Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 10, Issue 2, 2012

The following paper is an overview on stem cells therapy in patients with peripheral vascular diseases. Recent research shows the ability of stem cells to develop and strengthen the collateral network in ischemic legs. Here, we discuss this clinical and therapeutic approach. To date, research has been mainly focused on patients with ischemic ulcers without possibility of revascularization. Non-invasive stem cell therapy has been proposed as an alternative to the amputation of such patients, but when the ulcers appear it is sometime too late. In our point of view, the selection of patients is a very important issue and we believe that the best candidate for this treatment is the patient with intermittent claudication before the development of ulcers. This choice could allow the optimization of results by the type of treated patients and not only by the type of infused cells. Indeed, several variables still remain to be elucidated for stem cell therapy, including the type of cells to be used, the infusion route, and more importantly, the stage of patients to be treated.

Depression is a common co-morbidity in patients with cardiovascular diseases such as chronic coronary artery disease, acute coronary syndromes, post by-pass surgery and chronic heart failure. The presence of depression is independently associated with a decline in health status and an increase in the risk of hospitalization and death for patients with coronary artery disease or congestive heart failure. Novel treatment modalities such as selective serotonin re-uptake inhibitors (SSRIs) may improve depressive symptoms and prognosis of post-myocardial infarction and heart failure patients interacting with the common pathophysiological mechanisms of depression and cardiovascular disease. This review summarizes current experimental and clinical evidence regarding the effects of SSRIs on platelet functions, immune and neurohormonal activation, and cardiac rhythm disturbances in patients with cardiovascular disease.

For the last 60 years warfarin has been the cornerstone for chronic anticoagulation in prevention of ischemic strokes and systemic embolization. Warfarin therapy has several limitations including frequent monitoring and various food and significant drug interactions, which make it a less than ideal chronic oral anticoagulant. The continued search for safe, effective, medications with predictable pharmacokinetic profiles has led to newer alternatives. Dabigatran is a potent reversible, competitive direct thrombin inhibitor which is available as the prodrug, Dabigatran etexilate. It was first approved in Europe and recently in October 2010, the US food and drug administration (FDA) has approved the use of this novel oral anticoagulation for prevention of stroke in those with non valvular atrial fibrillation. This review will cover the chemical structure, mechanism of action, pharmacokinetic profile, clinical trials, dosage, clinical implication and adverse effects of dabigatran.

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

Background: Organ dysfunctions and medical complications, such as renal failure, liver impairment, coagulation disorders, cardiovascular and respiratory illnesses, may hamper an adequate pain management in haematological patients. Aim: To summarize current knowledge on pain management in hematological patients presenting major organ dysfunctions and comorbidity. We also attempted to provide recommendations to optimize analgesia and to minimize side effects in the setting of medically compromised and frail haematological patients. Methods: A systematic search of the literature, using relevant key words, was conducted in PubMed. Results and conclusions: Pain in hematological patients is a common symptom and is often multi-factorial. Most pharmacotherapeutic measures, including causal therapies, analgesics and adjuvant agents routinely applied in pain management, may also be used in the setting of clinical frailty and medical comorbidities; however, comprehensive clinical and functional patient’s evaluations and a careful consideration of expected benefits and potential adverse events are required.

Aim: The aim of the present study was to investigate by serial echocardiography and dosage of NT-pro-BNP, whether, in previously healthy subjects, long term therapy with clozapine may lead to subclinical cardiac toxicity. Methods and Results: 38 patients (24 males, 14 females, mean age 38.4 years) suffering from a severe personality disorder were enrolled. At inclusion duration of clozapine treatment averaged 66 months at a mean daily dose of 296 mg. Clinical evaluation, NT-pro-BNP dosage and echocardiography were performed at baseline, 3 and 12 months. At first visit 15 patients showed depression of left ventricular function (12 had LVEF between 50 and 55%, 2<50% and 1<30%). Biventricular dysfunction was observed in 10. NT-pro-BNP showed a significant inverse relation with LVEF (r2= -0.4619, p <0.0001). At 1 year the whole group did not show significant changes in clinical, ECG and echocardiographic measurement, however a LVEF decrease > 5% was found in 33% of patients with baseline normal LVEF while LVEF remained below 55% in 70% of group B patients. LVEF and NT-pro-BNP values were still significantly different in the two groups at the term of follow-up. Conclusions: subclinical heart dysfunction, frequently biventricular, occurs in 1/3 of young, previously healthy, clozapine treated patients. NT-pro-BNP values relate inversely with LVEF. At 1 year follow –up a LVEF decrease >5% occurred in 1/3 of patients with baseline normal left ventricular function.

The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide (LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg) prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced the elevated plasma 6-keto PGF1α levels in LPS treated rats, suggesting that PF-04886847 could be useful in preventing hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-α level. Pretreatment of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein (the zymogen form of plasma kallikrein) deficient patients have prolonged activated partial thromboplastin time (aPTT) without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847 was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events, PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both aPTT and prothrombin time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin mediated diseases.

The microvascular bed is an anatomical entity which comprises myriads of small arterioles, capillaries and venules. Microvessels and surrounding tissue metabolism are tightly coupled; consequently they are equipped with many, very specific and fine-tuned mechanisms allowing permanent, precise regulation of nutrient delivery. The review thoroughly describes the structure and physiology of arterioles and capillaries as well as the specialized means to investigate them. Microcirculation has been largely neglected for decades, mainly because of lack of technical possibilities for visualization and quantitation. However the past years have completely renewed the scientific interest, due to the combination of the availability of new techniques in human research and the recognition that the microcirculation is autonomically and causally involved in diseases previously thought to be essentially a question of macrocirculation. Today we start to see that microangiopathy is not only a consequence of large vessel diseases but can be the source of many pathologies in both cardiovascular and metabolic disorders, the best example –developed here- being the cardiometabolic syndrome or prediabetes. With very few exceptions, pentoxifylline and the antidiabetic metformin, no specific treatments have been developed for treating disorders at the microcirculatory level. Metformin has unique, intrinsic actions specifically at the level of terminal arterioles, which are completely independent of its antidiabetic effect. Other drugs are shortly described which have revealed a potential interest in this field. Our review aims at showing that microcirculation is entering a new era, starting with rapidly increasing knowledge of its intimate functioning and worth specific pharmacological developments.