中国非瓣膜性心房颤动患者华法林使用不足的相关因素分析

目的:评估中国首发缺血性卒中或短暂性脑缺血发作(TIA)的已知非瓣膜性心房颤动(NVAF)患者华法林的使用情况及使用不足的相关因素。方法:从中国国家卒中登记数据库(CNSR)中连续筛选首发缺血性卒中或TIA的NVAF患者,筛选已知心房颤动和新发心房颤动患者,评估华法林在适合抗凝治疗的已知心房颤动患者中的使用比例。采用多变量logistic回归模型评估华法林使用不足的相关因素。结果:在筛选出的11 080例首发缺血性卒中或TIA患者中,有996例(9.7%)患者存在NVAF且无抗凝治疗禁忌症,其中有592例既往已知存在心房颤动。在这些患者中,只有96例(16.2%)发病前服用了华法林,496例(83.8%)发病前未服用华法林。在服用华法林的患者中,只有1例患者入院时的国际标准化比值(INR)在治疗范围(2.0～3.0)内。依据CHADS2卒中风险评分,在卒中发生前的低危心房颤动患者中,有近20.2%的患者服用了华法林,而在中危及高危患者中,华法林的服用比例分别只有15.2%和16.4%。年老的和既往存在冠心病病史的患者服用华法林的可能性较小,而发病前服用抗血小板药物的患者更有可能服用华法林。结论:CNSR中首发缺血性卒中或TIA的NVAF患者中,适宜抗凝治疗的患者存在严重的华法林使用不足,即使接受抗凝治疗,达标率也极低。如果发病前给予合适的抗凝治疗并监测,许多由心房颤动导致的卒中和TIA就可避免。     

新型口服抗凝药在治疗非瓣膜性房颤中的研究进展

目的:为临床合理使用新型口服抗凝药(NOACs)治疗非瓣膜性房颤(NVAF)提供参考。方法:查阅近年来国内外相关文献,对NOACs在治疗NVAF中的研究进行归纳和分析。结果:凝血酶抑制剂达比加群酯和Ⅹa因子抑制剂利伐沙班、阿哌沙班、依度沙班和贝曲西班等NOACs相较于华法林在NVAF患者中,能显著降低卒中、颅内出血及死亡的发生率。NOACs服用方便、无需检测凝血指标、无需频繁调整剂量,在最新的房颤指南中得到推荐,但临床研究有限,价格昂贵,缺乏有效的拮抗药。结论:NOACs在治疗NVAF中有可观的临床发展前景。     

AECOPD患者抗凝药物应用调研与合理性评价

摘要：目的:探讨慢性阻塞性肺病急性加重期(AECOPD)患者抗凝药物的临床应用情况,并评价其应用合理性。方法:采用回顾性分析方法,收集2019年1～12月在我院接受抗凝治疗的AECOPD患者资料,包括性别、年龄、合并症、抗凝药物使用情况、凝血指标及不良反应信息等,评估患者肺栓塞和非瓣膜性心房颤动(NVAF)的危险因素,评价抗凝效果与抗凝药物使用合理性。结果:AECOPD患者预防用抗凝药物7～14 d后凝血功能指标较治疗前有明显改善(PSymbol|@@0.05);AECOPD伴静脉血栓栓塞症(VTE)发生率为21.35%,患者采用华法林治疗出院时INR达标率<50%,出院后继续抗凝比例<50%; AECOPD伴NVAF发生率为30.19%,患者出院后抗凝比例约61.39%。华法林是我院治疗AECOPD伴VTE或NVAF的首选药物,新型口服抗凝药物选择较少;抗凝药物致出血不良反应共6例。结论:我院AECOPD患者VTE及NVAF发生率高,临床治疗药物选择符合指南要求,华法林仍占主导地位,新型口服抗凝药(NOACs)选择相对较少,VTE及NVAF抗凝治疗存在明显不足,需引起临床高度重视。     

