Current Pharmaceutical Design - Volume 13, Issue 26, 2007

Atherosclerosis is the leading cause of death in the Western world and anti-thrombotic therapy plays a key role in the management of this disease. However, despite the importance of platelets in the disease process there has been little progress in developing novel anti-thrombotic agents. Current anti-thrombotic therapy revolves around aspirin, a drug that has been around for thousands of years. More recently GPIIb/IIIa a Read More

The platelet releasate comprises of a multitude of inflammatory and vasoactive substances, which can attract atherogenic leukocytes from the circulation, activate endothelial cells and stimulate vessel growth and repair by triggering vascular cell proliferation, migration, and inflammation. Thus, platelets are believed central in the development and progression of atherosclerotic lesions and recent progress in uncovering mo Read More

Platelets are the principle effectors of cellular haemostasis and key mediators in the pathogenesis of thrombosis. A variety of membrane receptors determine platelet reactivity with numerous agonists and adhesive proteins, and therefore represent key targets for the development of antiplatelet drug therapy. Here, we summarise recent advances in the analysis of the complex platelet membrane system achieved thro Read More

GAS6, the product of growth arrest specific (GAS) gene 6 is a ligand for the tyrosine protein kinase receptors Axl, Tyro3 and Mer whose signaling has been implicated in cell growth, survival, adhesion and migration. Although a secreted human vitamin Kdependent protein with close structural similarity with protein S, GAS6 does not exhibit anticoagulant properties but rather may be an important regulator of vascular homeosta Read More

Recent studies of the platelet transcriptome have shown it to be complex and readily analysed by modern techniques. Among the thousands of distinct transcripts are many not previously described in platelets. Differences in message abundance between groups are apparent, and these are reflected at the protein level. Platelets are enriched in messages for receptors, signal transduction proteins and cytokines. Categories of Read More

Although somewhat controversial, there is good evidence that long-distance travel in general is a risk factor for venous thromboembolism, even in the absence of other risk factors. This is probably due to effects consequent to prolonged sitting but air travel in particular may be associated with risk factors other than this. One likely factor is hypoxia caused by the low ambient pressure of aircraft cabins. There is an association be Read More

Platelets have important roles in atherosclerosis and thrombosis and their inhibition reduces the risk of these disorders. There is still a need for platelet inhibitors affecting pathways that reduce thrombosis and atherosclerosis while leaving normal hemostasis relatively unaffected, thus reducing possible bleeding complications. Although combinations show progress in achieving these goals none of the present inhibitors c Read More

The platelet receptor glycoprotein (GP)Ib-IX-V complex plays a dominant role in the first steps of platelet adhesion and arterial thrombus formation. Through its interaction with the multimeric plasma protein von Willebrand factor (VWF), which is bound to the damaged subendothelial structures, GPIb-IX-V tethers the platelets from the flowing blood thereby slowing them down. This step is a prerequisite for the collagen receptors t Read More

This issue of Current Pharmaceutical Design, for which I have the great pleasure to be Executive Guest Editor, addresses topical issues relating to the pathogenesis and treatment of diabetic complications, retinopathy, nephropathy and cardiomyopathy. Fletcher et al. [1] describes neuronal and glial cell dysfunction in diabetic retinopathy, and how these changes relate to vascular compromise. Marshall [2] discusses the importan Read More

Diabetes is known to cause significant alterations in the retinal vasculature. Indeed, diabetic retinopathy is the leading cause of blindness in those of working age. Considerable evidence is emerging that indicates that retinal neurons are also altered during diabetes. Moreover, many types of neuronal deficits have been observed in animal models and patients prior to the onset of vascular compromise. Such clinical tools as the Read More

Over the last five years, much work has underlined the important role of the podocyte in the development of diabetic nephropathy. The metabolic and haemodynamic abnormalities of the diabetic milieu act in concert, perhaps via the common effector path of oxidative stress and development of reactive oxygen species, to promote podocyte damage. There is loss of nephrin from the slit diaphragm, increased synthesis of some Read More

The prevalence of diabetes has reached epidemic proportions in the developed world and is expect to increase to 5.4% by 2025. This has resulted in an unprecedented number of patients experiencing the macro- and micro-vascular complications of diabetes, such as renal, retinal, neurological and cardiac dysfunction. Premature coronary artery disease and cardiac failure are vastly overrepresented in the diabetic population, w Read More

Angiotensin converting enzyme (ACE) is a key enzyme in the renin angiotensin system (RAS) and converts angiotensin (Ang) I to the vasoconstrictor Ang II, which is thought to be responsible for most of the physiological and pathophysiological effects of the RAS. This classical view of the RAS was challenged with the discovery of the enzyme, ACE2 which both degrades Ang II and leads to formation of the vasodilatory and anti-prolif Read More

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors affecting the regulation of various genes relevant to the pathogenesis of diabetic complications. A number of drugs have been developed to act as agonists of the three PPARs. To date, PPAR isoforms that have been identified are the α, β/δ, and γ isosforms. Fenofibrate and gemfibrozil are two drugs that act as PPARα agonists and are Read More