Pharmaceutical thrombosis prevention in cardiovascular disease

Cardiovascular diseases are a leading cause of morbidity and mortality in modern society. As a result of this, great efforts have been made to establish regimens for prophylaxis and treatment of such disorders. Pharmacological intervention is also a prerequisite for the success of other therapeutic approaches, e.g. coronary angioplasty. Prevention of platelet aggregation is a goal that can be achieved by counteracting various receptors on the platelet surface. The main attentions for such interventions are focused on inhibiting the glycoprotein IIb/IIIa receptor. So far, they are limited to intravenous usage. Adenosine diphosphate receptor inhibitors are available for intravenous and oral usage. Their effect is, at least partly, also exerted via the counteraction of adenosine diphosphate-mediated activation of the glycoprotein IIb/IIIa complex. An oral direct thrombin inhibitor is under clinical evaluation. This review focuses on atherothrombotic disorders, but recent advances within new fields of anticoagulation (i.e. treatment of severe septic shock and a novel approach to prevent thromboembolic disorder during surgery) should not be overlooked.     

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The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.     

Is there a role for oral blockade of platelet glycoprotein IIb/IIIa receptors in coronary and cerebrovascular disease?

The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.     

Glycoprotein IIb/IIIa receptor antagonists: clinical pharmacology in cardiovascular diseases of aging.

The aging process is accompanied by a series of anatomical and physiological cardiovascular changes, including a generalised loss of vascular compliance, neuroendocrine alterations and endothelial dysfunction. Superimposed on this, there is an age-related increase in common cardiovascular disorders, such that the majority of deaths and much disability in older populations are caused by coronary artery disease. Most acute vascular events are mediated by thrombosis in which the formation of platelet aggregates forms an integral part. Research over recent years has led to the characterisation of the platelet glycoprotein (GP) IIb/IIIa receptor as the ultimate mechanism by which activated platelets cross-link by binding fibrinogen and other ligands. This knowledge has resulted in novel pharmacological strategies targeting this receptor which have proven to be potent inhibitors of thrombosis. The prototype drug, abciximab, is a chimeric monoclonal antibody directed against GP IIb/IIIa. Synthesis of new drugs has followed, based on the identification of the molecular sequences to which GP IIb/IIIa is attracted. This includes the emergence of oral agents which can be used for long term therapy. Clinical trials with these agents in the setting of percutaneous coronary interventions and unstable ischaemic syndromes have demonstrated a beneficial effect on thrombosis-related end-points. Trials of GP IIb/IIIa antagonists for direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction have also shown benefit, while their use in combination with fibrinolytic drugs is currently being evaluated. Other potential indications including neurovascular disease and primary haematological disorders are also being explored.     

Inhibitors of platelets glycoprotein IIb/IIIa (GP IIb/IIIa) receptor: rationale for their use in clinical cardiology

The glycoprotein IIb/IIIa (GP IIb/IIIa) receptor is the most important receptor involved in platelet aggregation. A stable GP IIb/IIIa inhibition is required when a massive platelet activation triggers thrombosis. Three GP IIb/IIIa inhibitors are currently approved for clinical use: abciximab, tirofiban and integrilin. Their different pharmacodynamic and pharmacokinetic properties reflect a different efficacy in platelet inhibition.     

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In clinical trials in patients with acute or unstable coronary syndromes and/or undergoing percutaneous coronary intervention, oral glycoprotein (GP) IIb/IIIa antagonists did not show therapeutic benefit over aspirin during long-term administration. Moreover, high-dose oral administration of these agents was associated with greater fatality risk compared with that of lower doses. This article postulates that continuous exposure of the GP IIb/IIIa receptor (integrin αIIbβ₃) to these agents may result in some form of resistance or activation of other biological systems. These toxicological mechanisms may help explain some factors that could potentially contribute to the failure of these agents in clinical trials. Several hypotheses are presented: (i) modulation of platelet response because of long-term exposure to GP IIb/IIIa antagonists; (ii) role of related integrins and associated proteins to compensate for the loss of platelet activity because of dysfunctional GP IIb/IIIa receptors occupied by inhibitors; (iii) effects of the GP IIb/IIIa antagonists on other cellular systems such as the caspase and procaspase enzymes in apoptosis and possibly the ryanodine receptor involved in sarcoplasmic reticulum calcium release. These toxicological mechanisms could potentially limit the utility of these oral agents in long-term administration.     

