CYP2C19基因多态性与急性脑梗死患者氯吡格雷疗效的相关性研究

目的探讨急性脑梗死患者CYP2C19基因多态性与氯吡格雷疗效的相关性。方法采用限制性片段长度多态性PCR法对171例急性脑梗死患者进行CYP2C19基因多态性检测。所有患者给予氯吡格雷治疗2周。分别于治疗前及治疗后第1 d、第5 d进行血小板聚集率检测,于治疗前及治疗后第1周、第2周进行NIHSS和日常生活活动能力评价(ADL)评分。计算血小板聚集抑制率并进行分析。结果本组171例患者中野生型纯合子(A组)79例,均为CYP2C19*1/*1;野生型基因与突变基因杂合子(B组)71例,包括55例CYP2C19*1/*2及16例CYP2C19*1/*3;突变基因纯合子或杂合子(C组)21例,包括11例CYP2C19*2/*2、9例CYP2C19*3/*3及1例CYP2C19*2/*3。治疗后第1 d及第5 d时,3组间血小板聚集抑制率的比较差异均有统计学意义(均P0.05)。与治疗前比较,3组治疗后第1周、第2周NIHSS评分均显著降低,ADL评分均显著升高(均P0.05)。与A组比较,B组及C组治疗后第1周、第2周NIHSS评分均明显升高,ADL评分均明显降低(均P0.05)。多因素Logistic回归分析显示,吸烟(OR=1.584,95%CI:1.079~2.136,P=0.004)及CYP2C19基因多态性(OR=1.837,95%CI:1.106~2.540,P=0.002)均与急性脑梗死患者血小板聚集抑制率独立相关。结论 CYP2C19基因多态性可影响急性脑梗死患者氯吡格雷治疗的疗效。     

急性脑梗死患者基因多态性对氯吡格雷疗效及终点事件的影响

目的探讨急性脑梗死患者基因多态性对氯吡格雷疗效及终点事件的影响。方法选取2016-06—2017-06新乡市第一人民医院神经内科收治的急性脑梗死患者418例。口服氯吡格雷5 d后抽取外周肘静脉血,血栓弹力图仪测定血小板抑制率。采用改良多重高温连接酶检测反应技术(iMLDR)对患者CYP2C19与ABCBl基因多态性进行分型。出院后进行24个月的随访,记录主要终点事件发生类别及时间。结果根据CYP2C19*2/*3快速代谢型、中间代谢型、慢代谢型的血小板抑制率之间,以及ABCBl C3435T不同基因型之间差异均有统计学意义(P0.01);而ABCBlT(-620)C不同基因型的血小板抑制率之间差异无统计学意义(P0.05)。校正可能的混杂因素后,进行多元线性回归分析显示,CYP2C19*2/*3、ABCBl C3435T是血小板抑制率的独立影响因素;同时还发现体重指数(BMI)26 kg/m~2也是血小板抑制率的独立影响因素。共382例患者完成随访研究,终点事件发生率为13.61%(52/382),其中缺血性脑卒中复发36例(9.42%),心肌梗死4例(1.05%),血管性死亡12例(3.14%)。根据是否携带CYP2C19*2/*3基因分为2组,生存分析Log-Rank检验显示差异有统计意义(P0.05);而ABCBlT(-620)C、ABCBl C3435T基因的显性与阴性患者生存曲线间差异无统计学意义(P0.05)。多因素Cox回归分析显示,CYP2C19*2/*3基因携带是临床终点时间的独立危险因素;同时年龄也是临床终点时间的独立危险因素。结论携带CYP2C19*2/*3、ABCBl C3435T等位基因的急性脑梗死患者氯吡格雷疗效降低,其中携带CYP2C19*2/*3等位基因的患者终点事件风险增高。     