不同类型房颤患者使用新型口服抗凝药物和华法林预防卒中的疗效比较:Meta分析

目的比较新型口服抗凝药物(NOACs)与华法林预防不同类型心房颤动(房颤)患者卒中的有效性和安全性。方法应用计算机从PubMed、 Cochrane图书馆、 Elsevier、 Web of Science、中国知网、万方等电子数据库中检索自建库至2018年7月关于口服抗凝治疗预防房颤患者卒中的随机对照临床试验(RCTs)。获取数据资料后用RevMan 5.3和STATA软件进行荟萃及偏倚统计分析,比较口服抗凝治疗在阵发性房颤与持续性或永久性房颤患者卒中预防的有效性和安全性。结果通过筛选最终纳入了4项大型Ⅲ期RCTs,对其荟萃分析表明在阵发性房颤患者中,无论使用NOACs还是华法林,患者卒中和全身性栓塞发生率[NOACs组(2.58%, 197/7 642) vs.华法林组(3.25%, 193/5 929), RR=0.83, 95%CI:0.61～1.13, P=0.24, I2=57%]和大出血发生率[NOACs组(6.4%, 489/7 642) vs.华法林组(7.12%, 422/5 929),RR=0.88, 95%CI:0.78～1.00, P=0.06, I2=0%]无显著差异。在持续性或永久性房颤患者中,NOACs组卒中和全身性栓塞发生率显著低于华法林组[NOACs组(3.22%, 813/25 197) vs.华法林组(7.12%, 846/20 956), RR=0.82, 95%CI:0.75～0.90, P <0.000 1, I2=0%],同时大出血事件也显著降低[NOACs组(5.5%, 1 386/25 197) vs.华法林组(6.45%, 1 351/20 956), RR=0.85, 95%CI:0.73～0.99, P=0.03, I~2=77%]。结论阵发性房颤患者使用NOACs预防卒中的有效性和安全性与华法林相当,持续性或永久性房颤患者使用NOACs预防卒中的有效性和安全性较华法林好。     

新型抗凝药与华法林用于非瓣膜性房颤患者卒中防治的成本效果分析

目的:评估中国非瓣膜性房颤患者使用新型抗凝药预防卒中的成本效果,为中国房颤患者抗凝治疗药物的合理选用提供理论依据。方法:基于全球性临床试验ARISTOTLE、RE-LY及ROCKET-AF的研究数据及我国目前医疗成本,建立一年期决策树及长期外推Markov模型的方法,通过分别计算3种新型口服抗凝药物阿哌沙班(5 mg bid)、达比加群(150 mg bid、110 mg bid)、利伐沙班(20 mg qd)和华法林的调整质量生命年(QLAYs)及治疗成本,对新型抗凝药物用于中国房颤患者卒中预防的成本效果进行了分析和研究。结果:NOACs治疗的总成本为163586~582710元,使用NOACs患者可获得的质量调整生命年为6.812~7.010。以华法林为参考的增效成本效果分析显示,成本效果比(ICER)为177271~739480元/QLAY,ICER_利伐沙班> ICER_阿哌沙班> ICER_{达比加群150 mg}> ICER_{达比加群110 mg}。3种抗凝药物与华法林比较的ICER均大于我国人均国民生产总值(GDP)的3倍,但小于部分城市人均GDP的3倍。一维敏感度分析显示该成本效果分析结果稳定可靠。结论:目前在我国,与华法林相比,使用新型抗凝药物预防非瓣膜性房颤患者卒中不具备成本效果优势。目前仅在我国经济发达的某些城市,可推荐阿哌沙班或达比加群用于房颤卒中的治疗。     

达比加群酯在老年非瓣膜性房颤患者中的疗效及安全性分析

目的:比较新型口服抗凝药物达比加群酯和传统抗凝药物华法林在老年非瓣膜性房颤患者中的安全性。方法:收集2015年1月至2016年12月在北京大学第一医院老年科住院的接受达比加群酯或华法林抗凝治疗的老年非瓣膜性房颤患者109例,根据使用抗凝药物不同,分为达比加群酯组65例和华法林组44例,监测凝血功能指标,比较两组治疗后凝血功能的变化情况、血栓栓塞事件发生的情况。结果:老年非瓣膜性房颤患者存在危险因素多、伴随疾病多、需要联合使用抗血小板聚集药物比例高的特点。达比加群酯组血栓栓塞事件发生率3.06%,华法林组6.81%,两组比较无统计学差异(P0.05)。结论:新型口服抗凝药物达比加群酯与华法林抗栓效果相当,不良事件发生率更低。     

慢性肾功能不全合并非瓣膜房颤患者抗血栓药物治疗的有效性和安全性概述

摘 要约1/3的房颤（AF）患者伴发慢性肾脏疾病（CKD）。AF患者存在全身性栓塞风险,因抗凝药物的使用存在出血的风险。CKD,尤其是终末期CKD,增加了AF患者血栓栓塞以及大出血的风险。许多研究已评估了华法林在AF合并CKD,尤其是终末期CKD患者（包括血液透析患者）缺血性卒中,全身栓塞和大出血风险的影响,但研究结果不一致。新型口服抗凝药物（NOACs）已在Ⅲ期（中度）CKD患者中进行了研究,研究提示,经剂量调整后,NOACs可获得与华法林相近的预防血栓栓塞的疗效,并可明显减少致命性出血的风险。本文就CKD合并非瓣膜性AF患者使用华法林和NOACs的有效性和安全性做一综述。     

