bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular Effects of Androgens
Authors: Weidemann Wolfgang , Hanke Hartmut 
Published: August 2010

ABSTRACTIn the process of atherosclerosis sex steroids play a complex role in the vascular vessel wall system. Although a number of experimental studies have clearly documented an atheroprotective effect of estrogens, in recent clinical studies, estrogen replacement therapy has failed to reduce cardiovascular mortality. The effects of androgens on the cardiovascular system and cardiovascular diseases are even more controversial. Whereas in the past, androgens were mainly believed to exert adverse effects on the cardiovascular system, recent studies in men have documented a number of beneficial actions of testosterone in the arterial vascular system. Androgens affect lipid metabolism (e.g., LDL and HDL cholesterol, Lp(a)) and hemostasis (e.g., platelet aggregation and fibrinolytic activity). In addition, several other physiological and pathophysiological processes in the arterial vessel wall are influenced by androgens. Acute hemodynamic effects of testosterone on coronary vasomotion and stress‐test‐induced ischemia were reported. Additionally, recent animal andin vitrostudies have further documented an inhibitory effect of androgens on neointimal plaque formation. This review discusses different and, in part, contradictory effects of androgens on the cardiovascular system including potential signal transduction pathways in androgen target cells.
LDL Apheresis: An Effective and Safe Treatment for Refractory Hypercholesterolemia
Authors: Hudgins Lisa Cooper , Gordon Bruce R. , Parker Thomas S. , Saal Stuart D. , Levine Daniel M. , Rubin Albert L. 
Published: August 2010

ABSTRACTThrough the efforts of Edward H. Ahrens, LDL apheresis became available for the treatment of patients, often with familial hypercholesterolemia, who have no alternative therapy for severely elevated LDL cholesterol levels. In the U.S., the FDA has approved this treatment for individuals on maximum diet and drugs with an LDL cholesterol greater than 300 mg/dL or greater than 200 mg/dL with coronary artery disease. Unlike plasmapheresis, apolipoprotein B‐containing lipoproteins (LDL, Lp(a), and VLDL) are selectively removed by heparin precipitation or columns containing dextran sulfate cellulose or antibodies to apolipoprotein B. The acute lowering of LDL‐cholesterol by a typical 2 ‐ 3 h treatment is up to 80%, and the time‐averaged lowering in the 1 to 2 week interval between treatments is up to 50%, with very few side effects. The lowering of LDL‐cholesterol and other cardioprotective effects of LDL apheresis have reduced chest pain, prevented new disability and prolonged life. Whole blood compatible columns in development offer the possibility of simpler and less expensive treatments.
Protection of the Cardiovascular System by Imidapril, a Versatile Angiotensin‐Converting Enzyme Inhibitor
Authors: Hosoya Kazuyoshi , Ishimitsu Toshihiko 
Published: August 2010

ABSTRACTImidapril hydrochloride (imidapril) is a long‐acting, non‐sulfhydryl angiotensin‐converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (Tmax) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half‐lives (t1/2) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose‐dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild‐to‐moderate CHF [New York Heart Association (NYHA) functional class II‐III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose‐related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are its activity in the treatment of various cardiovascular diseases and lower incidence of cough compared with some of the older ACE inhibitors.
The Antiarrhythmic Drug BRL‐32872
Authors: Karle Christoph A. , Thomas Dierk , Kiehn Johann 
Published: August 2010

ABSTRACTBRL‐32872 is a new antiarrhythmic drug with balanced class‐III and class‐IV actions as categorized by the Vaughan‐Williams classification. BRL‐32872 blocks the rapid component of the cardiac delayed rectifier potassium channel IKr(IC50= 28 nM) and its molecular correlate HERG (“Human‐ether‐a‐go‐go related gene,” IC50of 19.8 nM in cell lines) at low concentrations. It also inhibits the L‐type calcium current (ICa) at higher concentrations (IC50= 2.8 μM). This dual concentration‐dependent profile of action at higher concentrations may possibly prevent “torsades de pointes” ventricular arrhythmias, which is a dangerous side effect of many other class‐III antiarrhythmic drugs. With BRL‐32872, an excessive prolongation of the action potential duration and consecutive QTc prolongation is prevented by a concentration‐dependent increase of calcium channel block, resulting in the so‐called “bell‐shaped” profile of antiarrhythmic drug action. BRL‐32872 is very effective in the treatment of ventricular arrhythmias in animal models of cardiac ischemia. In the ischemic hearts of animals the drug significantly reduced early afterdepolarization and ventricular tachycardia. The antiarrhythmic effect of BRL‐32872 has not yet been demonstrated in humans.
Pharmacologic Profile of the Selective Mitochondrial‐KATPOpener BMS‐191095 for Treatment of Acute Myocardial Ischemia
Authors: Grover Gary J. , Atwal Karnail S. 
Published: August 2010