CYP2C19基因多态性与首发缺血性卒中氯吡格雷二级预防复发风险的关联研究

目的探讨CYP2C19基因多态性与规律服用氯吡格雷预防缺血性卒中二级复发风险之间的关系。方法入组首次缺血性卒中的326例汉族患者,采用DNA微阵列芯片法检测CYP2C19基因多态性,随访患者缺血性卒中复发情况,分析规律服用氯吡格雷的患者卒中复发与CYP2C19基因多态性的关系。结果对入组患者经过1～37个月[平均(14.44±5.07)个月]的随访,共139例规律服用氯吡格雷,其中29(20.86%)例出现卒中复发。中代谢型和慢代谢型患者的复发风险较快代谢型升高,比值比(odds ratio,OR)分别为3.05[95%可信区间(confidence interval,CI)1.11～8.43,P=0.025]和9.17([95%CI2.39～35.16,P0.001]。携带*2(G681A)A等位基因患者的卒中复发风险是携带G等位基因患者的2.63倍(P0.001)。携带*2突变杂合子和纯合子患者卒中复发风险分别是野生型的2.82倍(P=0.026)和9.69倍(P0.001)。携带有1个失功能(loss of function,LOF)等位基因者卒中复发的风险是未携带者的3.02倍,(95%CI 1.13～8.05,P=0.030),携带2个LOF等位基因者卒中复发的风险是未携带者的11.01倍(95%CI 2.67～45.24,P0.001)。多因素Logistic回归分析提示携带LOF等位基因是卒中复发的独立危险因素。结论规律服用氯吡格雷进行二级预防的首发缺血性卒中患者,中慢代谢型患者的卒中复发风险较快代谢型升高,携带CYP2C19 LOF等位基因是首发缺血性卒中患者卒中复发的独立危险因素。     

CYP2C19基因多态性与奥氮平所致药物性肝损伤的关联性研究

目的:研究细胞色素酶CYP2C19基因多态性与奥氮平所致药物性肝损伤(DILI)间的关联性。方法:对127例单一服用奥氮平的精神分裂症患者的CYP2C19位点rs4244285、rs4986893、rs12248560进行基因分型检测,分析比较服药后出现药物性肝损伤(DILI)患者(DILI组)与未出现DILI患者(非DILI组)3个SNPs等位基因及基因型频率差异。结果:两组间3个等位基因和基因型频率、各代谢类型频率比较差异无统计学意义(P0.05),在3位点基因类型比较中,DILI组*1/*3基因频率低于非DILI组,差异有统计学意义(P=0.034)。结论:CYP2C19基因多态性与奥氮平所致DILI易感性可能有关,CYP2C19中*1/*3基因型可能是奥氮平所致DILI的保护性因素。     

细胞色素P450酶2C19基因多态性与缺血性脑血管病患者介入术后服用氯吡格雷临床预后的相关分析

目的 探讨细胞色素P450酶2C19(CYP2C19)基因多态性与缺血性脑血管病患者介入术后长期服用氯吡格雷临床预后的相关性.方法 入选南京卒中注册系统中2009年4月至2010年12月行脑血管支架植入术并长期服用氯吡格雷的缺血性卒中患者194例.采用多重高温连接酶检测反应技术对人选病例的CYP2C19*2和CYP2C19 * 3位点进行分型,并对这些患者进行随访.主要终点事件包括缺血性脑血管事件和死亡;次要终点事件包括出血性血管事件和其他血管事件.结果 平均随访(19.4±9.9)个月,主要终点事件发生率为16.5％ (32/194).CYP2C19*2基因位点分型结果显示,194例患者中,CYP2C19*1*1型患者87例(44.8％),CYP2C19*1 * 2型患者88例(45.4％),CYP2C19 * 2*2型患者19例(9.8％).携带CYP2C19 * 2基因的患者随访期间主要终点事件的发生率明显高于非携带者[24/107(22.4％)与8/87(9.2％),HR =2.74,95％ CI 1.23 ～6.10,p=0.01].CYP2C19*3基因位点分型结果显示,CYP2C19 * 1 * 1基因型患者181例(93.3％),CYP2C19 * 1 * 3基因型患者13例(6.7％).CYP2C19 * 1*1和CYP2C19*1*3的两组患者之间主要终点事件发生率的差异无统计学意义.将年龄、性别、体重指数、高血压、糖尿病等危险因素纳入多因素COX回归模型分析显示,CYP2C19*2是主要终点事件的发生独立危险因素(HR=2.89,95％ Cl 1.10 ～7.60,P=0.03).结论 CYP2C19*2基因位点的多态性可能是影响脑血管支架术后服用氯吡格雷的患者临床预后的重要影响因素.     

