Inhibitors of platelet signal transduction as anti-aggregatory drugs

In the treatment and prevention of cardiovascular diseases, inhibition of platelet aggregation is of fundamental importance. Inhibition of platelet aggregation can be achieved by either inhibition of membrane receptors or by interception of signalling pathways. While receptor antagonism provides high specificity, the inhibition of platelet signal transduction is more effective. The effectiveness results from the inhibition of platelets, regardless of the cause of activation. These common pathway inhibitors are either intercepting platelet activating mechanisms or amplifying the action of endogenous platelet inhibitors. The physiological anti-aggregants are the endothelial factors NO and prostacyclin, which elevate intracellular cGMP or cAMP content, respectively. By administration of NO-releasing agents, prostacyclin analogues or other cyclic nucleotide elevating drugs the platelet anti-aggregatory action of endothelial factors can be effectively mimicked. Besides antiplatelet activity these drugs also act on vascular smooth muscle causing relaxation and therefore vasodilation, an additional beneficial effect. Inhibition of phosphodiesterases causes elevation of platelet cyclic nucleotide content and thus inhibits platelet aggregation and causes vasodilation. Another relevant target for anti-aggregatory treatment is the arachidonic acid metabolic pathway. This pathway can be intercepted by blockade of either cyclooxygenase-1 (COX-1) or thromboxane synthase. Inhibition of these enzymes may be further amplified by additional antagonism of the thromboxane receptor thus not only preventing formation of thromboxane but also activation of thromboxane receptor by thromboxane precursors, which were particularly effective in clinical trials. In vivo these precursors may be metabolised to prostacyclin in the endothelium and consequently provide additional platelet anti-aggregatory activity. A rather new target for platelet anti-aggregatory treatment is the ecto-nucleotidase CD-39 which limits the plasma level of nucleotides. While several of the novel anti-aggregatory drugs were disappointing in clinical studies combinations of drugs with different effector enzymes showed potent antithrombotic efficacy.     

Peptides as receptor ligand drugs and their relationship to G-coupled signal transduction

Peptides act as effector agents that regulate and/or mediate physiological processes, serving as hormones, neurotransmitters and signal transducing factors. The low molecular weight peptides affect receptor-mediated events, which influence cardiovascular, gastrointestinal and neurocranial systems. While some peptides have been marketed as drugs, many have served as leads or templates for the development of non-peptide drugs that mimic peptide actions. This review presents the advantages and disadvantages of using peptides as drugs that bind as ligands to cell-surface receptors and considers their applications in such events. The value of both the peptides and their mimics is based on their participation in the biomodulation of physiological processes, which frequently employ scaffolding proteins acting in a cascading sequence of protein-to-protein interactions. The peptides bind to G-coupled surface receptors to initiate a signal that is transduced to the interior of the cell through multiple layers of phosphorylating enzymes and binding proteins. Peptides have been further employed to identify the molecular targets of signal transduction, the uncoupling of which might provide a means for various disease therapies. The exploitation of such peptide-mediated signal pathways, which are of primary importance to tumour cells, may provide an attractive strategy for anticancer therapy in the future.     

Inhibitors of Ras signal transduction as antitumor agents

Anarchic cell proliferation, observed in some leukemia and in breast and ovarian cancers, has been related to dysfunctioning of cytoplasmic or receptor tyrosine kinase activities coupled to p21 Ras. The growth factor receptor-bound protein 2 (Grb2) adaptor when complexed with Sos (Son of sevenless), the exchange factor of Ras, conveys the signal induced by tyrosine kinase-activated receptor to Ras by recruiting Sos to the membrane, allowing activation of Ras. This review shows how it is possible to stop the Ras-deregulated signaling pathway to obtain potential antitumor agents. Grb2 protein is comprised of one SH2 surrounded by two SH3 domains and interacts by means of its Src homology (SH2) domain with phosphotyrosine residues of target proteins such as the epidermal growth factor (EGF) receptor or the Shc adaptor. By means of its SH3 domains, Grb2 recognizes proline-rich sequences of Sos, leading to Ras activation. Inhibitors of SH2 and SH3 domains were designed with the aim of interrupting Grb2 recognition. On the one hand, using structural data and molecular modeling, peptide dimers or "peptidimers", made up of two proline-rich sequences from Sos linked by an optimized spacer, were developed. On the other, using the structure of the Grb2 SH2 domain complexed with a phosphotyrosine (pTyr)-containing peptide and molecular modeling studies, a series of N-protected tripeptides containing two phosphotyrosine or mimetic residues, with one pTyr sterically constrained, were devised. These compounds show very high affinities for Grb2 in vitro. They have been targeted into cells showing selective antiproliferative activity on tumor cells. These results suggest that inhibiting SH2 or SH3 domains of signaling proteins might provide antitumor agents.     

抗血小板药物对急性心肌梗死患者的临床观察

目的评估氯比格雷(Clopidogrel)与阿司匹林(Aspirin)对急性心肌梗死(acute myocardial infarc-tion,AMI)临床和血小板聚集性的影响。方法97例AMI患者被随机分为治疗组48例联用氯比格雷与阿司匹林和对照组49例单用阿司匹林治疗4周。观察复发心绞痛、心功能改善程度、死亡率等临床指标。治疗前后心电图梗死部位ST段、血小板最大聚集率及血液肝肾功能、白细胞、血小板和出、凝血时间等有关指标变化,行统计学分析。结果再发心绞痛治疗组∶对照组为10%∶20%;心功能改善的总频数为36·7%∶22·4,χ2=3·638,P=0·045;死亡率为4%∶8%。心电图梗死部位ST段治疗组由(0·36±0·13)mV降为(0·13±0·08)mV,对照组由(0·35±0·14)mV降为(0·16±0·90)mV,两组比较,t=3·012,P=0·04。腺苷(ADP)诱导血小板聚集率治疗组由(74·54±8·99)%降至(34·09±9·23)%,对照组由(72·30±7·78)%降至(56·54±6·92)%,两组比较,t=13·42,P<0·001。胶原(Coll)诱导血小板聚集率治疗组(82·09±6·31)%降至(77·20±6·17)%,t=3·949,P<0·001,对照组差异不显著(t=1·93,P=0·06)。两组均少见大出血、血小板减少性紫癜等严重副作用。结论AMI患者存在血小板聚集性增强,联用氯比格雷治疗能减少再发心绞痛、改善心功能、减少死亡率,改善心肌的再灌注,进一步抑制血小板的聚集性。     

服用双联抗血小板药物患者调整抑酸药的病例分析

抗血小板药物在外周动脉疾病的治疗中占有十分重要的地位,但其带来的风险是可能发生出血事件,临床多见部位为消化道损伤.因此,使用抑酸药预防消化道损伤在临床中被广泛应用.临床药师依托循证药学分析药物相互作用对抗血小板药物疗效的影响,参与患者抑酸药治疗方案的调整与优化.通过评估及平衡用药疗效与风险,为患者提供个体化的药学服务,...     

Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with β-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.     

非甾体抗炎药物在骨性关节炎中的应用

骨性关节炎是老年人中常见、多发的慢性进行性骨关节疾病,主要临床表现为缓慢发展的可使活动受限的关节疼痛、僵硬和肿胀,严重的能导致关节功能障碍.非甾体抗炎药物是目前治疗骨性关节炎等关节炎性疾病的最常用药物,作用机制为抑制环氧化酶活性、阻断该酶催化花生四烯酸转化为炎性物质前列腺素,从而发挥止痛、消炎作用.非甾体抗炎药物分为非选择性环氧化酶抑制剂和选择性环氧化酶-2抑制剂两类,应用广泛,但也存在多种不良反应,故选择用药时要严格掌握适应证,合理用药.     

非甾体抗炎药物在骨性关节炎中的应用

骨性关节炎是老年人中常见、多发的慢性进行性骨关节疾病,主要临床表现为缓慢发展的可使活动受限的关节疼痛、僵硬和肿胀,严重的能导致关节功能障碍。非甾体抗炎药物是目前治疗骨性关节炎等关节炎性疾病的最常用药物,作用机制为抑制环氧化酶活性、阻断该酶催化花生四烯酸转化为炎性物质前列腺素,从而发挥止痛、消炎作用。非甾体抗炎药物分为非选择性环氧化酶抑制剂和选择性环氧化酶-2抑制剂两类,应用广泛,但也存在多种不良反应,故选择用药时要严格掌握适应证,合理用药。     

Synthesis of 2-[2-(1-Imidazolyl)ethyl]-4-phenylcycloalka[g]phthalazin-1(2H)-ones as Thromboxane A2 Synthase Inhibitors

A series of 2-[2-(1-imidazolyl)ethyl]-4-phenylcycloalka[g]phthal-azin-1(2H)-ones ( 3a—d ) with variable cycloalkene ring size was prepared and tested in vitro for thromboxane A₂ synthase inhibitory activity.     

血小板活化信号转导机制研究进展

血小板是哺乳动物血液中固有成分之一，在止血、炎性反应、血栓形成以及器官移植排斥等生理与病理反 应中具有重要作用。血小板活化信号是激活、诱导血小板发挥生理作用的主要生理传导机制，一直是近年来生理学 领域研究的重点。本文将就黏附受体介导的钙离子水平调节新机制、模式识别受体诱导的血小板活化新观点以及 血小板环鸟苷酸信号通路新概念等方面作一综述。     

Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor

Background and purpose:

Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-N^G-monomethyl arginine (L-NMMA) on its actions.

Experimental approach:

The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated.

Key results:

Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline.

Conclusions and Implication:

These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor.     

The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis

Aim

The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs.

Methods

Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models.

Results

Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I² = 55%; P = 0.002). Significance was lost with analysis using a random effects model.

Conclusions

The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.     

非甾体类抗炎药抗肿瘤作用的分子机制

该文从非甾体类抗炎药(NSAIDs)的抗肿瘤作用入手,结合近年来的国外最新文献和我们的研究结果,概要介绍了NSAIDs抗肿瘤作用的可能分子基础。NSAIDs抗肿瘤作用机制因肿瘤的种类而有所不同,它可通过抑制在某些肿瘤发生过程中异常表达的环氧化酶2(COX2),减少前列腺素E2等的生物合成,通过调节相关下游基因蛋白的表达,抑制肿瘤新生血管生成、阻止肿瘤细胞增殖并促进其凋亡。它也可作为过氧化酶体增殖激动剂受体γ(PPARγ)的激动剂,诱导某些肿瘤细胞内COX2的表达,促进环戊烯酮前列腺素(cyPGs)的生物合成,通过后者介导PPARγ依赖性或PPARγ非依赖性的促进肿瘤细胞凋亡作用。由于NSAIDs对肿瘤细胞抗增殖、促凋亡的特殊作用机制,与其他抗肿瘤治疗可能产生明显的协同作用。     

依托咪酯对大鼠脑cAMP信号转导系统的影响

依托咪酯 (ｅｔｏｍｉｄａｔｅ,Ｅｔｏ)是一种非巴比妥类静脉全麻药 ,其全麻作用的机制目前仍不十分清楚。本实验通过观察大鼠依托咪酯麻醉时各脑区ｃＡＭＰ含量、ＡＣ和ＰＤＥ活性变化 ,以探讨ｃＡＭＰ信号转导系统在大鼠依托咪酯麻醉中的作用。1　材料与方法1.1　实验动物 　Ｓｐｒａｇｕｅ Ｄａｗｌｅｙ大鼠 ,体重 (2 16± 17)ｇ ,由徐州医学院动物实验中心提供。1.2　试剂　依托咪酯由连云港制药厂生产 ,批号 980 6 11。环磷酸腺苷测定试剂盒购自中国原子能研究院同位素研究所.3　ｃＡＭＰ含量、ＡＣ与ＰＤＥ活性测定　参见文献[1] ,采…     

抗血小板药物的遗传药理学研究进展

目前心脑血管疾病是导致人类死亡的主要病因,血小板的激活和聚集在其形成过程中起到核心作用。大量临床实践发现,不同个体对抗血小板药物的反应有着较大差异,有的患者甚至出现对这些药物产生抵抗的现象。研究表明,遗传因素是导致抗血小板药物疗效产生个体差异的重要原因之一。该综述概述了国内外对抗血小板药物在遗传药理学方面的最新研究进展。     

大脑中动脉深穿支单个腔隙性梗死临床特点及抗血小板药物疗效研究

目的:探讨大脑中动脉深穿支单个腔隙性梗死病灶的临床特点及抗血小板药物疗效。方法:收集2014年1月至2015年10月在北京市海淀医院神经内科住院的72 h以内发生大脑中动脉(middle cerebral artery,MCA)深穿支供血区域单个腔隙性梗死患者60例,将其根据梗死部位及载体动脉是否存在病变分为2组:腔隙性脑梗死伴有MCA病变组和腔隙性脑梗死不伴有MCA病变组,分别对这2组的病人进行脑血管病危险因素(性别、年龄、高血压、血压变异性、糖尿病、冠心病、脑卒中、吸烟)、临床特点(NIHSS评分、白质高信号)及抗血小板药物治疗3月后m RS评分比较。结果:两组在高血压、糖尿病、冠心病、脑卒中、吸烟、血压变异性、NIHSS、白质高信号及抗血小板物治疗3月后m RS方面有统计学差异(P<0.05)。结论:根据梗死部位及MCA病变,提示了MCA深穿支单个腔隙性梗死临床特点、病因及发病机制的多样性。因此需采取不同的治疗措施。     

The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia

Summary We have studied the effects of 12 weeks of lovastatin (20 mg per day) on platelet function and thromboxane formation in 18 patients with type II hypercholesterolaemia in a double-blind, placebo-controlled, prospective study.Lovastatin significantly reduced total serum and LDL-cholesterol by 20% and 25% respectively. Washed platelets of lovastatin-treated patients had significantly reduced collagen-induced aggregation and thromboxane formation ex vivo. There was no change in ADP-induced platelet aggregation, but a significant increase in prostacyclin (iloprost)-stimulated platelet cyclic AMP concentrations in lovastatin-treated patients. This was associated with a significant increase in the number of prostacyclin receptors in platelet membranes prepared from lovastatin-treated patients. There was also an increase in platelet thromboxane receptors. There were no such changes in the placebo group.These data confirm our original observation of normalization of platelet function in hypercholesterolaemia by HMGCoA reductase inhibitors and suggest changes in platelet membrane composition at the megakaryocyte level as a possible site of action.     

双联抗血小板联合质子泵抑制剂的应用调查与分析

目的：调查分析本院双联抗血小板（DAPT）患者使用质子泵抑制剂（PPI）进行消化道损伤和出血的预防情况。方法：统计2017年1月至12月联合使用DAPT患者消化道损伤及出血的高危人群及危险因素，患者联合使用PPI的比例，PPI使用种类等。结果：使用DAPT有1 521例，联合使用PPI者771例（占50.69%）；其中使用雷贝拉唑和泮托拉唑的分别为10例（占1.3%）和577例（占74.84%）；具有消化道损伤高危因素的分别是消化性溃疡及并发症病史215例（占14.14%）、消化道出血史114例（占7.50%）、联合抗凝治疗121例（占7.96%）、年龄65岁以上者616例（占40.50%）、使用糖皮质激素者为0、消化不良或胃食管反流病209例（占13.74%）。结论：DAPT是消化道损伤的独立风险因素，应预防使用PPI，但仅50.67%的患者使用PPI，存在应用不足的情况。调查中存在患者合并其他消化道损伤因素的情形，将增加消化道出血风险，尤需使用PPI。临床对PPI的选择基本合理，个别存在奥美拉唑、艾司奥美拉唑联用氯吡格雷的情形，可降低氯吡格雷的抗血小板效果，建议使用对CYP2C19依赖性较低的泮托拉唑和雷贝拉唑。     

Multiple dose trial of the thromboxane synthase inhibitor furegrelate in normal subjects

Summary Furegrelate sodium, a pyridinyl derivative thromboxane synthase inhibitor, was evaluated for its effects on thromboxane synthesis in normal volunteers after multiple dose administration. Twenty-four subjects were randomized to 200, 400, 800 or 1600 mg furegrelate or placebo treatment BID for 4 1/2 days. Furegrelate (800 or 1600 mg) significantly inhibited thromboxane synthesis throughout the dosing interval as assessed by thromboxane B₂ generation from platelet-rich plasma challenged with arachidonic acid or from serum. Platelet aggregation was inhibited, but the effect was variable and a clear dose response relationship was not apparent. Bleeding times were also variable but tended to increase at the higher doses. There was no clinically significant change in any coagulation parameters or in any safety laboratory evaluations. Peak serum concentrations occurred approximately 1 h after dosing; t_1/2k_e was approximately 2 h. There was no significant change in furegrelate's effects or pharmacokinetics over time (ie. Day 1 vs Day 5).     

Design and synthesis of 3,5-disubstituted-1,2,4-oxadiazoles as potent inhibitors of phosphodiesterase4b2

A series of 3,5‐disubstituted‐1,2,4‐oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5‐disubstituted‐1,2,4‐oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC₅₀ = 5.28 μm ). Structure–activity relationship studies of 3,5‐disubstituted‐1,2,4‐oxadiazoles revealed that substituents 3‐cyclopentyloxy‐4‐methoxyphenyl group at 3‐position and cyclic ring bearing heteroatoms at 5‐position are important for activity. Molecular modeling study of the 3,5‐disubstituted‐1,2,4‐oxadiazoles with PDE4B has shown similar interactions of 3‐cyclopentyloxy‐4‐methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3‐(3‐Cyclopentyloxy‐4‐methoxyphenyl)‐5‐(piperidin‐4‐yl)‐1,2,4‐oxadiazole ( 9a ) exhibited good analgesic and antiinflammatory activities in formalin‐induced pain in mice and carrageenan‐induced paw edema model in rat.