强化瑞舒伐他汀钙联合氯吡格雷及阿司匹林对高危短暂性脑缺血发作患者临床效果评价

目的探讨强化瑞舒伐他汀钙联合氯吡格雷及阿司匹林对高危短暂性脑缺血发作患者的临床效果及对颈动脉内中膜厚度、血脂及血小板参数的影响。方法入我科接受治疗的110例高危TIA患者随机分为试验组和对照组。试验组给予瑞舒伐他汀20 mg(14 d后减为10 mg)、氯吡格雷75 mg及阿司匹林100 mg(21 d后停服);对照组患者给予瑞舒伐他汀10 mg、氯吡格雷75 mg及阿司匹林100 mg(21 d后停服)治疗,对比治疗3 m后两组卒中发生率、颈动脉内中膜厚度、血脂、血小板参数及不良事件发生率。结果对照组脑梗死发病率11.5%,试验组脑梗死发病率5.2%,差异有统计学意义(P 0.05);试验组患者总胆固醇(TC)、甘油三酯(TG)及低密度脂蛋白-C(LDL-C)降低较对照组更明显(P 0.05)。治疗后试验组较对照组相比颈动脉内中膜厚度更低,差异有统计学意义(P 0.05);治疗后两组血小板计数(PLT)及血小板平均宽度(MPV)与治疗前相比均降低,差异有统计学意义(P 0.05);治疗后MPV两组组间相比差异有统计学意义(P 0.05)。结论早期强化瑞舒伐他汀钙联合氯吡格雷及阿司匹林对高危TIA患者能够显著减低卒中复发率,有效降低血脂水平,减轻颈动脉内中膜厚度,降低血小板计数及血小板平均体积。     

不同剂量阿托伐他汀联合氯吡格雷治疗短暂性脑缺血发作的疗效及对预后的影响

目的探讨不同剂量阿托伐他汀联合氯吡格雷治疗短暂性脑缺血发作(TIA)的疗效及对预后的影响。方法66例TIA患者随机分为2组,对照组予阿托伐他汀(20mg/d)联合氯吡格雷治疗,观察组予高剂量阿托伐他汀(40mg/d)联合氯吡格雷治疗,比较2组近期疗效及随访12个月TIA复发次数、脑梗死发生率。结果 2组总有效率比较差异无统计学意义(P0.05),但观察组基本痊愈率(75.76%)显著高于对照组(51.52%),差异有统计学意义(P0.05);随访12个月观察组TIA复发次数明显少于对照组,脑梗死发生率也低于对照组,差异均有统计学意义(P0.05)。结论高剂量阿托伐他汀(40mg/d)联合氯吡格雷治疗TIA可快速有效控制临床症状,减少复发并阻止TIA的进一步发展。     

瑞舒伐他汀联合氯吡格雷对脑梗死急性期患者血小板活化及聚集状态的影响

目的探讨瑞舒伐他汀联合氯吡格雷对脑梗死急性期患者血小板活化及聚集状态的影响。方法脑梗死急性期患者76例,随机分为2组。对照组给予氯吡格雷治疗,观察组给予瑞舒伐他汀联合氯吡格雷治疗。结果治疗后,观察组神经功能缺损评分及疗效优于对照组,差异具有统计学意义(P0.05)。治疗后,观察组CD63表达水平(0.2±0.1)%,CD62P表达水平(1.4±0.8)%均优于对照组(0.4±0.2)%、(2.6±1.0)%,差异有统计学意义(P0.05)%。治疗后,观察组AA水平(83.8±21.2)%及ADP途径诱导的血小板抑制率(50.0±18.1)%高于对照组的(65.5±21.9)%、(37.2±10.4)%,差异有统计学意义(P0.05)。结论瑞舒伐他汀联合氯吡格雷可有效抑制脑梗死急性期患者血小板活化及聚集,促进神经功能损伤恢复。     

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。     

大剂量阿托伐他汀联合氯吡格雷治疗急性脑梗死的临床疗效

目的评价大剂量阿托伐他汀联合氯吡格雷治疗急性脑梗死的临床疗效。方法选取我院收治的80例急性脑梗死患者随机分为治疗组与对照组各40例,对照组给予常规抗凝、溶栓等治疗,治疗组在常规治疗基础上加用阿托伐他汀80mg/d+氯吡格雷75mg/d,疗程为28d,比较2组患者血脂指标、神经功能评分及生活质量评分情况。结果 2组患者治疗前各项血脂指标、hs-CRP及ESS及ADL评分水平比较均无明显差异(P0.05),治疗28d后治疗组上述指标较治疗前及同期对照组均明显改善,差异具有统计学意义(P0.05)。结论应用大剂量阿托伐他汀联合氯吡格雷治疗急性脑梗死可有效改善神经功能、提高生活质量水平,可能与其改善内皮功能、抑制炎症反应等机制有关。     