ABSTRACTATP‐sensitive potassium channel (KATP) openers as a class protect ischemic myocardium. The protective effects are independent of vasodilator activity and effects on action potential shortening, actions typically associated with sarcolemmal KATPactivation. BMS‐191095 is a novel mitochondrial KATPopener which protects ischemic myocardium while having no electrophysiologic or vasodilator effects (determined in vitro and in vivo). The cardioprotective effects were determined in isolated rat hearts subjected to ischemia and reperfusion. Protective effects were deduced from increased time to contracture formation during ischemia, improved reperfusion recovery of contractile function, and reduced reperfusion LDH release. The cardioprotective effects of BMS‐191095 were observed at concentrations at which this compound selectively opened cardiac mitochondrial KATPchannels. This effect was consistent with the pharmacologic profile of this agent. The protective effects were abolished by mitochondrial KATPinhibition. Unlike first‐generation KATPopeners, BMS‐191095 is expected to protect ischemic myocardium with little hemodynamic sequelae and without any proarrhythmic potential. BMS‐191095 is potentially useful clinically as a cardioprotective agent. It is also a useful tool for basic research.
Nonpeptide Factor Xa Inhibitors: DPC423, a Highly Potent and Orally Bioavailable Pyrazole Antithrombotic Agent
Authors: Wong Pancras C. , Pinto Donald J. , Knabb Robert M. 
Published: August 2010

ABSTRACTDPC423, 1‐[3‐(aminomethyl)phenyl]‐N‐[3‐fluoro‐2′‐(methylsulfonyl)[1,1′‐biphenyl]‐4‐yl]‐3‐(trifluoromethyl)‐1H‐pyrazole‐5‐carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (Ki[nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC50]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 ± 0.4, 3.1 ± 0.4, and 1.1 ± 0.5 μM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half‐life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC50of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half‐life.
Enrasentan, an Antagonist of Endothelin Receptors
Authors: Cosenzi Alessandro 
Published: August 2010

ABSTRACTEndothelins are powerful vasoconstrictor agents produced by endothelial cells and identified by Yanagisawa et al. in 1988. Two types of receptors for endothelins have been identified: ETAreceptors are located on smooth muscle cells of the vascular wall and are responsible for endothelin‐induced vasoconstriction while ETBreceptors are located on endothelial cells and induce these cells to release NO and prostacyclin. Moreover, these peptides not only cause a potent and prolonged vasoconstriction but are also known to enhance cell proliferation and to stimulate extracellular matrix accumulation. High levels of plasma or tissue endothelins have been found in patients with heart failure, diabetes, stroke, primary pulmonary hypertension, liver cirrhosis and other diseases. Given these effects of endothelins, blocking their receptors might be a new way to reduce blood pressure and to treat other illnesses. Accordingly, many endothelin antagonists have been developed and evaluated in animals and humans. Enrasentan is a mixed ETAand ETBreceptor antagonist with a higher affinity for ETAreceptors, although it cannot be considered a selective antagonist. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan has been added to conventional treatment in patients with heart failure (NYHA Class 2‐3) and no addictive effect of the drug has been observed. This is in contrast with results obtained in animal models and still has not been explained. In conclusion, many possible clinical applications can be suggested for this drug, but further studies are necessary to better evaluate its therapeutic efficacy.
Zoniporide: A Potent and Selective Inhibitor of the Human Sodium‐Hydrogen Exchanger Isoform 1 (NHE‐1)
Authors: Tracey W. Ross , Allen Mary C. , Frazier Donald E. , Fossa Anthony A. , Johnson Celeste G. , Marala Ravi B. , Knight Delvin R. , Guzman‐Perez Angel 
Published: August 2010

ABSTRACTThe sodium‐hydrogen exchanger isoform‐1 (NHE‐1) plays an important role in the myocardial response to ischemia‐reperfusion; inhibition of this exchanger protects against ischemic injury, including reduction in infarct size. Herein we describe a novel, potent, and highly selective NHE‐1 inhibitor, zoniporide (CP‐597,396; [1‐(quinolin‐5‐yl)‐5‐cyclopropyl‐1H‐pyrazole‐4‐carbonyl] guanidine). Zoniporide inhibits human NHE‐1 with an IC50of 14nM, has >150‐fold selectivity vs. other NHE isoforms, and potently inhibitsex vivoNHE‐1‐dependent swelling of human platelets. This compound is well tolerated in preclinical animal models, exhibits moderate plasma protein binding, has at1/2of 1.5 h in monkeys, and has one major active metabolite. In bothin vitroandin vivorabbit models of myocardial ischemia‐reperfusion injury, zoniporide markedly reduced infarct size without adversely affecting hemodynamics or cardiac function. In the isolated heart (Langendorff), zoniporide elicited a concentration‐dependent reduction in infarct size (EC50= 0.25 nM). At 50 nM it reduced infarct size by 83%. This compound was 2.5–20‐fold more potent than either eniporide or cariporide (EC50s of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide. In open chest, anesthetized rabbits, zoniporide also elicited a dose‐dependent reduction in infarct size (ED50= 0.45 mg/kg/h) and inhibited NHE‐1‐mediated platelet swelling (93% inhibition at 4 mg/kg/h). Furthermore, zoniporide attenuated postischemic cardiac contractile dysfunction in conscious primates, and reduced both the incidence and duration of ischemia‐reperfusion‐induced ventricular fibrillation in rats. Zoniporide represents a novel class of potent and selective human NHE‐1 inhibitors with potential utility for providing cardio‐protection in a clinical setting.
DX‐9065a, a Direct Inhibitor of Factor Xa
Authors: Kaiser Brigitte 
Published: August 2010

ABSTRACTThe synthetic compound DX‐9065a represents a low molecular weight, direct, competitive inhibitor of factor Xa (FXa) with a high affinity and selectivity for the enzyme. Under experimental conditions DX‐9065a exerts strong anticoagulant actionsin vitroandin vivoand is antithrombotically effective in various thrombosis models. It inhibits proliferation of vascular smooth muscle cells in cell culture systems as well as inin vivomodels. As a small molecule inhibitor, DX‐9065a inactivates both free and fibrin‐bound FXa. By this mechanism it effectively affects the clot‐associated procoagulant activity which might be responsible for the propagation of intravascular thrombi as well as for recurrent thrombosis and thrombotic reocclusion after lysis. Although DX‐9065a is effective after oral administration, its oral bioavailability is relatively low and seems not to be sufficient for a long‐term therapeutic use of the drug. However, first clinical trials in healthy volunteers and in patients with cardiovascular diseases demonstrated a predictable pharmacokinetic and pharmacodynamic behavior of DX‐9065a after either intravenous bolus injection or constant infusion, as well as its high safety, especially a lower bleeding risk compared with other commonly used drugs. Further experimental studies and ongoing clinical trials will evaluate the inhibitory profile of the drug, its effectiveness and its possible superiority over other drug regimens in various cardiovascular indications.
The Antiatherogenic Effect of DiNAC: Experimental Findings Supporting Immunomodulation as a New Treatment for Atherosclerosis Related Diseases
Authors: Pettersson Knut , Bergstrand Håkan 
Published: August 2010

ABSTRACTInflammatory processes in the arterial wall are important in atherogenesis. The present review discusses the development of DiNAC as a potential new treatment modality for atherosclerosis related diseases. DiNAC,N,N'‐diacetyl‐L‐cystine, is the disulphide dimer of N‐acetyl cysteine, NAC. It was selected as an immunomodulating drug candidate due to its ability to modify contact sensitivity/delayed type hypersensitivity (CS/DTH) reactionsin vivo.Initial structure‐activity relationship (SAR) studies indicated that an intact disulfide bridge was essential for this effect. Antioxidants, like probucol and some close analogs with two sulphurs in close proximity (but not disulphides), were also found to have similar effects on CS/DTH reactions. These antioxidants have antiatherosclerotic effects, while structurally related compounds without sulphurs do not. Therefore, it was hypothesized that DiNAC might also possess antiatherosclerotic effects. This was investigated in WHHL rabbits and mice. In both species, DiNAC had antiatherosclerotic activity similar to that of probucol. The effect of DiNAC was not due to an alteration of lipid metabolism. Impaired endothelium mediated relaxation is known to be associated with atherosclerosis. DiNAC was shown to reverse this process in WHHL rabbits with advanced atherosclerosis, probably due to an action on the vessel wall itself that is not related to the extent of atherosclerosis or to plasma lipid levels. Preliminary data from a clinical investigation in hypercholesterolemic subjects suggest that DiNAC is likely to have similar effects also in patients. Taken together, these findings suggest immunomodulation to be a potential new therapy for atherosclerosis related diseases. DiNAC may represent a new treatment modality for such diseases.
Development of Novel Water‐Soluble Phytostanol Analogs: Disodium Ascorbyl Phytostanyl Phosphates (FM‐VP4): Preclinical Pharmacology, Pharmacokinetics and Toxicology
Authors: Ng Agatha W. K. , Lukic Tatjana , Pritchard P. Haydn , Wasan Kishor M. 
Published: August 2010