Optimal use of platelet glycoprotein IIb/IIIa receptor antagonists in patients undergoing percutaneous coronary interventions

Discovery of the central role of platelets in the pathogenesis of acute coronary syndromes (ACS) and ischaemic complications of percutaneous coronary interventions (PCI) has led to the widespread use of oral and parenteral platelet inhibitors to treat these conditions. Glycoprotein (GP) IIb/IIIa (also known as α(IIb)β(3)) receptors on the surface of platelets play an essential role in platelet aggregation and serve as a key mediator in the formation of arterial thrombus. When activated, GP IIb/IIIa receptors bind to fibrinogen, which serves as the 'final common pathway' in platelet aggregation. Of the numerous agents developed for modulating platelet activity, intravenous platelet GP IIb/IIIa receptor antagonists are the most potent. There are four agents in clinical use, including abciximab, eptifibatide, tirofiban and lamifiban, although lamifiban is not approved for use in the US. While all agents block fibrinogen binding to GP IIb/IIIa, they do so by different mechanisms. Abciximab is a humanized form of a murine monoclonal antibody directed against GP IIb/IIIa, eptifibatide is a synthetic, cyclic heptapeptide that contains a lysine-glycine-aspartic acid (KGD) sequence that mimics the arginine-glycine-aspartic acid (RGD) sequence found on GP IIb/IIIa, tirofiban is a non-peptide antagonist derived by optimization of the tyrosine analogue that structurally mimicks the RGD-containing loop of the disintegrin echistatin, and lamifiban is a synthetic, non-cyclic, non-peptide, low-molecular-weight compound. In clinical trials, use of these agents reduces ischaemic adverse cardiovascular events in patients with ACS undergoing PCI, but at a cost of increased bleeding.     

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.     

Antiplatelet mechanism of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent

The effects of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin-, arachidonic acid- and thapsigargin-induced aggregation of washed human platelets with the IC50 values of 22.2+/-0.7, 6.5+/-0.2, and 7.6+/-0.1 microM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate-conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen-glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin-induced increase in intracellular Ca2+ mobilization at the dose of 30 microM and ATP secretion in a dose-dependent manner. It also inhibited thrombin- and arachidonic acid-induced thromboxane A2 formation in human platelet dose-dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A2 formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.     

Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention

Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI (STEMI).     

Current strategies with high-dose tirofiban

The glycoprotein (GP) IIb/IIIa receptor is a platelet-specific adhesion receptor that mediates the formation of platelet aggregates. Pharmacologic blockade of the receptor is associated with a reduction in major cardiovascular adverse events after percutaneous coronary interventions and in the setting of acute coronary syndromes. Three intravenous GP IIb/IIIa receptor inhibitors are available: abciximab, tirofiban and eptifibatide. Tirofiban is a small, synthetic non-peptide, competitive GP IIb/IIIa antagonist with high specificity and high affinity for the GP IIb/IIIa receptor. In a head-to-head comparison, tirofiban 10-microg/kg bolus followed by a 0.15-microg/kg/min infusion was found to be inferior to standard dose of abciximab in patients undergoing percutaneous coronary intervention. Insufficient platelet inhibition with low-dose tirofiban may likely explain these results. Subsequently, a high-bolus dose of tirofiban (25 microg/kg bolus) followed by standard infusion was tested and evidence suggest that in this dosing tirofiban may be as effective as abciximab and have a comparable safety profile. Therefore, high-bolus dose tirofiban may be an appealing and cost-effective alternative to abciximab. However, further testing is warranted given the short follow up and limited statistical power of the available data.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

Intracoronary use of GP IIb/IIIa inhibitors in percutaneous coronary interventions

The glycoprotein (GP) IIb/IIIa receptor is critical to the process of platelet aggregation and thrombus formation as it serves as the final common pathway for platelet aggregation. For this reason, the development of GP IIb/IIIa inhibitors that block fibrinogen binding to the receptor has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. Presently, there are three commercially available GP IIb/IIIa inhibitors: abciximab, eptifibatide and tirofiban. All three drugs are commonly administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in patients at high risk, especially those undergoing percutaneous coronary interventions (PCI). Recently, several studies tested the intracoronary (IC) route for GP IIb/IIIa inhibitors in order to verify its safety and its possible superiority as compared to the intravenous (IV) route. The majority of the studies testing the IC route were conducted using abciximab and in patients with STEMI with better results in terms of myocardial reperfusion and infarct size and also promising results in terms of clinical outcome. On the IC administration of eptifibatide and tirofiban only some, even if promising, data are available. Larger and randomized studies are warranted to confirm the superiority of the IC route of administration of the GP IIb/IIIa inhibitors to the IV one in patients with coronary artery disease undergoing PCI.     

