“新四联”背景下伊伐布雷定治疗CHF的药物经济学评价

目的 从卫生体系角度出发,评价伊伐布雷定在“新四联”背景下治疗慢性心力衰竭（CHF）的经济性。方法 基于真实世界队列研究数据,根据CHF疾病自然发展进程构建Markov模型,循环周期设为3个月,研究时限为20年,贴现率为5%;以质量调整生命年（QALY）和增量成本-效果比（ICER）为产出指标,采用成本-效用分析法评价伊伐布雷定联合“新四联”方案相较于“新四联”方案治疗CHF的经济性,并通过单因素敏感性分析、概率敏感性分析验证基础分析结果的稳健性。结果 基础分析结果显示,伊伐布雷定联合“新四联”方案相较于“新四联”方案的ICER为165 065.54元/QALY,低于以3倍我国2022年人均国内生产总值（GDP）作为的意愿支付（WTP）阈值（257 094元/QALY）。单因素敏感性分析结果显示,贴现率对模型的稳健性影响最大。概率敏感性分析结果显示,在本研究的WTP阈值下,伊伐布雷定联合“新四联”方案具有经济性的概率为59.50%。结论 当采用3倍我国2022年人均GDP(257 094元/QALY)作为WTP阈值时,伊伐布雷定联合“新四联”方案治疗CHF具有经济性。     

贝伐珠单抗联合标准化疗方案治疗复发性宫颈癌患者的成本-效果分析

目的：评价BEV联合标准化疗与标准化疗对复发性宫颈癌患者的成本效果性。方法：根据转移性宫颈癌患者疾病进展与转归过程,基于GOG-240试验,选择马尔可夫(Markov)模型对两种化疗方案进行经济学评价。该模型包括三个相互排斥的健康状态：PFS状态、PD状态和death状态。,效用值与成本单价参考当地某三甲医院费用标准或文献,并对结果进行敏感度分析。结果：模型运行10年结果显示： BEV的加入使得总成本增加233974.10元(503336.67元 vs. 269362.57元)。相比标准化疗组,BEV的加入使总效用值增加0.17 QALY(0.94QALY VS. 0.77QALY),增量成本效果比为1376318.23元/QALY。一维敏感性分析分析结果显示：BEV+chemo组的PFS、BEV的成本、PFS状态的效用值依次为对该模型影响排名前三位的参数。概率敏感性分析结果显示：ICER值大于WTP(3倍GDP)的概率为100%。结论：相比标准化疗方案,BEV联合方案的增量成本效果比远远超过设定的意愿支付阈值,因此,考虑到BEV的单位成本以及其所带来的生存获益, BEV联合治疗不具有成本效果性。     

我国采用伊伐布雷定治疗心力衰竭对医保基金的预算影响分析

目的:评估我国采用伊伐布雷定治疗心力衰竭对医保基金的预算影响,为医保部门解决该药在医院门诊的报销准入以及医院制定进药目录提供相关经济学评价的支持证据。方法:采用Excel决策树模型,基于国内历年来的文献报道数据进行药物经济学分析。首先根据中国心衰患病率估算患病人数,并估算符合纽约心脏病协会(NYHA)心功能Ⅱ～Ⅳ级、收缩压功能失常、符合伊伐布雷定适应证的心衰患者人数,进而估算出患者使用伊伐布雷定而产生的药品费用;其次,估算住院总人次以及因心衰住院所产生的住院医疗费用;然后综合考虑伊伐布雷定的药品费用与因使用该药而使患者避免再次住院从而节省的治疗费用,并进行静态预算影响分析,以评估该药的使用对医保基金预算产生的影响。结果:2013年我国心衰患病率已上升到1.3%,全国35～75岁心衰患者人数估算为约851万,年总住院次数为约432万次。全国心衰患者住院的直接经济负担约为1 689.40亿元。因使用伊伐布雷定治疗后可避免18%患者再次住院从而可节省住院费用约304.10亿元,而服用该药的总药费约为175.25亿元,因此该药的使用可节省隐性医疗费用预算约128.86亿元,具有非常明显的成本-效益。静态预算影响分析结果显示,到2019-2020年,期望伊伐布雷定覆盖心衰患者的比例将增至8.70%,其销售总金额将达到约17.97亿元。增量病例节省费用比值(ICSCR)显示,每增加1例采用伊伐布雷定治疗的心衰患者,则可以节省住院费用约11 951元,扣除伊伐布雷定药品费用6 240元后,还可节余约5 711元。结论:采用伊伐布雷定治疗心衰患者节约下来的住院成本不仅足以抵消伊伐布雷定本身的药费,而且还有溢价的效果;该药在我国治疗心衰患者具有一定经济性。     

