bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Use of β3‐Adrenoceptor Antagonists in Heart Failure Therapy
Authors: Moniotte Stéphane , Balligand Jean‐Luc
Published: August 2010

Recently, a functional, negatively inotropic, β3‐adrenoceptor was characterized in the human heart. Several studies now suggest that this receptor might play an important role in the pathophysiology of heart failure, by counterbalancing the effects of a β1and β2‐stimulation. Therefore, this review summarizes the rationale and effects of β‐adrenergic blockade in chronic heart failure and specifically addresses the question of the potential use of β3‐adrenoceptor antagonists in the treatment of heart failure and other pathophysiological conditions associated with a decreased cardiac contractility.
Brain Natriuretic Peptide (Nesiritide) in the Treatment of Heart Failure
Authors: Bettencourt Paulo
Published: August 2010

Over the last decade brain natriuretic peptide (BNP) emerged as a cardiac hormone of clinical interest in diagnosis, prognosis and treatment of patients with Heart Failure (HF). The diagnostic potential of BNP is now well established both in patients with suspected HF as well as in patients with asymptomatic left ventricular systolic dysfunction. The prognostic information obtained from BNP levels in HF and acute myocardial infarction patients seems even more promising.

Nesiritide is a synthetic peptide, homologous to endogenous BNP. It is a balanced vasodilator with diuretic and natriuretic properties. It decreases the elevated levels of neurohormones resulting from activation of the sympathetic and renin‐aldosterone systems in HF. The results of clinical trials involving more than 2000 patients with decompensated HF are now available. In these trials nesiritide was administered by single or repeated bolus injections, as well as by sustained infusions.

Nesiritide has been shown to produce a potent, dose‐related vasodilator effect that is rapid in onset and sustained during infusion. Balanced vasodilation is reflected by decreases in systemic vascular resistance, pulmonary artery wedge pressure and right atrial pressure. No tachyphylaxis has been observed in these trials. Efficacy of nesiritide in the treatment of decompensated HF has been demonstrated. Trials comparing nesiritide with conventional treatment of decompensated HF showed that nesiritide compares favorably to standard agents. The safety profile has been excellent with a dose‐dependent hypotension as the major side effect. Ventricular arrhythmia was not more frequent in patients treated with nesiritide than with placebo. Thus, nesiritide appears to be useful as a first‐line agent in the treatment of patients with decompensated HF.
BQ‐788, A Selective Endothelin ETBReceptor Antagonist
Authors: Okada Megumu , Nishikibe Masaru
Published: August 2010

We describe characteristics of a selective endothelin (ET) ETBreceptor antagonist, BQ‐788 [N‐cis‐2,6‐dimethylpiperidinocarbonyl‐L‐γ‐methylleucyl‐D‐1‐methoxycarbonyltryptophanyl‐D‐norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETsin vitroandin vivo. In vitro, BQ‐788 potently and competitively inhibited125I‐labeled ET‐1 binding to ETBreceptors in human Girrardi heart cells (hGH) with an IC50of 1.2 nM, but only poorly inhibited the binding to ETAreceptors in human neuroblastoma cell line SK‐N‐MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ‐788 showed no agonistic activity up to 10 μ and competitively inhibited the vasoconstriction induced by an ETB‐selective agonist (pA2, 8.4). BQ‐788 also inhibited several bioactivities of ET‐1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET‐1. Thus, it is confirmed that BQ‐788 is a potent, selective ETBreceptor antagonist.In vivo, in conscious rats, BQ‐788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET‐1‐ or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)‐induced ETBreceptor‐mediated depressor, but not pressor responses. Furthermore, BQ‐788 markedly increased the plasma concentration of ET‐1, which is considered an index of potential ETBreceptor blockadein vivo.In Dahl salt‐sensitive hypertensive (DS) rats, BQ‐788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ‐788 also inhibited ET‐1‐induced bronchoconstriction, tumor growth and lipopolysaccharide‐induced organ failure. These data suggest that BQ‐788 is a good tool for demonstrating the role of ET‐1 and ETBreceptor subtypes in physiological and/or pathophysiological conditions.
Cardiovascular Effects of Androgens
Authors: Weidemann Wolfgang , Hanke Hartmut
Published: August 2010

