Current drug targets. Cardiovascular & haematological disorders最新文献

{"title":"An old drug with a new purpose: cardiovascular actions of acetaminophen (paracetamol).","authors":"Norell M Spiler,&nbsp;Tyler H Rork,&nbsp;Gary F Merrill","doi":"10.2174/156800605774370335","DOIUrl":"https://doi.org/10.2174/156800605774370335","url":null,"abstract":"<p><p>For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer cardioprotection by blocking the effects of hydroxyl radical, peroxynitrite, and hydrogen peroxide. The drug might inhibit cyclooxygenase, although its ultimate target(s) is (are) still unclear. Sadly, since most investigations of acetaminophen have focused on its analgesic/antipyretic properties and hepatotoxicity, the effects of the drug on other mammalian organ systems, including the heart and circulation, have been ignored. Recently, work in our laboratory has shown acetaminophen to have a protective role in the injured mammalian myocardium. The cardioprotection was first observed in isolated, perfused guinea pig hearts subjected to ischemia-reperfusion injury. Hearts pretreated with acetaminophen recovered greater ventricular function and exhibited improved myofibrillar ultrastructure when compared to vehicle-treated hearts. More recent in vitro investigations have suggested protective roles for acetaminophen in barbiturate-induced arrhythmogenesis and myocardial hypoxia-reoxygenation injury. We have also extended our work to the in vivo arena. There, we found that acetaminophen reduced infarct size in dogs exposed to 60 minutes regional myocardial ischemia and 180 minutes reperfusion. We invite and encourage readers of this review to repeat/duplicate our experiments. Such work is needed to either challenge or support our findings. Further, more clinically-relevant work depends on these basic and related translational experiments.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 5","pages":"419-29"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800605774370335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25658227","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":"Endothelial progenitor cells as potential drug targets.","authors":"T Thum,&nbsp;J Bauersachs","doi":"10.2174/1568006054553435","DOIUrl":"https://doi.org/10.2174/1568006054553435","url":null,"abstract":"<p><p>Endothelial progenitor cells (EPC) are bone marrow derived cells with the potential to differentiate into mature functional endothelial cells. First clinical trials have been performed investigating the effects of EPC transplantation into cardiac ischemic areas after myocardial infarction, in patients with peripheral atherovascular disease or on endothelialisation of artificial heart valves. Next to EPC transplantation, the pharmacological mobilisation and functional modification of EPC may also play a major role in future therapies. Studies have raised the concern that patients with coronary heart disease or severe heart failure may suffer from decreased amounts and impaired function of peripheral circulating EPC. Drug induced mobilization of EPC and normalization of EPC function may therefore improve prognosis of certain cardiovascular diseases. The underlying molecular events of a disturbed mobilisation, differentiation, homing and/or function of EPC are not well understood. In the present review we will highlight the current knowledge of the role of EPC dysfunction in various cardiovascular diseases and focus on potential causally related molecular mechanisms, which might be novel drug targets.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"277-86"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553435","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248454","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":"Endothelin receptor antagonists: another potential alternative for cardiovascular diseases.","authors":"Rita C A Tostes,&nbsp;Marcelo N Muscará","doi":"10.2174/1568006054553390","DOIUrl":"https://doi.org/10.2174/1568006054553390","url":null,"abstract":"<p><p>Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. The development of a range of peptidic and nonpeptidic ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular therapeutics. Endothelin antagonists improve endothelium-dependent relaxation and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis; interestingly, these beneficial effects seem to occur independently of their capacity to lower blood pressure. The comparison between selective ETA and combined ETA/ETB antagonists in experimental models of cardiovascular diseases reveals no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA receptor blockade leads to the prevention of vascular hypertrophy and renal function improvement, being likely that these effects are also mediated by ETB receptors based on the fact that the concomitant blockade of ETB receptors prevents the beneficial effects of ETA antagonists. As a whole, the available data indicate that the use of ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damage; however, the comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent target organ injuries in humans still remains to be investigated.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"287-301"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248455","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":"Monocyte cyclooxygenase-2 activity: a new therapeutic target for atherosclerosis?","authors":"J A Páramo,&nbsp;J A Rodríguez,&nbsp;O Beloqui,&nbsp;J Orbe","doi":"10.2174/1568006054553381","DOIUrl":"https://doi.org/10.2174/1568006054553381","url":null,"abstract":"<p><p>It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases of leukocyte recruitment to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. COX-2 has been detected in macrophages, smooth muscle cells and endothelial cells in human atherosclerotic lesions. Several studies have also reported the presence of COX-2 in the shoulder region of atherosclerotic plaques, mainly colocalizing with macrophages and MMPs, enzymes that are involved in the destabilization of atherosclerotic plaques, leading to rupture and atherothrombotic syndromes (i.e. acute myocardial infarction). We have recently assessed monocyte COX-2 activity and the production of PGE(2) in a population of apparently healthy subjects free from clinically overt atherosclerosis. We found an association between increased PGE(2) and increasing number of cardiovascular risk factors and carotid intima-media thickness, a noninvasive surrogate marker of atherosclerosis, independently of traditional and non traditional cardiovascular risk factors. Our findings support the notion that the COX-2/PGE(2)axis may have a role in atherosclerosis, and this might be an attractive therapeutic target. COX-2 inhibitors, collectively called coxibs (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise of improved treatment of arthritis without the gastrointestinal side effects associated with aspirin and other nonsteroidal anti-inflammatory drugs. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk. Only well designed large scale clinical trials can provide the answer as to the net effect of selective COX-2 inhibition on cardiovascular events before this new class of anti-inflammatory drugs can be incorporated into the armamentarium of atherosclerosis.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"303-11"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248456","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":"Reviewing the cardiovascular complications of HIV infection after the introduction of highly active antiretroviral therapy.","authors":"G Barbaro","doi":"10.2174/1568006054553444","DOIUrl":"https://doi.org/10.2174/1568006054553444","url":null,"abstract":"<p><p>Studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac disease.The introduction of HAART regimens, by preventing opportunistic infections and reducing the incidence of myocarditis, has reduced the prevalence of HIV-associated cardiomyopathy of about 30% and the prevalence of cardiac involvement of AIDS-associated malignancies of about 50%. However, HAART regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease (approximately 1.4 cardiac events per 1000 years of therapy according to the Framingham score). A careful stratification of the cardiovascular risk and cardiovascular monitoring of patients under HAART according to the most recent clinical guidelines is needed.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"337-43"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248459","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":"Drug eluting stents in interventional cardiology -- current evidence and emerging uses.","authors":"N Swanson,&nbsp;A H Gershlick","doi":"10.2174/1568006054553426","DOIUrl":"https://doi.org/10.2174/1568006054553426","url":null,"abstract":"<p><p>Intervention in coronary artery disease is an area of cardiology where novel drugs, in the form of drug-eluting stents (DES), are being used increasingly commonly. DES are used across the whole range of coronary intervention, from stable angina patients with single or multivessel disease, acute coronary syndromes and acute myocardial infarction (i.e. primary angioplasty). Most recently, they are being tested in a particularly challenging subset of patients, those experiencing symptoms due to restenosis within a previously stented area of vessel (in-stent restenosis, ISR). This article summarises the rationale for the use of DES, across all these areas, focussing specifically on the emerging results of trials and registries examining the effectiveness of DES in acute myocardial infarction (AMI) and ISR. Drug-eluting stents represent a significant shift in the use of locally-delivered drugs in interventional cardiology. On the basis of encouraging trial data, including in the specific areas of in-stent restenosis and myocardial infarction, their use is becoming extremely widespread in place of bare-metal (drug-free) stents. This change is happening despite their high costs, relatively short follow-up data and concerns of possible unwanted effects, because of the weight of evidence that they are superior in preventing restenosis in many patient groups. This reduction is highly significant in angiographic terms and, to a lesser degree, in the prevention of clinically important restenosis requiring revascularisation, but not clearly in terms of overall mortality.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"313-21"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553426","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248457","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":"Imaging of visceral adipose tissue: an emerging diagnostic tool and therapeutic target.","authors":"G Iacobellis","doi":"10.2174/1568006054553408","DOIUrl":"https://doi.org/10.2174/1568006054553408","url":null,"abstract":"<p><p>Several lines of evidence support the contention that excess visceral fat plays a significant role in the development of an unfavourable metabolic and cardiovascular risk profile. Hence, estimation of visceral adipose tissue (VAT), that is, the fat surrounding the internal organs, might be important for cardiovascular risk stratification. Classically, anthropometric measures have been employed to assess body fat distribution for risk assessment. But more recently, imaging methods for visceral fat quantitation have become a focus of attention particularly in a clinical research setting. Several imaging methods have evolved for estimation of VAT mass. Among these, magnetic resonance imaging (MRI) is fairly well established, but ultrasound and magnetic resonance spectroscopy (MRS) are also emerging as useful methods for quantitation of VAT and fat tissue content in vivo. Ultrasound is the most cost-effective and a convenient imaging tool whereas MRS is still in its infancy but it is highly promising because of its high sensitivity and specificity. There is a compelling need to quantify VAT not only for diagnostic purposes, but also for therapeutic interventions with weight reduction drugs or pharmaceuticals targeted to with adipose tissue. For example, changes in regional fat distribution can be used to estimate drugs effectiveness and their mechanism of action. Therefore, in this review I shall present briefly latest and main imaging techniques to detect the visceral adiposity, including the new ultrasound measurements of different visceral adipose tissue compartments. Some visceral adipose tissues which are not traditionally assessed, such as intraperitoneal, mediastinal and the relatively small depots, such as epicardial adipose tissue have also been recently studied and are now proposed as new markers of visceral adiposity.