Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 7, Issue 4, 2009

Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women and there are few treatment options. FSD is more typical as women age and is a progressive and widespread condition. Common symptoms associated with FSD include diminished vaginal lubrication, pain and discomfort upon intercourse, decreased sense of arousal and difficulty in achieving orgasm. Only a small percentage of women seek medical attention. In comparison to the overwhelming research and treatment for erectile dysfunction in males, specifically with the development of phosphodiesterase type 5 inhibitors, significantly less has been explored regarding FSD and treatment is primarily limited to psychological therapy. Several cardiovascular diseases have been linked with FSD including atherosclerosis, peripheral arterial disease and hypertension, all of which are also pathological conditions associated with aging and erectile dysfunction in men. Using animal models, we have expanded our understanding of FSD, however a tremendous amount is still to be learned in order to properly treat women suffering from FSD. The aim of this review is to provide the most current knowledge on FSD, advances in basic science addressing this dysfunction, and explore developing therapeutic options.

Cardiac troponin represents a sensitive and specific marker of ischemic myocardial damage in adult and neonatal populations. Cardiac function in neonates could be influenced by the severity of respiratory distress and its ventilatory management. This short review summarizes the experimental and clinical evidence regarding the role of cardiac troponin in assessment of cardiac function, in following findings: neonatal intensive care, respiratory distress syndrome, asphyxia, congenital heart disease and post cardiac surgery.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA are best known for their lipid-lowering effects but they also possess immunomodulatory properties that are, at least in part, independent of changes in serum cholesterol. Some recent clinical trials (eg. PROVE-IT) have shown that statins exert beneficial cardiovascular effects independently of the resultant level of LDL cholesterol. These “pleiotropic” effects seem to be due to inhibition of prenylation of several proteins such as the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins are able to modulate immune responses by modulating cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Over the past decade, a large number of studies reported a prominent role of inflammation and immune response in atherosclerosis, thus, the ability of statins to modulate immune-inflammatory processes could explain their cardiovascular beneficial effects beyond lipid-lowering effects. Moreover, various studies demonstrated beneficial effects of statins in inflammatory and auto-immune diseases, such as rheumatoid arthritis, multiple sclerosis, and others. The purpose of this review is to summarize clinical and experimental evidence of immunomodulatory properties of these drugs, highlighting their clinical and, thus, therapeutic implications.

Atherosclerotic cardiovascular disease is a major health problem worldwide. This article reviews studies clarifying the effects of gene-activating agents on the atherosclerotic vascular process, the occurrence of fatal and nonfatal atherosclerotic disease, and all-cause mortality. Studies originating in the 1970s linked drug-caused gene induction and high protein and cytochrome P450 concentrations in the liver with high apolipoprotein AI (apo AI) and HDL cholesterol (HDL-C) and reduced LDL cholesterol (LDL-C) levels in plasma and presented the view that the inducers, geneactivators, have beneficial exploitable effects against atherosclerosis. The following studies have shown that P450- enzymes respond to cholesterol accumulation and act in maintaining cholesterol homeostasis and that gene-activators act against the atherosclerotic process. The compounds include drugs indicated for dyslipidemias, such as statins, fibrates, niacin and cholestyramine, as well as compounds used for other purposes, including calcium channel blockers, angiotensin receptor blockers and glitazones. The compounds generate signaling mediators such as oxysterols and eicosanoids. The gene-activators upregulate, via the activation of nuclear receptors, genes encoding proteins such as apo AI and ATP-binding cassette (ABC) A1 transporters that efflux cellular cholesterol, transport it to the liver and excrete it into bile, and prevent cholesterol absorption in the intestine. Several statins, niacin, cholestyramine, calcium channel blockers, angiotensin receptor blockers, pioglitazone and etidronate regress atherosclerosis in coronary and /or carotid arteries. Other compounds, including fibrates, phenobarbital and alcohol also have positive antiatherogenic effects. Several gene-activators reduce mortality and / or morbidity from coronary heart disease and cerebrovascular disease, and also death from any cause.

Background: in the management of hematological malignancies, chemotherapy-induced mucositis is an increasingly recognized problem, leading to potentially severe clinical complications, treatment delays, increased costs and impairment of patient's quality of life. Many forms of cytotoxic treatments given in this setting may induce several degrees of mucositis. In particular, conditioning therapy with hematopoietic stem cell transplantation (HSCT) induces a disruption of the mucosal barrier function throughout the entire gastrointestinal tract facilitating the spreading of bacteria and endotoxin with subsequent increased risk of septicemia and, in the allogeneic setting, a worsening of Graft Versus Host Disease (GVHD). Objectives: to review the role of palifermin and of other existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology in the setting of hematological malignancies. Methods: we searched for palifermin and mucositis of any region of the gastrointestinal tract using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. Results/Conclusions: The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are highly required. In this regard, palifermin (recombinant human keratinocyte growth factor) has been demonstrated to reduce the severity and the duration of oral mucositis and to significantly improve several treatment outcomes in patients submitted to autologous HSCT; data are insufficient to recommend its use in the non-autologous HSCT settings, although interesting properties of this agent deserves other investigations in order to explore other possible indications.

Peripheral arterial occlusive disease (PAOD) of lower extremities is becoming more prevalent worldwide. The general prognosis is particularly negative with a high prevalence of coronary heart disease and cerebrovascular disease. Diabetic foot ulcers occur in 15% of all the patients with diabetes and proceed to lower-leg amputations. In diabetic ulcers, wound healing is impaired because of delayed angiogenesis. In both pathological conditions, therapeutic angiogenesis using angiogenic growth factors, particularly Vascular Endothelial Growth Factor VEGF, is expected to be a valuable treatment. The most used approaches are based on VEGF local delivery or gene therapy, but they failed to meet the expected primary goals of therapy. Adenosine receptor stimulation can induce VEGF expression in many types of cells and this may be achieved by stimulating the A2A or A2B receptor or both, following the signalling pathways activated by hypoxia. Polideoxyribonucleotide (PDRN) is obtained from sperm trout by an extraction process. The compounds hold a mixture of deoxyribonucleotides polymers with chain lengths ranging between 50 and 2000 bp. PDRN is able to stimulate VEGF production during pathological conditions of low tissue perfusion. It likely acts through the stimulation of A2A receptors. Furthermore, acute and chronic toxicity studies showed a good safety profile. PDRN has been shown to be effective in an experimental model of PAOD, hind limb ischemia, impaired wound healing and burn injury. Preliminary studies and ongoing clinical trials predict a significant therapeutic efficacy in patients. These data lead to hypothesize a role for PDRN in therapeutic angiogenesis.

Rho-kinase (ROCK) is one of the effectors of the small GTP-binding protein Rho. Accumulating evidence suggests that the Rho/ROCK system may play an important role in the pathogenesis of atherosclerosis and coronary vasospasm via its action in vascular smooth muscle cell contraction, endothelial function and the inflammatory process. Recent observations suggest that the beneficial cardiovascular effects of statins may, at least in part, derive from the inhibition of ROCKs. Fasudil is a ROCKs inhibitor which has potential benefits in coronary artery spasm and myocardial ischemia. In this review, we aim to describe the current understanding of ROCKs signaling and their roles in the pathophysiology of atherosclerosis and coronary spasm.