In 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.
XIVth World Congress of Pharmacology San Francisco, CA, July 7–12, 2002 New Cardiovascular Drugs
Authors: Scriabine Alexander
Published: August 2010

The XIVth World Congress of Pharmacology took place July 7–12, 2002 in Moscone Convention Center, San Francisco, CA. Over 4,000 scientists, exhibitors and guests attended the Congress. It consisted of 40 symposia, 11 workshops, 18 plenary lectures and ca. 1,400 posters. The Congress was sponsored by the American Society for Pharmacology and Experimental Therapeutics, Inspire Pharmaceuticals and GlaxoSmithKline. The major financial donors were: Eli Lilly and Company, Servier, Johnson & Johnson, Merck, Novartis, Roche, Schering‐Plough, Wyeth and Yamanouchi Foundation. This report covers only presentations and posters on drugs that were attended or viewed by the author.
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

Through 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

Imidapril 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

BRL‐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

ATP‐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

DPC423, 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

Endothelins 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

The 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

The 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

Inflammatory 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

FM‐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

Recent 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

NK3201 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.
Pitavastatin: Efficacy and Safety Profiles of A Novel Synthetic HMG‐CoA Reductase Inhibitor
Authors: Kajinami Kouji , Takekoshi Noboru , Saito Yasushi
Published: August 2010

The use of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis‐associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug‐drug interactions.

Pitavastatin (NK‐104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol‐lowering action. The short‐term and long‐term lipid‐modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type‐2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid‐lowering drug seems to be similar, or potentially superior, to that of atorvastatin.

According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4‐mediated metabolism of concomitantly administered drugs; P‐glycoprotein‐mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P‐glycoprotein activity.

It could be concluded that pitavastatin could provide a new and potentially better thera‐peutic choice for lipid‐modifying therapy than do the currently available statins. The ef‐ficacy and safety of higher dose treatment, as well as its long‐term effects in the pre‐vention of coronary artery disease, should be further investigated.
KB130015, A New Amiodarone Derivative with Multiple Effects on Cardiac Ion Channels
Authors: Mubagwa Kanigula , Macianskiene Regina , Viappiani Serena , Gendviliene Vida , Carlsson Bo , Brandts Bodo
Published: August 2010

KB130015 (KB015), a new drug structurally related to amiodarone, has been proposed to have antiarrhythmic properties. In contrast to amiodarone, KB015 markedly slows the kinetics of inactivation of Na+channels by enhancing concentration‐dependently (K0.5# 2 μM) a slow‐inactivatingINacomponent (#slow# 50 ms) at the expense of the normal, fast‐inactivating component (#fast# 2 to 3 ms). However, like amiodarone, KB015 slows the recovery from inactivation and causes a shift (K0.5. # 6.9 μM) of the steady‐state voltage‐dependent inactivation to more negative potentials. Despite prolonging the opening of Na+channels KB015 does not lengthen but often shortens the action potential duration (APD) in pig myocytes or in multicellular preparations. Only short APDs in mouse are markedly prolonged by KB015, which frequently induces early afterdepolarizations. KB015 has also an effect on other ion channels. It decreases the amplitude of the L‐type Ca2+current (ICa‐L) without changing its time course, and it inhibits G‐protein gated and ATP‐gated K+channels. Both the receptor‐activatedIk(ACH)(induced in atrial myocytes by either ACh, adenosine or sphingosylphosphorylcholine) and the receptor‐independent (GTPγS‐induced or background)Ik(ACH)are concentration‐dependently (K0.5# 0.6 – 0.9 μM) inhibited by KB015.Ik(ATP), induced in atrial myocytes during metabolic inhibition with 2,4‐dinitrophenol (DNP), is equally suppressed. However, KB015 has no effect onIK1or onIto. Consistent with the effects in K+currents, KB015 does not depolarize the resting potential but antagonizes the APD shortening by muscarinic receptor activation or by DNP. Intracellular cell dialysis with KB015 has marginal or no effect on Na+or K+channels and does not prevent the effect of extracellularly applied drug, suggesting that KB015 interacts directly with channels at sites more easily accessible from the extracellular than the intracellular side of the membrane. At high concentrations KB015 exerts a positive inotropic action. It also interacts with thyroid hormone nuclear receptors. Its toxic effects remain largely unexplored, but it is well tolerated during chronic administration.
CVT‐510: A Selective A1Adenosine Receptor Agonist
Authors: Cheung Jim W. , Lerman Bruce B.
Published: August 2010

