氯吡格雷抵抗与卒中防治

氯吡格雷是缺血性卒中治疗的基本药物,被多国卒中治疗指南所推荐,广泛应用于临床.有不少缺血性卒中患者在经过规范氯吡格雷治疗后仍然复发卒中,因此必须重视氯吡格雷抵抗现象.文章对氯吡格雷抵抗的生化机制、基因多态性、实验室检测及其应对措施进行了综述.     

氯吡格雷抵抗与基因多态性

氯吡格雷是目前广泛应用于临床的一种抗血小板药,已作为心肌梗死、缺血性卒中和周围血管病的二级预防用药.然而,氯吡格雷的抗血小板聚集效果存在显著的个体差异,很大一部分患者存在抵抗现象.氯吡格雷抵抗的机制尚不完全清楚,基因多态性是氯吡格雷抵抗的一个重要原因,包括ABCB1、CYP2C19、CYP3 A4、CYP3A5、P2Y...     

吡格雷治疗血小板聚集与募集

阿司匹林-氯吡格雷联合治疗可抑制血小板聚集,但对血小板的募集作用还不清楚.美国伊利诺伊大学医学院神经科的Helgason等对此进行了研究. 单用阿司匹林的30例慢性缺血性卒中患者在经阿司匹林-氯吡格雷联合治疗后进行了3个月的血小板反应性试验:即半体内血小板聚集、血小板募集和尿11-去氢-血栓素B2分泌.用方差分析比较了单用阿司匹林与阿司匹林-氯吡格雷对血小板聚集和募集的影响,采用纵向回归分析评价血小板随着时间延长的募集,用非线性映射确定每例患者变量之间的联系.     

缺血性卒中患者细胞色素P450 2C19基因多态性与氯吡格雷抗血小板聚集的关系

目的探讨缺血性卒中患者细胞色素P450 2C19(CYP2C19)基因多态性与服用氯吡格雷后血小板抑制率之间的关系。方法前瞻性纳入251例首都医科大学宣武医院门诊及住院需要服用氯吡格雷的缺血性卒中患者为研究对象。检测与氯吡格雷代谢相关的CYP2C19基因,依据CYP2C19基因位点分为快代谢型(*1/*1)97例、中间代谢型(103例*1/*2和18例*1/*3)1 2 1例、弱代谢型(2 4例*2/*2和9例*2/*3)3 3例。在服用氯吡格雷75 mg/d的第8天晨起抽取静脉血,用血栓弹力图检测二磷酸腺苷诱导的血小板抑制率。比较不同基因型患者的血小板抑制率及氯吡格雷敏感情况的差异。结果 (1)快代谢型患者氯吡格雷敏感65例(67.0%),中间代谢型患者氯吡格雷敏感70例(57.9%),弱代谢型患者氯吡格雷敏感17例(51.5%),不同代谢型间氯吡格雷敏感情况差异无统计学意义(χ~2=3.192,P=0.203)。(2)所有患者快代谢型、中间代谢型、弱代谢型患者的血小板抑制率中位数分别为39.5(20.9,56.5)%、35.6(21.1,59.8)%、30.3(11.4,48.1)%。三型之间的血小板抑制水平差异无统计学意义(H=3.287,P=0.193)。结论对于服用氯吡格雷的缺血性卒中患者,根据CYP2C19基因多态性尚不能准确预测氯吡格雷抗血小板聚集的疗效。     

血栓弹力图评估阿司匹林和氯吡格雷血小板抑制率的临床应用

目的 用血栓弹力图评估冠心病及冠心病支架术后患者正规使用阿司匹林及氯吡格雷后血小板抑制率的改变.方法 血栓弹力图检测300例住院患者血小板药物治疗后花生四烯酸(AA)通路和二磷酸腺苷(ADP)受体途径诱导的血小板抑制率.将抗血小板治疗的患者分为阿司匹林组、氯吡格雷组、阿司匹林和氯吡格雷联用组各100例.结果 阿司匹林与氯吡格雷组和阿司匹林和氯吡格雷联用组在血小板抑制率和临床治疗效果上无显著差异(P＞0.05).结论 阿司匹林与氯吡格雷联用在对血小板的抑制率无协同作用,由于患者可能存在阿司匹林或者氯吡格雷某一途径抵抗的情况下,可以得到另一途径的有效补充而使血小板抑制率达标.     

