抗血小板新药—氯吡格雷

抗血小板治疗可有效减少血栓形成性疾病患者血管性事件的发生。氯吡格雷是一种新颖的抗血小板药物,通过阻断二磷酸腺苷（ADP）受体而抑制血小板活性。本文综述了氯吡格雷的作用机制、药效学和药代动力学特性及其临床应用和安全性。     

抗血小板药物联合治疗在缺血性脑血管病中的应用

抗血小板药物具有不同的作用机制,用于治疗频发性动脉疾病,包括脑血管疾病。近期的脑血管及心血管试验表明,联合治疗可以有效的预防缺血性脑血管病。预防血栓形成的药物氯吡格雷,曾被誉为超级阿斯匹林,与阿斯匹林联合治疗脑缺血显示出比单独使用阿斯匹林更突出的功效。阿斯匹林与防治心绞痛控释药双嘧达莫联合治疗效果较为突出。尽管如此,缺血性脑血管病的抗血小板药物联合治疗仍然存在着某些争议。目前的研究旨在区分不同抗血小板联合剂的作用。     

Combination antiplatelet agents in ischemic cerebrovascular disease

Combination antiplatelet agents with multiple mechanisms of action are being used with increasing frequency for vascular disorders, including cerebrovascular disease. Limited data exist regarding the efficacy of combination antiplatelet therapy in the primary or secondary prevention of cerebral ischemia, and combination therapies are often used without adequate evidence of efficacy. However, over the last few years, several cerebrovascular and cardiovascular trials have provided some preliminary information on the effectiveness of various combination therapies in preventing cerebral ischemic disease. This article reviews recently completed cerebrovascular and cardiovascular trials that tested a combination antiplatelet regimen against aspirin alone, and that assessed cerebral ischemia as an outcome measure. Controversies pertaining to these trials and to the use of the various combination antiplatelet regimens are discussed. Based on cardiovascular studies, clopidogrel in combination with aspirin has not been proven superior to aspirin alone for the primary prevention of cerebral ischemia. No data exists regarding the combination of clopidogrel and aspirin for the secondary prevention of cerebrovascular disease. The combination of aspirin plus extended-release dipyridamole (xrDP) appears to be superior to aspirin alone in the secondary prevention of cerebral ischemia, but may compromise cardiovascular protection in patients with coexisting coronary artery disease. Combination therapy with aspirin and clopidogrel seems to increase the risk of major hemorrhages, whereas aspirin plus xrDP does not. Ongoing trials are expected to clarify the role of various combination antiplatelet regimens.     

Role of antiplatelet agents in cerebrovascular disease.

It is now generally accepted by neurologists that most transient ischaemic attacks, particularly in the carotid artery territory, have a thromboembolic basis. These emboli are, for the most part, fibrin-platelet aggregates. Others which contain atheromatous debris are more likely to produce longer lasting neurological deficits. If one assumes this hypothesis then it is reasonable to employ drugs which interfere with platelet aggregation in order to prevent cerebrovascular symptoms and signs. Acetylsalicylic acid (aspirin) prevents aggregation by inhibiting the 'release reaction' initiated by thromboxane A2. This inhibition lasts for the life of the affected platelets. Recent trials in the United States and Canada have demonstrated a positive clinical benefit from the employment of aspirin in patients suffering from transient cerebral ischaemic attacks and amaurosis fugax. There was a reduction or cessation of the attacks in both males and females and a 50% reduction of stroke morbidity and mortality in males.     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

相似文献   

The mechanism of action of KBT-3022, a new antiplatelet agent

• 1.1. The mechanism of action of a new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate) and its active main metabolite, desethyl KBT-3022, was investigated.
• 2.2. KBT-3022 and desethyl KBT-3022 inhibited cyclooxygenase from ovine seminal gland with IC₅₀ values of 0.69 and 0.43 μM, respectively.
• 3.3. At concentrations higher than those required for cyclooxygenase inhibition, desethyl KBT-3022 inhibited cAMP-phosphodiesterase, specific binding of U46619, and release of phosphatidic acid from thrombin-stimulated platelets.
• 4.4. Oral administration of KBT-3022 inhibited the production of thromboxane B₂ during blood coagulation more potently than the production of 6-keto-prostaglandin F_1α from aortic strips in guinea pigs.
• 5.5. These findings suggest that KBT-3022 may inhibit platelet activation principally via the inhibition of cyclooxygenase by desethyl KBT-3022.

     

Ticagrelor: a novel antiplatelet agent for patients with acute coronary syndrome

Ticagrelor is an oral, reversible blocker of the P2Y12 adenosine receptor. In clinical trials the antiplatelet agent reduced significantly vascular mortality and death from any cause when compared to clopidogrel in patients with acute coronary syndrome.     

Metrifonate: a new agent for the treatment of Alzheimer's disease.

The pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of metrifonate, a long-acting cholinesterase inhibitor, are discussed. Attempts to correct the central cholinergic deficits associated with Alzheimer's disease have included administration of cholinergic precursors, cholinergic agonists, and cholinesterase inhibitors. To date, two reversible cholinesterase inhibitors-tacrine and donepezil-have been marketed. Metrifonate, an organophosphate, is converted nonenzymatically to 2,2-dichlorovinyl dimethyl phosphate (DDVP), the active enzyme inhibitor. DDVP produces irreversible inhibition of brain cholinesterase that lasts for several days; enzyme recovery is dependent on synthesis of new enzyme. Several preclinical studies have demonstrated cognition-enhancing effects of metrifonate in animals. Trials in humans have shown improvement on the Alzheimer's Disease Assessment Scale, in Mini-Mental State Examination scores, and in the Clinician's Interview-Based Impression of Change with caregiver input. Clinical improvement noted with metrifonate appears similar to that seen with other cholinesterase inhibitors. Adverse effects noted in clinical trials have been associated primarily with the gastrointestinal tract and have been mild. Metrifonate appears to be a promising agent for the treatment of the symptoms of Alzheimer's disease.     

新型抗血小板药替卡格雷

替卡格雷为第一个可逆结合的、直接起效的、口服给药的血小板二磷酸腺苷P2Y12受体拮抗剂,比氯吡格雷起效更快,对血小板凝集的抑制作用更强。2011年7月20日,美国FDA批准替卡格雷用于降低急性冠脉综合征(acute coronary syndrome,ACS)患者的血栓性心血管事件的发生率。与氯吡格雷相比,替卡格雷起效更快,对血小板聚集的抑制作用更强,能显著降低心血管死亡、心肌梗死或卒中的发生率。在有效治疗的同时,替卡格雷并未显著增加主要出血事件的发生率。联合用药时,阿司匹林的维持剂量应为75～100 mg.d-1。本文对替卡格雷药理学特性、临床价值及不良反应进行综述。     

抗血小板新药替卡格雷临床应用争议

阿斯利康制药有限公司正在研发的抗血小板新药替卡格雷(ticagrelor,Brilinta)是首个可逆的结合型口服二磷酸腺苷受体拮抗剂,其临床应用颇具潜力.本文汇总近年有关重要国际会议上的专家意见,以便临床能正确合理应用本品,充分发挥其治疗优势.     

Identification of indothiazinone as a natural antiplatelet agent

Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in‐house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbβ3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbβ3. It also restricted thrombin‐ and adenosine diphosphate‐dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin‐induced activation of integrin αIIbβ3 presumably by inhibiting talin–integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action.     

抗癫痫新药瑞替加滨

瑞替加滨为神经元钾离子通道开放剂,是一种具有全新作用机制的抗癫痫药,临床上用于成人癫痫部分发作的辅助治疗。文中对瑞替加滨的作用机制、药效学、药代动力学、药物相互作用、临床评价和安全性等进行综述。     

Pentoxifylline: a new agent for intermittent claudication

Pentoxifylline is approved by the Food and Drug Administration for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. It is not a substitute for surgical bypass or removal of arterial obstructions, but will improve function and symptoms of the disease state. The mechanism by which pentoxifylline works is not well known, but appears to be related to erythrocyte adenosine triphosphate (ATP) concentrations and the phosphorylation of erythrocyte membrane proteins, both mechanisms resulting in an improvement in erythrocyte flexibility. Efficacy studies indicate that pentoxifylline is significantly more effective than placebo or nylidrin therapy. Adverse reactions are mainly of the gastrointestinal type and are minimized by the use of a controlled-release dosage form.     

抗糖尿病新药维格列汀

维格列汀(vildagliptin)是继西他列汀(sitagliptin)后的又一个二肽基肽酶-Ⅳ(DPP-Ⅳ)抑制剂,用于治疗2-型糖尿病.临床研究表明,维格列汀是一个口服有效、市场前景良好的药物,单用或与二甲双胍、胰岛素合用都有明显的降血糖作用,且服用安全,耐受性好,不良反应少.现对其作用机制、药效学、药动学、临床疗效进行综述.     

Research and development of cilostazol: an antiplatelet agent

In our study, we focused on the fact that platelets play a significant role in thrombus formation in the arterial vessels, and started exploratory research on the antiplatelet agent with a vasodilating action in order to discover a more effective drug for arterial thrombosis. We synthesized many 2(1H)-quinolinone derivatives and evaluated their inhibition of platelet aggregation and their vasodilating activities. First we found cilostamide, which has an amide moiety in the side chain. This compound possessed desired activities, but it caused a side effect of tachycardia, and so, unfortunately, we were unable to pursue its development. After many efforts to modify the side chain moiety to eliminate this side effect, we finally invented cilostazol (OPC-13013), a 2(1H)-quinolinone derivative with a tetrazol ring in the side chain. Cilostazol inhibited human platelet aggregation induced by various stimuli including shear stress in vitro and showed potent antiplatelet effects both in vitro and ex vivo. It was also shown that the drug has antithrombotic effects in experimental thrombus models and a vasodilating activity of the femoral artery and vertebral artery. The mechanism of the action for cilostazol is specific inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3). Cilostazol was marketed first in Japan in 1988 and later in seven other countries for the treatment of chronic arterial occlusion. It was launched in the U.S. in 1999, and approved in United Kingdom for the treatment of intermittent claudication. More recently, cilostazol was shown to be effective in a clinical prevention study on recurrence of cerebral infarction, and has been applied to the approval of the indication in Japan.     