Adenosine is an endogenous nucleoside that has potent antiarrhythmic effects on paroxysmal supraventricular tachycardia (PSVT) due to its negative dromotropic effects on the atrioventricular node. In addition to its electrophysiologic effects, adenosine has important effects on vascular smooth muscle cells, inflammatory cells, the central nervous system, and the kidney. Four known adenosine receptor subtypes (A1, A2A, A2B, and A3) mediate the pleiotropic effects of adenosine in humans. These receptors are coupled to a wide range of second messenger cascades. Activation of the A1adenosine receptor accounts for the negative chronotropic and dromotropic effects of adenosine, whereas A2A, A2Band A3adenosine receptor activation are responsible for such effects as coronary vasodilation, bronchospasm, inhibition of platelet aggregation, and neuronal stimulation. Elucidation of the specific properties of each of the adenosine receptor subtypes has led to the development of selective ligands as potential therapeutic agents. CVT‐510, N‐(3(R)‐tetrahydrofuranyl)‐6‐aminopurine riboside, was developed as a selective A1adenosine receptor agonist that specifically targets the atrioventricular node for termination of PSVT. Preliminary clinical trials have shown that CVT‐510 is effective in terminating PSVT and eliminating many of the undesirable adverse effects of adenosine. CVT‐510 is also being explored as a potential agent for controlling the ventricular rate of atrial fibrillation and flutter.
KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties
Authors: John Gareth W. , Létienne Robert , Le Grand Bruno , Pignier Christophe , Vacher Bernard , Patoiseau Jean‐Francois , Colpaert Francis C. , Coulombe Alain
Published: August 2010

KC 12291 was designed as a voltage‐gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+current, and markedly reduces sustained (or slowly or non‐inactivating) Na+current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+current.

In isolated atria and Langendorff‐perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activityin vivoin the absence of major hemodynamic effects.

Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+current, represent, therefore, promising potential antiischemic and cardioprotective drugs.
Guinea Pigs as Models to Study the Hypocholesterolemic Effects of Drugs
Authors: West Kristy L. , Luz Fernandez Maria
Published: August 2010

Guinea pigs are useful models to investigate the mechanisms of the hypocholesterolemic effects of drugs. Like humans, guinea pigs are one of the few species that carry the majority of cholesterol in LDL. This animal model has also been shown to develop atherosclerosis when challenged with hypercholesterolemic diets. In addition, plasma lipid profiles in males, females and ovariectomized guinea pigs, a model for menopause, follow similar patterns to those observed in humans. In this report, drugs aimed at lowering plasma cholesterol and triglycerides in hyperlipidemic individuals are reviewed. Studies analyzing the hypolipidemic effect of HMG‐CoA reductase inhibitors, acyl CoA cholesterol acyltransferase inhibitors, fibrates, bile acid resins, apical sodium bile acid transporter inhibitors, and others show that guinea pigs and humans have comparable responses to drug therapy. In addition, results from the limited clinical reports addressing specific effects of drugs on LDL catabolism or VLDL synthesis are in agreement with observations in guinea pigs. From the review of these studies, it is apparent that the guinea pig is a useful animal model to further explore the mechanisms of action of lipid lowering drugs including effects on specific receptors and regulatory enzymes involved in cholesterol metabolism and on early atherosclerosis development.
Pharmacological Effects of Xanthones as Cardiovascular Protective Agents
Authors: Jiang De‐Jian , Dai Zhong , Li Yuan‐Jian
Published: August 2010

