Drugs for cardiac arrhythmmias, antithrombotic drugs and lipid modulating drugs

13.1 Drugs for cardiac arrhythmias 13.1.1 Introduction to cardiac arrhythmias 13.1.2 Cardiac action potentials 13.1.3 Mechanisms of cardiac arrhythmias 13.1.3 Class I 13.1.4 Class II 13.1.5 Class III 12.1.6 Class IV 13.1.7 Amiodarone 13.1.8 Adenosine 13.2 Antithrombotic drugs 13.2.1 Thrombus formation 13.2.2 Platelet aggregation and anti-platelet drugs 13.2.3 Coagulation 13.2.4 Anticoagulants 13.2.5 Fibrinolysis and fibrinolytics 13.3. Lipid modulating drugs 13.3.1 Cholesterol 13.3.2 Statins 13.3.3 Fibric acid derivatives 13.3.4 Ezetimibe

A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention.

Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: Orally effective anti-inflammatory drug candidates

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 mu mol/kg, acting mainly as a non-selective COX inhibitor. (C) 2009 Elsevier Ltd. All rights reserved.

Exploration of the Antiplatelet Activity Profile of Betulinic Acid on Human Platelets

Betulinic acid, a natural pentacyclic triterpene acid, presents a diverse mode of biological actions including antiretroviral, antibacterial, antimalarial, and anti-inflammatory activities. The potency of betulinic acid as an inhibitor of human platelet activation was evaluated, and its antiplatelet profile against in vitro platelet aggregation, induced by several platelet agonists (adenosine diphosphate, thrombin receptor activator peptide-14, and arachidonic acid), was explored. Flow cytometric analysis was performed to examine the effect of betulinic acid on P-selectin membrane expression and PAC-1 binding to activated platelets. Betulinic acid potently inhibits platelet aggregation and also reduced PAC-1 binding and the membrane expression of P-selectin. Principal component analysis was used to screen, on the chemical property space, for potential common pharmacophores of betulinic acid with approved antithrombotic drugs. A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists (PGI2), and the importance of its carboxylate group in its antiplatelet activity was determined. The present results indicate that betulinic acid has potential use as an antithrombotic compound and suggest that the mechanism underlying the antiplatelet effects of betulinic acid is similar to that of the PGI2 receptor agonists, a hypothesis that deserves further investigation.

Future treatment strategies in ST-segment elevation myocardial infarction

Over the past five decades, management of acute ST-segment elevation myocardial infarction (STEMI) has evolved substantially. Current treatment encompasses a systematic chain of network activation, antithrombotic drugs, and rapid instigation of mechanical reperfusion, although pharmacoinvasive strategies remain relevant. Secondary prevention with drugs and lifestyle modifications completes the contemporary management package. Despite a tangible improvement in outcomes, STEMI remains a frequent cause of morbidity and mortality, justifying the quest to find new therapeutic avenues. Ways to reduce delays in doing coronary angioplasty after STEMI onset include early recognition of symptoms by patients and prehospital diagnosis by paramedics so that the emergency room can be bypassed in favour of direct admission to the catheterisation laboratory. Mechanical reperfusion can be optimised by improvements to stent design, whereas visualisation of infarct size has been improved by developments in cardiac MRI. Novel treatments to modulate the inflammatory component of atherosclerosis and the vulnerable plaque include use of bioresorbable vascular scaffolds and anti-proliferative drugs. Translational efforts to improve patients' outcomes after STEMI in relation to cardioprotection, cardiac remodelling, and regeneration are also being realised. This is the third in a Series of three papers about ST-segment elevation myocardial infarction.

Antiplatelet and Antithrombotic Activities of Non-Steroidal Anti-Inflammatory Drugs Containing an N-Acyl Hydrazone Subunit

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Antithrombotic actions of statins involve PECAM-1 signalling

Statins are widely prescribed cholesterol-lowering drugs that are a first-line treatment for coronary artery disease and atherosclerosis, reducing the incidence of thrombotic events such as myocardial infarction and stroke. Statins have been shown to reduce platelet activation, although the mechanism(s) through which this occurs is unclear. Since several of the characteristic effects of statins on platelets are shared with those elicited by the inhibitory platelet adhesion receptor PECAM-1, we investigated a potential connection between the influence of statins on platelet function and PECAM-1 signalling. Statins were found to inhibit a range of platelet functional responses and thrombus formation in vitro and in vivo. Notably, these effects of statins on platelet function in vitro and in vivo were diminished in PECAM-1-/- platelets. Activation of PECAM-1 signalling results in its tyrosine phosphorylation, the recruitment and activation of tyrosine phosphatase SHP-2, the subsequent binding of phosphoinositol 3-kinase (PI3-K) and diminished PI3-K signalling. Statins resulted in the stimulation of these events, leading to the inhibition of Akt activation. Together, these data provides evidence for a fundamental role of PECAM-1 in the inhibitory effects of statins on platelet activation, which may explain some of the pleiotropic actions of these drugs.