氯吡格雷与阿托伐他汀联用对急性脑梗死患者神经功能缺损的影响

目的：分析氯吡格雷与阿托伐他汀联用对急性脑梗死患者神经功能缺损情况的影响。方法选取我院2012—2014年收治的急性脑梗死患者120例,随机分为观察组和对照组。2组均给予阿托伐他汀进行常规药物治疗,观察组在此基础上给予口服氯吡格雷治疗,对比2组患者神经缺损及预后情况。结果观察组将氯吡格雷与阿托伐他汀联用治疗急性脑梗死,效果显著。观察组神经功能的恢复程度和预后效果均优于对照组,差异具有统计学意义（ P＜0.05）。结论氯吡格雷与阿托伐他汀联用对急性脑梗死患者神经功能缺损的疗效较好,可促进患者脑神经功能的恢复和预后康复,且安全性较高。     

瑞舒伐他汀与阿托伐他汀对急性脑梗死患者血脂、血清超敏C反应蛋白及颈动脉粥样硬化斑块作用的比较

目的比较瑞舒伐他汀与阿托伐他汀对急性脑梗死患者血脂、超敏C反应蛋白(hs-CRP)及颈动脉粥样硬化斑块的影响。方法在标准缺血性脑卒中治疗的基础上,瑞舒伐他汀组加用瑞舒伐他汀10mg/d,阿托伐他汀组加用阿托伐他汀片20 mg/d,治疗6个月。于治疗前及治疗后6个月,检测患者血脂、hsCRP水平,颈动脉超声检查颈动脉粥样硬化斑块情况。结果与治疗前比较,瑞舒伐他汀组与阿托伐他汀组6个月时总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和hs-CRP水平均显著降低(均P0.05)。6个月时,瑞舒伐他汀组TC、TG、LDL-C及hs-CRP水平显著低于阿托伐他汀组及对照组(均P0.05)。3组间治疗前内-中膜厚度(IMT)差异无统计学意义;与治疗前及对照组比较,瑞舒伐他汀组与阿托伐他汀组6个月时IMT及低回声斑块比率显著降低,高回声斑块率显著增高(均P0.05)。瑞舒伐他汀组、阿托伐他汀组及对照组患者第6个月的NIHSS评分及mRS评分均显著低于治疗前(均P0.05)。治疗前及治疗后6个月时,3组间NIHSS评分及mRS评分差异无统计学意义。结论瑞舒伐他汀与阿托伐他汀能显著降低急性脑梗死患者血脂及血清hs-CRP水平,抑制动脉粥样硬化斑块的形成。瑞舒伐他汀的降脂及抗炎作用比阿托伐他汀更强。     

阿托伐他汀联合氯吡格雷稳定老年脑梗死患者颈动脉粥样斑块效果分析

目的 观察阿托伐他汀联合氯吡格雷对老年脑梗死患者颈动脉粥样斑块的治疗效果.方法 选择河南省人民医院神经内科自2006年7月至2010年9月收治的老年脑梗死患者80例,其中联合应用阿托伐他汀和氯吡格雷治疗40例(观察组),单纯使用氯吡格雷治疗40例(对照组),治疗后4、12、24周检查患者三酰甘油(TG)、血清总胆固醇(CH)、低密度脂蛋白胆固醇(LDL-C)、乳酸脱氢酶(LDH)、血粘滞度及血小板最大聚集率(MAR)并评定斑块积分.结果 与治疗前比较,治疗后24周对照组患者TG、LDL-C、MAR,12周观察组患者TG、CH,24周观察组患者TG、CH、LDL-C、MAR均降低,差异有统计学意义(P<0.05);与对照组比较,观察组患者治疗后12周CH,治疗后24周TG、CH、LDL-C较低,差异有统计学意义(P<0.05);与对照组比较,治疗后24周观察组患者粥样斑块积分较低.差异有统计学意义(P<0.05).结论 联合应用阿托伐他汀联合氯吡格雷可以稳定老年脑梗死患者颈动脉粥样硬化斑块,且安全可靠.     

阿托伐他汀联合氯吡格雷稳定老年脑梗死患者颈动脉粥样斑块效果分析

目的 观察阿托伐他汀联合氯吡格雷对老年脑梗死患者颈动脉粥样斑块的治疗效果.方法 选择河南省人民医院神经内科自2006年7月至2010年9月收治的老年脑梗死患者80例,其中联合应用阿托伐他汀和氯吡格雷治疗40例(观察组),单纯使用氯吡格雷治疗40例(对照组),治疗后4、12、24周检查患者三酰甘油(TG)、血清总胆固醇(CH)、低密度脂蛋白胆固醇(LDL-C)、乳酸脱氢酶(LDH)、血粘滞度及血小板最大聚集率(MAR)并评定斑块积分.结果 与治疗前比较,治疗后24周对照组患者TG、LDL-C、MAR,12周观察组患者TG、CH,24周观察组患者TG、CH、LDL-C、MAR均降低,差异有统计学意义(P<0.05);与对照组比较,观察组患者治疗后12周CH,治疗后24周TG、CH、LDL-C较低,差异有统计学意义(P<0.05);与对照组比较,治疗后24周观察组患者粥样斑块积分较低.差异有统计学意义(P<0.05).结论 联合应用阿托伐他汀联合氯吡格雷可以稳定老年脑梗死患者颈动脉粥样硬化斑块,且安全可靠.     