CYP2C19基因多态性与急性脑梗死患者氯吡格雷抵抗的关系

目的探讨CYP2C19基因多态性与急性脑梗死患者氯吡格雷抵抗的关系。方法检测118例急性脑梗死患者的CYP2C19基因,根据基因型分为野生型组、突变杂合型组及突变纯合型组。使用血栓弹力图测定二磷酸腺苷(ADP)诱导的血小板聚集抑制率,比较各组结果。结果根据基因分型,将患者分为野生型组45例(38.1%),突变杂合型组54例(45.8%)及突变纯合型组19例(16.1%)。与野生型组比较,突变纯合型组与突变杂合型组的血小板抑制率均显著下降(均P0.01),氯吡格雷抵抗率明显增高(P0.05~0.01)。与突变杂合型组比较,突变纯合型组的血小板抑制率显著下降(P0.01),氯吡格雷抵抗率差异无统计学意义。Logistic多元回归分析显示,携带CYP2C19突变杂合型等位基因及突变纯合型等位基因与血小板抑制率呈正相关,是氯吡格雷抵抗的独立危险因素(OR=2.13,95%CI:1.78~4.28,P=0.013;OR=4.44,95%CI:3.31~6.41,P=0.001)。结论 CYP2C19突变型等位基因是氯吡格雷低应答的独立危险因素。     

CYP2C19基因型与复发性脑梗死患者氯吡格雷抵抗的关系研究

目的通过CYP2C19基因检测及血小板聚集率综合评估氯吡格雷抵抗,指导复发性脑梗死患者合理用药。方法对2018年1-10月就诊于嘉兴市第二医院神经内科,诊断为复发性脑梗死的患者进行CYP2C19基因测序,分别收集氯吡格雷快代谢、中代谢、慢代谢基因型患者各30例,比较3组患者年龄、性别、BMI、吸烟、高血压、糖尿病及高脂血症等一般临床资料。3组均给予常规剂量氯吡格雷75 mg/d治疗,检测患者使用氯吡格雷前及使用7 d后的血小板聚集率。根据血小板聚集抑制率判断氯吡格雷抵抗情况,分析CYP2C19基因型与患者氯吡格雷抵抗的关系。筛选出氯吡格雷抵抗者(血小板聚集抑制率10%)分至氯吡格雷抵抗组,改用西洛他唑100 mg 2次/日,氯吡格雷半反应(10%≤血小板聚集抑制率30%)及氯吡格雷敏感(血小板聚集抑制率≥30%)者分至非氯吡格雷抵抗组,继续氯吡格雷75 mg/d治疗。3个月后再次检测血小板聚集率,比较不同药物的血小板聚集抑制情况,并观察终点事件发生情况(主要终点:再发脑梗死;次要终点:脑出血和死亡)。结果最终入组患者90例,其中男性49例(54.4%),年龄40～89岁,平均年龄68.27±10.14岁。快、中、慢代谢3组糖尿病(P=0.036)和氯吡格雷抵抗发生率(P0.001)差异均有统计学意义,其中慢代谢组合并糖尿病比率高于中代谢组(P=0.010),慢代谢组氯吡格雷抵抗发生率高于快代谢组(P0.001)及中代谢组(P=0.006)。氯吡格雷抵抗组患者22例(24.4%),非氯吡格雷抵抗组患者68例(75.6%)。Logistic回归分析提示,吸烟(OR 7.792,95%CI 1.899～31.968,P=0.004)、糖尿病(OR 4.466,95%CI 1.122～17.778,P=0.034)及CYP2C19基因慢代谢(OR 13.713,95%CI 2.352～79.959,P=0.004)是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。非氯吡格雷抵抗组(49.51%±4.33%vs 63.73%±7.84%,P0.001)和氯吡格雷抵抗组(55.42%±6.63%vs 76.95%±7.42%,P0.001)患者3个月后的血小板平均聚集率较7 d时均下降,差异有统计学意义。3个月后较非氯吡格雷抵抗组,氯吡格雷抵抗组血小板聚集抑制率更高(21.53%±4.30%vs 14.23%±6.90%,P0.001)。入组患者随访3个月均无终点事件发生。结论吸烟、合并糖尿病及CYP2C19慢代谢基因型是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。西洛他唑能有效抑制血小板聚集,可以作为氯吡格雷抵抗的复发性脑梗死患者的替代性用药。     