ABSTRACTFM‐VP4 is a novel inhibitor of cholesterol absorption that has lipid lowering and body weight reducing properties. In vitro and in vivo studies were performed to investigate the lipid‐lowering effects, mechanism of action, pharmacokinetics, and toxicity of FM‐VP4. FM‐VP4 decreased cholesterol accumulation in Caco‐2 cells by approximately 50%; its activity appeared to be independent of pancreatic lipase, p‐glycoprotein, or cholesterol incorporation in micelles. In animal studies, FM‐VP4 was added to the diet or drinking water and the following results were obtained. In gerbils 2% FM‐VP4 produced mean 56 and 53% reduction in total cholesterol (TC) after 4 and 8 weeks, respectively. This reduction was entirely due to the loss of the low‐density lipoprotein (LDL) pool, which was reduced to undetectable levels at either time point. At 8 weeks, high‐density lipoprotein (HDL) concentration had risen by a mean of 34% whereas total triglyceride (TG) concentrations had decreased by a mean of 60%. FM‐VP4 also had a profound effect on body weight in these animals. At 8 weeks, the mean body weight was in the 4% FM‐VP4 treatment group 25% lower than in the control group. No hepatic or renal toxicity was associated with these changes. In Apo E‐deficient mice, after 4‐ and 8‐week treatments FM‐VP4 caused a significant decrease in both TC and TG concentrations compared to controls. After 12 weeks, the areas of atherosclerotic lesion involvement in the aortic roots were decreased by a mean of 80% in the 0.5, 1, and 2% FM‐VP4 treatment groups compared to controls. Taken together, these results suggest that FM‐VP4 is a potential new drug with lipid‐lowering and weight loss potential, without apparent toxicity.
Eplerenone: A Selective Aldosterone Blocker
Authors: Stier Charles T. 
Published: August 2010

ABSTRACTRecent studies suggest that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, vascular necrosis and inflammation, impaired endothelial function, reduced fibrinolysis, hypertension, left ventricular hypertrophy (LVH), congestive heart failure, and cardiac arrhythmias. In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Eplerenone is a selective aldosterone receptor blocker that displays little interaction with androgen and progesterone receptors. Eplerenone has already been approved for the treatment of systemic hypertension and has been evaluated in numerous hypertension subgroups, including patients with low plasma renin activity; diabetes; LVH; uncontrolled blood pressure while receiving monotherapy with angiotensin‐converting enzyme inhibitors, angiotensin‐receptor blockers, calcium channel blockers, or beta‐blockers; and in black patients. Results of these trials indicate that eplerenone lowers blood pressure and reduces end‐organ damage. Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). In this large‐scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalization by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. The advent of selective aldosterone blockers, such as eplerenone, should prove to be of great therapeutic value in hypertension control and prevention of cardiovascular disease and associated end‐organ damage.
Application of a Chymase Inhibitor, NK3201, for Prevention of Vascular Proliferation
Authors: Takai Shinji , Miyazaki Mizuo 
Published: August 2010

ABSTRACTNK3201 is an orally active chymase inhibitor. Its inhibitory activity leads to formation of acyl‐intermediate between active serine residue of the enzyme and di‐ketone structure of NK3201. NK3201 inhibits human, dog and hamster chymases with IC50of 2.5, 1.2, and 28 nM, respectively. On the other hand, NK3201 does not inhibit other types of serine proteases, tryptase, thrombin, elastase, plasmin, and plasminogen activator. In dogs, at 8 h after oral administration of NK3201, 1 mg/kg, the drug levels in plasma, heart, and aorta reached 470, 195, and 78 nM, respectively. In a dog model NK3201, 5 mg/kg/day, increased chymase activity in grafted veins, and suppressed vascular proliferation. After balloon injury in dog vessels, chymase activity was increased locally, in the injured artery, and NK3201, 1 mg/kg/day was effective in preventing vascular proliferation. On the other hand, NK3201, unlike angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, did not affect blood pressure. These findings indicate that local angiotensin II production by chymase is involved only in vascular proliferation, as seen in the injured vessels. Therefore, NK3201 may be useful for preventing vascular proliferation without affecting blood pressure.