Aspirin and antiplatelet agent resistance: implications for prevention of secondary stroke

Oral antiplatelet drugs, including aspirin, clopidogrel and extended-release dipyridamole, are widely prescribed for the secondary prevention of vascular events, including stroke. Despite the benefits of antiplatelet therapy, 10?20% of patients experience a recurrent vascular event while taking antiplatelet medication. This article discusses the concept of antiplatelet resistance in general, focusing on aspirin resistance in particular, as a poorly defined cause of recurrent vascular events. Factors such as the lack of a standardized method to diagnose aspirin resistance and a poor clinical correlation with laboratory assays make the treatment of aspirin nonresponders difficult. In addition, there are confounding conditions such as diabetes mellitus that can affect aspirin resistance and determine a different course of treatment for these patients. Other antiplatelet options may also have resistant subpopulations; thus, alternative strategies for the secondary stroke patient must be explored.     

Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment

Alzheimer's disease (AD) is the most common cause of dementia, clinically characterized by loss of memory and progressive deficits in different cognitive domains. An emerging disease-modifying approach to face the multifactorial nature of AD may be represented by the development of Multi-Target Directed Ligands (MTDLs), i.e., single compounds which may simultaneously modulate different targets involved in the neurodegenerative AD cascade. The structure of tacrine, an acetylcholinesterase (AChE) inhibitor (AChEI), has been widely used as scaffold to provide new MTDLs. In particular, its homodimer bis(7)tacrine represents an interesting lead compound to design novel MTDLs. Thus, in the search of new rationally designed MTDLs against AD, we replaced the heptamethylene linker of bis(7)tacrine with the structure of cystamine, leading to cystamine-tacrine dimer. In this study we demonstrated that the cystamine-tacrine dimer is endowed with a lower toxicity in comparison to bis(7)tacrine, it is able to inhibit AChE, butyrylcholinesterase (BChE), self- and AChE-induced beta-amyloid aggregation in the same range of the reference compound and exerts a neuroprotective action on SH-SY5Y cell line against H(2)O(2)-induced oxidative injury. The investigation of the mechanism of neuroprotection showed that the cystamine-tacrine dimer acts by activating kinase 1 and 2 (ERK1/2) and Akt/protein kinase B (PKB) pathways. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

Tresperimus: a new agent for transplant tolerance induction

Tresperimus is a novel agent that induces allogeneic transplant tolerance. It is structurally related to deoxyspergualin (DSG) but has been modified to resist rapid hydrolysis in aqueous solution, which simplifies administration. Despite this modification, tresperimus’s actions in experimental models seem almost identical to DSG. Initially, DSG was developed as an antitumour agent. Its antitumour efficacy appears limited but DSG and tresperimus have favourable effects on transplant rejection. A short course of tresperimus has been shown to have similar or greater quantitative effects to cyclosporin in bone marrow, cardiac and skin transplant models. However, qualitatively the effects are different. Prevention of rejection is due to induction of donor-specific tolerance without affecting immunity to third party antigens. In addition, CD4+ T-cells from tresperimus-treated animals can transfer donor specific tolerance to naïve animals, an effect not seen with cyclosporin or other traditional immunosuppressive drugs. The mechanism by which tolerance is induced is not clear. Tresperimus (like DSG) binds to Hsc70, which among other effects inhibits nuclear localisation of NF-κB. NF-κB nuclear localisation is induced by CD40 ligation in antigen-presenting cells, an important early step in T-cell co-stimulation. NF-κB is also required for CD28 ligation signalling, important in late co-stimulation. It also is involved in B-cell activation, via CD40 ligation and kappa light chain production. Hsc70 is also required for efficient cytosolic peptide chaperoning to MHC class I molecules. Presumably, it is disruption of T-cell/dendritic cell interaction that leads to induction of T-cell anergy. Tresperimus is well-tolerated. The main dose limiting side effects are orthostatic hypotension and peri-oral numbness. These effects are dependant on blood drug levels and, due to its short half-life, correspond to the rate of infusion. Phase II/III clinical studies are accruing patients and results have not yet been reported. Tresperimus shows promise in the move from immunosuppression to tolerance induction as the way to prevent transplant rejection and graft-versus-host disease (GvHD). However, its role in tolerance induction and effect in combination with other tolerance inducing agents e.g., CTLA-4-Ig and anti-CD40L antibodies remains unclear.     

Flavodilol: a new antihypertensive agent

Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.