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"345-53"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553408","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25249550","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":"The Na(+)/H(+) exchanger: a target for cardiac therapeutic intervention.","authors":"M Karmazyn,&nbsp;M Sawyer,&nbsp;L Fliegel","doi":"10.2174/1568006054553417","DOIUrl":"https://doi.org/10.2174/1568006054553417","url":null,"abstract":"<p><p>The Na(+)/H(+) exchanger (NHE) is a ubiquitous protein present in mammalian cells. In higher eukaryotes this integral membrane protein removes one intracellular H(+) for one extracellular Na(+) protecting cells from intracellular acidification. NHE is of essential importance in the myocardium. It prevents intracellular acidosis that inhibits contractility. NHE also plays a key role in damage to the mammalian myocardium that occurs during ischemia and reperfusion and is involved in hypertrophy of the myocardium. NHE is composed of a membrane bound domain of approximately 500 amino acids plus a hydrophilic regulatory cytoplasmic domain of approximately 315 amino acids. The NHE1 isoform is the only significant plasma membrane isoform present in the myocardium. The activity of NHE1 is elevated in animal models of myocardial infarcts and in left ventricular hypertrophy. During ischemia and reperfusion of the myocardium, NHE activity catalyzes increased uptake of intracellular sodium. This in turn is exchanged for extracellular calcium by the Na(+)/Ca(2+) exchanger resulting in calcium overload and damage to the myocardium. Numerous inhibitors of NHE have been developed to attempt to break this cycle of calcium overload. In animal models excellent success has been obtained in this regard. However in humans, clinical trials have resulted in only modest success and recently, significant detrimental side effects were note of one NHE inhibitor. The mechanisms by which these inhibitors affect NHE activity are presently being investigated and regions of the protein important in NHE activity and inhibitor efficacy are related but not identical. Future studies may develop superior inhibitors that may circumvent recently reported side effects. Recently, NHE inhibition has been shown to be remarkably effective in preventing hypertrophy in some animal models. Whether this proves to be a practical treatment for hypertrophy in humans has yet to be determined.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 4","pages":"323-35"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054553417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248458","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":"Antibody mediated rejection in pig-to-nonhuman primate xenotransplantation models.","authors":"Emanuele Cozzi,&nbsp;Michela Severo,&nbsp;Erika Bosio,&nbsp;Federica Besenzon,&nbsp;Ermanno Ancona","doi":"10.2174/1568006054064799","DOIUrl":"https://doi.org/10.2174/1568006054064799","url":null,"abstract":"<p><p>Antibody-mediated mechanisms are central to the rejection that occurs when pig organs are transplanted into primates. In this article, the histopathological features of the humoral rejection process in these species combinations, namely hyperacute rejection and acute humoral xenograft rejection, will be illustrated. The profile of the natural and elicited antibodies involved will also be discussed. It has now been demonstrated that the natural immune response to a porcine xenograft is primarily directed to Galalpha1-3Gal (alphaGal) specificities, whilst the elicited immune response is directed to both alphaGal and non-alphaGal antigens. The principal characteristics of anti-alphaGal, anti-non-alphaGal and polyreactive antibodies will be described, together with the identification of the molecules recognised by natural and elicited xenoreactive antibodies. The role of the humoral immune response in the rejection of porcine islets in the primate is still uncertain and the current views on the subject will be discussed. Finally, a concise but comprehensive review of the different strategies that have been attempted to prevent the onset of antibody-mediated rejection is presented. These strategies encompass approaches aimed at interfering with the binding of xenoreactive antibodies with their targets, the use of conventional or novel immunosuppressants and splenectomy. It is undeniable that significant progress has been recently achieved in understanding the humoral rejection process of pig organs transplanted into primates. It is expected that a more comprehensive elucidation of the mechanisms underlying accommodation and tolerance may, in the not too distant future, further extend survival of pig organs transplanted into primates.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 3","pages":"233-53"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054064799","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24862395","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":"Modulating alloimmune responses with plasmapheresis and IVIG.","authors":"Daniel S Warren,&nbsp;Christopher E Simpkins,&nbsp;Matthew Cooper,&nbsp;Robert A Montgomery","doi":"10.2174/1568006054064735","DOIUrl":"https://doi.org/10.2174/1568006054064735","url":null,"abstract":"<p><p>Antibody-mediated barriers to renal transplantation, including donor specific anti-HLA and anti-blood group antibodies, have become an increasingly important issue over the last forty years as the organ shortage has continued to expand. The inevitable result of the unmet demand for compatible organs has been a continuous increase in recipient waiting times. Over the last decade, two treatment strategies have been developed to address this problem. These regimens rely on the immunomodulatory properties of intravenous immunoglobulin (IVIG) administered alone at relatively high doses, or at lower doses in combination with the non-selective depletion of antibodies from plasmapheresis. Both protocols have been successfully used for desensitization of patients with donor-specific anti-HLA antibody and have allowed for renal transplantation with excellent outcomes. The combined strategy of plasmapheresis/IVIG has also been successfully employed for renal transplantation in recipients of ABO blood group incompatible kidneys. This review will provide an overview of these therapies and their application to incompatible renal transplantation.</p>","PeriodicalId":84523,"journal":{"name":"Current drug targets. Cardiovascular & haematological disorders","volume":"5 3","pages":"215-22"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568006054064735","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24862393","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}