急性缺血性脑卒中患者CYP2C 19基因分型与临床预后的相关性分析

目的探讨急性缺血性脑卒中患者CYP2C 19基因分型与临床预后的相关性。方法选取本院收治的156例应用氯吡格雷治疗的急性缺血性脑卒中患者作为研究对象,对患者进行CYP2C19*2和CYP2C19*3基因型检测,根据检测结果分为野生型组(GG)和突变型组(GA/AA)。对比两组的血小板抑制率、氯吡格雷疗效及临床预后情况。结果野生型组患者的平均血小板抑制率为(42. 42±2. 74)%,突变型组为(32. 41±2. 69)%,突变型组的平均血小板抑制率显著低于野生型组(P <0. 05)。突变型组的氯吡格雷抵抗发生率为26. 32%,显著高于野生型组的1. 25%(P <0. 05)。突变型组的预后不良发生率显著高于野生型组,卒中复发率及心脑血管不良事件总发生率也显著高于野生型组(P <0. 05)。与野生型组相比,突变型组患者随访期间累积无再发心脑血管不良事件的生存率明显更低(P <0. 05)。结论急性缺血性脑卒中患者的CYP2C 19基因分型与血小板抑制率、临床预后密切相关,携带CYP2C19突变型基因型的患者,血小板抑制率更低,氯吡格雷敏感性越差,预后不良风险越高。     

丙戊酸药物浓度与CYP286基因多态性的相关性研究

目的:探讨丙戊酸(VPA)药物浓度与细胞色素P4502B6(CYP2B6)基因多态性的关系。方法:选择符合入选条件的癫患者72例,提取外周血DNA,应用聚合酶链反应和限制性核酸内切酶方法分析患者的CYP2B6基因型及等位基因;应用荧光偏振免疫法测定患者VPA的血药浓度。结果:72例癫患者中CYP2B6基因型为*1/*1为39例(54.2%),*1/*6为29例(40.3%),*6/*6为4例(5.5%),根据基因型将患者分为两组,A组(CYP2B6*1/*1)和B组(CYP2B6*1/*6或CYP2B6*6/*6)。B组患者VPA的标准血药浓度平均值较A组高,且差异有统计学意义(P<0.05)。结论:CYP2B6是VPA的代谢酶,CYP2B6基因多态性可影响VPA的血药浓度,对含有CYP2B6*6等位基因的患者应用VPA时,其血药浓度高,提示对VPA药物代谢有影响。     

CYP2C19基因多态性对氯吡格雷药效的影响

氯吡格雷一种广泛应用的抗血小板聚集药物,在缺血性脑血管病二级预防中起着重要的作用。然而,在临床实践中不断发现,不同的患者对氯吡格雷的反应性差异比较大,某些患者对氯吡格雷的反应性较低或无反应,称之为氯吡格雷低反应或氯吡格雷抵抗,氯吡格雷的低反应或抵抗在缺血性脑血管病复发中起到重要的作用。参与氯吡格雷反应下降的因素有很多,包括基因的多态性(如细胞色素P450、ABCB1及P2Y12基因多态性)、药物的互相作用(质子泵抑制剂、他汀类等)、患者的依从性、Ⅱ型糖尿病、慢性肾病等,但目前机制尚未完全清楚。而CYP2C19作为细胞色素P450(CYP450)家族中一类重要的亚型,在多种药物代谢中体现出其重要性。氯吡格雷作为一种常见的抗血小板药物,其代谢也受CYP2C19基因多态性的影响,不同基因型患者对氯吡格雷的治疗反应性不同。文中就CYP2C19的几个主要基因多态性位点对氯吡格雷代谢的影响作综述。     

Mechanism of action of tubocurarine on nicotinic cholinoreceptors of neurons of the sympathetic ganglia of rats

Tubocurarine (Tc) effect on membrane currents elicited by acetylcholine (ACh) was studied in isolated superior cervical ganglion neurons of rat using patch-clamp method in the whole-cell recording mode. The "use-dependent" block of ACh current by Tc was revealed in the experiments with ACh applications, indicating that Tc blocked the channels opened by ACh. Mean lifetime of Tc-open channel complex, tau, was found to be 9.8 +/- 0.5 s (n = 7) at -50 mV and 20-24 degrees C. tau exponentially increased with membrane hyperpolarization (e-fold change in tau corresponded to the membrane potential shift by 61 mV). Inhibition of the ACh-induced current by Tc (3-30 microM/1) was completely abolished by membrane depolarization to the level of 80-100 mV. Inhibition of ACh-induced current was augmented at increased ACh doses. It is concluded that the open channel block produced by Tc is likely to be the only mechanism for Tc action on nicotinic acetylcholine receptors in superior cervical ganglion neurons of rat.     