阿替利珠单抗治疗转移性非小细胞肺癌的成本效用分析

目的： 评价阿替利珠单抗联合贝伐珠单抗及化疗（ABCP方案）一线治疗转移性非鳞状非小细胞肺癌的经济性。方法： 根据IMpower150临床试验,从中国卫生体系角度建立Markov模型。模型包括疾病未进展、疾病进展和死亡3个健康状态。模型的主要结果为总成本、生命年（life-year,LY）、质量调整生命年（quality adjusted LY,QALY）和增量成本效用比,还进行了一元敏感性分析和概率敏感性分析探讨参数的不确定性。结果： 基线分析结果显示：接受ABCP方案治疗比贝伐珠单抗联合化疗（BCP方案）治疗的患者增加了0.41 QALYs（0.45 LYs）,相应的总成本也增加了690 997元;增量成本效用比为1 688 482元/QALY（1 519 390元/LY）。一元敏感性分析结果显示：对增量成本效用比影响最大的参数是阿替利珠单抗的每周期成本。概率敏感性分析结果显示：增量成本效用比大于意愿支付阈值（212 676元/QALY）的概率为100%。结论： 与BCP方案相比,ABCP方案治疗转移性非鳞状非小细胞肺癌不具有经济性。     

伊伐布雷定治疗慢性心力衰竭的快速卫生技术评估

目的:快速评价伊伐布雷定的有效性、安全性和经济性,为决策者提供证据参考。方法:采用快速卫生技术评估方法,系统检索PubMed、Embase、the Cochrane Library、CNKI、万方等数据库,同时检索相关HTA网站与数据库。使用AMSTAR对系统评价/Meta分析进行质量评价,CHEERS量表对药物经济学文章进行质量评价,由2位评价者根据纳入与排除标准独立筛选文献、提取资料和评价质量后,对有效性、安全性和经济性结果进行定性综合比较与分析。结果:初始检索共获得442篇题录,最终共纳入2篇HTA报告、5篇Meta分析和6篇经济学研究。有效性方面,对于使用心衰标准治疗药物后心率仍未达标或不耐受者,联合使用伊伐布雷定与对照组相比,可降低心率水平、提高LVEF值,差异有统计学意义(P<0.05);但对全因死亡率、心血管死亡率、因心力衰竭住院率等指标的影响差异无统计学意义(P>0.05)。安全性方面,联合伊伐布雷定与未联合相比,不良反应发生率差异无统计学意义。经济性方面,国内外研究均显示,伊伐布雷定可延长患者的QALY并具有较好的成本效果。结论:伊伐布雷定治疗使用SMT后心率仍未达标或不耐受的患者可显著改善部分临床结局指标、不增加安全性风险且具有经济性;但对于心血管死亡率等终点结局还需进一步研究。     

贝伐珠单抗联合标准化疗方案治疗复发性卵巢癌患者的成本-效果分析

目的：评价BEV联合化疗（紫杉醇+卡铂）与单纯化疗对复发性卵巢癌患者的成本效果性。方法：根据复发性卵巢癌患者疾病进展与转归过程,基于GOG-0213试验,选择马尔可夫（Markov）模型对2种化疗方案进行经济学评价。该模型包括三个相互排斥的健康状态：PFS状态、PD状态和death状态。效用值与成本单价参考当地某三甲医院费用标准或文献,并对结果进行敏感度分析。结果：模型运行10年结果显示：BEV的加入使得总成本增加272 607.18元（385 094.06元vs.112 486.88元）。相比标准化疗组,BEV的加入使总效用值增加0.40 QALY（2.19 QALY vs.1.79 QALY）,增量成本效果比为681 517.95元/QALY。一维敏感性分析分析结果显示：BCP组的PFS、BEV的成本、PD状态效用值是依次为对模型影响最大的参数。概率敏感性分析结果显示：ICER值大于WTP（3倍GDP）的概率为100%。结论：相比标准化疗方案,BEV联合方案的增量成本效果比远远超过设定的意愿支付阈值,因此,考虑到BEV的单位成本以及其所带来的生存获益,BEV联合紫杉醇+卡铂方案不具有成本效果性。     

两种方案治疗小儿癫痫的成本-效用比较

目的评价两种治疗小儿癫痫的方案的疗效和经济性,探索成本-效用方法的应用。方法对63例小儿癫痫患者分为两组(A:门诊随访组,B:住院治疗组),使用自编小儿癫痫生命质量量变表对患者进行评价,提取评分法获得效用值,进行成本-效用分析。结果B组的成本-效用比(CUR)为32169.49元/QALY,A组的CUR值为38350.15元/QALY,敏感度分析得到一致结果,增量成本效用分析表明每增加1QALY,A组至少需追加花费23892.69元,故认为B方案在一定条件下更为经济、有效。结论对于慢性病患者采用CUA分析,能够全面评价患者生命质量,保证卫生资源的合理利用。     

伊伐布雷定临床应用合理性和安全性分析

目的：调查住院患者接受伊伐布雷定治疗的情况,了解该药的应用现状和不良反应并分析其危险因素,为规范其临床合理应用提供依据。方法：汇总国内外伊伐布雷定相关指南、文献和专家共识,形成伊伐布雷定临床应用的合理性评价标准,回顾性调查广州医科大学附属第二医院2020年上半年住院患者中使用伊伐布雷定的病例,按照已制订的评价标准进行合理性和安全性分析,并提出合理化用药建议。结果： 2020年上半年共有173例患者应用了伊伐布雷定,其中有效病例169例,不合理使用病例共81例,不合理使用率达47.93%,以用法用量不适宜和特殊人群用药不合理为主要原因;不良反应共5例,发生率为2.96%,以心房颤动、窦性心动过缓和房室传导阻滞等不良反应为主;临床使用期间应多关注患者的血压和心电监护指标,关注伊伐布雷定的用法用量、特殊人群用药和不良反应等方面。结论：伊伐布雷定减慢心率的作用在临床应用越来越普遍,针对其不合理应用情况和不良反应事件,临床药师应密切留意伊伐布雷定临床指南和专家共识等最新信息,制定合理性评价标准和用药建议,做到实时点评和加强医患沟通,促进伊伐布雷定的合理使用。     

LC-MS/MS法测定我国健康受试者48h内伊伐布雷定和去甲伊伐布雷定的尿排泄率

目的:研究健康受试者单次和多次口服盐酸伊伐布雷定片后,伊伐布雷定和其活性代谢产物去甲伊伐布雷定的尿排泄特征。方法:10例健康受试者单次和多次口服盐酸伊伐布雷定片5 mg。在服药前以及服药后48 h内分不同时间段采集尿样,记录尿液体积,用LC-MS/MS检测尿液中伊伐布雷定和去甲伊伐布雷定的浓度,计算伊伐布雷定和去甲伊伐布雷定的平均累计排泄率。结果:受试者单次口服盐酸伊伐布雷定片后,尿液中伊伐布雷定48 h的平均累积排泄率为(14.03±4.65)%;去甲伊伐雷定的平均累积排泄率为(2.02±0.44)%。受试者多次口服盐酸伊伐布雷定片,尿液中伊伐布雷定48 h的平均累积排泄率为(22.63±4.01)%;去甲伊伐雷定的平均累积排泄率为(3.60±1.12)%。结论:本研究所建立的LC-MS/MS方法简便、灵敏、专一性强,可以用于尿液中伊伐布雷定和去甲伊伐布雷定的检测。健康受试者口服盐酸伊伐布雷定片后,尿液中以原型及活性代谢产物去甲伊伐布雷定排泄的量较少。     

帕博利珠单抗联合一线化疗方案治疗晚期胃癌的药物经济学评价

摘要：目的:从中国医疗卫生体系角度出发,对治疗晚期胃癌的帕博利珠单抗、帕博利珠单抗联合化疗、单纯化疗等3种化疗方案进行药物经济学评价,为国内外晚期胃癌患者治疗提供决策参考。方法:基于Ⅲ期临床试验的研究数据,通过文献获取相关的参数,利用TreeAge软件建立Markov模型,对3种用药方案进行成本-效果分析,并用敏感性分析验证模型分析结果的稳定性。结果:根据Markov模型分析结果,相对于帕博利珠单抗方案,单纯化疗方案可增加4.6个质量调整生命年(QALY),同时成本增加104 927.91元,其增量成本-效果比(ICER)为22 810.42元/QALY,低于我国的意愿支付阈值(242 928元/QALY);而帕博利珠单抗联合化疗方案增加3.92 QALY、同时成本增加360 754.87元,其ICER为92 020.30元/QALY;单因素敏感性分析提示,年贴现率、稳定期效用值和进展期效用值对成本-效果分析结果有较大的影响;概率敏感性分析提示随着我国人均国内生产总值(GDP)的增长,相对于帕博利珠单抗方案,单纯化疗方案与帕博利珠单抗联合化疗方案均是优选的方案。结论:相对于帕博利珠单抗治疗晚期胃癌的方案,帕博利珠单抗联合一线化疗方案具有一定的成本-效果,而单纯化疗方案具有明显的经济性优势。     

Role of glutathione in reduction of arsenate and of gamma-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.     