Developing drugs for use before, during and soon after percutaneous coronary intervention.

INTRODUCTION Percutaneous coronary intervention (PCI) is a milestone for treating coronary artery disease (CAD). Antithrombotic therapy is essential to prevent ischemic complications, including the microvascular no-reflow, while minimizing bleeding events. Areas covered: This overview discusses available and developing drugs for PCI including anticoagulants, antiplatelets and treatment of no-reflow. Expert opinion: For years unfractionated heparin (UFH) has been the unique anticoagulant to be used before and during PCI. Enoxaparin showed similar efficacy and safety, yet, based on recent trials, bivalirudin has been shown to have some benefits, particularly for patients with ST-segment elevation myocardial infarction (STEMI). The evidence concerning new anticoagulants is still preliminary, except for new oral anticoagulants, particularly rivaroxaban that showed intriguing findings and is currently under investigation. Dual antiplatelet therapy (DAPT) is the standard of care after PCI, but new developments have recently emerged. Indeed, ticagrelor and prasugrel are currently recommended over clopidogrel due to their significant reduction of ischemic events in acute coronary syndrome (ACS) whereas clopidogrel remains the choice in stable CAD. Among new agents, vorapaxar and cangrelor showed positive but limited evidence and might be considered at least in selected patients. Conversely, evidence on effective treatments for no-reflow remains limited and would require future dedicated research.

Antithrombotic therapy in TAVI patients: changing concepts.

The clinical and demographic characteristics of patients undergoing TAVI pose unique challenges for developing and implementing optimal antithrombotic therapy. Ischaemic and bleeding events in the periprocedural period and months after TAVI still remain a relevant concern to be faced with optimised antithrombotic therapy. Moreover, the antiplatelet and anticoagulant pharmacopeia has evolved significantly in recent years with new drugs and multiple possible combinations. Dual antiplatelet therapy (DAPT) is currently recommended after TAVI with oral anticoagulation (OAC) restricted for specific indications. However, atrial fibrillation (which is often clinically silent and unrecognised) is common after the procedure and embolic material often thrombin-rich. Recent evidence has therefore questioned this approach, suggesting that DAPT may be futile compared with aspirin alone and that OAC could be a relevant alternative. Future randomised and appropriately powered trials comparing different regimens of antithrombotic therapy, including new antiplatelet and anticoagulant agents, are warranted to increase the available evidence on this topic and create appropriate recommendations for this frail population. Meanwhile, it remains rational to adhere to current guidelines, with routine DAPT and recourse to OAC when specifically indicated, whilst always tailoring therapy on the basis of individual bleeding and thromboembolic risk.

Screening for drugs in oral fluid : illicit drug use and drug driving in a sample of urban and regional Queensland motorists

Police services in a number of Australian states and overseas jurisdictions have begun to implement or consider random road-side drug testing of drivers. This paper outlines research conducted to provide an estimate of the extent of drug driving in a sample of Queensland drivers in regional, rural and metropolitan areas. Oral fluid samples were collected from 2657 Queensland motorists and screened for illicit substances including cannabis (delta 9 tetrahydrocannibinol [THC]), amphetamines, ecstasy, and cocaine. Overall, 3.8% of the sample (n = 101) screened positive for at least one illicit substance, although multiple drugs were identified in a sample of 23 respondents. The most common drugs detected in oral fluid were ecstasy (n = 53), and cannabis (n = 46) followed by amphetamines (n = 23). A key finding was that cannabis was confirmed as the most common self-reported drug combined with driving and that individuals who tested positive to any drug through oral fluid analysis were also more likely to report the highest frequency of drug driving. Furthermore, a comparison between drug vs. drink driving detection rates for one region of the study, revealed a higher detection rate for drug driving (3.8%) vs. drink driving (0.8%). This research provides evidence that drug driving is relatively prevalent on Queensland roads, and may in fact be more common than drink driving. This paper will further outline the study findings’ and present possible directions for future drug driving research.

Alcohol and other drugs in the Australian construction industry : A national evaluation and the best way forward

Anecdotal evidence highlights issues of alcohol and other drugs (AODs) and its association with safety risk on construction sites. Information is limited however regarding the prevalence of AODs in the workplace and there is limited evidential guidance regarding how to effectively address it. This research aimed to scientifically evaluate the use of AODs within the Australian construction industry in order to reduce the potential resulting safety and performance impacts and engender a cultural change in the workforce. A national qualitative and quantitative evaluation of the use of AODs was conducted with approximately 500 employees. Results indicate that as in the general population, a proportion of those sampled in the construction sector may be at risk of hazardous alcohol consumption and support the need for evidence-based, tailored responses. This is the first known study to scientifically evaluate the use of AODs and potential workplace safety impacts in the construction sector.

New findings with old drugs for osteoporosis

Background : Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods : This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results : Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions : As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.

Safeguarding rural Australia : addressing masculinity and violence in rural settings. Data report No. 4 - Risky behaviour - misuse of alcohol, illicit drugs, firearms use and abuse, other risky behaviour

This report focuses on our examination of extant data which have been sourced with respect to personally and socially risky behaviour associated with males living in regional and remote Australia . The AIHW (2008: PHE 97:89) defines personally risky behaviour, on the one hand, as working, swimming, boating, driving or operating hazardous machinery while intoxicated with alcohol or an illicit drug. Socially risky behaviour, on the other hand, is defined as creating a public disturbance, damaging property, stealing or verbally or physically abusing someone while intoxicated with alcohol or an illicit drug. Additional commentary resulting from exploration, examination and analyses of secondary data is published online in complementary reports in this series.

Drugs, dental professionals and the law

Dentists have the privilege of possessing, administering and prescribing drugs, including highly addictive medications, to their patients. But because drugs are often vulnerable to being abused by all members of society, including dentists and their patients, and because drugs can be dangerous, they are tightly regulated in Canada by the federal and provincial/territorial governments. Regulatory and professional dental bodies also provide guidance for their members about how to best administer and prescribe drugs. This chapter outlines the regulation by federal and provincial/territorial governments in this area, examines the professional practice requirements set out by regulatory/professional bodies and the issue of drug abuse by dental professional and patients. It is important to note from the outset that governmental and professional regulations, policies and practices differ from province to province and territory to territory. This chapter aims to alert dentists to possible legal and professional issues surrounding the possession, administration and prescription of drugs. For detailed specific information about regulation, policies, ethical standards and professional practice standards in Canada or their province/ territory, dentists should contact their insurer or professional association.

Safety impacts of alcohol and other drugs in the construction industry : a research methodology

Anecdotal evidence from the infrastructure and building sectors highlights issues of drugs and alcohol and its association with safety risk on construction sites. Operating machinery and mobile equipment, proximity to live traffic together with congested sites, electrical equipment and operating at heights conspire to accentuate the potential adverse impact of drugs and alcohol in the workplace. While most Australian jurisdictions have identified this as a critical safety issue, information is limited regarding the prevalence of alcohol and other drugs in the workplace and there is limited evidential guidance regarding how to effectively and efficiently address such an issue. No known study has scientifically evaluated the relationship between the use of drugs and alcohol and safety impacts in construction, and there has been only limited adoption of nationally coordinated strategies, supported by employers and employees to render it socially unacceptable to arrive at a construction workplace with impaired judgement from drugs and alcohol. A nationally consistent collaborative approach across the construction workforce - involving employers and employees; clients; unions; contractors and sub-contractors is required to engender a cultural change in the construction workforce – in a similar manner to the on-going initiative in securing a cultural change to drink-driving in our society where peer intervention and support is encouraged. This study has four key objectives. Firstly, using the standard World Health Organisation AUDIT, a national qualitative and quantitative assessment of the use of drugs and alcohol will be carried out. This will build upon similar studies carried out in the Australian energy and mining sectors. Secondly, the development of an appropriate industry policy will adopt a non-punitive and rehabilitative approach developed in consultation with employers and employees across the infrastructure and building sectors, with the aim it be adopted nationally for adoption at the construction workplace. Thirdly, an industry-specific cultural change management program will be developed through a nationally collaborative approach to reducing the risk of impaired performance on construction sites and increasing workers’ commitment to drugs and alcohol safety. Finally, an implementation plan will be developed from data gathered from both managers and construction employees. Such an approach stands to benefit not only occupational health and safety, through a greater understanding of the safety impacts of alcohol and other drugs at work, but also alcohol and drug use as a wider community health issue. This paper will provide an overview of the background and significance of the study as well as outlining the proposed methodology that will be used to evaluate the safety impacts of alcohol and other drugs in the construction industry.