Clinical pharmacokinetics of tirofiban, a nonpeptide glycoprotein IIb/IIIa receptor antagonist: comparison with the monoclonal antibody abciximab

Tirofiban is a nonpeptide tyrosine derivative that antagonises platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptors. It is one of three GP IIb/IIIa antagonists approved by the US Food and Drug Administration for the treatment of patients with acute coronary syndromes. The clinical effect of tirofiban has been shown in large studies such as PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (PRISM - Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomised Efficacy Study of Tirofiban for Outcomes and Restenosis). Tirofiban is administered as an intravenous infusion. Volume of distribution ranges from 21 to 87 L, and binding to human plasma proteins is modest at 64%. Metabolism in humans is negligible, and most drug is excreted renally with systemic clearance ranging from 4.8 to 25.8 L/h. Renal function may influence the excretion of tirofiban, but concurrent disease or other drugs generally used in patients with ischaemia seem not to do so. This review updates what is known about the pharmacokinetics of tirofiban in humans, especially in comparison with the monoclonal antibody against the IIb/IIIa receptor, abciximab.     

Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in acute ischaemic stroke: scientific rationale and available evidence

Acute ischaemic stroke is the result of an abrupt interruption of focal cerebral blood flow. In the majority of cases, this interruption is caused by an acute thromboembolism. Based on clinical experience in the treatment of acute coronary syndromes, platelet glycoprotein (GP) IIb/IIIa receptor antagonists alone, in combination with reduced doses of thrombolytic agents, or as complementary therapy for short-term mechanical interventions merit consideration as a class of agents with potential use in ischaemic stroke. Research to date and extrapolation from the cardiac literature suggest significant, but as yet unproven, potential for the use of GP IIb/IIIa receptor antagonists in the treatment of acute ischaemic stroke. This potential exists both at the site of the thromboembolic occlusion and at the distal microvascular level. This article reviews the scientific rationale and available evidence for the potential use of platelet GP IIb/IIIa receptor antagonists in acute ischaemic stroke.     

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.     

Oral Glycoprotein IIb/IIIa Inhibitors

Despite their promise as orally active potent inhibitors of platelet aggregation, the oral platelet glycoprotein IIb/IIIa inhibitors have failed to provide a reduction in late ischemic events. In fact, with five large-scale randomized trials now complete, including over 42000 patients, these agents have been associated with a surprising, yet consistent, excess in mortality. Peculiarly, this fatality risk has occurred in the absence of a commensurate increase in other ischemic end-points. While these findings have curtailed the further clinical development of this class of potent platelet inhibitors, the obvious dissociation between platelet suppression and adverse outcome requires further clarification. Multiple putative explanations for this excess in ischemic events with oral glycoprotein IIb/IIIa inhibitors have been proposed, but definitive data implicating a specific mechanism are currently not available. While the lack of concurrent aspirin may account for some of this effect, it is unlikely to fully explain the mortality excess. Potential mechanisms include partial agonist activity leading to increased expression of platelet-leukocyte adhesion molecules, sub-optimal inhibition of platelet aggregation, genetic polymorphisms, especially phospholipase A₂ polymorphism, and promotion of cardiac myocyte apoptosis via activation of caspase 3. Definitive elucidation of these adverse mechanisms will be required if further clinical development of the oral platelet glycoprotein IIb/IIIa inhibitors is to be pursued.     

Antiplatelet Mechanism of 2‐Chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an Antithrombotic Agent

Abstract: The effects of 2‐chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin‐, arachidonic acid‐ and thapsigargin‐induced aggregation of washed human platelets with the IC₅₀ values of 22.2±0.7, 6.5±0.2, and 7.6±0.1 μM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate‐conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen‐glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin‐induced increase in intracellular Ca²⁺ mobilization at the dose of 30 μM and ATP secretion in a dose‐dependent manner. It also inhibited thrombin‐ and arachidonic acid‐induced thromboxane A₂ formation in human platelet dose‐dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A₂ formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.     

Platelet glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions: a pharmacological and clinical review

One of the most significant advances of the last decade has been the development of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors. A large series of randomised, controlled clinical trials of these agents have shown a significant reduction in ischaemic events, not only in acute coronary syndrome patients, but also in patients who undergo elective percutaneous coronary interventions. Even though the use of oral antiplatelet and antithrombotic therapies in addition to percutaneous coronary interventions have had a significant impact in clinical outcomes after acute coronary syndromes, the use of GP IIb/IIIa inhibitors provide additional protection against recurrent ischaemia and has been identified as the pivotal mediator of platelet aggregation, making it a logical target for the control of platelet response to vascular injury. A series of key trials performed over the last few years with GP IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention, have shown a reduction in the risk of short-term death and non-fatal myocardial infarction. The pharmacology and molecular basis of GP IIb/IIIa receptor inhibition and the use of these agents in patients undergoing percutaneous coronary intervention (during acute coronary syndromes and in elective procedures) and their safety issues will be reviewed. A special emphasis has been made on the role of these agents in diabetic patients and their beneficial effect in reducing peri-procedural creatine kinase myocardial band fraction elevation and associated complications.