Current Pharmaceutical Design - Volume 16, Issue 31, 2010

In the last decade, a number of new antithrombotic therapies as well as new approaches have been appearing for the management of patients with or at risk for arterial and venous thrombosis. Considering new drugs, direct thrombin inhibitors (dabigatran etixilate) or Factor Xa inhibitors (rivaroxaban and apixaban) are now available for the prophylaxis for venous thromboembolism (VTE) during orthopedic procedures. Hopefully soon, new oral anticoagulants (dabigatran etexilate) will replace warfarin in the prevention of stroke in patients with chronic atrial fibrillation (AF). What are the advantages of these new drugs over warfarin? Mainly, they do not need laboratory monitoring, since direct thrombin or factor Xa inhibitors are administered at fixed doses. Some investigations showed also a greater efficacy without increasing the risk for bleeding; however, most of the studies were designed as non-inferiority trials, therefore strong conclusions about their superiority are not easy to attempt. In this issue, all the most relevant topics on new approaches for the management of arterial and venous thrombosis are discussed. Dr. Douketis [1] analyses the pharmacological profiles of the new anticoagulants and, very interestingly, implications for their use during perioperative management. This topic is still debated in patients who receive warfarin and several approaches have been published. Dr. Lyp et coworkers [2, 3] addressed in two papers new issues related to arterial thrombosis. Particularly, Dr. Butt [2] evaluated the role of endothelial dysfunction as a marker for cardiovascular diseases, while Dr. Potpara [3] highlighted the strategies and future perspectives for the prevention of arterial thromboembolism in patients with AF. New issues on VTE were analyzed by Dr Lepic and Dr. Garcia [4, 5]. The first author reports on new anticoagulants for the prevention of venous thrombosis during orthopedic surgery [4], a population at high-risk for postoperative Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in whom heparin antithrombotic prophylaxis can be further ameliorate in terms of efficacy. Dr. Garcia analyzed the new oral anticoagulants for the treatment of DVT and PE, highlighting the potential advantages over coumarin specially in case of long-term treatment [5]. Dr. Romualdi addressed a very important topic: how to manage anticoagulated patients receiving warfarin or the new thrombin or factorXa inhibitors [6]. This topic is extremely important, especially in case of therapy with the new anticoagulants, since they do not have a specific antagonist. Along with new drugs, new approaches to establishing the individual risk for recurrent VTE are discussed. Malato et al. briefly analyzes the use of well reproducible markers as D-dimer (D-d) and detection of residual vein thrombosis (RVT) that has been demonstrated to drive the optimal duration of oral anticoagulants in patients with a first episode of DVT [7]. Finally, Dr. Huisman explores the potential advantages of administering new anticoagulants in settings, where indications are still under evaluation or await for approval or areas, where these novel drugs have not yet been evaluated [8]. In the last two review Fazio et al. analyzed the importance of thrombotic complications in the presence of PFO or in patients that used some oral contraceptives [9-10]. In general, this issue furnishes a comprehensive framework of the most recent approaches for the management of patients with or at highrisk for venous or arterial thrombosis....

The past decade has witnessed an explosion in the clinical development of new orally-administered anticoagulant drugs aimed at complementing vitamin K antagonists and heparins for the prevention and treatment of venous thromboembolism, for the prevention of stroke in patients with chronic atrial fibrillation, and for treatment of acute coronary syndromes. This review will focus on those new oral anticoagulants that are most relevant to the practicing clinician. These drugs consist of dabigatran, a direct thrombin inhibitor and rivaroxaban, a factor Xa inhibitor, both of which have been recently approved for clinical use. In addition, apixaban will be reviewed, which is another factor Xa inhibitor that is in the final stages of clinical development. The objectives of this review are: 1) to provide a clinician-oriented overview of the key pharmacokinetic and pharmacodynamic properties of dabigatran, rivaroxaban and apixaban; and 2) to consider the implications of these drugs pharmacologic properties in the perioperative setting for patients who require elective or urgent surgery, focusing on pre- and post-operative dosing, laboratory monitoring and reversal of anticoagulant effect.

The endothelium is a thin monocellular layer lining the entire human vascular system, separating blood from interstitium. It plays a core role in the vascular tone by releasing a variety of vasoactive substances, such as nitric oxide (NO) and endothelin. In addition to regulating vasomotion, the healthy endothelium also has anti-thrombotic (through prostacyclins), anti-inflammatory (through developmental endothelial locus-1{Del-1}) and anti-proliferative (through NO and prostaglandin I2) properties. All such mechanisms are regulated by a strict balance amongst several agonist and antagonist biochemical substances secreted by the endothelium. Endothelial dysfunction (ED) is a systemic process in which the endothelium loses the ability/capacity to maintain vascular equilibrium. ED is strongly associated with cardiovascular risk factors/diseases and can be assessed by a number of invasive and non invasive methods. Strict physiological and/or pharmacological management of cardiovascular risk factors improves the functional status of the endothelium and reduces the risk of future cardiac events. This review will provide an overview of the modern perception of endothelial biology, the methods of its assessment and interaction of the endothelium with cardiovascular risk factors and prognosis.

Arterial thromboembolism is a sudden obstruction of arterial blood flow caused by dislodgment of a blood clot from the site of its formation. Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major risk factor for arterial thromboembolism in clinical practice. Most of AF-related arterial thromboembolic events affect the cerebral circulation, leading to increased mortality or longterm disability from stroke. In the setting of AF, stroke is more likely to be fatal or associated with longer hospitalization, greater disability and higher rates of recurrence. Anticoagulant therapy reduces the risk of stroke, and the greatest benefit is achieved in patients at highest absolute risk. Aspirin is a less effective option, and should not be considered as an equivalent alternative for AF patients with a moderate stroke risk, who are eligible for oral anticoagulation. Nonetheless, anticoagulant therapy remains underused in AF patients with high stroke risk, particularly in the elderly, whilst it might perhaps be overused in the low risk patients. This could also be related to limitations in current risk stratification schemas for stroke and bleeding complications of anticoagulant therapy in AF patients in contemporary clinical practice. In this review article, we present an overview of current therapeutic strategies, new developments and future perspectives for the prevention of arterial thromboembolism in the context of AF and thromboembolism. We also discuss risk factors for stroke and bleeding complications, current risk stratification issues and emerging strategies for more accurate identification of AF patients who should be anticoagulated.

The traditional agents used for thromboprophylaxis are effective and safe but have limitations particularly related to ease of administration. Newer agents targeting single coagulation factors such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban have demonstrated efficacy and safety for thromboembolism prophylaxis in the orthopedic population and have the additional benefit of oral administration and predictable pharmacokinetics. Pharmacology of the new anticoagulants and published data on the use of these agents in total knee and hip replacement patients will be reviewed in this article.

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are widely regarded as manifestations of a single disease, venous thromboembolism (VTE). An evidence-based approach to the treatment of acute VTE will be reviewed here. Currently available therapeutic options will be emphasized; possible future treatment approaches will be discussed briefly. The chronic management of VTE involves assessment of the risks and benefits of prolonged anticoagulation and is discussed in more detail elsewhere in this issue.

An increasing number of patients receive anticoagulant therapy to prevent and treat arterial or venous thromboembolism. The major complication of anticoagulant therapy is the increase of the individual bleeding risk. All anticoagulant drugs can cause haemorrhages, that can sometimes be life-threatening. Although heparins and the vitamin K antagonists have been the most widely used anticoagulants for decades, the correct management of bleeding complications associated with these agents has been poorly studied. More recently, new anticoagulant drugs, both parenteral and oral, have been approved for clinical use. Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event. The aim of this article is to describe the haemorrhagic risk and the management of bleeding complications associated with the principal anticoagulant drugs.

Long-term anticoagulant treatment is highly effective in preventing recurrent Venous Thrombo-Embolism (VTE) in patients with idiopathic Deep Vein Thrombosis (DVT) of the lower limbs, though associated with an increased risk for major bleeding that may offset the benefits of anticoagulation. Accordingly to recent guidelines, patients with idiopathic DVT should be treated for at least 3 months and then should be evaluated for the risk-benefit ratio of long-term therapy. However, such ‘time for decision’ is often unclear and the optimal duration of VKA remains debatable. In recent studies, markers for the assessment of the individual risk for recurrent thrombosis have been proposed, which can be of help to establish the optimal duration of VKA treatment; among them, the D-dimer (D-d) assay and the Residual Vein Thrombosis (RVT) assessment by Compression Ultra-Sonography (CUS) were shown to be the most suitable. Studies' results showed that negative results of these parameters after 3 to 6 months of therapy, identify a group of patients at low-risk for recurrent thrombosis in whom VKA treatment can be withheld. In the present review we will discuss advantages and potential limits of using these individual markers for the management of patients with a first episode of DVT of the lower limbs.

In recent years new oral anticoagulants have been evaluated in the prevention of venous thromboembolism (VTE) after elective hip or knee arthroplasty, atrial fibrillation to prevent ischemic stroke and in the treatment of acute VTE. While two oral anticoagulants, dabigatran and rivaroxaban, have become available for the prevention of VTE in orthopaedic surgery, other indications still are under evaluation or await approval. There are also areas where these novel drugs have not yet been evaluated. These include patients with acute VTE and cancer, pregnant patients with acute VTE and patient with either rheumatic heart valve disease or artificial heart valves. Finally, in acute care settings, where anticoagulant reversibility is critical, such as during and after coronary artery bypass surgery or acute PCI setting in patients with high bleeding risk, novel intravenous anticoagulant drugs with either short half life or specific antidotes may have added value. This article will focus on these unresolved issues.

