皖南地区CYP2C19基因多态性对PCI术后氯吡格雷抗血小板聚集的影响

目的：研究皖南地区CYP2C19基因型分布及其多态性对PCI术后患者氯吡格雷临床疗效的影响。方法：选取我院2017年7月至2017年10月行冠脉造影检查和PCI术治疗的患者100例,采用荧光染色原位杂交技术检测CYP2C19基因型,采用TEG血栓弹力图仪检测血小板聚集抑制率,比较CYP2C19不同基因型及相关指标对血小板聚集抑制率、氯吡格雷抵抗的影响。结果及结论：结果表明,CYP2C19弱代谢型是氯吡格雷抵抗的独立危险因素。氯吡格雷抵抗与CYP2C19弱代谢型相关。     

缺血性脑卒中患者CYP2C19基因代谢型、联用药物与氯吡格雷抵抗关系的研究

目的 探讨CYP2C19基因代谢型、联用药物与氯吡格雷抵抗的关系.方法 选择缺血性脑卒中患者102例,连续口服氯吡格雷75 mg/d,共7d.检测患者CYP2C19各基因型及血小板聚集率,以1年内发生缺血性脑卒中复发终点事件为观察指标.结果 CYP2C19基因弱代谢型15例,中间代谢型39例,强代谢型48例,氯吡格雷抵抗发生率在弱代谢型较中间代谢型高,中间代谢型较强代谢型发生率高,差异均有统计学意义(P＜0.05);氯吡格雷联用阿司匹林、他汀类药可明显减少卒中复发事件(P＜0.05).结论 采用基因分型法可预测缺血性脑卒中患者氯吡格雷疗效,指导临床个体化给药.氯吡格雷联用阿司匹林、他汀类药的应用效果较好.     

CYP2C19、ABCB1和PON1基因多态性与氯吡格雷抑制血小板聚集作用的相关性研究

目的:探讨CYP2C19、ABCB1和PON1基因多态性与氯吡格雷抑制血小板聚集作用的相关性。方法:纳入诊断为急性缺血性脑卒中或接受经皮冠状动脉介入术(PCI)后服用氯吡格雷和阿司匹林治疗的患者59例,测定CYP2C19(rs4244285、rs4986893)、ABCB1(rs1045642)和PON1(rs662)基因型及血栓弹力图(TEG),并对患者进行1年的随访,记录临床终点事件。应用单因素和多因素回归,分析患者CYP2C19、ABCB1、PON1基因型、一般情况及临床因素对氯吡格雷抑制血小板聚集作用的影响,比较不同基因型患者的氯吡格雷疗效。结果:59例患者中氯吡格雷治疗相关的血小板高反应性(HTPR)的发生率为8.5%。CYP2C19快代谢型、中间代谢型和慢代谢型患者血小板抑制率分别为(86.0±10.1)%、(78.4±17.3)%和(66.4±23.0)%,快代谢型和慢代谢型之间血小板抑制率差异有显著性(P=0.047),ABCB1和PON1各基因型之间血小板抑制率的差异无显著性(P>0.05),全变量多因素logistic回归分析未发现CYP2C19、ABCB1、PON1基因型与HTPR相关(P=0.681)。随访1年中,CYP2C19快代谢型、中间代谢型、慢代谢型患者的临床事件分别有2、3和3例;ABCB1携带TT、TC、CC等位基因患者的临床事件分别有1,3和4例;PON1携带AA、AG、GG等位基因患者的临床事件分别有4,2和2例,各基因型之间患者临床终点事件差异无显著性(P>0.05)。结论:根据CYP2C19、ABCB1和PON1基因多态性尚不能预测服用氯吡格雷后的临床疗效。     

细胞色素P450基因多态性对心血管药物疗效的影响

目的探讨细胞色素P450酶2C19基因(CYP2C19)681G/A多态性对氯吡格雷治疗冠状动脉粥样硬化性心脏病(CAHD)的影响。方法选取佛山市南海区第二人民医院心内科CADH患者274例,其中130例口服氯吡格雷,选取佛山市111例调查的自然人群为对照组,口服氯吡格雷患者中52例进行了择期经皮冠状动脉介入术(PCI)治疗,比较氯吡格雷治疗后患者各基因型与实验室氯吡格雷抵抗之间的关系,并分别比较不同基因型组间血小板聚集率、实验室氯吡格雷抵抗和不良心血管事件的再发生情况。结果氯吡格雷治疗后CYP2C19681AA型平均血小板聚集率降低幅度最小,GA型次之,GG型最高;PCI患者CYP2C19681A等位基因携带者组不良心血管事件再发率高、平均血小板聚集率降低幅度小、实验室氯吡格雷抵抗发生率高。结论 CYP2C19681G/A突变是CAHD患者口服氯吡格雷治疗疗效及预后欠佳的主要影响因素,它减弱了氯吡格雷对血小板的抑制作用。     

