脓毒症特异性治疗药物的研究进展

脓毒症是针对感染的宿主反应失调引起的致命性器官功能障碍。该病患者院内病死率高达10%以上,导致临床治疗费用高,医疗资源消耗大,已经对人类健康造成了巨大威胁。抗生素、抗病毒药物、血管活性药等均用于脓毒症传统治疗,但尚未有足够的针对脓毒症发病机制的特异性药物投入临床实践。如何及时纠正脓毒症发生发展过程中的全身性炎症反应、凝血功能障碍和免疫功能紊乱,尽早恢复机体促炎–抗炎动态平衡,有效改善患者预后,也成为了脓毒症治疗药物研究首先要考虑的问题。根据针对脓毒症发病阶段和治疗目的的不同,脓毒症特异性治疗药物主要分为针对失控炎症反应的药物、针对凝血功能障碍的药物、针对免疫功能抑制的药物和整体调节的现代中药4大类。主要对上述脓毒症特异性治疗药物进行综述。     

中医药对于脓毒症凝血功能障碍及血小板囊泡分泌功能影响的研究进展

脓毒症是严重创伤、休克、感染、外科大手术等常见的并发症,是临床危重患者的主要死亡原因,凝血功能紊乱是脓毒症加重的重要环节;Rab27b是血小板及其囊泡表面重要的信号转导分子,Rab27b的功能不全可能成为脓毒症时炎症失调与凝血功能紊乱的重要机制。研究中医药干预脓毒症凝血功能异常患者的血小板及其囊泡分泌功能,可能更好地揭示中医药治疗脓毒症的作用机制。     

他汀类药物改善脓毒症患者内皮细胞功能的机制研究进展

脓毒症是感染引起的失控的全身炎症反应综合征。脓毒症时全身炎症平衡紊乱可导致进行性的内皮细胞（EC）功能障碍,白细胞和血小板被激活,凝血纤溶破坏,最终导致多器官功能衰竭^[1]。EC功能障碍是脓毒症发展恶化的中心环节。脓毒症的发病率逐年上升,有资料显示^[2],脓毒症的病死率为25%～80%。近年来国外有研究证明他汀类药物治疗脓毒症能够降低其发病率及病死率,其主要机制之一可能与保护内皮细胞功能有关。现对他汀类药物保护脓毒症内皮细胞（EC）功能的机制作一综述。     

脓毒症相关性凝血病治疗药物的研究进展

脓毒症作为一种由感染导致的一系列病理生理异常和自身组织损伤而出现的一种威胁生命的状况,是重症监护病房(ICU)的常见疾病之一。在脓毒症病程发展过程中,病原相关分子模式(PAMP)、炎性介质、中性粒细胞胞外诱捕网(NET)等多种因素在诱导炎症反应的同时,激活患者机体的凝血功能。凝血系统的过度激活可能对宿主机体造成伤害,致脓毒症相关性凝血病和弥散性血管内凝血(DIC)的发生,进而发展为危及生命的多器官功能障碍(MODS),大大增加了患者的死亡风险。如何及时纠正脓毒症相关性凝血病与凝血功能障碍,有效改善患者预后,也成为了脓毒症治疗领域的研究热点之一。主要对重组人活化蛋白C(rhAPC)、重组人可溶性血栓调节蛋白(rhsTM)、抗凝血酶ⅢI(ATⅢ)、重组组织因子途径抑制剂(rTFPI)、肝素和血必净注射液等脓毒症相关性凝血病治疗药物的研究进展进行综述。     

