药物的心脏毒性及其评价方法的研究进展

药物的心脏毒性研究已经成为药物临床安全性评价的一项重要内容。随着上市药物的逐步增多,心脏毒性药物不良反应的报道也呈现上升趋势,近年来药物心脏毒性评价的研究也越来越受到国内外学者的青睐,但是药物心脏毒性评价还没有建立一套客观准确的体外方法。拟全面归纳了心脏毒性药物的分类,整合了药物心脏毒性评价的方法,并对药物心脏毒性评价新技术进行了介绍,为心脏毒性药物的安全性评价工作的开展提供了思路。     

高龄ST段抬高急性心肌梗死患者急诊介入治疗分析

目的评价急诊经皮冠状动脉介入治疗(PCI)对高龄ST段抬高急性心肌梗死患者的治疗效果与安全性。方法选择急诊PCI的高龄急性心肌梗死患者64例为PCI组,并选择同期采取药物保守治疗的65例高龄急性心肌梗死患者作为对照组,评价两组患者手术成功率、病死率、相关并发症及随访期间心脏不良事件发生情况。结果 PCI组介入成功率为98.4%(63/64)、出血等并发症10.9%(7/64)、院内外死亡率1.6%(1/64)、经随访表明主要心脏不良事件12.5%(8/64)。药物治疗组介入成功率为95.4%(62/65),院内外死亡率为12.3%(8/65),经随访主要心脏不良事件16.9%(11/65)。两组院内外死亡率比较,差异有统计学意义(P<0.01),而心脏不良事件比较,差异无统计学意义(P>0.05)。结论高龄患者急性心肌梗死急诊介入治疗成功率高,比药物治疗的并发症少、存活率高,并发症处理及时,能够很好地控制病情。     

转基因小鼠在药物致癌性评价中的应用

致癌性实验是药物非临床安全性评价的重要内容,用以考察药物对动物的潜在致癌作用,辅以机制研究等以评价和预测人体长期用药带来的风险。转基因小鼠肿瘤模型的建立为肿瘤研究带来了巨大变化,转基因动物模型也成为致癌性研究的重要选择之一。本文主要参考国际现有指导原则和已上市药品评价资料,概述当前常用转基因动物的特征及其在药物安全性评价中的实际应用情况,为我国致癌性评价中转基因动物的应用提供参考。     

大环内酯类抗菌药物辅助治疗肺部铜绿假单胞菌感染疗效和安全性的系统评价

目的:系统评价大环内酯类抗菌药物辅助治疗肺部铜绿假单胞菌(PA)感染的疗效和安全性,以为临床治疗提供循证参考。方法:计算机检索Pub Med、Ovid、中国期刊全文数据库、中文科技期刊数据库、中国生物医学文献数据库、万方数据库,收集PA敏感药物联用大环内酯类抗菌药物(试验组)对比PA敏感药物单用(对照组)治疗肺部感染PA的随机对照试验(RCT),提取资料并对纳入研究进行Jadad质量评分后,采用Rev Man 5.2统计软件对同质性结果进行合并分析。结果:共纳入13项RCT,合计872例患者。Meta分析结果显示,试验组患者临床有效率[OR=6.42,95%CI(4.23,9.74),P<0.001]和PA清除率[OR=6.10,95%CI(4.10,9.09),P<0.001]显著高于对照组,体温恢复至正常时间[MD=-1.14,95%CI(-1.35,-0.94),P<0.001]、咳嗽咳痰消失时间[MD=-1.70,95%CI(-1.97,-1.44),P<0.001]、血象恢复至正常时间[MD=-1.24,95%CI(-2.04,-0.43),P<0.001]显著短于对照组,差异均有统计学意义。两组患者不良反应发生率比较差异无统计学意义[OR=1.30,95%CI(0.73,2.31),P=0.37]。结论:大环内酯类抗菌药物辅助治疗肺部PA感染的疗效与安全性较好。受纳入研究方法学质量限制,该结论有待大样本、高质量的RCT进一步验证。     

儿童用药物非临床安全性评价

目前,主要是由成年动物和成人研究的安 全性资料支持儿童用药,但这并不足以能评估药物 对儿童人群特定发育过程中可能存在的影响,而且 有些影响难以在临床试验中或通过常规的上市后监 督来发现,因而需要进行幼年动物的非临床安全性 评价。本文参考FDA的相关指导原则,对幼年动物 安全性评价的一般性考虑、与临床研究对应的幼年 动物研究的时间安排、试验设计和评价等方面进行 讨论,以期为我国儿童用药物非临床安全性研究与 评价提供参考,为将来制定我国的相关指导原则积 累经验。     