对380例非瓣膜病性房颤抗栓治疗的调查与分析

收集2014年1月至2016年12月间入住苏州大学附属第一医院的380例非瓣膜病性房颤（NVAF）患者的病历资料。通过卒中和出血风险评估制定抗栓治疗方案,作基因型检测和国际标准化比值（INR）监测等,并对未抗凝治疗的原因进行分析。结果显示,NVAF患者的总体抗凝率为61.84%,其中CHA2DS2-VASc评分≥2分的抗凝率为63.33%,在289例抗栓治疗的患者中,有59.52%选择华法林抗凝,21.80%选择达比加群酯抗凝;172例华法林抗凝的患者出院时INR的达标率为22.09%,行CYP2C9和VKORC1基因型检测的患者其INR达标率（40.74%）明显高于未检测者。     

达比加群酯用药教育

华法林是过去半个世纪证实抗凝疗效确切、安全、价格便宜的口服抗凝药,在心脑血管血栓疾病的防治中地位相当重要。但由于其治疗窗比较窄,个体差异大,起效缓慢、药物相互作用常见,需频繁监测凝血时间及国际标准化比值（ INR）,影响了其在临床实践中的广泛应用［1］。新型口服抗凝药（ NO_ACs）克服了华法林的上述缺点,以其剂量固定,出血风险更低以及药物相互作用小的优势而更受医师及患者的青睐。达比加群酯即为其中一种,但同其他同类 NOACs 一样亦存在如下弊端：（1）半衰期短,对药物依从性要求高;（2）存在部分药物相互作用;（3）暂未发现特异性拮抗剂。特别需要说明的是达比加群酯80％从肾脏排泄,对特殊人群使用应如何调整剂量有待于进一步评价。故临床药师有必要了解该药物相关知识,对患者进行用药教育,从而配合医师保障患者抗凝治疗的安全、有效。笔者以临床药师角度对达比加群酯的用药教育进行阐述,以期保证达比加群酯的安全、合理用药。现报道如下。     

新型口服抗凝药物在房颤治疗及预后方面的研究进展

华法林是防治房颤卒中最有效抗凝药物。出血、频繁监测INR值等缺点限制了华法林临床使用率。新近一些新型口服抗凝药物的研究不断涌现,许多研究结果表明这些新型口服抗凝药物在预防卒中的作用中不劣于华法林,且出血风险可能较华法林低,故有望取代华法林这一传统抗凝药。本文系统回顾近年有关口服抗凝药的相关研究,并将这些研究进展综述如下。     

Effet de l''intoxication experimentale par l''alcool sur la reponse d''immunite a mediation cellulaire de la souris

Repeated ip injection of ethyl alcohol in a relatively high dose depressed the immune response, to a greater degree in Swiss mice than in C57BL/6 mice, as shown by a diminution in granuloma size and in the hypersensitivity reaction to tuberculin compared with untreated controls. The control of bacillary multiplication in the popliteal lymph node was more efficient in alcohol-treated Swiss mice than in the corresponding controls, but was less efficient in alcohol-treated C57BL/6 animals than in their controls. Alcohol treatment caused no reduction in the number of circulating lymphocytes, and no modification of the distribution of B and T lymphocytes in the spleen, or of the stimulation of T lymphocytes in the presence of mitogens.     

知母宁对低氧高二氧化碳肺心病大鼠心肌、肝组织丙二醛和SOD含量的影响

目的:观察知母宁对慢性低O2高CO2肺心病大鼠心肌及肝脏组织超氧化物歧化酶(superox-ide dismutase,SOD)、丙二醛(malondialdehyde,MDA)的影响。方法:将SD大鼠分为正常对照组、4周低O2高CO2组(模型组)、4周低O2高CO2+知母宁组(知母宁组);制备慢性低O2高CO2肺心病大鼠模型,观察各组心肌、肝组织病理学改变;测定心肌、肝组织超氧化物歧化酶(SOD)、丙二醛(MDA)的含量。结果:光镜下模型组大鼠心肌损伤、肝组织脂肪变性明显,知母宁组上述改变不明显;模型组大鼠肝组织MDA较正常组显著升高,而SOD显著下降,知母宁组大鼠肝组织MDA较模型组显著降低,而SOD显著升高;模型组大鼠心肌组织MDA较正常组显著升高,而SOD显著下降,知母宁组大鼠心肌组织MDA较模型组显著降低,而SOD显著升高。结论:慢性低O2高CO2肺动脉高压状态下大鼠心肌、肝脏组织脂质过氧化增加,知母宁能减轻慢性低O2高CO2大鼠心肌、肝脏组织脂质过氧化作用。     