止凝血研究在脓毒症中的进展

在脓毒症所致的多器官功能障碍的病理发展过程中,外周微循环的干扰,白细胞和活化补体对组织和细胞的损害,使患者内皮细胞、血小板和凝血系统功能紊乱,从而导致弥漫性血管内凝血(DIC)的发生。研究表明,止凝血系统的功能紊乱与患者预后密切相关,尽管有关脓毒症的相关抗凝血治疗研究获得进展,但除了活化蛋白C替代疗法外,近期几乎所有的关于脓毒症抗凝、抗炎的临床试验均未成功[1]。脓毒症仍伴随很高的病死率。对于脓毒症的研究目前已经逐步拓展到对于DIC的早期诊断、预后评估以及血管内皮损伤等领域,现就相关脓毒症止凝血研究现状综述如下。     

脓毒症大鼠肾脏功能与其线粒体生物修复机制的实验研究

脓毒症是各种微生物及免疫原性物质引起的全身炎症反应和宿主自身免疫性损伤,其本质是大量炎症因子和炎症介质失控性释放导致的宿主自身免疫性损伤（autoimmunity injury）。脓毒症是当今医学所面临的主要挑战之一,也是儿科疾病的死亡原因之一,进一步发展可引起严重脓毒症（severe sepsis）、脓毒症休克(septic shock)和多器官功能障碍综合征(Multiple Organ Dysfunction Syndrome MODS)甚至死亡。脓毒症的发病机制尚不十分明确,可能的发病机制包括：炎症因子风暴、凝血系统紊乱和微循环、线粒体功能障碍等。线粒体功能障碍在脓毒症,尤其是脓毒症休克患者的病情发展中起了很重要的作用。但在脓毒症恢复过程中,线粒体机制尚不明确。线粒体生物修复（Mitochondrial biogenesis）是维持及恢复线粒体结构与功能的一种细胞程序,在脓毒症恢复中起着重要的作用。在某些因素(尚未明确)的启动下,脓毒症器官线粒体再生修复的相关基因表达增加,可增加线粒体 DNA 的复制与转录,使线粒体相关的功能与结构蛋白表达增加,恢复线粒体的功能。肾脏是机体重要器官,是脓毒症时易损器官。本课题对脓毒症大鼠肾脏的功能状态,肾脏线粒体功能状态、超微形态结构及线粒体生物修复基因表达进行研究,探讨脓毒症肾脏功能损伤与线粒体损伤及修复间的关系,进一步了解脓毒症的病理生理机制。     

乌司他丁对中重度脓毒症患者肾损伤的保护作用机制分析

<正>脓毒症多由休克、严重感染等危急重疾病引起,其发生与炎症反应密切相关,治疗重点在于抑炎~([1])。脓毒症一般病情严重,常伴凝血功能障碍、脏器功能衰竭,是导致多器官功能障碍综合征的高危因素,病死率高。相关报道称脓毒症易出现急性肾损伤,增加治疗难度,是导致患者死亡的重要原因之一~([2])。     

脓毒症的发病机制研究

脓毒症是病人对严重感染的反应,死亡率高,严重影响患者的生活质量。理想状态下,病原体第一次进入体内,炎症系统就会清除该病原体,使宿主恢复稳态。但脓毒症患者机体的调节机制失常,中性粒细胞、单核/单核巨噬细胞等的持续激活,淋巴细胞凋亡增加,中性粒细胞凋亡的延迟、细胞/组织等坏死的增加,影响了免疫功能和凝血功能,都会影响脓毒症的发展进程。     

1例脓毒症伴血小板进行性下降患者的药学监护

目的探讨临床药师对脓毒症伴血小板进行性下降患者的药学监护。方法临床药师参与重症监护病房(intensive care unit,ICU)的1例脓毒症伴血小板进行性下降患者的会诊与治疗,分析脓毒症患者特殊的病理、生理情况,与临床医师共同制定用药与治疗方案,对患者实施药学监护。结果本例脓毒症伴血小板进行性下降患者的治疗中,积极输注血小板联合胸腺肽α1的升血小板效果显著。结论对于脓毒症伴血小板进行性下降患者的药物治疗中应该尽量避免使用易致血小板降低的药物,并积极给予患者输注血小板联合胸腺肽α1进行增强免疫降低炎症辅助升血小板治疗。     