基于加权TOPSIS法的罗沙司他在治疗肾性贫血中的合理性评价

目的建立罗沙司他药物合理性评价标准,为治疗肾性贫血临床合理应用罗沙司他提供参考依据。方法参考罗沙司他的药品说明书、专家推荐意见和应用指南等制定罗沙司他药物合理性评价细则,并应用加权优劣解距离法(TOPSIS)对亳州市人民医院2020年1月至2021年7月116例应用罗沙司他的出院病历进行评价。结果116份病历中,与最优方案的相对接近程度(Ci)大于0.9的15例(占12.93%),Ci在0.8~0.9之间的2例(占1.72%),Ci在0.7~0.8之间的27例(占23.28%),Ci在0.6~0.7之间的31例(占26.72%),Ci小于0.6的41例(35.35%)。结论基于加权TOPSIS法制定的罗沙司他在治疗肾性贫血中的药物合理性评价方法切实可行,评价结果显示,该院罗沙司他使用存在不合理现象,医院需在用法用量、治疗过程实验室参数监测和肾性贫血评估等方面进一步规范罗沙司他的合理使用。     

基于熵权TOPSIS评价我院围手术期预防用抗菌药物的合理性

目的:采用熵权优劣解距离法(TOPSIS)评估我院围手术期预防用抗菌药物的合理性,为临床合理用药提供参考。方法:依据《抗菌药物临床应用指导原则》(2015年版),参照药物说明书及相关文献,建立基于熵权TOPSIS的围手术期预防抗菌药物利用评价细则,统计我院2020年1月～2021年7月围手术期病历,并进行合理性评价。结果:评价的428份病历中,与最优方案接近程度(Ci)大于80%的308例(占比72.0%),Ci在60%～80%的39例(占比9.1%),小于60%的81例(占比18.9%)。熵权值最大的指标是给药剂量,主要问题集中在心脏科预防使用头孢呋辛的剂量问题。结论:基于熵权TOPSIS模型的围手术期预防抗菌药物合理性评价方法可以综合多个指标进行评价,结果显示我院围手术期预防抗菌药物使用基本合理。通过熵权法提示药物剂量合理性是我院存在的主要问题,应通过重点监控来减少相关不合理性的发生,为临床合理用药提供了更有效的管控介入点。     

模式生物斑马鱼在心功能评价中的应用

斑马鱼繁殖力强、体积小、易饲养、发育快速、胚胎透明,与人类基因组同源性高,心脏结构和功能与哺乳类动物高度相似。基于斑马鱼模型的药物实验具有用药量少、周期短、指标易观察等优势,近年来斑马鱼模型在药物心血管安全性评价和心脏保护活性筛选领域得到了广泛应用。结合课题组前期研究及国内外文献,综述斑马鱼心功能评价应用进展,以期为斑马鱼在心血管药物安全性和活性评价中的应用提供参考。     

《药物非临床研究质量管理规范》知识简介

新药研发必须经过一系列严格、科学的实验检验，所研制的药品必须符合安全、有效和质量可控的原则。药物安全性评价的目的就是对新药可能对人体健康造成的危害和危害程度进行评价，工作范围包括单次给药毒性试验、反复给药毒性试验、生殖毒性试验、遗传毒性试验、致癌试验、局部毒性试验、免疫原性试验、依赖性试验、毒动学试验、安全性药理评价，以及与评价药物安全性有关的其他试验。我国法律规定，药物非临床研究安全性评价机构应建立完善的组织管理体系，各部门应配备专业人员。安全性评价机构的建设包括硬件(如试验场地、设施、仪器设备)和软件(包括工作人员培训、操作规程和检查规程)建设。同时，国家食品药品监督管理局还推行了对药物非临床研究安全性评价机构的认证工作。随着各项法律法规的健全，我国对药物研究的监管也将进一步加强。     

药品临床前慢性毒理实验质量控制因素分析

药品临床前大鼠慢性毒性实验是药物非临床安全性研究的重要组成部分,是药物非临床毒理学研究中综合性最强、获得信息最多和对临床指导意义最大的研究。该文结合我国药品非临床前大鼠慢性毒理实验规定及实验室十余个大鼠慢性毒理学实验的经验和教训,分析探讨了实验中动物实验质量的控制问题。认为大鼠实验技术因素的质量控制和值得关注的影响动物实验结果的环境控制、动物福利控制、误差控制决定着大鼠慢性毒理学实验结果的客观性,直接影响药物的安全性评价结果,其标准化问题应引起新药研发人员及管理机构的重视。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Trichinellosis in immigrants in Switzerland

We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia.