New perspectives in antiplatelet therapy

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbβ3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.     

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.     

Inhibition of platelet P2Y12 and alpha2A receptor signaling by cGMP-dependent protein kinase

The important role of cGMP and cGMP-dependent protein kinase (cGPK) for the inhibition of platelet activation and aggregation is well established and due to the inhibition of fundamental platelet responses such as agonist-stimulated calcium increase, exposure of adhesion receptors and actin polymerization. The diversity of cGMP binding proteins and their synergistic interaction with cAMP signaling in inhibiting platelets indicates that a variety of cGMP targets contribute to its antiplatelet action. Since stimulation of G(i)-proteins was recently shown to be essential for complete platelet activation/aggregation, the possibility that G(i)-signaling events are cGMP/cGPK targets was investigated. Thus, the effect of elevated cGMP levels and selective cGPK activation on purinergic and adrenergic receptor-evoked decrease of platelet cAMP content was closely examined. Experiments with a selective activator of cGPK demonstrate for the first time a cGMP-caused G(i)-protein inhibition and our data suggest that this effect is mediated by cGPK. Considering the essential role of G(i)-signaling for platelet activation, we propose that inhibition of G(i)-mediated signaling by cGMP/cGPK is an important mechanism of action underlying the platelet inhibition by cGMP-elevating endothelium derived factors and drugs.     

Monitoring of the antiplatelet drugs effect in patients with coronary artery disease: what is the real clinical impact?

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical "gold standard" test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100, VerifyNow) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.     

Mechanisms of platelet activation in acute coronary syndromes

Platelets are known to play a fundamental role in acute coronary syndromes. After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. Today there are promising results from recently developed antiplatelet agents. However, morbidity and mortality from acute coronary syndromes remain significant despite the administration of combination therapies (aspirin, thienopyridines). Sharing similar mechanisms, platelets may also form a thin monolayer in areas of damaged endothelium contributing to primary hemostasis. For this reason, administration of antiplatelet drugs is often associated with increased bleeding risk. As a result, currently available antiplatelet therapy cannot be characterized as optimal. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. The study of basic mechanisms of platelet adhesion, activation and aggregation after atherosclerotic plaque rupture may help to define new targets for their inhibition. In the future, newer antiplatelet agents may offer more comprehensive platelet inhibition without interfering with primary hemostasis, thus offering greater protection with lower hemorrhagic risk.     

Current concepts of platelet activation: possibilities for therapeutic modulation of heterotypic vs. homotypic aggregation

Thrombogenic and inflammatory activity are two distinct aspects of platelet biology, which are sustained by the ability of activated platelets to interact with each other (homotypic aggregation) and to adhere to circulating leucocytes (heterotypic aggregation). These two events are regulated by distinct biomolecular mechanisms that are selectively activated in different pathophysiological settings. They can occur simultaneously, for example, as part of a pro-thrombotic/pro-inflammatory response induced by vascular damage, or independently, as in certain clinical conditions in which abnormal heterotypic aggregation has been observed in the absence of intravascular thrombosis. Current antiplatelet drugs have been developed to target specific molecular signalling pathways mainly implicated in thrombus formation, and their ever increasing clinical use has resulted in clear benefits in the treatment and prevention of arterial thrombotic events. However, the efficacy of currently available antiplatelet drugs remains suboptimal, most likely because their therapeutic action is limited to only few of the signalling pathways involved in platelet homotypic aggregation. In this context, modulation of heterotypic aggregation, which is believed to contribute importantly to acute thrombotic events, as well to the pathophysiology of atherosclerosis itself, may offer benefits over and above the classical antiplatelet approach. This review will focus on the distinct biomolecular pathways that, following platelet activation, underlie homotypic and heterotypic aggregation, aiming potentially to identify novel therapeutic targets.     

Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders

Individuals with neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease are benefiting from drugs developed to act on a single molecular target. However, current pharmacological approaches are limited in their ability to modify significantly the course of the disease, and offer incomplete and transient benefit to patients. New therapeutic strategies comprise drug candidates designed specifically to act on multiple neural and biochemical targets for the treatment of cognition impairment, motor dysfunction, depression and neurodegeneration. Examples include the development of single molecular entities that combine two or more of the following properties: (i) cholinesterase inhibition; (ii) activation or inhibition of specific subtypes of acetylcholine receptors or alpha-adrenoceptors; (iii) anti-inflammatory activity; (iv) monoamine oxidase inhibition; (v) catechol-O-methyl transferase inhibition; (vi) nitric oxide production; (vii) neuroprotection; (viii) anti-apoptotic activity; and (ix) activation of mitochondrial-dependent cell-survival genes and proteins. These bi- or multi-functional compounds might provide greater symptomatic efficacy, and better utility as potential neuroprotective disease-modifying drugs.     

Involvement of p38 MAPK phosphorylation and nitrate formation in aristolochic acid-mediated antiplatelet activity

Aristolochic acid (AsA) is produced from Aristolochia fangchi, and has been used as a Chinese herbal medicine. AsA possesses various biological activities including antiplatelet, antifungal, and anti-inflammatory properties. The aim of this study was to examine the mechanisms of AsA in inhibiting platelet aggregation. AsA (75 - 150 microM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen (1 microg/mL) than other agonists. AsA (115 and 150 microM) inhibited collagen-induced platelet activation accompanied by [Ca+2)]i mobilization, thromboxane A2 (TxA2) formation and phosphoinositide breakdown. On the other hand, AsA also markedly increased levels of NO/cyclic GMP, and cyclic GMP-induced vasodilator-stimulated phosphoprotein phosphorylation. AsA inhibited p38 MAPK but not ERK1/2 phosphorylation in washed platelets. In conclusion, the most important findings of this study suggest that the inhibitory effects of AsA possibly involve the (1) inhibition of the p38 MAPK-cytosolic phospholipase A2-arachidonic acid-TxA2-[Ca+2)]i cascade, and (2) activation of NO/cyclic GMP, resulting in inhibition of phospholipase C. These results imply that Aristolochia fangchi treatment alone or in combination with other antiplatelet drugs, may result in alteration of hemostasis in vivo.     

Clopidogrel

Dual antiplatelet therapy with acetylsalicylic acid (aspirin) and clopidogrel is a guideline-recommended standard of care for patients with acute coronary syndromes (ACS) and those who undergo percutaneous coronary intervention (PCI). Despite a large body of clinical evidence obtained from randomized clinical trials and patient registries supporting the efficacy and safety of aspirin plus clopidogrel therapy in these patients, questions concerning the optimal use of dual antiplatelet therapy remain. Widely debated topics pertaining to dual antiplatelet therapy in patients with ACS or undergoing PCI include (i) the appropriate clopidogrel loading dose; (ii) the optimal time to initiate the clopidogrel loading dose; (iii) the optimal duration of dual antiplatelet therapy following ACS or PCI; (iv) impact of variability of platelet response on patient outcomes; and (v) the role of other recommended and emerging P2Y₁₂ antagonists. This review discusses these ongoing controversies regarding the optimal use of dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS or those undergoing PCI.     

Resistance to aspirin and thienopyridines in diabetes mellitus and metabolic syndrome

Platelets from patients affected by diabetes mellitus and metabolic syndrome show an impaired sensitivity to physiological antiaggregating agents and an enhanced activation state, mirrored by an increased expression of membrane activation markers; furthermore, they are more prone to form spontaneous microaggregates with ADP receptor involvement. These abnormalities are responsible for a pro-thrombotic condition, contributing to a high cardiovascular risk. This pattern of platelet abnormalities provides a strong rationale for aggressive antiplatelet therapy strongly recommended by guidelines both in diabetes mellitus and in metabolic syndrome, not only in the setting of acute coronary syndromes, but also for the long-term prevention of the cardiovascular events. Antiplatelet therapy in these pathological conditions, however, is still a matter of intense debate, especially because a high prevalence of "resistance" to these drugs (and to aspirin in particular) has been described in these patients. This may result in non-significant reductions in cardiovascular events. Different factors seem to be involved, including: i) genetic polymorphisms; ii) hyperglycemia and poor metabolic control; iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory and/or pro-thrombotic status, and, v) increased oxidative stress. This review will take into consideration: i) the results of the most relevant studies addressing the effects of the anti-aggregating treatment in patients affected by diabetes mellitus and/or metabolic syndrome, and, ii) the biochemical mechanisms accounting for the impaired sensitivity to aspirin and thienopyridines in the above mentioned clinical conditions.     

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

PARP inhibitors combined with DNA-damage inducing cytostatic agents can lead to effective tumor therapy. However, inhibition of poly(ADP-ribose) polymerase (PARP-1; EC 2.4.2.30) induces the activation of PI-3-kinase-Akt pathway, which can counteract the effectiveness of this therapy. To understand the role of Akt activation in the combined use of cytostatic agent and PARP inhibition, we used taxol (paclitaxel) as an antineoplastic agent, which targets microtubules and up-regulates mitochondrial ROS production, together with (i) pharmacological inhibition (PJ-34), (ii) siRNA knock-down and (iii) transdominant expression of the DNA binding domain of PARP-1. In all cases, PARP-1 inhibition leads to suppressed poly-ADP-ribosylation of nuclear proteins, prevention of NAD⁺ depletion and significant resistance against taxol induced caspase-3 activation and apoptotic cell death. Paclitaxel induced a moderate increase in Akt activation, which was significantly augmented by PARP inhibition, suggesting that PARP inhibition-induced Akt activation could be responsible for the cytostatic resistance. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance. Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinase-Akt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.     

The pharmacodynamics of antiplatelet compounds in thrombosis treatment

Introduction: As it is importance to understand the involvement of platelets in the initiation and propagation of thrombosis, antiplatelet drugs have come to the forefront of atherothrombotic disease treatment. Dual antiplatelet therapy of aspirin plus clopidogrel has its benefits, but it also has its limitations with regard to its pharmacologic properties and adverse effects. For these reasons, within the last decade or so, the investigation of novel antiplatelet agents has prospered.

Areas covered: In this review, we discuss the unique pharmacodynamic properties of several antiplatelet drugs with their possible potential molecular of mechanisms on inhibiting platelet aggregation.

Expert opinion: Considering multiple synergetic pathways of platelet activation and their close interplay with coagulation, the current treatment strategies are not only based on platelet inhibition, they also rely on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current guidelines recommend various antiplatelet agents in addition to aspirin for patients with acute coronary syndromes. The advantages of these agents, as repute mortality, may be associated with off-target effects of the drug. Hence, further studies are required to facilitate the physician’s choice of the most appropriate antiplatelet agents for each patient for thrombosis treatment.     

Novel Antiplatelet Therapy in Acute Coronary Syndromes: What is New in the Pipeline?

Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an "one-size fits all" concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients' groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role.     

Antiplatelet therapy in patients with diabetes mellitus

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate receptor, phosphodiesterase inhibitors, and protease-activated receptor antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.     

Pathophysiology of platelet resistance to anti-aggregating agents in insulin resistance and type 2 diabetes: implications for anti-aggregating therapy

The insulin resistance syndrome, which presents among its many facets obesity and type 2 diabetes mellitus, is a major risk factor for cardiovascular events. Thus, therapeutic guidelines recommend multifactorial treatment programs including, especially in the presence of type 2 diabetes, antiplatelet drugs. Few data, however, are available about the protective effect of antiplatelet therapy in both obese and type 2 diabetic patients. Furthermore, some reports showed a decreased sensitivity to the platelet antiaggregating effect of acetylsalicylic acid in diabetic patients. In the first part of this review, we focused our attention to alterations of platelets from insulin resistant subjects with or without type 2 diabetes, underlining that platelet hyperactivation is explained, at least in part, by: i) a reduced sensitivity to agents exerting an inhibitory modulation of platelet responses, ii) an altered intracellular milieu with elevated cytosolic Ca2+, iii) an enhanced thromboxane A2 synthesis, and iv) an increased number and/or function of GPIIb/IIIa complexes on platelet membranes. Furthermore, oxidative stress, which increases isoprostane production from arachidonic acid, may be involved in platelet hyperactivation, since isoprostanes activate platelets by interplaying with thromboxane receptors. These defects explain why antiplatelet therapy for both chronic atherosclerotic vascular disease and acute coronary syndromes should be specifically tailored in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus. Thus, in the second part of this review we carried out a critical overview of the clinical trials in subjects with metabolic syndrome and type 2 diabetes mellitus with or without macroangiopathy.     

Inhibiting PAR-1 in the prevention and treatment of atherothrombotic events

Importance of the field: Aspirin, an irreversible inhibitor of thromboxane A₂ production, in combination with clopidogrel, an inhibitor of PY₁₂ ADP platelet receptors, represents the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations.

Areas covered in this review: The inhibition of protease-activated receptors (PAR)-1, is the target for novel antiplatelet drugs, which showed a good safety profile in preclinical studies. The drugs most developed are vorapaxar (SCH530348) and atopaxar (E5555), which will be further evaluated in ongoing Phase III and II clinical trials respectively.

What the reader will gain: This review is focused on the current knowledge of PAR-1 antagonists, analyzing the pharmacological and early phase clinical investigation findings on these new drugs.

Take home message: The PAR-1 receptor offers a new target for the inhibition of platelet activation and aggregation. Preliminary results showed the good safety profile of these new agents. The results of the Phase III ongoing trials will provide important clinical insight into the blockade of thrombin-induced platelet activation.     

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.     

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.     

Resistance to antiplatelet drugs: current status and future research

Platelet reactivity and activation are important factors during the development of atherothrombotic processes and subsequent ischaemic complications. Pharmacological agents that suppress platelet function are proved to be the most efficient in the prevention and treatment of thrombotic complications. As the activation of platelets during thrombus generation involves many complex and redundant pathways, simultaneous use of different antiplatelet drugs that are directed against different targets have been effective in reducing adverse clinical events. The main antiplatelet drugs are aspirin (which inhibits thromboxane synthesis), thienopyridines (which block P2Y12 receptors) and glycoprotein IIb/IIIa antagonists (which block glycoprotein IIb/IIIa receptors). In recent years, resistance or nonresponsiveness to antiplatelet therapy has been reported and, more importantly, are linked to the occurrence of adverse cardiovascular events. New treatment strategies to overcome nonresponsiveness are being sought. A focus on the development of simple, reproducible and user friendly point-of-care methods to determine aspirin/clopidogrel responsiveness should be undertaken to assist clinicians in tailoring antiplatelet therapy to the individual patient.     

Modified fatty acids and their possible therapeutic targets in malignant diseases

Fatty acids and other lipids have multiple roles in the cell, functioning as structural components, participating in intracellular signalling and serving as metabolic fuel. Various compounds that influence cellular lipid metabolism can reduce the growth of malignant cells, and dietary as well as pharmacological strategies for modulating lipid metabolism have therefore been suggested as possible approaches for cancer prevention and treatment. By chemically modifying fatty acids (e.g., butyrates, retinoids), new potential anticancer agents have been produced that possess increased metabolic stability and more specific and potent biological activity compared to the natural fatty acids. Possible therapeutic targets for such modified fatty acids include: i) Histone deacetylase; ii) nuclear hormone receptors (retinoid receptors), peroxisome proliferator-activated receptors; iii) cyclooxygenase-2; iv) intracellular signalling involving protein farnesylation and Ras activation; and v) various mitochondrial functions. Although several fatty acid derivatives have been thoroughly investigated in experimental models, clinical data on toxicity and pharmacological interactions are not available for the majority of these agents. However, several promising novel compounds are now being evaluated in preclinical and early clinical studies, and future research will hopefully reveal new formulations and therapy schedules that will improve the outcome of patients with malignant disorders.