阿司匹林加缓释双嘧达莫与氯吡格雷预防再发卒中对比研究

再发卒中是缺血卒中患者生命中非常严重的血管事件、是残疾的常见原因。已有多个随机临床试验证实抗血小板治疗具有预防非心源栓塞性卒中的效果。“阿司匹林加缓释双嘧达莫与氯吡格雷预防再发卒中对比研究”观察了抗血小板药物阿司匹林加缓释双嘧达莫（ASA＋ERDP）与氯吡格雷（clopidogrel）预防再发卒中的效果和安全性。     

冠心病患者氯吡格雷低反应性的研究进展

氯吡格雷是临床常用的抗血小板药物,但近年来的研究发现,部分患者存在氯吡格雷低反应性,也就是氯吡格雷抵抗或氯吡格雷无反应性,即描述服用氯吡格雷而不能提供充分抗血小板作用的一种现象。氯吡格雷低反应者血小板聚集率高,易发生心血管事件。现对目前有关氯吡格雷低反应性的定义、可能发生的机制和解决方法进行综述。     

甘油三酯–葡萄糖指数与缺血性卒中患者氯吡格雷治疗期间血小板高反应性的相关性

目的探讨甘油三酯–葡萄糖(triglyceride-glucose, TyG)指数与缺血性卒中患者氯吡格雷治疗期间血小板高反应性(high on-treatment platelet reactivity, HTPR)的相关性。方法回顾性纳入2017年1月至2021年3月在广东省中医院神经内科住院并接受维持剂量氯吡格雷(75 mg/d)治疗的缺血性卒中患者。TyG指数最高四分位数(Q4)定义为胰岛素抵抗。通过血栓弹力图评估血小板反应性, 将二磷酸腺苷诱导的凝块强度MAADP>47 mm定义为氯吡格雷HTPR。应用多变量回归模型分析TyG指数与血小板反应性的独立相关性。结果共纳入83例患者, TyG指数与MAADP呈线性相关。根据TyG指数四分位数将患者分为4组。氯吡格雷HTPR发生率随TyG指数四分位数增加显著增高(P趋势=0.017)。多变量分析显示, 胰岛素抵抗与氯吡格雷HTPR存在显著独立相关性(优势比4.597, 95%置信区间1.285～16.446;P=0.019)。结论在接受氯吡格雷治疗的缺血性卒中患者中, 氯吡格雷HTPR发生率随TyG指数四分位数增高而逐渐增高,...     

缺血性脑卒中氯吡格雷抵抗的研究进展

<正>卒中是导致成年人残疾和死亡的主要原因之一,缺血性卒中为我国卒中的主要亚型,约占卒中的41%~79%[1]。抗血小板聚集治疗能使缺血性卒中或短暂性缺血发作(transient ischemic attack,TIA)患者非致死性卒中复发风险降低25%[2],为防治缺血性卒中的核心策略之一。目前常用的抗血小板药物有阿司匹林、氯吡格雷和噻氯吡啶等。氯吡格雷作为一种噻吩吡啶类化合物,经肝脏代谢之后,选择     

急性心肌梗死患者氯吡格雷与替格瑞洛抗血小板作用的比较研究

目的比较急性心肌梗死患者行急诊冠状动脉介入治疗后,服用替格瑞洛与氯吡格雷抗血小板效果的差异。方法入选因急性心肌梗死行急诊冠状动脉介入术并接受负荷及维持剂量抗血小板药物治疗的患者,其中氯吡格雷组131例,替格瑞洛组58例。术后24-48小时应用Verifynow检测残余血小板反应单位(PRU),并随访。结果189例患者中,高残余血小板反应(RPRU≥230)者51例,占比26.98%。氯吡格雷组平均血小板反应单位195.8(26~329)。替格瑞洛组平均血小板反应单位101.8(6~322)。替格瑞洛组高残余血小板反应发生率显著低于氯吡格雷组(p0.0001)。30天及6个月随访结果显示,MACCE事件、出血及卒中的发生率,在两组之间无明显差异。结论服用负荷及维持剂量的替格瑞洛或氯吡格雷24小时后,仍有较大比例患者存在血小板抑制不充分,但替格瑞洛对血小板的抑制作用明显强于氯吡格雷。     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.