The effect of age of onset of PD on risk of dementia

Background Dementia occurs in the majority of patients with Parkinson’s disease (PD). Late onset of PD has been reported to be associated with a higher risk for dementia. However, age at onset (AAO) and age at baseline assessment are often correlated. The aim of this study was to explore whether AAO of PD symptoms is a risk factor for dementia independent of the general effect of age. Methods Two community-based studies of PD in New York (n = 281) and Rogaland county, Norway (n = 227) and two population-based groups of healthy elderly from New York (n = 180) and Odense, Denmark (n = 2414) were followed prospectively for 3–4 years and assessed for dementia according to DSM-IIIR. All PD and control cases underwent neurological examination and were followed with neurological and neuropsychological assessments. We used Cox proportional hazards regression based on three different time scales to explore the effect of AAO of PD on risk of dementia, adjusting for age at baseline and other demographic and clinical variables. Findings In both PD groups and in the pooled analyses, there was a significant effect of age at baseline assessment on the time to develop dementia, but there was no effect of AAO independent of age itself. Consistent with these results, there was no increased relative effect of age on the time to develop dementia in PD cases compared with controls. Interpretation This study shows that it is the general effect of age, rather than AAO that is associated with incident dementia in subjects with PD. Received in revised form: 22 December 2005     

Limits of deinstitutionalization--perspectives of relatives of psychiatric patients

After a hopeful beginning, the social process of the reintegration of those with severe mental illness has come to a standstill. I am led to wonder whether "the community" really wants to live together with people suffering from severe mental illness, and if so, how closely? As long as the medical treatment of mental illness provided by the general practitioners is fundamentally deficient, as they are not able to prescribe the necessary interventions--such as out-patient psychiatric nursing, and service providers in the out-patient sector are content with offering increasingly intensive forms of care for the less seriously ill at the cost of the Social Welfare System--the reintegration of those with serious mental illness remains an illusion--which is mainly to the benefit of providers of residential care in homes and hostels.     

Denervation study of synapses of organ of corti of old world monkeys

Fine structural characteristics of synapses in the spiral organ of Corti were examined, with reference to differences between inner and outer haircell systems, and to location of neurons of origin of efferent axons. Surgical interruption of crossed olivocochlear bundle, of vestibular nerve, of facial nerve, and excision of superior cervical ganglia were used to determine the pathways of efferent axons. Interruption of the vestibular nerve near the brainstem results in degeneration of all efferent terminals on outer hair cells. Mid-line lesions at, and caudal to, the facial colliculus result in degeneration of about half of these efferent terminals. Efferent synaptic bulbs to the inner hair-cell system are small, of the order of one micron, and form type 2 junctions with afferent dendrites. They tend to have more large dense-core vesicles (about 80 nm) than the large efferent terminals of the outer hair-cell system, and appear to be the terminals of axons in the habenula perforata, which exhibit varicosities laden with large dense core vesicles. The varicosities are unaffected by excision of the superior cervical ganglia. So far as our material can reveal, it appears that the varicosities in the habenula perforata do not survive vestibular root interruption, nor do the efferent processes in the internal spiral bundle or at the base of inner hair cells. Most interestingly, the afferent processes of the inner hair-cell system, as identified for example by their relation to pre-synaptic bodies in the inner hair cells, are subject to a trans-synaptic reaction after severance of the vestibular root. They undergo a dramatic cytological transformation, characterized by increase of volume, engorgement with microtubules, microfilaments, microvesicles of various sizes, and clusters of lysosomes. Thus, both the efferent and afferent terminals of the inner hair-cell system show marked cytological differences from the corresponding terminals of the outer hair cell system.