CYP2C19基因多态性与氯吡格雷ADP抑制率的临床研究

目的探讨CYP2C19基因多态性与氯吡格雷ADP抑制率间的临床关系,以期为个体化的抗血小板治疗方案提供用药参考。方法选取本院2014年10月至2015年10月收治的120例急性冠状动脉综合征患者作为临床研究对象,患者术前均进行CYP2C19基因型测定并完成经皮冠状动脉介入术治疗,患者按基因型分为慢代谢组、中等代谢组及快代谢组,每组40例。入院当天给予患者过量氯吡格雷和标准剂量阿司匹林,之后按规律常规给予氯吡格雷75 mg/d,于第1天和第7天测定患者ADP抑制率,并根据结果筛选出抗氯吡格雷患者,加大氯吡格雷用量后7 d再次测定患者ADP抑制率,并进行前后差异比对。结果与服用前相比,服用氯吡格雷7 d后3组患者的血小板聚集率均明显下降,其中快代谢型患者显著优于中间代谢型和慢代谢型者(P<0.05)。氯吡格雷抵抗患者增加药物剂量后7 d,ADP抑制率无明显改变,差异无显著性(P>0.05)。结论针对急性冠状动脉综合征患者,采用适时的CYP2C19基因多态性检测对于指导选用药物治疗具有一定临床意义,但仅通过基因分型还无法完全预测氯吡格雷的给药剂量,对于氯吡格雷抵抗患者单纯增加氯吡格雷剂量不能同时达到提高血小板抑制率的效果,治疗方案还需进一步探讨和深入研究。     

CYP2C19和ABCB1基因检测指导患者氯吡格雷个体化给药

目的利用CYP2C19和ABCB1基因检测结果指导患者氯吡格雷个体化用药。方法选取某院2018年8月~2019年6月30例使用氯吡格雷的患者,采用荧光原位杂交法检测患者氯吡格雷相关基因(CYP2C19*17、CYP2C19*3、CYP2C19*2和ABCB1)的基因型,根据检测结果为患者提供给药建议。另选取1例冠状动脉粥样硬化心脏病PCI术后患者,测定氯吡格雷相关基因型,为患者提供个体化给药建议。结果CYP2C19基因检测结果显示,30例患者中1例为超快代谢型,8例为快代谢型,18例为中间代谢型,3例为慢代谢型;ABCB1 CC野生型13例,CT突变杂合型14例,TT突变纯合型3例。1例冠状动脉粥样硬化心脏病患者PCI术后规律双联抗血小板治疗仍反复胸闷胸痛,CYP2C19基因检测为CYP2C19*1/*2中间代谢型,无ABCB1突变,药物代谢减慢,建议氯吡格雷更换为替格瑞洛。结论通过基因检测指导患者氯吡格雷个体化给药,促进临床合理用药。     

我国北方汉族冠心病人群氯吡格雷抵抗相关影响因素的回顾研究

目的:探讨影响我国北方汉族冠心病人群氯吡格雷抵抗的相关影响因素。方法:选择425例首次行经皮冠状动脉介入术的患者,根据血小板聚集率结果将患者分为氯吡格雷抵抗(CRG)组和氯吡格雷敏感(CSG)组。检测其基因型,分析其CYP2C19*2等位基因携带状态,并分析血小板聚集率等实验室指标和冠心病易感指标等与其是否发生氯吡格雷抵抗的相关性。结果:CYP2C19基因G681A突变携带者(GA、AA)在CRG组与CSG组的分布率分别为64.4%和33.1%,携带突变基因与否在两组间的分布比较差异具有统计学意义(P<0.000 1),而其他非遗传性指标在两组间比较差异无统计学意义(P>0.05)。结论:CYP2C19*2等位基因的携带与氯吡格雷抵抗有显著的相关性,G681A突变基因的携带是导致氯吡格雷抵抗的危险因素,其他非遗传因素与氯吡格雷抵抗的关联不大。     