血必净对脓毒症患者凝血功能影响的临床观察

目的:观察血必净对脓毒症患者凝血功能的影响.方法:将脓毒症患者分为凝血功能正常A组及异常B组,B组分血必净治疗B1组和对照B2组,每组20 例.结果:A组患者在血必净使用前后凝血功能各指标以及血小板计数无变化;B1组患者凝血功能各值在治疗后有改善,较B2组患者的数据有统计学意义.结论:血必净注射液在凝血功能正常的脓毒症患者中使用,对凝血无影响.在异常组中的应用能改善患者的凝血功能.     

Targeting von Willebrand factor as a novel anti-platelet therapy; Application of ARC1779, an Anti-vWF aptamer, against thrombotic risk

Excessive activation of platelets is a causative factor for thrombotic diseases such as acute coronary syndrome or stroke, and various anti-platelet drugs were developed. Aspirin and clopidogrel have been used as gold standards for anti-platelet therapies, however, their clinical limitations including bleeding problem have increased the demand driving development of novel anti-platelet drugs with new targets. Among several activating pathways leading to platelet aggregation, the interaction between von Willebrand factor (vWF) and glycoprotein Ib, which mainly occurs under high shear stress in arterioles, is recently suggested to be a new promising target. The anti-thrombotic efficacy of anti-vWF agents, such as ARC1779, has been proved in several preclinical and clinical studies. Here, we will discuss the potential benefits of targeting vWF as a novel antiplatelet therapy, providing an insight into the role of vWF in increased thrombotic risk.     

Cilostazol down-regulates the height of mural platelet thrombi formed under a high-shear rate flow in the absence of ADAMTS13 activity

Cilostazol is an anti-platelet drug that reversibly inhibits phosphodiesterase III (PDE-III), which is ubiquitously expressed in platelets and various tissues. PDE-III converts cyclic adenosine monophosphate (cAMP) to 5'-AMP and up-regulates the intracellular concentration of cAMP, a potent inhibitor of platelet aggregation. Unlike other anti-platelet drugs, cilostazol is unique because patients receiving this drug do not have a significantly prolonged bleeding time, but the reasons for this difference are still unknown. In this study, we have examined how cilostazol inhibits platelet thrombus formation using anti-coagulated normal whole blood in which the platelets were labeled with a fluorescent dye in comparison with the anti-GPIIb/IIIa agent, tirofiban. We used an in vitro assay to examine mural platelet thrombus growth on a collagen surface under a high-shear rate flow in the absence of ADAMTS13 activity. These experimental conditions mimic the blood flow in patients with thrombotic thrombocytopenic purpura. Using this model, we clearly determined that cilostazol down-regulates the height of mural platelet thrombi formed on a collagen surface in a dose-dependent manner, without affecting the surface coverage. The concentration of cilostazol used in this study was relatively high (60-120μM) compared to clinically relevant concentrations (1-3μM), which may be due to the in vivo synergistic effects of PDE-III present in other tissues aside from platelets. Cilostazol does not affect the initial formation of platelet thrombi, but does inhibit the height of thrombi. These results showed a sharp contrast to tirofiban, and address why cilostazol does not significantly prolong bleeding time, despite its strong anti-platelet activity.     

Cilostazol and primary-PCI: mirage or good alternative?

Oral anti-platelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients undergoing percutaneous coronary interventions. Advancements in the design of stents and catheters are pushing the technique towards treatment of high risk lesions whose failure would expose patients to catastrophic events. Success of these complex procedures largely lays on efficacy of anti-platelet drugs and the limitation of stent restenosis and/or thrombosis. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopidogrel, the most important of which is the wide response variability of platelet inhibition. Thus, clinicians are facing challenges in treating patients where high inhibition of platelets is necessary and the response to clopidogrel may be insufficient. In the last few years, cilostazol, a phosphodiesterase (PDE) 3 inhibitor, has been tested in the setting of acute coronary syndromes: it exerts not only anti-platelet actions, but also pleiotropic effects, including inhibition on neointimal hyperplasia, therefore preventing both stent restenosis and thrombosis. Therefore, cilostazol may be considered, on top of our current anti-platelet therapy, as a potential candidate to achieve optimal platelet inhibition especially in patients undergoing primary-PCI (p-PCI) or high risk procedures. This review will focus on the pharmacological characteristics of cilostazol and the initial evidences that support the use of this drug in the setting of p-PCI.     

