bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Effects of Raloxifene Hydrochloride
Authors: Saitta Antonino , Morabito Nunziate , Frisina Nicola , Cucinotte Domenico , Corrado Francesco , D'Anna Rosario , Altavilla Domenica , Squadrito Giovanni , Minutoli Letteria , Arcoraci Vincenzo , Cancellieri Francesco , Squadrito Francesco
Published: August 2010

Raloxifene hydrochloride binds to the estrogen receptor and shows tissue‐selective effects; thus, it belongs to a class of drugs recently described asselective estrogen receptor modulators(SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen‐agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene has been shown to reduce total and low‐density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene does not increase high‐density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene increases the nitric oxide/endothelin‐1 ratio, and improves endothelium‐dependent vasomotion in post‐menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post‐menopausal women raloxifene reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene may represent an alternative in women who are at risk of coronary artery disease.
Role of Tissue Factor Pathway Inhibitor in the Regulation of Tissue Factor‐Dependent Blood Coagulation
Authors: Golino Paolo , Ragni Massimo , Cimmino Giovanni , Forte Lavinia
Published: August 2010

Tissue factor pathway inhibitor (TFPI) is a multivalent, Kunitz‐type plasma proteinase inhibitor that modulates tissue factor‐dependent coagulation in vivo. TFPI possesses a peculiar two‐step mechanism of action; it directly inhibits activated factor X and subsequently produces feedback inhibition of the factor VIIa/tissue factor catalytic complex in a factor Xa‐dependent fashion. TFPI biochemistry and physiology have been extensively studied during the last decade. Its pathophysiologic role in thrombotic disorders has, however, only recently started to be unraveled. In particular, circulating plasma TFPI levels have been found to modulate the activity of the tissue factor‐dependent coagulation cascade. In animal models, neutralization of circulating TFPI activity results in restoration of intravascular thrombus formation previously abolished by aspirin. In patients with acute myocardial infarction, TFPI plasma levels measured in blood samples obtained from the coronary sinus were significantly lower than those measured in blood obtained from the ascending aorta, indicating acute consumption of TFPI within the coronary circulation of patients with intracoronary thrombosis. Finally, recent data indicate that transfection of the arterial wall with the gene coding for TFPI is an effective therapeutic intervention to prevent intravascular thrombus formation. Taken together, these observations underline the pathophysiologic importance of TFPI in regulating the procoagulant activity of tissue factor and open new potential therapeutic approaches for the treatment of thrombotic disorders.
Olprinone: A Phosphodiesterase III Inhibitor with Positive Inotropic and Vasodilator Effects
Authors: Mizushige Katsufumi , Ueda Takashi , Yukiiri Kazushi , Suzuki Hitoshi
Published: August 2010

Olprinone is a newly developed phosphodiesterase III inhibitor characterized by several properties. First, olprinone has positive inotropic and vasodilator actions and improves myocardial mechanical efficiency. Second, olprinone augments cerebral blood flow by a direct vasodilatory effect on cerebral arteries. The cerebrovascular reactivity to olprinone is marked in patients with impaired cerebral circulation. Third, olprinone selectively improves carotid artery distensibility, which may be attributable to differences in the arterial structural components or the reactivity of smooth muscle cells to olprinone. Fourth, olprinone improves inadequate redistribution of brain perfusion and may prevent cerebral metabolic abnormalities in heart failure.
Dual ACE and NEP Inhibitors: A Review of the Pharmacological Properties of MDL 100,240
Authors: Rossi Gian Paolo
Published: August 2010