氯吡格雷在老年缺血性脑卒中患者的应用及CYP2C19 基因多态性对预后的影响

目的 探讨氯吡格雷在老年缺血性脑卒中患者中的应用及细胞色素P4502C19(CYP2C19)基因多态性对预后的影响.方法 选取收治的老年缺血性脑卒中患者144例,依据氯吡格雷抵抗情况将这些患者分为抵抗组(n=45)和非抵抗组(n=99)两组,测定两组患者的血小板聚集功能并检测其基因型,然后对2个单核苷酸多态性(SNPs)的等位基因频率及基因型频率、两组患者的2个SNPs分布情况进行统计分析.结果 CYP2C19(636G>A,rs4986893)(681G>A,rs4244285)等位基因及基因频率均和Hardy-Weinberg相符(P>0.05);抵抗组患者的CYP2C19?2(rs4244285)GG型分布率显著低于非抵抗组(P<0.05),GA+AA型分布率显著高于非抵抗组(P<0.05),且GA+AA型分布率显著高于GG型(P<0.05),但两组患者的CYP2C19?3(rs4986893)GG型、AG+AA型分布率之间均差异无统计学意义(P>0.05).结论 老年缺血性脑卒中患者的氯吡格雷抵抗和CYP2C19?2(rs4244285)GA+AA型关系密切,检测该基因型能够为氯吡格雷的临床科学应用提供有效指导,值得临床充分重视.     

CYP2C19基因多态性与急性缺血性脑卒中氯吡格雷抵抗相关性研究

目的：探讨CYP2C19基因多态性与急性缺血性脑卒中氯吡格雷抵抗(CR)相关性。方法：选取2020年10月至2022年10月广州医科大学附属第五医院神经内科住院治疗的200例急性缺血性脑卒中患者为研究对象，按随机1:1的原则分成2组，其中未接受基因检测的100例患者设为A组，接受CYP2C19基因检测的100例患者设为B组，并根据CYP2C19基因型分为B1组(快代谢型，n=33)、B2组(中间代谢型，n=46)、B3组(慢代谢型，n=21),所有患者均口服氯吡格雷和阿司匹林，比较各组患者一般资料、不同基因型组患者血小板抑制率、氯吡格雷抵抗发生率，并统计心脑血管不良事件发生情况。结果：A组和B组患者一般资料比较，差异均无统计学意义(P>0.05)。B1组血小板抑制率高于B2组和B3组；B1组CR率为30.30%低于B2组54.35%和B3组66.67%(P<0.05)。B3组不良事件发生率为28.57%,高于B2组8.70%和B1组6.06%。结论：急性缺血性脑卒中患者CYP2C19基因多态性与CR具有相关性，其中携带CYP2C19*2/*2、*3/*3、*2/*3突变基因...     

CYP2C19、P2Y12基因多态性与缺血性脑卒中患者氯吡格雷抵抗的相关性研究

目的：考察CYP2C19、P2Y12受体的基因多态性与氯吡格雷抵抗的相关性研究.方法：96例中国缺血性脑卒中患者持续服用氯吡格雷75 mg,收集全血提取DNA,采用Sequenom MassARRAY iPLEX（R）基因型分析技术进行CYP2C19＊ 2（681G＞A,rs4244285）、CYP2C19＊3（636 G＞A,rs4986893）及P2Y12受体（52G＞T,rs6809699） （744T＞C,rs2046934）4个SNPs的基因型分析.采用二磷酸腺苷（ADP）诱导光比浊法测定血小板聚集功能.采用Chi-square检验或Fisher确切概率法分析相关性.结果：患者分为氯吡格雷抵抗（CR）组与非抵抗组,CYP2C19＊ 2（rs4244285）及P2Y12受体（rs2046934）基因型分布在两组间的差异有统计学意义（P=0.027,P=0.034）.其中,CYP2C19＊2 GA＋ AA基因型为CR发生的风险因素（OR=2.607,95％CI：1.062～6.399）.CYP2C19＊3（rs4986893）及P2Y12受体（rs6809699）基因型分布在两组比较中差异无统计学意义（P＞0.05）.结论：在中国缺血性脑卒中患者中,CYP2C19＊2（rs4244285） GA＋ AA型与氯吡格雷抵抗的发生密切相关,该基因型检测将有助于指导氯吡格雷的临床合理应用.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.