Tuberculosis in patients with systemic rheumatic or pulmonary diseases treated with glucocorticosteroids and the preventive role of isoniazid: a review of the available evidence

Development of tuberculosis (TB) is a concern in patients who receive glucocorticosteroids for the treatment of chronic rheumatic or pulmonary diseases. However, the incidence of development of TB in such patients and the prophylactic role of isoniazid (INH) are unclear. We evaluated the available evidence from 20 relevant prospective and retrospective cohort and case–control studies identified in the PubMed and Cochrane databases. The frequency of development of TB in the populations studied varied from 0% to 13.8%. This figure was low in studies performed in countries with a low incidence of TB (0% in the USA and Greece, 0.6% in France and 1.35% in Spain). In contrast, the frequency of development of TB in the studied cohorts was high in studies performed in countries with a moderate to high incidence of TB (from 2.5% in South Korea to 13.8% in The Philippines). Isoniazid prophylaxis (INHP) was found to decrease the incidence of development of TB in two of four studies that examined this intervention. The available evidence suggests that patients who receive steroids for the treatment of chronic rheumatic or pulmonary diseases and who live in countries with a high incidence of TB have a high risk of development of TB in contrast to patients who live in countries with a low incidence of the infection. However, the role of INHP even for patients living in countries where TB is endemic is unclear because the effectiveness of INH in preventing TB development in such patients is not well established and there are cost-effectiveness and safety issues.     

Heroin use and HIV risk-taking behaviour among women injecting drug users

This study compares drug use, injecting and sexual risk-taking behaviour among pregnant injecting drug users (IDUs) enrolled in methadone maintenance treatment (MMT), non-pregnant women IDUs enrolled in MMT and women IDUs not enrolled in treatment. There was no significant difference between pregnant IDUs enrolled in MMT and women IDUs not enrolled in treatment in terms of their injecting risk-taking behaviour. Both groups reported significantly higher levels of injecting risk-taking behaviour compared to (non-pregnant) women enrolled in MMT. Pregnant women enrolled in MMT reported a significantly lower methadone dose compared to non-pregnant women in MMT. There was a trend for pregnant women enrolled in MMT to report a higher level of heroin use compared to non-pregnant women in MMT. The lack of evidence for a difference in level of injecting risk-taking behaviour between pregnant IDUs enrolled in MMT and women IDUs not enrolled in treatment suggests the need for additional strategies among pregnant IDUs to reduce IDU and injecting risk-taking behaviour. Possible strategies include maintenance on higher doses of methadone and the application of relapse prevention strategies.     

The contribution of in vitro toxicity data in hazard and risk assessment: current limitations and future perspectives

This paper discusses the role of in vitro toxicology in hazard and risk assessment. A short historical overview of the development of the field of in vitro toxicology is given, showing the possibilities, as well as the limitation for using in vitro methods in screening and in studying mechanisms of toxicity. Although the development of the use of in vitro methods over the last two or three decades is vast, the application in risk assessment is still limited. The need for a more integrated approach, i.e. using in vitro data not in isolation, but in combination with data on structure-activity and in silico biokinetic models is discussed. It is foreseen that the role of in vitro methods in future risk assessments will greatly enhance, also in the light of recent developments in technologies such as genomics and systems biology.     

制药工业展望

简要评述了世界制药工业２０年取得突破的新药，在开发中的具有 新作用机制的药物，药理滨革命性进展以及新药研究开在采用的新研究手段，在此基础上对世界医药市场与制药工业作了展望。     

Effects of acipimox and cholestyramine on serum lipoproteins,non-cholesterol sterols and cholesterol absorption and elimination

Summary The hypolipidaemic and metabolic effects of cholestyramine combined with acipimox or placebo have been evaluated in a double-blind ninety-day study in 18 patients with xanthomatous familial hypercholesterolaemia.Serum LDL-cholesterol was reduced by 35% in the cholestyramine group and 39% in the acipimoxcholestyramine group. The latter treatment increased the HDL-cholesterol level. Serum VLDL-cholesterol and triglyceride concentrations were unchanged.Cholesterol absorption efficiency was significantly reduced, and bile acid synthesis and faecal cholesterol elimination in both groups were increased. The metabolic changes were similar in the two treatment groups, but the increase in faecal neutral sterol excretion was significant only when acipimox was added.The serum cholesterol precursor sterol contents were similarly increased during the two treatments, indicating enhancement of endogenous cholesterol synthesis.The decrease in cholesterol absorption and the increase in neutral sterol excretion were more pronounced in subjects with >30% than in those with <30% reduction in LDL-cholesterol.The changes in serum total and LDL-cholesterol levels and cholesterol metabolism were not related to apoE phenotype, but the increase in HDL-cholesterol was higher in E4 then in E3 subjects.     

Interseasonal variability in biomarkers of exposure in fish inhabiting a southwestern Australian estuary

The Swan-Canning Estuary, in southwestern Australia, undergoes distinct seasonal changes, with freshwater discharge predominant in the winter (wet) season and low flow with high salinity predominant in the dry summer season. To investigate seasonal variability in biomarkers of exposure in fish, black bream (Acanthopagrus butcheri) were collected from seven sites in the Swan-Canning Estuary in winter 2000 and in summer 2001. No interseasonal or intersite differences in serum sorbitol dehydrogenase concentration were found, indicating the measured mixed-function oxygenase (MFO) enzymes were not influenced by liver damage. The ethoxyresorufin-O-deethlyase (EROD) activity of the postspawning females was higher in summer than in winter but was significantly lower than that in males in both seasons, suggesting estradiol suppression in females. Sexual differences in ethoxycoumarin-O-deethylase (ECOD) activity were not evident in either season. Both EROD and ECOD activities and polycyclic aromatic hydrocarbons (PAH) biliary metabolites had significantly different patterns of induction between seasons. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was significantly higher in summer, indicating the sources of petroleum hydrocarbons were petrogenic compared to in winter, when the source was a mixture of pyrogenic and petrogenic PAHs. There was no upstream or downstream gradient of response in any biomarker in either season, demonstrating that there were multiple sources of contaminant input into the estuary. Although winter biomarker levels were triggered by the discharge runoff from major roads and drains, summer biomarker levels appear to have been related to recreational boating use on the estuary.     

Influence of shock-induced fighting and social factors on dopamine turnover in cortical and limbic areas in the rat

The present experiments investigated changes in dopaminergic mesocorticolimbic neurones originating from the A10 cell group, in animals exposed to electric shocks in pairs or individually, in comparison to animals receiving no shock and tested in pairs or alone. The social setting under which shock occured had no influence on the increases in DOPAC levels observed in animals exposed acutely or chronically to electric shocks. In contrast, subordinate rats in the paired shock condition had lower tyrosine hydroxylase activity in the accumbens than dominant rats. Pairing of animals in the test cage without shock induced an increase in accumbens DOPAC levels.     

Extraversion as a modifying factor in catecholamine and behavioral responses to ethanol

Individual differences in catecholamine response to stress and ethanol were tested in extraverts and introverts on the basis of Eysenck's drug postulate claiming that introverts would be less susceptible to sedative drugs like ethanol. Forty-four healthy males received either 0.8 g/kg ethanol mixed into a drink of caffeine-free cola or a respective placebo and were tested with a stressful mental arithmetic task before and 40 min after the intake of the drink. Plasma catecholamines were determined from blood samples drawn at five defined intervals from an indwelling cannula and self-ratings on deactivation, relaxation, and anxiety were obtained as well as quality and quantity of performance in the arithmetic task. Results showed that there was no difference in catecholamine stress responses between introverts (Ex –) and extraverts (Ex +) before the drink, but that the intake of the fluid (both ethanol and placebo) resulted in higher norepinephrine (NE) increases in Ex – than in Ex +. The combined effects of ethanol and stress yielded larger responses of longer durations in Ex– than in Ex +. The concomitant psychological changes showed larger reductions in anxiety and increases in relaxation as well as larger decrements in quality of performance (% errors) in introverts in spite of their higher catecholamine increases. Thus, the predictions on the basis of arousal theory could not be verified experimentally and the drug postulate has to be modified in the sense that introverts probably have a higher depletion of NE in the central nervous system under physical but not under mental stress which is reflected by higher levels in the plasma and respective decreases in performance and activation.