Current drug targets. Cardiovascular & haematological disorders最新文献

{"title":"A rationale for combined therapy with a calcium channel blocker and a statin: evaluation of basic and clinical evidence.","authors":"R Preston Mason","doi":"10.2174/156800605774962112","DOIUrl":"https://doi.org/10.2174/156800605774962112","url":null,"abstract":"<p><p>Calcium channel blockers and HMG-CoA reductase inhibitors are widely used for the management of hypertension and dyslipidemia, respectively. The use of these agents in the prevention and treatment of cardiovascular disease remains largely based on their actions in lowering blood pressure and lipids. Recent clinical trials, however, indicate that certain members of these two drug classes may slow progression of disease to an extent that cannot be solely attributed to risk factor reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the basis for such effects, along with potential synergies, we will review the basic and clinical evidence that indicate a broader opportunity for treatment and protection of cardiovascular events by atheroprotection with these agents beyond risk factor management.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"489-501"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging pharmacological strategies for the prevention of atherosclerotic disease progression.","authors":"Paul Schoenhagen,&nbsp;Steven E Nissen","doi":"10.2174/156800605774962013","DOIUrl":"https://doi.org/10.2174/156800605774962013","url":null,"abstract":"","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"431-2"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocannabinoid receptor antagonists and other emerging pharma-cological strategies for weight reduction.","authors":"Kishore M Gadde","doi":"10.2174/156800605774962095","DOIUrl":"https://doi.org/10.2174/156800605774962095","url":null,"abstract":"<p><p>Overweight and obesity are recognised as significant risk factors for coronary heart disease (CHD). Weight reduction leads to reduction in associated CHD risk factors. The discovery that endocannabinoid system is involved in regulation of food intake and other reward behaviours has led to development of cannabinoid receptor antagonists. Recent studies with rimonabant, a cannabinoid type 1 receptor (CB(1)) antagonist, demonstrate clinically significant weight loss as well as reduction in metabolic syndromme burden in obese patients.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"549-56"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive atherosclerosis imaging: use to assess response to novel or combination lipid therapies.","authors":"Todd C Villines,&nbsp;Allen J Taylor","doi":"10.2174/156800605774962059","DOIUrl":"https://doi.org/10.2174/156800605774962059","url":null,"abstract":"<p><p>Despite significant protection from cardiovascular events by HMG-CoA reductase inhibitors (statins), the extent of event reduction is incomplete and persistent lipid abnormalities remain prevalent. As such, the use of combination lipid modification regimens is a clinical reality. While we await large, randomized clinical outcomes trials assessing the benefits of combination or novel lipid management therapies, non-invasive imaging tests such as B-mode ultrasound to measure carotid intima-media thickness (CIMT), coronary computed tomography (CT) and cardiovascular magnetic resonance imaging (CMR) are increasingly being utilized to accurately assess the impact of lipid modifying therapies on atherosclerosis. Based on knowledge that atherosclerosis progression is a validated surrogate for increased cardiovascular risk, use of atherosclerosis imaging surrogates in studies allows for smaller sample sizes, shortens study duration, demonstrates clinically meaningful changes prior to clinical event and provides potentially useful pathophysiologic information. CIMT measurement is currently the most studied and validated non-invasive imaging study used to assess atherosclerosis longitudinally in response to lipid modification therapies. Quantification of coronary calcium using coronary CT has been utilized to study atherosclerosis longitudinally, however, calcium scoring to assess response to lipid modifying therapies is not recommended due to several limitations of this assessment of the atherosclerosis process. These include the fact that non-calcified atherosclerosis is not quantified, that the calcification process in atherosclerosis is diverse and that the effects of statins on tissue calcification are complex. Use of contrast coronary CT to image non-calcified coronary atherosclerosis is promising. Modern CMR imaging, aided by high reproducibility and image resolution, is rapidly advancing and early studies imaging non-coronary and coronary atherosclerosis are impressive.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"557-64"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventing atherosclerosis with angiotensin-converting enzyme inhibitors: emphasis on diabetic atherosclerosis.","authors":"T J Allen,&nbsp;K A Jandeleit-Dahm","doi":"10.2174/156800605774962068","DOIUrl":"https://doi.org/10.2174/156800605774962068","url":null,"abstract":"<p><p>The incidence of diabetes is increasing at an alarming rate to the point where it is becoming an epidemic. An ageing population, sedentary lifestyle and an unhealthy diet are considered to have contributed toward this. What we must now consider is not only the burden of the disease but the complications that arise from diabetes, in particular kidney and heart disease. Foremost, more than half of the diabetic population will die from cardiovascular-related causes. Whilst diabetes is most often associated with hypertension, dyslipidaemia and obesity, these factors do not fully account for the increased burden of cardiovascular disease in people with diabetes. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease, and more specifically, diabetes-associated atherosclerosis. In addition to the recognised metabolic abnormalities associated with diabetes, upregulation of putative pathological pathways such as advanced glycation endproducts, renin-angiotensin system, oxidative stress and increased expression of growth factors and cytokines have been observed in the setting of diabetes. All of these have been shown to play a causal role in atherosclerotic plaque formation and thus may explain the increased risk of macrovascular complications in those patients with diabetes. In this review the effect of inhibiting the renin-angiotensin system with angiotensin converting enzyme inhibition and a comparison to angiotensin II receptor antagonism is discussed, with the results of clinical trails reflecting the more recently discovered, non-haemodynamic, proatherogenic actions of angiotensin II. The need for experimental models of diabetes-associated atherosclerosis will be covered, with particular emphasis given to the streptozotocin-diabetic apolipoprotein E knockout mouse. Finally, growth factors, including vascular endothelial growth factor and platelet-derived growth factor are discussed in detail.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"503-12"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis.","authors":"I Gouni-Berthold,&nbsp;W Krone","doi":"10.2174/156800605774962022","DOIUrl":"https://doi.org/10.2174/156800605774962022","url":null,"abstract":"<p><p>The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARs heterodimerize with the retinoid X receptor (RXR) and modulate the function of many target genes. They were originally described as regulators of various metabolic, pathways, but have been recently found to also exert modulating actions in the vascular wall. PPARalpha is activated by endogenous ligands, such as polyunsaturated fatty acids and by synthetic agonists such as the fibrates. PPARalpha is expressed mainly in the liver, kidney and skeletal muscle and is involved in fatty acid oxidation. However, it is also expressed in vascular cells such as the endothelial cells, vascular smooth muscle cells and macrophages, where it exerts anti-inflammatory and antioxidant effects. Since atherosclerosis is both a chronic inflammatory and a lipid disorder and since PPARalpha is expressed in vascular cells and regulates the expression of genes involved in lipid metabolism and inflammation, PPARalpha activators may constitute useful agents for the prevention of atherosclerosis, beyond their effects on lipid metabolism. This review will focus on the functions of PPARalpha on lipid metabolism, on vascular inflammation and its relationship to atherosclerosis. Furthermore, the currently available preclinical and clinical data on PPARalpha activators as well as their future perspectives will be discussed.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"513-23"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver x receptors: potential novel targets in cardiovascular diseases.","authors":"Dennis Bruemmer,&nbsp;Ronald E Law","doi":"10.2174/156800605774961988","DOIUrl":"https://doi.org/10.2174/156800605774961988","url":null,"abstract":"<p><p>The Liver X Receptors, LXRalpha and LXRbeta are members of the nuclear hormone receptor superfamily which have recently been implicated as novel pharmacological targets for the treatment of cardiovascular diseases. The identification of natural and synthetic ligands for LXRs and the generation of LXR-deficient mice have been crucial for our understanding of the function of these receptors and for the identification of LXR-regulated target genes, particularly with respect to the role of LXRs in regulating cholesterol homeostasis. Synthetic LXRalpha/beta agonists induce cholesterol efflux and reverse cholesterol transport, improve glucose metabolism, inhibit macrophage-derived inflammation, and suppress the proliferation of vascular smooth muscle cells. By regulating the expression of multiple genes involved in these pathways, LXR agonists prevent the development and progression of atherosclerosis and inhibit neointima formation following angioplasty of the arterial wall. In this review, we will summarize the important roles of LXR in metabolism and vascular biology and discuss its implications as potential molecular drug target for the treatment of cardiovascular diseases.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"533-40"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774961988","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol absorption blockade with ezetimibe.","authors":"Peter P Toth,&nbsp;Michael H Davidson","doi":"10.2174/156800605774962086","DOIUrl":"https://doi.org/10.2174/156800605774962086","url":null,"abstract":"<p><p>The reduction of circulating atherogenic lipoproteins through lifestyle modification and pharmacologic intervention is an important therapeutic goal in patients at risk for acute cardiovascular events. A large number of clinical trials have demonstrated that the reduction of low-density lipoprotein cholesterol (LDL-C) is associated with significant decreases in the incidence of all cause mortality, stroke, fatal and nonfatal myocardial infarction, and the need for revascularization with coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) are the agents of choice for treating a variety of dyslipidemias, particularly when LDL-C levels are elevated. The statins are highly efficacious; however, not all patients are able to tolerate the higher doses of these medications due to adverse side-effects such as hepatoxicity and myotoxicity. Moreover, many patients cannot achieve their various lipoprotein targets at even the highest doses of these medications. Ezetimibe is a novel cholesterol absorption inhibitor that blocks the translocation of dietary and biliary cholesterol from the gastrointestinal lumen into the intracellular space of jejunal enterocytes. Ezetimibe undergoes enterohepatic recirculation with minimal systemic exposure and not does not adversely impact the pharmacokinetic profile of statins. Ezetimibe significantly reduces serum LDL-C. It is safe when used as monotherapy or when used in combination with statins. Ezetimibe is indicated in the management of hyperlipidemia, familial hypercholesterolemia, and sitosterolemia and significantly increases the percentage of patients able to reach their lipid-lowering goals.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"455-62"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increasing high-density lipoprotein cholesterol through cholesteryl Ester transfer protein inhibition: a next step in the fight against cardiovascular disease?","authors":"W A Van der Steeg,&nbsp;K El-Harchaoui,&nbsp;J A Kuivenhoven,&nbsp;J J P Kastelein","doi":"10.2174/156800605774961997","DOIUrl":"https://doi.org/10.2174/156800605774961997","url":null,"abstract":"<p><p>Over the past decades, lowering of LDL-cholesterol (LDL-c) levels has been established as the foundation for preventing atherosclerotic disease. It is, however, widely accepted that additional risk reduction has to come from modifying other risk factors than LDL-c. In this context, increasing HDL-cholesterol (HDL-c) levels by pharmacological inhibition of the cholesteryl ester transfer protein (CETP) is currently under intense investigation. Two small-molecule compounds, JTT-705 and Torcetrapib, have been shown to effectively increase HDL-c levels in humans, without inducing clinically significant side effects when used as monotherapy or combined with statins. Whether this approach will translate into a reduction in risk of atherosclerotic disease has not yet been established. Data from studies focusing on genetic CETP deficiency as well as those studying the relationship between CETP plasma levels and risk of atherosclerosis do not provide clear answers. Several long-term clinical studies addressing this crucial issue have recently been initiated, results of which will follow within the next few years. This review focuses on CETP, its role in human lipid metabolism and its relation to atherosclerotic disease. Furthermore, it summarizes the currently available data regarding pharmacological CETP inhibition. Finally, it will highlight a number of issues basic to the considerations of whether CETP inhibition will fulfill its promises.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"481-8"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774961997","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ApoA-I Milano/phospholipid complexes emerging pharmacological strategies and medications for the prevention of atherosclerotic plaque progression.","authors":"Sanjay Kaul,&nbsp;Prediman K Shah","doi":"10.2174/156800605774962004","DOIUrl":"https://doi.org/10.2174/156800605774962004","url":null,"abstract":"<p><p>Epidemiologic and experimental observations suggest high density lipoprotein (HDL) has a protective effect against atherothrombotic vascular disease. These findings have stimulated considerable interest to promote HDL as a potential therapeutic strategy. Several exciting therapeutic strategies have recently emerged and currently are the focus of intense research interest. One approach is the direct administration of HDL or its components such as apolipoprotein A-I (apoA-I). Recently, much attention has focused on a naturally occurring variant of apoA-I, apoA-I(Milano) (apoA-IM) characterized by a cysteine for arginine substitution that is associated with low rates of vascular disease and significant longevity in its carriers, despite markedly reduced HDL and elevated triglyceride levels. The mutation alters the characteristics of the protein resulting in apoA-IM being functionally more effective than normal apoA-I. A number of animal and laboratory studies have demonstrated significant antiatherogenic, antiproliferative, antirestenotic, antiplatelet, antithrombotic, antiinflammatory, and antioxidant properties of apoA-IM. Furthermore, apoA-IM has been shown to promote reverse cholesterol transport, improve endothelial dysfunction and induce rapid mobilization of tissue cholesterol resulting in regression and alteration of plaque composition in animal models of atherosclerosis. Recently, a pilot clinical trial of recombinant apoA-IM demonstrated significant and rapid regression of atherosclerosis as measured by intravascular ultrasound in patients with acute coronary syndromes. These promising data provide the rationale for the development of reconstituted HDL utilizing recombinant apoA-IM as a potential therapeutic approach for atherothrombotic vascular disease in humans.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 6","pages":"471-9"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774962004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25877639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}