The Angiotensin I converting enzyme (ACE, EC 3.4.14.1, kininase II) and neutral endopeptidases (NEP, NEP 24.11) are mechanistically related metallopeptidases. They play a key role in the regulation of blood pressure, body fluid homeostasis and cell growth. Therefore, they are implicated in the pathogenesis of arterial hypertension, congestive heart failure, left ventricular remodeling after myocardial infarction and other cardiovascular diseases. Furthermore, since these two metallopeptidases possess some subsite and substrate similarities, as indicated by their interaction with certain mercaptoalkanoyl inhibitors, they are regarded as an important common target for pharmacological inhibition with a single drug. MDL 100,240 is a pro‐drug that, upon conversion to MDL 100,173, acts as a potent dual inhibitor of ACE and NEP with a balanced activity on both enzymes. Only very limited pharmacokinetic studies with MDL 100,240 have been published. These studies used a high pressure liquid chromatography method with UV absorbance detection to quantify the drug. According to the studies in dogs the terminalt1/2of MDL 100,173 was 35.7 h. The area under the curve for total MDL 100,173 was nearly 10‐fold greater than the sum of the areas under the curve for MDL 100,240 and for unconjugated MDL 100,173. These results support the hypothesis that MDL 100,240 is hydrolyzed in plasma to the active thiol, MDL 100,173, which is rapidly conjugated with endogenous plasma thiols thus providing a pathway for elimination. Studies in vivo in experimental models of hypertension and congestive heart failure confirmed the vasodilatory and natriuretic effects of MDL, which appear to be independent of the degree of activation of the renin‐angiotensin‐aldosterone system. In addition, MDL 100,240 showed an impressive effectiveness both in preventing and in regressing hypertension‐induced vascular remodeling and cardiac hypertrophy. Accordingly, MDL 100,240 is being developed for the treatment of cardiovascular diseases, including hypertension and congestive heart failure. If the promises of this novel therapeutic strategy are fulfilled, clinical trials are expected to demonstrate advantages of MDL 100,240 over pure ACE inhibitors.
Lipoprotein Lipase Activator NO‐1886
Authors: Yin Weidong , Tsutsumi Kazuhiko
Published: August 2010

Lipoprotein lipase (LPL) is a rate‐limiting enzyme that hydrolyzes circulating triglyceride‐rich lipoproteins such as very low‐density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high‐density lipoprotein cholesterol (HDL‐C). The increase in plasma TG and decrease in plasma HDL‐C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL‐C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO‐1886.

NO‐1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO‐1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL‐C. Long‐term administration of NO‐1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL‐C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO‐1886 or other possible LPL activating agents are potentially beneficial for the treatment of hyper‐triglyceridemia, hypo‐HDL cholesterolemia, and protection from atherosclerosis.
Ezetimibe: A First‐in‐Class, Novel Cholesterol Absorption Inhibitor
Authors: Lipka Leslie J.
Published: August 2010

Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)‐designated low density lipoprotein cholesterol (LDL‐C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid‐lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid‐lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL‐C, as well as incremental increases in high‐density lipoprotein cholesterol (HDL‐C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL‐C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2‐ to 3‐fold upward titration of the corresponding statin dose. Ezetimibe‐statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid‐lowering mechanisms, ezetimibe coadministered with a statin offers an effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease.
RWJ‐58259: A Selective Antagonist of Protease Activated Receptor‐1
Authors: Damiano Bruce P. , Derian Claudia K. , Maryanoff Bruce E. , Zhang Han‐Cheng , Gordon Patricia Andrade
Published: August 2010

Protease activated receptor‐1 (PAR‐1) is a key mediator of the cellular actions of α‐thrombin. Thus, antagonism of this unique G‐protein coupled receptor with a small molecule represents a means of selectively inhibiting thrombin's cellular actions without inhibiting its proteolytic activity. RWJ‐58259 ((αS)‐N‐[(1S)‐3‐amino‐1‐[[(phenylmethyl)‐amino]carbonyl]propyl]‐α‐[[[[[1‐(2,6‐dichlorophenyl)methyl]‐3‐(1‐pyrrolidinylmethyl)‐1H‐indazol‐6‐yl]amino]carbonyl]amino]‐3,4‐difluorobenzenepropanamide) is a potent and selective inhibitor of PAR‐1 identified as part of a synthetic chemistry program based upon ade novodesign approach. RWJ‐58259 inhibited thrombin‐induced platelet aggregation in human platelets with an IC50of 0.37 μM without inhibiting thrombin's proteolytic activity or aggregation induced by other agonists. RWJ‐58259 was not effective in guinea pig models of thrombosis. This reflected the presence of a second thrombin‐sensitive receptor system in guinea pigs (PAR‐3/4) and the selectivity of RWJ‐58259 for PAR‐1. However, RWJ‐58259 was effective in a non‐human primate model of thrombosis. Because human platelets have a PAR expression profile similar to the non‐human primate, PAR‐1 antagonism has the potential to be antithrombotic in humans. RWJ‐58259 also inhibited thrombin‐induced intracellular calcium signaling and proliferation in rat vascular smooth muscle cells. Perivascular application of RWJ‐58259in vivosignificantly inhibited arterial injury‐induced stenosis in a rat model of balloon angioplasty. These preclinical results suggest a potential clinical utility of RWJ‐58259 for treatment of thrombotic disorders and vascular injury associated with acute coronary interventions and atherosclerosis. Given the potential role of PAR‐1 in thrombin's actions in other cell types and disease states, RWJ‐58259 provides a means for assessing additional clinical utilities of PAR‐1 antagonism in disease conditions such as inflammation, cancer and neurodegeneration.
Stem cell therapy in ischemic heart disease
Authors: Sunkomat Julia N. E. , Gaballa Mohamed A.
Published: August 2010

Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be addressed. To name a few: 1) Which patient population should be considered for stem cell therapy? 2) What type of stem cell should be used? 3) What is the best route for cell delivery? 4) What is the optimum number of cells that should be used to achieve functional effects? 5) Is stem cell therapy safer and more effective than conventional therapies? The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of ischemia, species of donors and recipients, techniques of cell delivery, cell types, cell numbers and timing of the experiments have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseases in the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Non‐ischemic cardiomyopathy, peripheral vascular disease, and aging may be treated by stem cells. Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with pharmacological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.
Ramatroban (BAY u 3405): A Novel Dual Antagonist of TXA2 Receptor and CRTh2, a Newly Identified Prostaglandin D2 Receptor
Authors: Ishizuka Toshiaki , Matsui Takemi , Okamoto Yasuhiro , Ohta Atsuko , Shichijo Michitaka
Published: August 2010

It is known that thromboxane A2 (TXA2) contributes to various diseases such as bronchial asthma, ischemic heart disease, cerebrovascular disorders and allergic rhinitis. A number of TXA2 synthase inhibitors and TXA2 receptor (TP receptor) antagonists have been developed to treat these diseases. Ramatroban (BAY u 3405) was developed as a potent TP receptor antagonist with excellent efficacy against allergic rhinitis in many animal models and patients. Recent studies also revealed that ramatroban can block the newly identified PGD2 receptor, chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTh2). PGD2 induces migration and degranulation of eosinophils through CRTh2 and contributes to late‐phase inflammation and cell damage. Accordingly, it was considered that ramatroban suppresses the late‐phase inflammation via TP receptor and CRTh2 blockade. In terms of the efficacy on vascular systems, it was revealed that ramatroban can suppress the expression of monocyte chemoattractant protein‐1 (MCP‐1) and adhesion molecules in endothelial cells and prevent exacerbation of inflammation by blocking these responses. According to our recent studies in hypercholesterolemic rabbits ramatroban prevents macrophage infiltration through MCP‐1 downregulation and neointimal formation after balloon injury and attenuates vascular response to acetylcholine. Therefore, ramatroban may be beneficial in the treatment of atherosclerosis.
Bimatoprost: A Novel Antiglaucoma Agent
Authors: Woodward D. F. , Phelps R. L. , Krauss A. H‐P. , Weber A. , Short B. , Chen J. , Liang Y. , Wheeler L. A.
Published: August 2010

The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts.

Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a β‐adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs.

Bimatoprost is a structural analog of PGF2α‐ethanolamide (prostamide F2α), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase‐2 (COX‐2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG‐ and endocannabinoid‐sensitive receptors. Extensive ocular distribution/metabolism studies in non‐human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide‐mimetic properties.
Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist, Nebivolol
Authors: Kuroedov Alexey , Cosentino Francesco , Lüscher Thomas F.
Published: August 2010

Nebivolol is a racemic mixture of d‐ and 1‐enantiomers. The drug is characterized by β1‐adrenoceptor selectivity and long‐acting β1‐blockade exerted predominantly by d‐enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial‐dependent mechanism involving stimulation of β3‐adrenoceptors as well as by endothelial‐independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium‐dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion‐induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional β‐adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24‐h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough‐to‐peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo‐controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.
Clinical Potential of Lomerizine, a Ca2+ Channel Blocker as an Anti‐Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage
Authors: Hara Hideaki , Toriu Nobuko , Shimazawa Masamitsu
Published: August 2010