Disseminated intravascular coagulation. Approach to treatment.

Disseminated intravascular coagulation (DIC) is a syndrome caused by the systemic generation of thrombin. Most cases are due to pathological activation of the intrinsic coagulation systems (e.g. in sepsis), and/or the extrinsic system (e.g. in malignancy and head trauma). Diagnosis is made by finding abnormalities in at least 3 of 4 laboratory values, namely prothrombin time, platelet count, fibrinogen and fibrinogen/fibrin degradation products. The most common clinical manifestation of DIC is bleeding, with thrombosis in less than 10% of acute cases but more frequently encountered in chronic DIC associated with malignancy. Acute DIC must first be treated by specific therapy of the underlying disease and general support measures. If serial clinical and laboratory monitoring improves, no further treatment is required. If severe or life-threatening haemorrhage occurs or a thrombotic event ensues, heparin anticoagulation followed by aggressive replacement with platelets, fresh plasma and possibly cryoprecipitate is indicated. Heparin doses should be 'therapeutic' (i.e. adequate to overcome the coagulant forces that may have produced a relative heparin-resistant state in the blood). Chronic DIC with haemorrhage, or more usually thrombosis, should also be treated with heparin; warfarin is ineffective. If DIC persists because, for example, a tumour does not regress, long term outpatient subcutaneous heparin therapy may be required.     

Thrombus models and mechanisms of action of anti-platelet drugs]

Thrombus formation is initiated by platelet aggregation, followed by activation of the blood coagulation system, so that anti-thrombotic drugs can be classified into anti-platelet drugs, anti-coagulation drugs and fibrinolytic drugs. A variety of thrombus models in animals have been reported. Microthrombus formation in arterioles in the microcirculation is useful for analyzing the nature of the thrombus and the process of thrombus formation. Platelet aggregation can be divided into two types: (a) reversible aggregation (Rev-Aggr), in which platelets do not release their granular contents and are able to return to the resting discoid shape and (b) irreversible aggregation (Irrev-Aggr), in which platelets release their granular contents. Irrev-Aggr is inhibited by aspirin and not by PGI2 at the maximum aggregation, whereas Rev-Aggr is not inhibited by aspirin and inhibited by PGI2 even at the maximum aggregation. Thrombi corresponding to either type of platelet aggregation can be produced in arterioles in the microcirculation. An ADP-induced thrombus, which is composed of Rev-Aggr of platelets and disaggregated automatically, is not inhibited by indomethacin, but inhibited by PGI2. In contrast, a stable thrombus, which is composed of Irrev-Aggr of platelets and keeps its initial shape for a longer period, is sensitive to indomethacin, but resistant to PGI2. Thus, anti-thrombotic drugs should be developed and used for targeting the individual processes of thrombus formation.     

Future prospects in anti-platelet therapy: a review of potential P2Y12 and thrombin receptor antagonists

Atherothrombosis is an acute complication that develops on the surface of a ruptured atheromatous plaque or as a consequence of endothelial erosion that may cause myocardial infarction or ischemic stroke. Anti-platelet therapy has been highly effective at reducing atherothrombotic risk. However, patients continue to experience thrombotic events despite the use of agents such as aspirin and clopidogrel. Many of these events occur, in part, because of the inadequate response to these drugs. This has prompted the pursuit of novel agents with aspirations of optimizing anti-platelet therapy. New opportunities have emerged to address the deficiencies in current anti-platelet agents. Among these are thrombin receptor antagonists, such as SCH530348 and P2Y12 receptor antagonists, such as prasugrel, cangrelor, and AZD6140. The patents describe these novel compounds and compositions, their ability to inhibit platelet activation and/or aggregation and their use in the treatment of atherothrombotic diseases. These drugs have pharmacologic properties that translate into increased potency, more rapid onset of action, and less variability in response compared to standard therapy. In this review, we highlight the current data on these potential drugs and the role they could play in atherothrombotic disease.     

