Cardiovascular & Haematological Disorders - Drug Targets - Volume 10, Issue 1, 2010

Acute promyelocytic leukemia (APL) is frequently associated, often from the earliest phases, with a lifethreatening coagulation/bleeding syndrome; disseminated intravascular coagulation (DIC) is described in majority of patients. We report a case of 49-year-old male, without cardiovascular risk factors, who suddenly developed ischemic stroke and splenic infarction as presenting symptoms of APL and related DIC. The patient was immediately treated with all-trans retinoic acid (ATRA) and the alterations of hemocoagulation parameters promptly returned in normal range. The coagulation/ bleeding syndrome of the onset of APL is associated with high mortality; both diagnostic and therapeutic approaches require special and timely consideration of this condition. Treatment with ATRA is essential.

Advanced glycation end-products (AGEs) are involved in mediating the effects of hyperglycaemia in diabetes. The most important receptor for AGEs is the receptor for advanced glycation end-products (RAGE). Binding of AGEs to RAGE converts transient cellular stimulation into sustained cellular dysfunction driven by long-term activation of the proinflammatory transcription factor NF-kB. Different splice variants of RAGE exist, including a soluble form that binds to AGEs but lacks the intracellular domain and thus fails to induce signal transduction. In this context, soluble RAGE may act as a therapeutic agent for AGE-induced effects. The balance between the synthesis of sRAGE and full-length RAGE may be an important determinant of AGE-induced dysfunction. An increasing amount of evidence suggests that AGEs either directly or via their interaction with RAGE play a pivotal role in the development and acceleration of atherosclerotic cardiovascular disease. These effects will be summarised in this review, together with the effects of therapeutic strategies targeting AGE/RAGE interactions. These treatments appear to have significant clinical potential, most likely in combination with currently used agents such as inhibitors of the renin-angiotensin system or statins, to reduce the major burden of diabetes, its associated cardiovascular disease.

The endothelium entered the field of regenerative medicine with the discovery of endothelial progenitor cells (EPCs). These cells participate in endothelial homeostasis and are actively involved in physiological and pathological neovascularization. Despite the unresolved discussion about the very phenotype of these cells, great efforts have been devoted to study the role of EPCs in cardiovascular diseases. EPCs are very rare in peripheral circulation and are further reduced in association with cardiovascular diseases. Therefore, finding therapies to improve EPCs could unleash the way to promising cell-based therapies. Ex-vivo expansion of EPCs is a critical step to augment EPCs number, but it still needs several improvements. An alternative strategy to partially overcome these limitations is to target EPCs with available drugs. In this review we will discuss how disparate pharmacological compounds have been used to improve EPCs number and functions.

Normal pregnancy is associated with significant hemodynamic changes and vasodilation in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Hypertension in pregnancy (HTN-Preg) and preeclampsia (PE) are major complications and life-threatening conditions to both the mother and fetus. PE is precipitated by various genetic, dietary and environmental factors. Although the initiating events of PE are unclear, inadequate invasion of cytotrophoblasts into the uterine artery is thought to reduce uteroplacental perfusion pressure and lead to placental ischemia/hypoxia. Placental hypoxia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II receptor. These bioactive factors affect the production/activity of various vascular mediators in the endothelium, smooth muscle and extracellular matrix, leading to severe vasoconstriction and HTN. As an endothelial cell disorder, PE is associated with decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin, angiotensin II and thromboxane A2. PE also involves enhanced mechanisms of vascular smooth muscle contraction including intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Changes in extracellular matrix composition and matrix metalloproteases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Characterization of the predisposing risk factors, the biologically active factors, and the vascular mediators associated with PE holds the promise for early detection, and should help design specific genetic and pharmacological tools for the management of the vascular dysfunction associated with HTN-Preg.

The popular over-the counter analgesic drug diclofenac has recently been associated with increased rates of myocardial infarction among patients with cardiovascular risk as well as among healthy populations. Although other traditional non-steroidal anti-inflammatory drugs (tNSAID) have also been accused to exert this risk, literature data at present gives reason to believe that the hazard of myocardial infarction is mainly associated with diclofenac. Large retrospective analyses of clinical data have repeatedly shown that diclofenac, similar as some selective COX-2 inhibitors, increases the propensity to experience adverse cardiovascular and atherothrombotic events. These associations cannot be explained with the deteriorating effect of NSAID on arterial hypertension, as the statistical associations only have been found conclusively for diclofenac and not for other tNSAID. The reasons for this novel side-effect of diclofenac may be based on the specific pharmacology of diclofenac, which, similar to selective COX-2 inhibitors, alters vascular levels of platelet active prostaglandins in a way that favours arterial thrombosis. In this review, we summarize the clinical evidence about adverse atherothrombotic events associated with diclofenac and dissect the pharmacological reasons beyond this phenomenon in comparison to other tNSAID.

The European Medicines Agency (EMEA) recently issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors (PPIs) and recommended that the product information for all medicines containing clopidogrel be amended to discourage concomitant use of PPIs unless absolutely necessary. This follows a prior alert issued by the United States Food and Drug Administration (FDA) earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel. However, several experts have voiced their concern that the clopidogrel-PPI interaction has been given undue importance, given that all clinical studies suggesting this problem are observational. In this review, we critically analyze the available data and make practical suggestions for the clinician regarding appropriate use of PPIs in patients receiving clopidogrel. Based on currently available evidence, we suggest that the decision to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis balancing the gastrointestinal risk with the possible thrombotic risk and that PPIs should only be used for truly appropriate indications.

Amiodarone, an iodinated benzofuran derivative, introduced in 1960's as an anti-anginal agent, emerged as a potent anti-arrhythmic agent by 1970's and is currently one of the most commonly prescribed drugs in US for ventricular and atrial arrhythmias. Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent. Because of its minimal negative inotropic activity and very low rate of pro-arrhythmia, it is considered safe in treating arrhythmias in patients with Coronary Artery Disease and Left ventricular systolic dysfunction. Despite these advantages, long-term oral therapy with amiodarone is limited by side effect profile involving various organs like thyroid, lung, heart, liver, skin etc. Though the side effects can be decreased significantly, by keeping the maintenance dose at 200 to 300 mg/day, patients on amiodarone should be followed closely. Amiodarone interacts with medications such as Warfarin, Digoxin, Macrolides, Floroquinolones etc., which share Cytochrome P450 metabolic pathway. Hence reducing their doses prior to starting amiodarone is recommended. Amiodarone, a category D drug, is contraindicated in pregnant and breast feeding women. This review discusses the pharmacokinetics of amiodarone, its evolving clinical indications, management of toxicity and drug interactions.