＯꎬ２０１９. [１０]ＨＥＩＮＥＭＡＮＮＶꎬＶＯＮＷＥＩＫＥＲＳＴＨＡＬＬＦꎬＤＥＣＫＥＲＴꎬｅｔａｌ.ＦＯＬＦＩＲＩｐｌｕｓｃｅｔｕｘｉｍａｂｖｅｒｓｕｓＦＯＬＦＩＲＩｐｌｕｓｂｅ￣ｖａｃｉｚｕｍａｂａｓｆｉｒｓｔ－ｌｉｎｅｔｒｅａｔｍｅｎｔｆｏｒｐａｔｉｅｎｔｓｗｉｔｈｍｅｔａ￣ｓｔａｔｉｃｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ(ＦＩＲＥ－３):ａｒａｎｄｏｍｉｓｅｄꎬｏｐｅｎ－ｌａｂｅｌꎬｐｈａｓｅ３ｔｒｉａｌ[Ｊ].ＬａｎｃｅｔＯｎｃｏｌꎬ２０１４ꎬ１５(１０):１０６５－１０７５.[１１]ＶＡＮＣＵＴＳＥＭＥꎬＬＥＮＺＨＪꎬＫＯＨＮＥＣＨꎬｅｔａｌ.Ｆｌｕｏｒｏｕ￣ｒａｃｉｌꎬｌｅｕｃｏｖｏｒｉｎꎬａｎｄｉｒｉｎｏｔｅｃａｎｐｌｕｓｃｅｔｕｘｉｍａｂｔｒｅａｔｍｅｎｔａｎｄＲＡＳｍｕｔａｔｉｏｎｓｉｎｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ[Ｊ].ＪＣｌｉｎＯｎｃｏｌꎬ２０１５ꎬ３３(７):６９２－７００.[１２]ＢＯＫＥＭＥＹＥＲＣꎬＢＯＮＤＡＲＥＮＫＯＩꎬＭＡＫＨＳＯＮＡꎬｅｔａｌ.Ｆｌｕｏｒｏｕｒａｃｉｌꎬｌｅｕｃｏｖｏｒｉｎꎬａｎｄｏｘａｌｉｐｌａｔｉｎｗｉｔｈａｎｄｗｉｔｈｏｕｔｃｅｔｕｘｉｍａｂｉｎｔｈｅｆｉｒｓｔ－ｌｉｎｅｔｒｅａｔｍｅｎｔｏｆｍｅｔａｓｔａｔｉｃｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ[Ｊ].ＪＣｌｉｎＯｎｃｏｌꎬ２００９ꎬ２７(５):６６３－６７１.[１３]ＱＩＮＳꎬＬＩＪꎬＷＡＮＧＬꎬｅｔａｌ.ＥｆｆｉｃａｃｙａｎｄＴｏｌｅｒａｂｉｌｉｔｙｏｆＦｉｒｓｔ－ＬｉｎｅＣｅｔｕｘｉｍａｂＰｌｕｓＬｅｕｃｏｖｏｒｉｎꎬＦｌｕｏｒｏｕｒａｃｉｌꎬａｎｄＯｘａｌｉｐｌａｔｉｎ(ＦＯＬＦＯＸ－４)ＶｅｒｓｕｓＦＯＬＦＯＸ－４ｉｎＰａｔｉｅｎｔｓＷｉｔｈＲＡＳＷｉｌｄ－ＴｙｐｅＭｅｔａｓｔａｔｉｃＣｏｌｏｒｅｃｔａｌＣａｎｃｅｒ:ＴｈｅＯｐｅｎ－ＬａｂｅｌꎬＲａｎｄｏｍｉｚｅｄꎬＰｈａｓｅＩＩＩＴＡＩＬＯＲＴｒｉａｌ[Ｊ].ＪＣｌｉｎＯｎｃｏｌꎬ２０１８ꎬ３６(３０):３０３１－３０３９.[１４]ＶＥＲＭＯＲＫＥＮＪＢꎬＭＥＳＩＡＲꎬＲＩＶＥＲＡＦꎬｅｔａｌ.