The use of oral contraceptives first became widespread some 40 years ago, and reports of an excess risk of cardiovascular disease among women who used these agents soon followed. Few drugs have been the object of such intensive epidemiological research, the outcome of which has provided clinicians with detailed information about risks not only of specific thrombotic diseases but also important non-contraceptive benefits from the pill. Recently, oral contraceptives have been classified by some according to “generation” (first, second, third, and most recently, fourth generation): first-generation formulations containing lynestrenol or norethindrone, secondgeneration formulations containing levonorgestrel, third-generation formulations containing desogestrel or gestodene, and oral contraceptives containing an estrogen and other progestagens (cyproterone or norgestimate) or a progestagen alone. The results of several studies was that the use of the older high-dose oral contraceptives increased the risk of cardiovascular disease by modifying the Low-density lipoprotein and High-Density lipoprotein cholesterol level, increasing triglyceride serum level, reducing glucose tolerance, raising blood pressure, and promoting clotting mechanisms. In this review we investigate the mechanism of the oral contraceptives and performed a risk assessment of every generation.

The foramen ovale, an atrial septal defect, which is essential in the fetal circulation, remains patent through adulthood in approximately 25% of the general population and therefore it represents the most common persistent abnormality of fetal origin. Patent foramen ovale (PFO) allows interatrial right-to-left blood shunting during those periods of the cardiac cycle in which the right atrial pressure exceeds the left one. An increasing number of pathological manifestations of PFO has been recently identified; among these, paradoxical systemic embolism, refractory hypoxemia in patients with right ventricular myocardium infarction or severe pulmonary disease, orthostatic oxygen desaturation in the rare platypnea-orthodeoxia syndrome, neurological decompression illness in divers, high altitude pilots and astronauts, and finally, migraine headache with aura. Nowadays, many techniques allow to detect a PFO. In this study, we investigated each of them, assessing their potential diagnostic role even in comparison with the main features of the other methods.

The genus Marrubium (Lamiaceae) is comprised of about forty species, distributed in Europe, Asia and Brazil. Some species are traditionally used to treat various diseases, including asthma, pulmonary infections, inflammation and hypotension, as cholagogues and sedative agents, and for pain relief. A literature review on the chemical and biological aspects of these plants indicates antimicrobial activity against gram positive bacteria, analgesic properties, and anti-hypertensive, antidiabetic, antioxidant properties, among others, particularly related to the presence of diterpenes, sterols, phenylpropanoids and flavonoids. This review shows the main chemical and pharmacological aspects of the genus Marrubium, with emphasis on M. vulgare, which grows in Brazil and has been studied by us and other authors.

Sigma receptors (subtypes sigma-1 and sigma-2) are a unique class of binding sites expressed throughout the mammalian body. The endogenous ligand for these sites has not been identified, but steroid hormones (particularly progesterone), sphingolipidderived amines and N,N-dimethyltryptamine can bind with fairly high affinity. Sigma receptors are overexpressed in rapidly proliferating cells, like cancer cells. Particularly the sigma-2 subtype is upregulated when cells divide and down regulated when they become quiescent. Sigma ligands, especially sigma-2 agonists, can inhibit proliferation and induce apoptosis by a mechanism involving changes in cytosolic Ca2+, ceramide and sphingolipid levels. Tumor cells are much more sensitive to such treatment than cells from their tissue of origin. Sigma ligands induce apoptosis not only in drug-sensitive but also in drug-resistant cancer cells (e.g., cells with p53 mutations, or caspase dysfunction). Moreover, sigma ligands may abrogate P-glycoprotein-mediated drug resistance and at subtoxic doses, they can potentiate the effect of conventional cytostatics. Thus, sigma-2 agonists may be developed as antineoplastic agents for the treatment of drug-resistant tumors. A large number of radiolabeled sigma ligands has been prepared for SPECT (single-photon emission computed tomography) and PET (positron emission tomography) imaging. Such radiopharmaceuticals can be used for tumor detection, tumor staging, and evaluation of anti-tumor therapy. There is still a need for the development of ligands with (1) high selectivity for the sigma-2 subtype, (2) defined action (agonist or antagonist) and (3) optimal pharmacokinetics (low affinity for P-glycoprotein, high and specific tumor uptake, and rapid washout from non-target tissues).