Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

Platelets play an important role in atherothrombotic disease. The currently available antiplatelet drugs target key steps of platelet activation including thromboxane A₂ synthesis, ADP-mediated signaling, and glycoprotein IIb/IIIa-mediated platelet aggregation. The improvement of our understanding on the pharmacokinetic and pharmacodynamic characteristics of these drugs enables the tailoring of the most appropriate anti-thrombotic therapy to the individual patient and risk situation in the daily clinical practice. However, current antiplatelet therapies are associated with increased bleeding risk. Thus, further research on platelet functions may give rise to numerous new antiplatelet agents with high anti-thrombotic efficiency and low adverse hemorrhagic side effects.     

Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

Platelets play an important role in atherothrombotic disease. The currently available antiplatelet drugs target key steps of platelet activation including thromboxane A(2) synthesis, ADP-mediated signaling, and glycoprotein IIb/IIIa-mediated platelet aggregation. The improvement of our understanding on the pharmacokinetic and pharmacodynamic characteristics of these drugs enables the tailoring of the most appropriate anti-thrombotic therapy to the individual patient and risk situation in the daily clinical practice. However, current antiplatelet therapies are associated with increased bleeding risk. Thus, further research on platelet functions may give rise to numerous new antiplatelet agents with high anti-thrombotic efficiency and low adverse hemorrhagic side effects.     

Mechanism of antiplatelet action of hypolipidemic,antidiabetic and antihypertensive drugs by PPAR activation: PPAR agonists: New antiplatelet agents

Given the prevalence of cardiovascular disease in patients with cardiovascular risk factors (i.e., hypertension, diabetes, smoking and obesity) and that platelet activation plays an important pathogenic role in cardiovascular diseases, it is very important to identify the drugs that have multiple targets. In this sense, the present article describes the mechanism of antiplatelet action of hypolipidemic (statins and fibrates), antidiabetic (thiazolidinediones) and antihypertensive (nifedipine) drugs via peroxisome proliferator-activated receptor (PPAR) activation. The mechanism of antiplatelet action of the drugs is by direct activation of PPARs with the inhibition of cyclooxygenase-1, protein kinase C-alpha, calcium mobilization, thromboxane A2, sCD40L, platelet microparticles and cAMP-phosphodiesterase, and the stimulation of proteins kinase G and A. Thus, these observations highlight PPARs as a novel therapeutic target for the treatment and prevention of cardiovascular diseases.     

Proteasome inhibitors as therapeutic agents: current and future strategies

In cells, protein degradation is a key pathway for the destruction of abnormal or damaged proteins as well as for the elimination of proteins whose presence is no longer required. Among the various cell proteases, the proteasome, a multicatalytic macromolecular complex, is specifically required for the degradation of ubiquitinated proteins. In normal cells, the proteasome ensures the elimination of numerous proteins that play critical roles in cell functions throughout the cell cycle. Defects in the activity of this proteolytic machinery can lead to the disorders of cell function that is believed to be the root cause of certain diseases. Indeed, many proteins involved in the control of cell cycle transitions are readily destroyed by the proteasome once their tasks have been accomplished. Moreover, because proteasome inhibitors can provoke cell death, it has been suggested that proteasomes must be continually degrading certain apoptotic factors. For these reasons, proteasome inhibition has become a new and potentially significant strategy for the drug development in cancer treatment. The proteasome possesses three major peptidase activities that can individually be targeted by drugs. Different classes of proteasome inhibitors are reviewed here. In addition, we present new pseudopeptides with the enriched nitrogen backbones bearing a side chain and a modified C-terminal position that inhibit proteasome activity.     

抗生素作用新靶点的发掘策略

抗生素的大量使用和滥用所造成的细菌广泛的耐药性迫使科研人员要加速寻找结构新颖的抗生素。抗生素作用靶点的发掘对药物发现非常重要,本文综述了近几年来国际上运用基因组学、基因芯片等现代生物信息学技术,利用细菌体内的各种酶反应与理化特性,发掘抗生素传统作用新靶点如脂肪酸合成酶、非传统作用新靶点如双信号转导调控系统、群体感应器等的研究进展,这对新抗生素的发现具有一定的指导意义。     

新的抗肝癌分子靶及相关药物研究

目前临床上有效的抗肝癌药物很少,普遍存在着疗效差、毒性大、易产生耐药性等问题,发现新的肝癌分子靶,并以此发展高效低毒的抗肝癌药物是解决问题的关键之一。相关研究表明启动子甲基化、肝细胞生长因子及其受体、血管内皮生长因子及其受体、环氧化酶 2可能是抗肝癌药物有效的分子靶,相应的配体化合物已展示了潜在的应用前景。此外三氧化二砷等其他类型的化合物也显示了一定的抗肝癌疗效。     