Ｐｌａｔｉｎｕｍ－ｂａｓｅｄｃｈｅｍｏｔｈｅｒａｐｙｐｌｕｓｃｅｔｕｘｉｍａｂｉｎｈｅａｄａｎｄｎｅｃｋｃａｎｃｅｒ[Ｊ].ＮＥｎｇｌＪＭｅｄꎬ２００８ꎬ３５９(１１):１１１６－１１２７. [１５]任炳楠ꎬ赵越ꎬ薛朝军ꎬ等.治疗转移性结直肠癌的抗血管生成单克隆抗体的药品遴选量化评估[Ｊ].中国新药与临床杂志ꎬ２０２２ꎬ４１(６):３６７－３７３.[１６]中国医师协会外科医师分会ꎬ中华医学会外科分会胃肠外科学组ꎬ中华医学会外科分会结直肠外科学组ꎬ等.中国结直肠癌肝转移诊断和综合治疗指南(Ｖ２０２０)[Ｊ].中华结直肠疾病电子杂志ꎬ２０２１ꎬ１０(１):２－１５.[１７]国家卫生健康委员会医政医管局ꎬ中华医学会肿瘤学分会.中国结直肠癌诊疗规范(２０２０年版)[Ｊ].中国实用外科杂志ꎬ２０２０ꎬ４０(６):６０１－６２５.[１８]陈功ꎬ王屹.２０１７版欧洲肿瘤学会直肠癌指南解读[Ｊ].中华胃肠外科杂志ꎬ２０１７ꎬ２０(１１):１２３６－１２４２.[１９]龙飞ꎬ胡桂ꎬ马敏ꎬ等.２０２１.Ｖ１版ＮＣＣＮ临床实践指南:结肠癌/直肠癌更新解读(外科部分)[Ｊ].临床外科杂志ꎬ２０２１ꎬ２９(５):４０１－４０４.(收稿日期:２０２４－０１－０９)(上接第３９０页)[３８]ＹＯＵＹＰ.Ｅｐｉｇａｌｌｏｃａｔｅｃｈｉｎｇａｌｌａｔｅｅｘｔｅｎｄｓｔｈｅｔｈｅｒａｐｅｕｔｉｃｗｉｎｄｏｗｏｆｒｅｃｏｍｂｉｎａｎｔｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒｔｒｅａｔ￣ｍｅｎｔｉｎｉｓｃｈｅｍｉｃｒａｔｓ[Ｊ].ＪＳｔｒｏｋｅＣｅｒｅｂｒｏｖａｓｃＤｉｓꎬ２０１６ꎬ２５(４):９９０－９９７.[３９]ＺＵＯＷꎬＹＡＮＦꎬＺＨＡＮＧＢꎬｅｔａｌ.ＳａｌｉｄｒｏｓｉｄｅｉｍｐｒｏｖｅｓｂｒａｉｎｉｓｃｈｅｍｉｃｉｎｊｕｒｙｂｙａｃｔｉｖａｔｉｎｇＰＩ３Ｋ/ＡｋｔｐａｔｈｗａｙａｎｄｒｅｄｕｃｅｓｃｏｍｐｌｉｃａｔｉｏｎｓｉｎｄｕｃｅｄｂｙｄｅｌａｙｅｄｔＰＡｔｒｅａｔｍｅｎｔ[Ｊ].ＥｕｒＪＰｈａｒｍａｃｏｌꎬ２０１８(８３０):１２８－１３８.[４０]ＪＥＡＮＬＥＢＬＡＮＣＮꎬＭＥＮＥＴＲꎬＰＩＣＡＲＤＫꎬｅｔａｌ.ＣａｎｏｎｉｃａｌＷｎｔｐａｔｈｗａｙｍａｉｎｔａｉｎｓｂｌｏｏｄ－ｂｒａｉｎｂａｒｒｉｅｒｉｎ￣ｔｅｇｒｉｔｙｕｐｏｎｉｓｃｈｅｍｉｃｓｔｒｏｋｅａｎｄｉｔｓａｃｔｉｖａｔｉｏｎａｍｅｌｉｏｒａｔｅｓｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒｔｈｅｒａｐｙ[Ｊ].ＭｏｌＮｅｕｒｏｂｉｏｌꎬ２０１９ꎬ５６(９):６５２１－６５３８.[４１]ＷＡＮＧＷꎬＬＩＭꎬＷＡＮＧＹꎬｅｔａｌ.ＧＳＫ－３βｉｎｈｉｂｉｔｏｒＴＷＳ１１９ａｔｔｅｎｕａｔｅｓｒｔＰＡ－ｉｎｄｕｃｅｄｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒ￣ｍａｔｉｏｎａｎｄａｃｔｉｖａｔｅｓｔｈｅＷｎｔ/β－ｃａｔｅｎｉｎｓｉｇｎａｌｉｎｇｐａｔｈｗａｙａｆｔｅｒａｃｕｔｅｉｓｃｈｅｍｉｃｓｔｒｏｋｅｉｎｒａｔｓ[Ｊ].ＭｏｌＮｅｕｒｏ￣ｂｉｏｌꎬ２０１６ꎬ５３(１０):７０２８－７０３６.[４２]ＷＡＮＧＴꎬＤＵＡＮＹＭꎬＦＵＱꎬｅｔａｌ.ＩＭ－１２ａｃｔｉｖａｔｅｓｔｈｅＷｎｔ－β－ｃａｔｅｎｉｎｓｉｇｎａｌｉｎｇｐａｔｈｗａｙａｎｄａｔｔｅｎｕａｔｅｓｒｔＰＡ－ｉｎｄｕｃｅｄｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒｍａｔｉｏｎｉｎｒａｔｓａｆｔｅｒａｃｕｔｅｉｓｃｈｅｍｉｃｓｔｒｏｋｅ[Ｊ].ＢｉｏｃｈｅｍＣｅｌｌＢｉｏｌꎬ２０１９ꎬ９７(６):７０２－７０８.[４３]ＬＩＵＣꎬＳＵＮＳꎬＸＩＥＪꎬｅｔａｌ.ＧＬＰ－１ＲａｇｏｎｉｓｔＥｘｅｎｄｉｎ－４ｐｒｏ￣ｔｅｃｔｓａｇａｉｎｓｔｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒｍａｔｉｏｎｉｎｄｕｃｅｄｂｙｒｔＰＡａｆｔｅｒｉｓｃｈｅｍｉｃｓｔｒｏｋｅｖｉａｔｈｅＷｎｔ/β－Ｃａｔｅｎｉｎｓｉｇｎａｌｉｎｇｐａｔｈ￣ｗａｙ[Ｊ].ＭｏｌＮｅｕｒｏｂｉｏｌꎬ２０２２ꎬ５９(６):３６４９－３６６４.[４４]ＲＥＮＷꎬＨＵＡＮＧＣꎬＣＨＵＨꎬｅｔａｌ.Ｐｅｐｔｉｄｅ５ａｔｔｅｎｕａｔｅｓｒｔＰＡｒｅｌａｔｅｄｂｒａｉｎｍｉｃｒｏｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｃｅｌｌｓｒｅｐｅｒｆｕ￣ｓｉｏｎｉｎｊｕｒｙｖｉａｔｈｅＷｎｔ/β－ｃａｔｅｎｉｎｓｉｇｎａｌｌｉｎｇｐａｔｈｗａｙ[Ｊ].ＣｕｒｒＮｅｕｒｏｖａｓｃＲｅｓꎬ２０２１ꎬ１８(２):２１９－２２６.[４５]ＺＨＡＮＧＬꎬＸＵＳꎬＷＵＸꎬｅｔａｌ.Ｃｏｍｂｉｎｅｄｔｒｅａｔｍｅｎｔｗｉｔｈ２－(２－ｂｅｎｚｏｆｕ－ｒａｎｙｌ)－２－ｉｍｉｄａｚｏｌｉｎｅａｎｄｒｅｃｏｍｂｉｎａｎｔｔｉｓ￣ｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒｐｒｏｔｅｃｔｓｂｌｏｏｄ－ｂｒａｉｎｂａｒｒｉｅｒｉｎ￣ｔｅｇｒｉｔｙｉｎａｒａｔｍｏｄｅｌｏｆｅｍｂｏｌｉｃｍｉｄｄｌｅｃｅｒｅｂｒａｌａｒｔｅｒｙｏｃ￣ｃｌｕｓｉｏｎ[Ｊ].ＦｒｏｎｔＰｈａｒｍａｃｏｌꎬ２０２０(１１):８０１.[４６]ＯＲＳＥＴＣꎬＡＲＫＥＬＩＵＳＫꎬＡＮＦＲＡＹＡꎬｅｔａｌ.ＣｏｍｂｉｎａｔｉｏｎｔｒｅａｔｍｅｎｔｗｉｔｈＵ０１２６ａｎｄｒｔ－ＰＡｐｒｅｖｅｎｔｓａｄｖｅｒｓｅｅｆｆｅｃｔｓｏｆｔｈｅｄｅｌａｙｅｄｒｔ－ＰＡｔｒｅａｔｍｅｎｔａｆｔｅｒａｃｕｔｅｉｓｃｈｅｍｉｃｓｔｒｏｋｅ[Ｊ].ＳｃｉＲｅｐꎬ２０２１ꎬ１１(１):１１９９３.[４７]ＫＮＥＣＨＴＴꎬＳＴＯＲＹＪꎬＬＩＵＪꎬｅｔａｌ.Ａｄｊｕｎｃｔｉｖｅｔｈｅｒａｐｙａｐ￣ｐｒｏａｃｈｅｓｆｏｒｉｓｃｈｅｍｉｃｓｔｒｏｋｅ:ｉｎｎｏｖａｔｉｏｎｓｔｏｅｘｐａｎｄｔｉｍｅｗｉｎｄｏｗｏｆｔｒｅａｔｍｅｎｔ[Ｊ].ＩｎｔＪＭｏｌＳｃｉꎬ２０１７ꎬ１８(１２):２７５６.[４８]ＹＩＮＢꎬＬＩＤＤꎬＸＵＳＹꎬｅｔａｌ.Ｓｉｍｖａｓｔａｔｉｎｐｒｅｔｒｅａｔｍｅｎｔａ￣ｍｅｌｉｏｒａｔｅｓｔ－ＰＡ－ｉｎｄｕｃｅｄｈｅｍｏｒｒｈａｇｅｔｒａｎｓｆｏｒｍａｔｉｏｎａｎｄＭＭＰ－９/ＴＩＭＰ－１ｉｍｂａｌａｎｃｅｉｎｔｈｒｏｍｂｏｅｍｂｏｌｉｃｃｅｒｅｂｒａｌｉｓｃｈｅｍｉｃｒａｔｓ[Ｊ].ＮｅｕｒｏｐｓｙｃｈｉａｔｒＤｉｓＴｒｅａｔꎬ２０１９(１５):１９９３－２００２.[４９]ＬＩＵＤＬꎬＨＯＮＧＺꎬＬＩＪＹꎬｅｔａｌ.