Many epidemiological studies indicate that consumption of dietary polyphenolic compounds is beneficial in the prevention of cardiovascular diseases. Xanthones are a class of polyphenolic compounds that commonly occur in plants and have been shown to have extensive biological and pharmacological activities. Recently, the pharmacological properties of xanthones in the cardiovascular system have attracted great interest. Xanthones and xanthone derivatives have been shown to have beneficial effects on some cardiovascular diseases, including ischemic heart disease, atherosclerosis, hypertension and thrombosis. The protective effects of xanthones in the cardiovascular system may be due to their antioxidant, antiinflammatory, platelet aggregation inhibitory, antithrombotic and/or vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide synthase inhibitors by xanthones may represent the basis for improved endothelial function and for reduction of events associated with atherosclerosis.
Treatment of Portal Hypertension with NCX‐1000, a Liver‐Specific NO donor. A Review of Its Current Status
Authors: Fiorucci Stefano , Antonelli Elisabetta , Tocchetti Paola , Morelli Antonio
Published: August 2010

Portal hypertension, a life threatening complication of liver cirrhosis, results from increased intrahepatic resistance and increased portal blood inflow through a hyperdynamic splanchnic system. The increased intrahepatic vascular tone is the result of an enhanced activity of endogenous vasoconstrictors and a deficiency of nitric oxide (NO) release by sinusoidal endothelial cells. These pathophysiological events provide the rational basis for using NO‐based therapies for the treatment of portal hypertension. Clinical studies have demonstrated that nitrate therapy results in a significant reduction of portal pressure as assessed by hepatic venous portal gradient but causes vasodilation in both systemic arterial and venous vascular beds, aggravating the progression of the vasodilatory syndrome of cirrhotic patients. For this reason, the ideal drug for the treatment of portal hypertension should act by decreasing intrahepatic vascular resistance, without worsening the splanchnic/systemic vasodilatation.

NCX‐1000 is the prototype of a family of NO‐releasing derivatives of ursodeoxycholic acid (UDCA). These compounds are releasing selectively, from parenchymal and non‐parenchymal hepatic cells, biologically active NO into the liver microcirculation with no detectable effect on systemic circulation. Preclinical studies have shown that long‐ and short‐term administration of NCX‐1000 to rodents with chronic liver injury protects against the development of portal hypertension and reduces the intrahepatic hyperreactivity to α1‐adrenoceptor agonists. The finding of increased liver nitrite/nitrate content in NCX‐1000‐treated animals together with an increase in cGMP levels in their liver homogenates suggests that this nitro‐compound behaves as a liver‐selective NO donor. In contrast to conventional NO‐donors such as isosorbide mono‐ and di‐nitrate, which are also used for primary and secondary prevention of gastrointestinal bleeding, NCX‐1000 has no effect on mean arterial pressure in either normal or cirrhotic animals indicating the absence of adverse systemic effect. In summary, these data suggest that NCX‐1000 may provide a novel therapy for the treatment of patients with portal hypertension.
Prevention of Cardiovascular Complications of Diabetes Mellitus by Aspirin
Authors: Nobles‐James Candi , James Erskine A. , Sowers James R.
Published: August 2010