Cancer stem cells and novel targets for antitumor strategies

Cancer stem cells (CSCs) were identified in human leukemias in landmark studies of John Dick and his colleagues. Subsequently, similar cancer stem-like cells were identified in solid tumors of the breast, colon, brain and other sites. CSCs have distinct markers and are highly tumorigenic compared to other subsets. They can differentiate into all the cell phenotypes of the parental tumor. Other key features include activation of pluripotency genes (Oct4, Sox2, Nanog), self-renewal, formation of tumor spheres in low-adherence cultures, and multi-drug resistance. Clinically, drug resistance is probably the most important feature, because CSCs resist conventional cancer therapies and are likely to play a major role in cancer relapse. Based on their properties, several molecules have been targeted for therapy with drugs as follows. 1) The self-renewal pathways Wnt/β-catenin, Hedgehog and Notch. 2) The aryl hydrocarbon receptor (AHR), with tranilast and other AHR agonists. 3) Cytokines and inflammatory pathways (e.g., IL-6, IL-8, NF-κB). 4) TGF-β and epithelial- to-mesenchymal transition (EMT) pathways. 5) Homing molecules involved in metastasis; most notably CXCR4 or its ligand CXCL12. 6) Growth factors, their receptors and coreceptors (such as neuropilin-1), and signaling components (e.g., tyrosine kinases). 7) Cell-surface markers (CD44 and integrins). Several drugs have been identified by screening or other observations (salinomycin, metformin, tesmilifene, sulforaphane, curcumin, piperine and others). Some of these drugs are at preclinical or early clinical phases of development, and it remains to be seen how many will progress to clinical application. This review focuses on some promising new developments in anti-CSC drug therapy.     

Neurotherapeutics in multiple sclerosis: novel agents and emerging treatment strategies

New insights into the complex immunopathogenesis of multiple sclerosis have led to a proliferation of promising new therapeutic strategies. While the current armamentarium of immunomodulatory medications has demonstrated beneficial effects on the disease, more effective and tolerable therapies are needed. Several novel therapeutic strategies under investigation include oral therapies, monoclonal antibodies, symptomatic treatments, insights into neuroprotection and repair as well as combination regimens. New therapies may prove more efficacious and tolerable than the available arsenal of treatments; however, decisions regarding first-line therapies will expectedly become more complicated, with greater influence if risk-to-benefit ratios in light of premature safety data. Biomarker profiles may help elucidate disease subtypes as well as therapeutic response in an effort to individualize treatment choice. This review will highlight recent promising therapeutic strategies under investigation in the field of MS.     

Mitochondria as targets for established and novel anti-cancer agents.

Chemoresistant cells have acquired the ability to evade the action of multiple classes of anti-neoplastic compounds. One mechanism by which tumor cells survive in the presence of chemotherapy is by increasing their apoptotic threshold. Since mitochondria are central players in drug-induced apoptosis, recent efforts to eradicate chemorefractory cells have focused on the identification of compounds that directly affect mitochondrial function. A number of reports indicate that mitochondria are direct targets for multiple classes of experimental compounds. A few clinically available anticancer agents like DNA damaging compounds and anti-microtubule agents are also reported to act directly on mitochondria. The purpose of this mini-review is to discuss recent advances in the interactions between anti-cancer agents and mitochondria, and highlight potential mitochondrial targets for novel chemotherapeutic interventions.     

Protein kinases as potential targets for novel anti-schistosomal strategies

Schistosome parasites are the causative pathogens of schistosomiasis (bilharzia), a disease of worldwide significance. In terms of patient numbers, schistosomiasis ranks second to malaria as a parasitosis affecting more than 200 million people of the tropics and subtropics. Since the 1970s Praziquantel (PZQ) is the drug of choice and nearly exclusively used for treatment. However, drug resistance is an increasing threat, particularly with respect to large-scale PZQ administration programs. Last decade's research indicated that resistance against PZQ can be induced under laboratory conditions, and field studies provided first indications for the possibility of reduced PZQ efficacy. Furthermore, clear evidence for the molecular armamentarium of schistosomes with multidrug transporters was found, one of which was responding to PZQ challenge. Also the development of a vaccine still represents an elusive goal, although effort and time have been invested in this subject. In light of these facts it is commonly accepted that new drugs are urgently needed. Research on signal transduction processes in Schistosoma mansoni has provided an unexpected and novel perspective towards this end. Molecular, biochemical, and physiological studies elucidating principles of schistosome development have demonstrated the essential role of protein kinases (PKs). In humans, PKs are known to be involved in cancer development. Since a variety of approved anticancer drugs targeting PKs exist, first studies have been performed to investigate whether these drugs are able to also inhibit schistosome PKs. Indeed, promising results have been obtained indicating the potential of PKs as privileged targets for new concepts in fighting schistosomes.     

Collagen receptors as potential targets for novel anti-platelet agents

Platelets have important roles in atherosclerosis and thrombosis and their inhibition reduces the risk of these disorders. There is still a need for platelet inhibitors affecting pathways that reduce thrombosis and atherosclerosis while leaving normal hemostasis relatively unaffected, thus reducing possible bleeding complications. Although combinations show progress in achieving these goals none of the present inhibitors completely fulfill these requirements. Collagen receptors offer attractive possibilities as alternative targets at early stages in platelet activation. Three major collagen receptors are assessed in this review; the alpha2beta1 integrin, responsible primarily for platelet adhesion to collagen; GPVI, the major signaling receptor for collagen; and GPIb-V-IX, which is indirectly a collagen receptor via von Willebrand factor. Several thrombosis models and experimental approaches suggest that all three are interesting targets and merit further investigation.     

Platelet activation, inflammatory mediators and hypercholesterolemia

Atherogenic cofactors, such as altered cholesterol metabolism, may impact locally on inflammatory responses in atherosclerotic lesions. Blood levels of inflammatory markers (e.g., C-reactive protein, fibrinogen) have been associated with hypercholesterolemia and with overt atherothrombotic disorders. More recently. cytokines (e.g., interleukin-6, interleukin-1beta) and soluble adhesion molecules (e.g., selectins, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) have been associated with both hypercholesterolemia and atherosclerotic disease, suggesting their use as potential therapeutic targets for the non-specific "anti-inflammatory" treatment of atherosclerosis. The inflammatory response associated with hypercholesterolemia involves not only the intrinsic cells of the artery wall. but also circulating cells. Platelets participate in this disease process through the release of a wide variety of biologically active substances. An imbalance of the hemostatic system and persistent in vivo platelet activation can be observed in hypercholesterolemia and may have pathophysiological implications in the development and progression of atherosclerotic plaques. Recent findings on the inflammatory actions of platelets have established the potential for a previously unrecognized biologic role for platelets in inflammation and vascular injury, and have opened new perspectives in the comprehension of the pathogenetic mechanism(s) of atherosclerosis. Stimulated platelets actively synthesize proinflammatory cytokines (e.g., CD40L, IL-1beta) and are able to release chemokines (i.e., platelet factor-4, RANTES) which have been all involved in the inflammatory process associated with hypercholesterolemia. This review will summarize the present understanding of the interplay between hypercholesterolemia, inflammation and platelet activation in the development and progression of atherosclerosis, and we also discuss the effects of lipid-lowering treatment on these phenomena.     

Current strategies with eptifibatide and other antiplatelet agents in percutaneous coronary intervention and acute coronary syndromes

Antiplatelet and anticoagulation therapies are essential for the prevention of thromboembolic-induced myocardial ischaemia in non-ST-elevation acute coronary syndromes and the ischaemic complications of percutaneous coronary intervention. Although heparin, direct thrombin inhibitors and oral platelet activation inhibitors provide substantial benefit, only glycoprotein (GP) IIb/IIIa inhibitors block the final common pathway leading to platelet aggregation, and the American College of Cardiology/American Heart Association guidelines recommend GP IIb/IIIa inhibitors as an integral component of care in these patients. Abciximab, eptifibatide and tirofiban all act through the GP IIb/IIIa receptor; however, variations in clinical outcomes among patients receiving these agents may be related to their structural and pharmacological differences, as well as to patient demographics. Data indicate that eptifibatide, at the current recommended dosing schedule, achieves the highest level of consistent platelet inhibition compared with current doses of abciximab and tirofiban.     

ABC transporters and inhibitors: new targets,new agents

P-glycoprotein (P-gp), a plasma membrane pump associated with multidrug resistance (MDR), is a member of the superfamily of ATP-binding cassette (ABC) transporters. The discovery that inhibitors of drug efflux can increase drug accumulation and reverse drug resistance in the laboratory has led to the clinical development of a number of P-gp inhibitors. Initial studies were performed with agents already in use in the clinic for other indications, the 'first generation' studies. Second generation inhibitors were taken into clinical trials in leukemia, breast cancer, ovarian cancer and sarcoma, malignancies for which there is evidence that P-gp is expressed, and in some cases, associated with a poorer therapeutic outcome. One major limitation of these trials, however, was the reduction in anticancer drug doses that was required with concurrent administration of inhibitor. The reduction in drug dose needed in these combination studies, may have confounded the results and contributed to disappointing outcomes. Functional assays to verify the role of P-gp inhibition in MDR, such as sestamibi imaging are proving helpful in assessing the development of improved inhibitors that are providing hope for the future. This review focuses on attempts aimed at overcoming resistancemediated by ABC transporters and evaluates the prospects for addition of new inhibitors to the anticancer armamentarium.     

ADP receptors: inhibitory strategies for antiplatelet therapy

The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y(1) and P2Y(12)) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y(12) ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y(12) antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y(12) antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y(1), are under development and may prove to be effective antithrombotic agents.     

Vascular NADPH oxidases as drug targets for novel antioxidant strategies

Reactive oxygen species (ROS) play important roles in the pathogenesis of cardiovascular disease. Surprisingly, large clinical trials have shown that ROS scavenging by antioxidant vitamins is ineffective or harmful. Therefore, prevention of ROS formation, by targeting specific sources of superoxide anion and other ROS, might prove beneficial. Potential targets include the NADPH oxidases (Nox enzymes), xanthine oxidase, endothelial nitric oxide synthase and mitochondrial oxidases. Nox enzymes play a central role because they can regulate other enzymatic sources of ROS. Statins, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists block upstream signaling of Nox activation, which contributes to their clinical effectiveness. Here, we discuss novel possibilities where drugs that directly inhibit Nox activation could successfully inhibit oxidative stress.     

Antiangiogenic agents and targets: A perspective

The first generation of clinically useful antiangiogenic agents focused on VEGF and targets in the VEGF pathway. The strengths and limitations of these therapeutics are now clear. Some tumors do not respond to VEGF-directed therapies de novo and others become non-responsive or resistant over time by switching to other angiogenic pathways. The next generation of angiogenesis-directed therapeutics will expand the field beyond the VEGF pathway and become more disease selective. Placental growth factor, a protein closely related to VEGF, is induced as tumors lose responsiveness to VEGF-directed therapies. Angiopoietins 1 and 2 are being targeted with a unique peptibody, a human recombinant Fc constant region fused to peptides, in clinical trials. The HGF/c-Met pathway is upregulated in some tumors as an alternate angiogenic pathway. The CXCL12 (SDF-1)/CXCR4 pathway represents a stromal chemokine axis involved in tumor angiogenesis. CXCR2 is a G-protein coupled receptor with several ligands including interleukin-8 and other angiogenic cytokines and may represent a useful target for antiangiogenic agents. The notch pathway is being investigated as a target in the setting of tumor angiogenesis. Sphingosine-1-phosphate is a bioactive lipid that can be neutralized with a monoclonal antibody. The anti-S-1-P antibody is under investigation as an antiangiogenic agent. Finally, several multi-targeted kinase inhibitors each with a unique pattern of inhibitory potency are in clinical trial with a focus on antiangiogenic activity. The expansion of the scope of potential antiangiogenic agents in or entering clinical trial should allow the development of antiangiogenic combination regimens and single agents that address diseases refractory to VEGF-directed therapeutics.     

The relationship between inflammation, platelet activation and antiplatelet resistance

Even though there is a strong evidence suggestive of benefits and safety of dual (aspirin plus clopidogrel) antiplatelet therapy, decreased responsiveness or "resistance" to mono- and/or dual antiplatelet therapy has been described in association with an increased thrombotic risk. Various mechanisms contribute to antiplatelet resistance, with abundant production of inflammatory markers being of particular importance. The current review overviews implications of inflammation in antiplatelet resistance.     

Antineoplastic agents in the management of ovarian cancer: current status and emerging therapeutic strategies

The intent of this review is to critically examine the status of the current chemotherapeutic management of ovarian cancer and possible future directions. Standard systemic chemotherapy includes a platinum agent (cisplatin or carboplatin) and a taxane (paclitaxel or docetaxel), a strategy that has not changed in more than a decade. Phase-III-trial data have revealed the superior efficacy of intraperitoneal cisplatin, compared with systemic platinum delivery, in small-volume residual advanced ovarian cancer, but in general this approach is associated with greater toxicity. Several regimens have been shown to be active in recurrent and platinum-resistant ovarian cancer, but an optimal management strategy has not been defined. Although 'targeted therapeutic approaches' are currently being explored in this disease, with the important exception of anti-angiogeneic agents, to date, limited biological and clinical activity have been demonstrated.