微透析取样技术在中药体内分析中的应用研究进展

本文综述了微透析取样技术在中药体内分析中的应用,介绍微透析取样技术的原理、组成、探针类型、特点,重点阐述了微透析取样技术在测定脑、血液、皮肤等组织器官中中药有效成分浓度的应用实例。表明微透析取样技术在中药药效研究中具有广阔的前景。     

应用PASS系统分析我院2010年住院医嘱

目的:了解我院2010年住院患者的合理用药情况,探讨如何利用合理用药监测系统( PASS)提高合理用药水平.方法:利用PASS对我院2010年15 966例住院患者的1 184 997条用药医嘱进行监测,以黑色警示医嘱为依据,收集不合理用药信息,并对监测结果进行统计、分析.结果:不合理用药医嘱50 261条,发生率为4.24％.绝对禁止黑色医嘱5441条,主要为药物相互作用(66.54％)、注射液体外配伍(17.86％)、用法用量(15.46％)、儿童警告(1.14％).结论:应用PASS系统能有效监测医嘱中的不合理用药情况,有利于提高临床合理用药水平,但PASS系统尚存在局限性,有待进一步完善.     

Changes in levels of dependency and predictors of mortality in elderly people in institutional care in Dunedin

The 1983 study of dependency of subjects in institutional care in Dunedin was repeated two years later. A significant increase in levels of dependency in residential homes, particularly in the Religious and Welfare sector was found. In 1983 there were 29 high dependency residents and 73 medium dependency residents in residential homes. In 1985 these numbers had increased to 55 and 86 respectively. There was no change in the number of low dependency residents. In 1983, 6 high dependency residents had been admitted to residential home care in the year prior to the study. In 1985 the number of high dependency residents recently admitted had increased to 23. There had also been a significant increase in the dependency of patients in Religious and Welfare continuing care hospitals. Of the 933 subjects in institutional care in 1983 who were able to be followed, 354 (37.9%) died in the following 2 years. Mortality rate was higher for those in hospital care (48.1%) than for those in residential home care (29.6%). Mortality rates were higher in more dependent subjects and this was evident for each measure of dependency.     

应用PASS系统对我院2008年住院医嘱的分析

目的监测分析2008年我院住院患者用药情况。方法将PASS系统嵌入医生工作站、临床药学工作站等子系统,构建合理用药计算机网络系统,对住院医嘱进行及时监测,将监测结果向医生反馈,并对其进行统计、分析。结果2008年共监测医嘱3 620 241条,不合理医嘱908条,占0.02%。不合理医嘱中,配伍禁忌(381条)占41.96%,用法用量(381条)占41.96%,药物相互作用(108条)占11.89%,儿童用药(38条)占4.19%。经与医生沟通后,更改不合理医嘱856条,占94.27%。结论PASS系统可有效监测医嘱中的不合理用药,通过与医生交流,大大减少药物不良事件的发生,值得临床推广应用,也为临床药师开展工作带来了极大的便利。但PASS系统尚存在局限性,有待进一步完善。     

Role of desacetylation in the detoxification of cephalothin in renal cells in culture

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.     

2009年某院住院患者抗真菌药用药调查

目的:分析讨论某院抗真菌药使用的合理性,为临床安全有效地使用抗真菌药提供参考。方法:回顾性统计分析某院2009年住院患者抗真菌药用药信息。结果:2009年某院住院患者抗真菌药DDDs排名前3名分别为:氟康唑、制霉菌素和伊曲康唑;使用金额排名前3名分别为:氟康唑、米卡芬净及卡泊芬净;更换一种抗真菌药进行治疗的患者数为176人,在全部患者中占13.4%。结论:应进一步强化用药指征的意识,提高标本送检率,同时改善某些抗真菌用药不合理更换的现象,以避免耐药性发生,从而更好更长远地体现抗真菌药的治疗价值。     

Kinetics of in vitro metabolism of methoxyphenamine in rats

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.     

Comparison of in vitro cell models in predicting in vivo brain entry of drugs

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates.