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.     

抗血小板药物在脓毒症治疗中的应用

对于脓毒症的医疗投入逐年增加,但脓毒症的病死率却居高不下。目前研究已发现,脓毒症是炎症反应过度和凝血功能紊乱共同导致的,而血小板在其中起着重要作用。血小板形成的微血栓可加重器官功能障碍,甚至继发弥散性血管内凝血,还可加重炎症反应。如能在监测血小板功能情况下,适时地予以抗血小板治疗以减轻脓毒症对机体的损害,同时又不增加出血风险,这或将成脓毒症治疗新的方向。抗血小板药物为临床常用药物,且价格低廉,已在心脑血管疾病中广泛应用,但在脓毒症的治疗中报道较少。本文就抗血小板药物在脓毒症治疗中的可行性作一综述。     

Section Review—Cardiovascular & Renal: Recent Developments in Antithrombotic Agents

During the past decade, many significant developments in the clinical management of thrombotic and vascular disorders have occurred. In particular, several newer approaches for the prophylactic and therapeutic management of such disorders as venous thrombosis, acute myocardial infarction and stroke have been introduced. This has only been possible due to the understanding of the molecular mechanisms involved in the thrombogenic process which plays a key role in the pathophysiology of thrombotic and vascular disorders. With the increased knowledge of the pathophysiology of thrombosis have come advances in drug treatment possibilities. Advances in biotechnology and separation techniques have contributed to the development of many newer antithrombotic, anticoagulant and thrombolytic drugs. Many new drugs and devices based on newer concepts are currently being tested in various clinical trials. Hirudin, hirulog, Gpllb/llla targeting antibodies and tissue factor pathway inhibitor (TFPI), are some examples. From these current developments, it can be appreciated that antithrombotic drugs represent a wide spectrum of natural, synthetic, semisynthetic and biotechnology produced agents with marked differences in chemical composition, physico-chemical properties, biochemical actions and pharmacologic effects. The use of physical means to treat thrombotic disorders and advanced means of drug delivery add to the expanding nature of treatment. The endogenous actions of the antithrombotic drugs are quite complex. It is no longer valid to assume that an antithrombotic drug must produce an anticoagulant action in blood, as do the classical heparin and oral anticoagulants. Many of these new drugs do not produce any alteration of currently measurable blood clotting parameters, yet they are effective therapeutic agents because of their interactions with the elements of the blood and the vasculature. Another perspective is that several of these agents require endogenous transformation to become active products. Therefore, it becomes important to rely on the pharmacodynamic actions of these agents rather than on other in vitro characteristics to assess potency or efficacy. Haematologic and vascular modulation play a key role in the mediation of the antithrombotic actions of these drugs involving red cells, white cells, platelets, endothelial cells and blood proteins. Thus, an optimal antithrombotic drug/approach will include the targeting of all possible sites involved in thrombogenesis. Polytherapeutic approaches utilising combinations of drugs may turn out to be the most effective in the management of thrombotic disorders.     

Advances in antithrombotic agents

Thrombosis is the condition where an imbalance in the homeostatic mechanism results in unwanted intravascular thrombus formation. Imbalances in this highly regulated process of coagulation and anticoagulation can lead to a variety of pathophysiological conditions leading to stroke, pulmonary heart attack and other serious conditions. In the western world, thromboembolic diseases are the leading cause of morbidity and mortality. Remarkable progress has occurred over the last decade in the development of antithrombotic drugs, which can be classified into 3 major categories - Anticoagulants, Antiplatelets and thrombolytics. Increased understanding of the pathobiology of thrombotic and vascular disorders has helped researchers to target novel pathways involving the coagulation, thrombolytic, fibrinolytic and integrin systems. Traditionally aspirin and unfractionated heparin was used for myocardial infarction. Newer antiplatelet agents such as, clopidogrel, GP IIb/IIIa inhibitors, low molecular weight heparin, direct thrombin inhibitors and several improved thrombolytic agents have been introduced for clinical use. This review will discuss different important drugs, which have been launched in recent years and also some new targets pursued by different companies.     

Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation

Cellular interactions among platelets, leukocytes and endothelial cells are considered as a major cause of inflammation and atherosclerosis in many diseases. Via exposed surface receptors and released soluble substances, activated platelets play a crucial role in the initiation of inflammatory processes, resulting in endothelial injury and leading to formation of atherosclerotic plaque with possible thrombotic complications. Classic anti-platelet treatments (e.g. cyclooxygenase inhibitor or ADP-receptor antagonist) have favorable effects in patients with vascular diseases, but they also have several limitations such as increased bleeding risk or non-responsiveness. Thus, the need and opportunities for developing novel therapeutic inhibitors for platelet-mediated events are obvious. Animal and (pre)clinical human studies have suggested that some recently produced specific antagonists of P-selectin from α-granules, as well as its main ligand/receptor P-selectin Glycoprotein Ligand-1, the two major platelet chemokines CXCL4 and CCL5, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation. In this review, we summarize the pathophysiological roles of these effectors in platelet activation and acute or chronic inflammation, and discuss the latest findings on promising antagonistic agents in basic and clinical studies in the prevention of platelet-mediated cellular interactions.     

抗血栓药物的研究进展

血栓栓塞性疾病是引起人类疾病死亡的主要原因之一．随着人们对其发病机制研究与认识的不断深入以及药物设计和筛选技术的日臻成熟,针对各种靶点的新型抗血栓药物不断涌现,如二磷酸腺苷受体阻滞剂、Xa因子抑制剂、凝血酶抑制剂等,我国药学研究者也在这些靶向抗血栓药物研究领域取得一定进展。综述我国学者近些年在国内外学术期刊上发表的相关研究论文中所涉及的各类新型抗血小板药物、抗凝血药物和血栓溶解剂的结构、活性和构效关系。     

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.     

Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents

Cardiovascular and cerebrovascular diseases continue to be the leading cause of death throughout the world. Over the past two decades, great advances have been made in the pharmacological treatment and prevention of thrombotic disorders (e.g., tissue plasminogen activators, platelet GPIIb/IIIa antagonists, ADP receptor antagonists such as clopidogrel, low-molecular weight heparins, and direct thrombin inhibitors). New research is leading to the next generation of antithrombotic compounds such as direct coagulation FVIIa inhibitors, tissue factor pathway inhibitors, gene therapy, and orally active direct thrombin inhibitors and coagulation Factor Xa (FXa) inhibitors. Animal models of thrombosis have played a crucial role in discovering and validiting novel drug targets, selecting new agents for clinical evaluation, and providing dosing and safety information for clinical trials. In addition, these models have provided valuable information regarding the mechanisms of these new agents and the interactions between antithrombotic agents that work by different mechanisms. This review briefly presents the pivitol preclinical studies that led to the development of drugs that have proven to be effective clinicallly. The role that animal models of thrombosis are playing in the discovery and development of novel antithrombotic agents is also described, with specific emphasis on FXa inhibitors. The major issues regarding the use of animal models of thrombosis, such as the use of positive controls, appropriate pharmacodynamic markers of activity, safety evaluation, species-specificity, and pharmacokinetics, are highlighted. Finally, the use of genetic models in thrombosis/hemostasis research and pharmacology is presented using gene-therapy for hemophilia as an example of how animal models have aided in the development of these therapies that are now being evaluated clinically. In summary, animal models have contributed greatly to the discovery of currently available antithrombotic agents and will play a primary role in the discovery and characterization of the novel antithrombotic agents that will provide safe and effective pharmacological treatment for life-threatening thrombotic diseases.     

Drug therapy of cancer

Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success. However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic myelogenous leukemia by imatinib, inhibiting the bcr-abl-activated tyrosine kinase and thereby interrupting the signal transduction pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has been little progress in other malignancies such as metastatic malignant melanoma, although very recently, clinical trials with new targeted drugs have shown increased survival. All major pharmaceutical companies now have ambitious development programs in the cancer area. However, the high costs of the novel drugs cause economic distress in the health care system in many countries leading to an intense debate on the cost-effectiveness of these drugs in relation to other health care activities.     

Big science for small cells: systems approaches for platelets

Platelets are dynamic blood cells that form life-threatening thrombi in response to a variety of pathological conditions such as atherosclerosis, diabetes, metastatic cancer, sickle cell disease and obesity. These thrombi can lead directly to myocardial infarction (MI), stroke and other thrombotic events that contribute to over a million deaths every year in the United States. Even though multiple, effective drugs have been developed to combat these pathologies by antagonizing platelet receptors and their ligands, clinical use of these drugs can result in serious bleeding consequences. With the advent of increasingly powerful and accessible systems biology approaches, however, new opportunities are available to identify novel platelet targets and elucidate potentially safer antiplatelet strategies. Here we provide an overview of some of these exciting systems approaches ranging from genomics to aptamer discovery and emphasize the importance of identifying and exploiting novel platelet targets for therapeutic benefit.     

Pharmacological control of platelet function.

Advancement in the understanding of the mechanisms of platelet activation, as well as the development of new techniques for studying platelet function, have led to the availability of new classes of platelet inhibiting drugs. Initially, characterization of arachidonic acid metabolism in platelets furthered an understanding of the utility of cyclooxygenase inhibitors, most notably aspirin. The discovery and characterization of platelet receptors such as the adenosine diphosphate (ADP) receptor and glycoprotein IIb/IIIa has been associated with the development of novel classes of anti-platelet drug, such as thienopyridine derivatives and glycoprotein IIb/IIIa receptor antagonists, respectively. Future development in receptor pathway inhibitors also includes glycoprotein Ib/IX as well as the potential use of platelet signaling pathway inhibitors.     

Cancer immunotherapy--revisited

Our insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been hampered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies, the percentage of patients who benefited from these interventions has remained too small to justify the general use of such strategies. However, the recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer.     

Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders

Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.     

Platelets and anti-platelet therapy

Platelets play a central role in the hemostatic process and consequently are similarly involved in the pathological counterpart, thrombosis. They adhere to various subendothelial proteins, exposed either by injury or disease, and subsequently become activated by the thrombogenic surface or locally produced agonists. These activated platelets aggregate to form a platelet plug, release agonists which recruit more platelets to the growing thrombus, and provide a catalytic surface for thrombin generation and fibrin formation. These platelet-rich thrombi are responsible for the acute occlusion of stenotic vessels and ischemic injury to heart and brain. A range of anti-platelet drugs are currently used, both prophylactically and therapeutically, in regimens to manage thrombo-embolic disorders. These include inhibitors of the generation, or effects, of locally produced agonists; several large clinical trials have supported roles for cyclooxygenase inhibitors, which prevent thromboxane generation, and thienopyridine derivatives, which antagonize ADP receptors. Similarly intravenous alpha IIb beta 3 antagonists have been shown to be effective anti-thrombotics, albeit in highly selective situations; in contrast, to date studies with their oral counterparts have been disappointing. Recent advances in understanding of platelet physiology have suggested several novel, if yet untested, targets for anti-platelet therapy. These include the thrombin receptor, the serotonin handling system, and the leptin receptor.     

4-甲(乙)氧基-1,3-苯二甲酰胺类化合物的合成及其体外抗血小板聚集活性

目的本文参照前期吡考他胺衍生物的构效关系,设计制得10个4-乙氧基-1,3-苯二甲酰胺类化合物(系列2);为了评价和比较其体外抗血小板聚集活性,同时进行了相应10个4-甲氧基-1,3-苯二甲酰胺类化合物(系列1)的合成,以期寻找新的抗血栓药物。方法以2,4-二甲基苯酚为起始原料,经Willianmson反应、氧化、氯代和胺解反应共制得10个未见文献报道的目标化合物(系列2),各化合物结构均经1H-NMR、IR和MS确证。采用Born比浊法对20个目标化合物进行了体外抗血小板聚集活性初筛。结果与结论在新制得的10个4-乙氧基系列化合物中,2b的活性最高,2a、2b、2d、2f的活性优于阳性对照药物吡考他胺。结果表明,新制得的4-乙氧基系列化合物与系列1各化合物相比,在抗血小板聚集方面同样具有研究价值。     

Development of new cancer therapeutic agents targeting mitosis

Targeting cellular proliferation persists as a mainstay of cancer therapeutic strategy. Although microtubule-targeting drugs (such as taxanes and vinca alkaloids) have been used successfully in the clinic to treat a variety of cancers, they carry substantial liabilities that have spurred drug companies to aggressively pursue new tubulin-targeting drug candidates with improved efficacy and toxicity profiles. The recent discoveries of new mitotic targets for cancer therapy (such as kinesin spindle protein, Aurora kinases and Polo-like kinase-1) have also stimulated intense work focused on identifying novel antimitotic drugs directed at these new targets. A number of novel antimitotic drugs have demonstrated encouraging activity in preclinical models and have progressed into clinical development. This review focuses on selected new antimitotic drugs under evaluation in clinical trials.     

Metabolic syndrome, new onset diabetes, and new end points in cardiovascular trials

Metabolic syndrome affects approximately 44% of the US population over the age of 50 years. Although conflicting definitions exist, the syndrome is typically characterized by abdominal obesity, dyslipidemia, hypertension, and insulin resistance. Thus, it is a major risk factor for both coronary heart disease and type 2 diabetes. Furthermore, the risk of cardiovascular (CV) death is significantly increased in patients with diabetes and/or the metabolic syndrome. Although very few studies exist in patients with the metabolic syndrome, lifestyle changes and drug intervention targeted at the individual components have been shown to reduce the risk of developing diabetes and the incidence of CV disease in high-risk patients. Because many of the conventional antihypertensive drugs may affect the development of new onset diabetes, both positively and negatively, the choice of therapy is particularly important in this population. However, the long-term clinical trials to date have either not included new onset diabetes as a protocol end point or used various different criteria, making comparisons difficult. This review assesses the need for future research into metabolic syndrome and discusses whether clinical surrogates for CV end points, such as new onset diabetes, should be included in clinical trials of new drugs, new regimens, or new indications.     

Targeting tumorangiogenesis in lung cancer by suppression of VEGF and its receptor - results from clinical trials and novel experimental approaches

Tumor vascularisation, the formation of blood vessels is a central process to allow tumor growth beyond limited sizes and to facilitate metastasis formation. Angiogenesis is regulated by a balance of stimulatory and inhibitory factors. Angiogenic factors have been the focus of intense research since the prospects of new therapeutic approaches seemed enormous. Vascular endothelial growth factor (VEGF) has emerged as the most potent and most specific growth factor for endothelial cells and therefore a relevant target for novel anticancer therapy. A wide range of agents have been designed for their ability to interfere the VEGF signalling pathway. In addition, several drugs are currently in advanced clinical development. This review describes the current experimental strategies to inhibit VEGF and will also summarize and discuss the results of recent clinical trials involving anti-VEGF compounds either as standalone therapy or in combination with chemotherapy in lung cancer.     

Anti-platelet therapy and aspirin resistance - clinically and chemically relevant?

Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes.     

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。