Eighteen million Americans have type 2 Diabetes Mellitus (DM) while another 40 million have impaired glucose tolerance. Atherosclerotic heart disease is the leading cause of death in patients with diabetes mellitus. In addition to the increased risk for Cardio Vascular Disease (CVD), patients with diabetes have a worse prognosis than nondiabetics when they suffer an ischemic event. Insulin resistance is increasingly recognized as a chronic, low‐level, inflammatory state. Hyperinsulinemia has been proposed as the forerunner of hypertension, low high‐density lipoprotein cholesterolemia, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary vascular disease. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, due to the actions of proinflammatory cytokines. The dynamic inflammatory milieu found in diabetes explains the susceptibility of diabetics to CVD and the potential mechanism by which aspirin may prevent CVD in diabetics. Aspirin decreases the risk for CVD in diabetic patients by a variety of established and novel mechanisms. Therapeutic strategies that lesson the CVD risk in diabetic patients, including the use of aspirin for primary and secondary prevention, are potentially very important. This review article addresses the antiatherosclerotic effects of aspirin, the potential anti‐diabetic effects of aspirin, and the clinical trial evidence for CVD prevention by aspirin in diabetics. We also present recommendations for the use of aspirin in the diabetic population and the current guidelines put forth by the American Heart Association and by the American Diabetes Association.
Pharmacodynamic, Pharmacokinetic and Clinical Effects of Clevidipine, an Ultrashort‐Acting Calcium Antagonist for Rapid Blood Pressure Control
Authors: Nordlander Margareta , Sjöquist Per‐Ove , Ericsson Hans , Rydén Lars
Published: August 2010

Clevidipine is an ultrashort‐acting vasoselective calcium antagonist under development for short‐term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4‐dihydropyridine that inhibits L‐type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg). and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half‐life in patients undergoing cardiac surgery is less than one min.

Unlike sodium nitroprusside, a drug commonly used for the short‐term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate.

In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min‐long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside.
The Preclinical Pharmacology of BIBN4096BS, a CGRP Antagonist
Authors: Hay Debbie L. , Poyner David
Published: August 2010

CGRP is an important neuropeptide found throughout the cardiovascular system. However, until recently it has been difficult to define its pharmacology or physiological role because of the lack of suitable antagonists. BIBN4096BS is a high‐affinity, non‐peptide antagonist that shows much greater selectivity for human CGRP1receptors compared to any other drug. Its pharmacology has been defined with studies on transfected cells or cell lines endogenously expressing receptors of known composition. These have allowed confirmation that in many human blood vessels, CGRP is working via CGRP1receptors. However, it also interacts with other CGRP‐activated receptors, of unknown composition.In vivo, clinical studies have shown that BIBN4096BS is likely to be useful in the treatment of migraine. It has also been used to define the role of CGRP in phenomena such as plasma extravasation and cardioprotection following ischemia.
Bunazosin, a Selective α1 ‐Adrenoceptor Antagonist, as an Anti‐glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage
Authors: Hara Hideaki , Ichikawa Masaki , Oku Hidehiro , Shimazawa Masamitsu , Araie Makoto
Published: August 2010

Bunazosin hydrochloride is a potent and selective α1‐adrenoceptor antagonist that has been clinically used both as a systemic antihypertensive as well as an ocular hypotensive drug. In a number of studies, we have examined some effects of bunazosin hydrochloride that might indicate its potential as an anti‐glaucoma drug. In normal rabbit eyes, topically instilled bunazosin hydrochloride reached the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine‐ or endothelin‐1 (ET‐1)‐induced constriction of retinal arteries. Furthermore, bunazosin hydrochloride improved the impairment of optic nerve head (ONH) blood flow, the prolongation of visual‐evoked potentials (VEP) implicit time, the enlargement of the optic disk cup, and the decrease in the number of retinal ganglion cell layer cells induced by repeated injections of ET‐1 in rabbits. Topically instilled bunazosin hydrochloride improved the reductions in ONH capillary blood flow and VEP amplitude induced in rabbit eyes by nitric oxide synthase inhibition. In rat primary retinal cultures, bunazosin hydrochloride reduced glutamate‐induced neuronal cell death, presumably through a Na+channel blocking effect. In healthy humans, topically instilled bunazosin hydrochloride reportedly increases blood velocity in the ONH, retina and choroid, without significantly altering either blood pressure or heart rate. These results indicate that bunazosin hydrochloride exerts both an improvement effect within the ocular circulation and a direct neuroprotective effect. Hence, bunazosin hydrochloride may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that are associated with disturbances of the ocular circulation.