Safety and efficacy of targeting platelet proteinase-activated receptors in combination with existing anti-platelet drugs as antithrombotics in mice

BACKGROUND AND PURPOSE

Developing novel anti-platelet strategies is fundamental to reducing the impact of thrombotic diseases. Thrombin activates platelets via proteinase-activated receptors (PARs), and PAR antagonists are being evaluated in clinical trials for prevention of arterial thrombosis. However, one such trial was recently suspended due to increased bleeding in patients receiving a PAR₁ antagonist in addition to anti-platelet drugs that most often included both aspirin and clopidogrel. Therefore, it remains unclear how to best manipulate PARs for safe antithrombotic activity. To address this, we have examined potential interactions between existing anti-platelet drugs and strategies that target PARs.

EXPERIMENTAL APPROACH

We used in vivo mouse models in which interactions between various anti-platelet strategies could be evaluated. We examined the effects on thrombosis and haemostasis in PAR₄−/− mice (platelets unresponsive to thrombin) treated with therapeutic doses of either aspirin or clopidogrel.

KEY RESULTS

Using a model in which occlusive thrombosis occurred in PAR₄−/− mice or wild-type mice treated with aspirin or clopidogrel, PAR₄−/− mice treated with either anti-platelet agent showed marked protection against thrombosis. This antithrombotic effect occurred without any effect on haemostasis with aspirin, but not clopidogrel. Furthermore, specifically targeting thrombin-induced platelet activation (via PARs) improved the therapeutic window of non-specifically inhibiting thrombin functions (via anticoagulants).

CONCLUSIONS AND IMPLICATIONS

Our results indicate that PAR antagonists used in combination with aspirin provide a potent yet safe antithrombotic strategy in mice and provide insights into the safety and efficacy of using PAR antagonists for the prevention of acute coronary syndromes in humans.     

The prothrombotic state in hypertension and the effects of antihypertensive treatment

Hypertension is associated with the flow of blood under high pressures, yet the complications of hypertension, such as myocardial infarction or stroke are paradoxically thrombotic rather than haemorrhagic. This could be explained by increasing evidence which suggests that hypertension fulfils the pre-requisites of the Virchow's triad for thrombogenesis, leading to a prothrombotic or hypercoagulable state. Hypertension leads to changes in the platelets, endothelium and the coagulation and fibrinolytic pathways which help to promote the induction and the maintenance of this prothrombotic state. These changes can to a certain extent be reversed by the treatment of hypertension, although different antihypertensive agents may have variable effects in reversing these changes. Some of the effects may be simply related to normalisation of blood pressure, but certain groups of drugs such as those acting on the renin-angiotensin-aldosterone system appear to have an effect over and above this. Anti-platelet agents have also been shown to confer a degree of benefit to lsqou;high risk' hypertensive patients. The study of the prothrombotic state in hypertension is therefore of paramount importance, as understanding the pathogenic processes underlying it can help prevent many of the complications associated with this condition.     

1例氯吡格雷引起TTP并发支架内血栓患者的用药分析

1例急性心肌梗死PCI术后抗血小板双联治疗的患者发生血栓性血小板紫癜（TTP）,住院过程中发生亚急性支架内血栓。临床药师分析认为,与双联抗血小板的治疗方案相关,建议调整用药方案,最终选择阿司匹林与替格瑞洛联合抗血小板治疗,取得良好效果。