Helen Vosper

Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis.

Dyslipidaemia is a major risk factor in the development of atherosclerosis, and lipid lowering is achieved clinically using fibrate drugs and statins. Fibrate drugs are ligands for the fatty acid receptor peroxisome proliferator-activated receptor (PPAR)alpha, and the lipid-lowering effects of this class of drugs are mediated by the control of lipid metabolism, as directed by PPARalpha. PPARalpha ligands also mediate potentially protective changes in the expression of several proteins that are not involved in lipid metabolism, but are implicated in the pathogenesis of heart disease. Clinical studies with bezafibrate and gemfibrozil support the hypothesis that these drugs may have a significant protective effect against cardiovascular disease. The thiazolidinedione group of insulin-sensitising drugs are PPARgamma ligands, and these have beneficial effects on serum lipids in diabetic patients and have also been shown to inhibit the progression of atherosclerosis in animal models. However, their efficacy in the prevention of cardiovascular-associated mortality has yet to be determined. Recent studies have found that PPARdelta is also a regulator of serum lipids. However, there are currently no drugs in clinical use that selectively activate this receptor. It is clear that all three forms of PPARs have mechanistically different modes of lipid lowering and that drugs currently available have not been optimised on the basis of PPAR biology. A new generation of rationally designed PPAR ligands may provide substantially improved drugs for the prevention of cardiovascular disease.

Niacin: a re‐emerging pharmaceutical for the treatment of dyslipidaemia

Dyslipidaemias, particularly those characterized by the ‘atherogenic profile’ of high low‐density lipoprotein‐cholesterol and triglycerides and low high‐density lipoprotein‐cholesterol, are the major modifiable risk factor for atherosclerosis. The search for drugs to favourably alter such lipid profiles, reducing the associated morbidity and mortality, remains a major research focus. Niacin (nicotinic acid) is the most effective agent available for increasing high‐density lipoprotein‐cholesterol, but its use is associated with side effects that negatively affect patient compliance: these appear to arise largely as a result of production of prostaglandin D2 and its subsequent activation of the DP1 receptor. Desire to reduce the side effects (and improve pharmacokinetic parameters) has led to the development of a number of agonists that have differing effects, both in terms of clinical potency and the severity of adverse effects. The recent discovery of the niacin G‐protein‐coupled receptor HM74A (GPR109A) has clarified the distinction between the mechanism whereby niacin exerts its therapeutic effects and the mechanisms responsible for the generation of side effects. This has allowed the development of new drugs that show great potential for the treatment of dyslipidaemia. However, recent advances in understanding of the contribution of prostaglandin metabolism to vascular wall health suggest that some of the beneficial effects of niacin may well result from activation of the same pathways responsible for the adverse reactions. The purpose of this review is to emphasize that the search for agonists that show higher tolerability must take into account all aspects of signalling through this receptor.

The peroxisome proliferator activated receptor δ is required for the differentiation of THP-1 monocytic cells by phorbol ester

BackgroundPPARδ (NR1C2) promotes lipid accumulation in human macrophages in vitro and has been implicated in the response of macrophages to vLDL. We have investigated the role of PPARδ in PMA-stimulated macrophage differentiation.The THP-1 monocytic cell line which displays macrophage like differentiation in response to phorbol esters was used as a model system. We manipulated the response to PMA using a potent synthetic agonist of PPARδ , compound F. THP-1 sub-lines that either over-expressed PPARδ protein, or expressed PPARδ anti-sense RNA were generated. We then explored the effects of these genetic modulations on the differentiation process.ResultsThe PPARδ agonist, compound F, stimulated differentiation in the presence of sub-nanomolar concentrations of phorbol ester. Several markers of differentiation were induced by compound F in a synergistic fashion with phorbol ester, including CD68 and IL8. Over-expression of PPARδ also sensitised THP-1 cells to phorbol ester and correspondingly, inhibition of PPARδ by anti-sense RNA completely abolished this response.ConclusionsThese data collectively demonstrate that PPARδ plays a fundamental role in mediating a subset of cellular effects of phorbol ester and supports observations from mouse knockout models that PPARδ is involved in macrophage-mediated inflammatory responses.

Extended release niacin-laropiprant in patients with hypercholesterolemia or mixed dyslipidemias improves clinical parameters.

The progression of atherosclerosis remains a major cause of morbidity and mortality. Plaque formation is an immunological response driven by a number of risk factors, and reduction of risk is the primary goal of treatment. The role of LDL-C is well established and statins have proved effective drugs, although the relative risk reduction is only around 30%. The importance of other factors—notably low HDL-C and high TGs—has become increasingly clear and the search for alternative strategies continues. Niacin is particularly effective in achieving normalization of HDL-C but is clinically underutilized due to the side effect of cutaneous flushing. The discovery that flushing is mediated by mechanisms distinct from the lipid-lowering effects has led to the development of combination drugs with reduced side effects. This review considers the evidence regarding the clinical efficacy of extended-release niacin and the DP1 antagonist laropiprant in the treatment of hypercholesterolemia and mixed dyslipidemias.

Twelve tips for embedding human factors and ergonomics principles in healthcare education

Abstract Safety and improvement efforts in healthcare education and practice are often limited by inadequate attention to human factors/ergonomics (HFE) principles and methods. Integration of HFE theory and approaches within undergraduate curricula, postgraduate training and healthcare improvement programs will enhance both the performance of care systems (productivity, safety, efficiency, quality) and the well-being (experiences, joy, satisfaction, health and safety) of all the people (patients, staff, visitors) interacting with these systems. Patient safety and quality improvement education/training are embedded to some extent in most curricula, providing a potential conduit to integrate HFE concepts. To support evolving curricula and professional development at all levels – and also challenge prevailing “human factors myths and misunderstandings” – we offer professional guidance as “tips” for educators on fundamental HFE systems and design approaches. The goal is to further enhance the effectiveness of safety and improvement work in frontline healthcare practice.

Lipid Regulation with Niacin Extended-Release (Niaspan-R™)

Recent clinical trial data indicates that while normalizing serum LDL levels remains an important target in reducing adverse cardiovascular outcomes, it is not the whole story. Statins are very effective drugs for reducing LDL, but they are not sufficient to prevent the majority of cardiovascular events. The focus is now shifting towards a combined approach: reducing LDL, but also increasing HDL, low levels of which often persist despite statin treatment. Niacin is the single most effective agent for increasing HDL, but its use has been limited because of tolerability issues affecting compliance. Niaspan-R™ is an extended-release formulation designed to reduce flushing and has been shown clinically to be as effective as immediate-release preparations. There is also a significant body of clinical evidence demonstrating the particular value of Niaspan-R™ when used in combination with existing lipid-lowering therapy. This review will consider this data and discuss the role of Niaspan-R™ in future treatment of mixed dyslipidemias.

Creative ‘Tips’ to Integrate Human Factors/Ergonomics Principles and Methods with Patient Safety and Quality Improvement Clinical Education

The goal of these 12 tips is to enhance the effectiveness of safety and improvement work in frontline healthcare practice by providing a framework for integration of Human Factors and Ergonomics (HFE) theory and approaches within undergraduate curricula, postgraduate training and healthcare improvement programs. This paper offers both support and challenges to healthcare educators when planning the inclusion of HFE principles within existing curricula. The 12 tips include the systems framework (Tip 1, 3), HFE tools and competency (Tips 2, 7), misunderstandings (Tips 4, 5), and ideas for implementation (Tip 6, 8, 9, 10, 11, 12). They will support the goal of enhancing the performance of care systems (productivity, safety, efficiency, quality) and the wellbeing of all the people (patient outcomes, staff presenteeism).

A UK Perspective on Human Factors and Patient Safety Education in Pharmacy Curricula

Objective. To take a systematic approach to exploring patient safety teaching in health care curricula, particularly in relation to how educators ensure students achieve patient safety competencies. Findings. There is a lack of formally articulated patient safety curricula, which means that student learning about safety is largely informal and influenced by the quality and culture of the practice environment. Human Factors and Ergonomics appeared largely absent from curricula. Summary. Despite its absence from health care curricula, Human Factors and Ergonomics approaches offer a vehicle for embedding patient safety teaching. The authors suggest a possible model, with Human Factors and Ergonomics forming the central structure around which the curriculum can be built.Objectives. Avoiding unnecessary harm is increasingly a priority for healthcare organisations and this focus has seen the emergence of patient safety as a distinct discipline. The value of Human Factors and Ergonomics (HFE) approaches in underpinning this safety science is becoming recognised. This shift in professional priorities has been slow to filter into educational curricula, and little is known about how providers support students in developing safety competence. With respect to pharmacy education, this is problematic, given the high occurrence of drug-related adverse events. The aim of this review was to take a systematic approach to exploring patient safety teaching in healthcare curricula. Findings. Key findings included a lack of formally articulated patient safety curricula, which means that student learning about safety is largely informal and influenced by the quality and culture of the practice environment. Human Factors and Ergonomics appeared largely absent from curricula. Summary. Despite its absence from healthcare curricula, Human Factors and Ergonomics approaches offer a vehicle for embedding patient safety teaching. The authors suggest a model for a future curriculum.

The Prevention of Atherothrombotic Events in Adults with Acute Coronary Syndromes

The term acute coronary syndrome is used to describe a range of conditions that share a common underlying pathology of interrupted blood flow and subsequent damage to the myocardium. Acute coronary events are unpredictable and can rapidly become life-threatening, largely as a result of clot formation, and one of the primary treatment aims is to limit thrombosis. Such events are a major cause of hospitalization and death worldwide and thus the impact of advances in thrombocardiology is enormous. Acute coronary syndromes can be difficult to diagnose, and a successful clinical outcome depends on accurate assessment of individual risk which is then used to determine the treatment strategy. Recent advances fall in to two main areas: firstly the improvement in understanding of the clinical markers that allow more accurate risk stratification and, secondly, the development of new anti-thrombotic drugs. This review considers current approaches for the management of acute coronary syndromes, highlighting recent advances.