ＰｈｔｈａｌｉｄｅｄｅｒｉｖａｔｉｖｅＣＤ２１ａｔｔｅｎｕａｔｅｓｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒ－ｉｎｄｕｃｅｄｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒｍａｔｉｏｎｉｎｉｓｃｈｅｍｉｃｓｔｒｏｋｅｂｙｅｎｈａｎｃｉｎｇｍａｃｒｏｐｈａｇｅｓｃａｖｅｎｇｅｒｒｅｃｅｐｔｏｒ１－ｍｅｄｉａｔｅｄＤＡＭＰ(ｐｅｒｏｘｉｒｅｄｏｘｉｎ１)ｃｌｅａｒａｎｃｅ[Ｊ].ＪＮｅｕｒｏｉｎｆｌａｍｍａ￣ｔｉｏｎꎬ２０２１ꎬ１８(１):１４３.[５０]ＬＩＹꎬＺＨＵＺＹꎬＬＵＢＷꎬｅｔａｌ.Ｒｏｓｉｇｌｉｔａｚｏｎｅａｍｅｌｉｏｒａｔｅｓｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒ－ｉｎｄｕｃｅｄｂｒａｉｎｈｅｍｏｒｒｈａｇｅａｆｔｅｒｓｔｒｏｋｅ[Ｊ].ＣＮＳＮｅｕｒｏｓｃｉＴｈｅｒꎬ２０１９ꎬ２５(１２):１３４３－１３５２. [５１]ＩＳＭＡＥＬＳꎬＮＡＳＯＯＨＩＳꎬＹＯＯＡꎬｅｔａｌ.ＶｅｒａｐａｍｉｌａｓａｎａｄｊｕｎｃｔｔｈｅｒａｐｙｔｏｒｅｄｕｃｅｔＰＡｔｏｘｉｃｉｔｙｉｎｈｙｐｅｒｇｌｙｃｅｍｉｃｓｔｒｏｋｅ:ｉｍｐｌｉｃａｔｉｏｎｏｆＴＸＮＩＰ/ＮＬＲＰ３ｉｎｆｌａｍｍａｓｏｍｅ[Ｊ].ＭｏｌＮｅｕｒｏｂｉｏｌꎬ２０２１ꎬ５８(８):３７９２－３８０４.[５２]ＬＵＤꎬＬＩＵＹꎬＭＡＩＨꎬｅｔａｌ.Ｒｏｓｕｖａｓｔａｔｉｎｒｅｄｕｃｅｓｎｅｕｒｏｉｎ￣ｆｌａｍｍａｔｉｏｎｉｎｔｈｅｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒｍａｔｉｏｎａｆｔｅｒｒｔ－ＰＡｔｒｅａｔｍｅｎｔｉｎａｍｏｕｓｅｍｏｄｅｌｏｆｅｘｐｅｒｉｍｅｎｔａｌｓｔｒｏｋｅ[Ｊ].ＦｒｏｎｔＣｅｌｌＮｅｕｒｏｓｃｉꎬ２０１８(１２):２２５.[５３]ＣＨＥＮＨꎬＧＵＡＮＢꎬＷＡＮＧＢꎬｅｔａｌ.Ｇｌｙｃｙｒｒｈｉｚｉｎｐｒｅｖｅｎｔｓｈｅｍｏｒｒｈａｇｉｃｔｒａｎｓｆｏｒｍａｔｉｏｎａｎｄｉｍｐｒｏｖｅｓｎｅｕｒｏｌｏｇｉｃａｌｏｕｔ￣ｃｏｍｅｉｎｉｓｃｈｅｍｉｃｓｔｒｏｋｅｗｉｔｈｄｅｌａｙｅｄｔｈｒｏｍｂｏｌｙｓｉｓｔｈｒｏｕｇｈｔａｒｇｅｔｉｎｇｔｅｒｏｘｙｎｉｔｒｉｔｅ－ｍｅｄｉａｔｅｄＨＭＧＢ１ｓｉｇｎａｌｉｎｇ[Ｊ].ＴｒａｎｓｌＳｔｒｏｋｅＲｅｓꎬ２０２０ꎬ１１(５):９６７－９８２.(收稿日期:２０２３－０４－２６)。