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。     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

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.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

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.     

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.     

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.