阿托伐他汀联合阿司匹林及氯吡格雷治疗轻中度急性脑梗死

目的分析阿托伐他汀联合阿司匹林及氯吡格雷治疗轻中度急性脑梗死的临床疗效及安全性。方法收集轻中度急性脑梗死(NIHSS≤13分)住院患者120例,随机分为阿托伐他汀联合阿司匹林及氯吡格雷治疗组(观察组)、阿托伐他汀联合阿司匹林或氯吡格雷治疗组(对照1组)及阿司匹林或氯吡格雷治疗组(对照2组)各40例,疗程21d。对比各组治疗前后NIHSS评分、生活自理量表评分(ADL)、改良Rankin量表评分(mRS)、hs-CRP、血脂及不良反应发生情况。结果治疗后观察组和对照1组中TC、TG、LDL-C及hs-CRP与治疗前相比,P0.05;治疗后观察组及对照1组TC、TG、LDL-C及hs-CRP与对照2组相比,P0.05。治疗后观察组及对照1组NIHSS及ADL评分与对照2组相比,P0.05。观察组及对照1组NIHSS评分增加≥4者与对照2组相比,P0.05。结论阿托伐他汀联合阿司匹林及氯吡格雷治疗轻中度急性脑梗死的早期具有安全性高、改善不良预后、降低神经功能恶化、协同抗氧化应激及抗炎症反应等作用。     

Association of CYP3A4*1G and CYP3A5*3 With the 1-year Outcome of Acute Ischemic Stroke in the Han Chinese Population

Background and purpose: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. Methods: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. Results: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. Conclusions: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.     

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

Purpose: Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug‐resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co‐localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival. Methods: Brain specimens were obtained from eight patients undergoing resection to relieve drug‐resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti‐CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography–ultraviolet (HPLC‐UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells. CYP3A4 expression was correlated to DAPI) condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with 4′,6‐diamidino‐2‐phenylindole (CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability. Key Findings: CYP3A4 was expressed by blood–brain barrier (BBB) endothelial cells and by the majority of neurons (75 ± 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized. Significance: CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain.     

Adverse drug reactions following nonresponse in a depressed patient with CYP2D6 deficiency and low CYP 3A4/5 activity

A 47-year-old male taxi driver experienced multiple adverse drug reactions during therapy with clomipramine (CMI) and quetiapine for major depressive disorder, after having been unsuccessfully treated with adequate doses of mirtazapine and venlafaxine. Drug serum concentrations of CMI and quetiapine were significantly increased and pharmacogenetic testing showed a poor metabolizer status for CYP2D6, low CYP3A4/5 activity and normal CYP2C19 genotype. After reduction of the CMI dose and discontinuation of quetiapine, all ADR subsided except for the increase in liver enzymes. The latter improved but did not normalize completely, even months later, possibly due to concomitant cholelithiasis.     

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response

Background and purpose

The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine.

Methods

In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache.

Results

Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found.

Conclusion

The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.     

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms

Recent studies of the association between the metabotropic glutamate receptor 3 gene (GRM3) and schizophrenia have produced conflicting results, although GRM3 is a promising candidate gene. Fujii et al. found a single nuclear polymorphism (SNP) for within this gene, rs1468412 to have a positive association to schizophrenia in Japanese patients. To investigate this further, we genotyped 7 SNPs around GRM3 including rs1468412, in 752 Chinese patients with schizophrenia and 752 controls using Taqman technology. We did not detect any association between rs1468412 and schizophrenia, however we found differences in the allele frequency distribution of SNP rs2299225 (p=0.0297, odds ration [OR]=1.44, 95% confidence interval 1.05-1.99) between cases and controls. Moreover, the overall frequency of haplotypes constructed from three SNPs including rs2299225 showed significant differences between cases and controls (p=0.0017). Our results partially support the previous studies in other ethnic groups and indicate that the GRM3 gene may play an important role in the etiology of schizophrenia in the Han Chinese.     

Whole deletion of CYP2A6 gene (CYP2A6AST;4C) and smoking behavior

The relationship between nicotine metabolism of CYP2A6 and the smoking behavior in a Japanese population was investigated. The CYP2A6 genotypes were determined by the PCR method. There was a significant difference in the frequency of the CYP2A6AST;4C allele, which is a whole deleted allele for the human CYP2A6 gene, between smokers and nonsmokers. The frequency of the CYP2A6AST;4C allele was higher in nonsmokers than in smokers, whereas the frequency of CYP2A6AST;1A/AST;1B heterozygotes with a higher activity of nicotine metabolism was lower. In this study it was suggested that the CYP2A6AST;4C allele may prevent the carrier from smoking and the CYP2A6AST;1A/AST;1B heterozygote may be at risk for developing smoking behavior.