Glaucoma is defined as an optic neuropathy with characteristic changes in the optic nerve head and ultimate loss of visual field. Previous studies have suggested that (a) mechanical damage due to raised intraocular pressure and (b) a compromised tissue circulation in the optic nerve head play significant roles in the development of glaucomatous damage in the optic nerve head. Recently, we found that lomerizine, a new Ca2+ channel blocker, increased ocular circulation and protected neuronal cells against retinal neurotoxicity both in vitro and in vivo with minimal cardiovascular side effects. We examined the effect of lomerizine on the ocular circulation and compared it with those of other Ca2+ channel blockers in normal rabbits and in rabbits with an endothelin‐1‐disturbed circulation in the optic nerve head. In anesthetized rabbits, lomerizine and the other Ca2+ channel blockers increased the ocular circulation and also inhibited the hypoperfusion induced in optic nerve head tissue by an intravitreous injection of endothelin‐1. Whereas the other Ca2+ channel blockers produced changes in blood pressure and heart rate, the effects of lomerizine on these parameters were slight. In healthy humans, lomerizine increased blood velocity in the optic nerve head, without significantly altering blood pressure or heart rate. Moreover, lomerizine reduced retinal damage in rats both in vitro and in vivo, presumably through a Ca2+ channel blocking effect via an action that may involve a direct protection of retinal neurons as well as an improvement in the ocular circulation. These results indicate that lomerizine may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that involve a disturbance of the ocular circulation.
Candesartan
Authors: Gleiter Christoph H. , Jägle Christine , Gresser Ursula , Mörike Klaus
Published: August 2010

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non‐competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. Clinical trials have demonstrated its efficacy at a dose range of 2 to 32 mg once daily in hypertension of all grades, heart failure, in reducing urinary albumin excretion in diabetes mellitus and in coexisting hypertension and renal failure.

Pharmacokinetic properties of candesartan cilexetil in elderly patients are not significantly different from those in younger individuals. Hepatic impairment does not change pharmacokinetics of candesartan cilexetil at doses up to 12 mg/day. No dose adjustment is necessary in patients with mild or moderate renal impairment.

Tolerability of candesartan cilexetil is not much different from that of placebo. All adverse events are usually of mild to moderate severity and not dose‐related. The most common adverse events were headache, upper respiratory tract infection, back pain, and dizziness. The incidence of these adverse effects, as well as of cough, was similar in patients treated with candesartan cilexetil or placebo. The incidence of adverse events in long‐term trials was not different from that in short‐term trials. Tolerability of candesartan cilexetil does not differ with either age or gender.
SEA0400: A Novel Sodium‐Calcium Exchange Inhibitor with Cardioprotective Properties1
Authors: Lee Candace , Hryshko Larry V.
Published: August 2010

The cardiac sodium‐calcium exchanger (NCX) plays an important role in calcium homeostasis. It is the primary mechanism for removing calcium ions that enter myocytes through L‐type calcium channels on a beat‐to‐beat basis. Its direction of transport is determined by the membrane potential and the ionic concentrations of Na+and Ca2+, with the forward (or Ca2+‐efflux) mode of transport being the dominant mode under physiological conditions. In contrast, the Ca2+‐influx mode (or reverse mode) of NCX becomes important in certain pathophysiological conditions, such as myocardial ischemia and reperfusion. Recent discovery of compounds that inhibit the Ca2+‐influx mode (or reverse mode) of NCX has generated intense research interest in the pharmacology of NCX. Among the newer NCX inhibitors described to date, 2‐[4‐[(2,5‐difluorophenyl)methoxy]‐phenoxy]‐5‐ethoxyaniline (SEA0400) appears particularly promising in attenuating cardiac, renal, and cerebral ischemia/reperfusion injuries in various experimental models. Moreover, the mixed results that have emerged from clinical trials evaluating the efficacy and safety of inhibitors of the sodium‐hydrogen exchanger (an upstream target in relation to the sodium‐calcium exchanger) in myocardial protection stimulated interest in evaluating NCX as an alternative therapeutic target. This article reviews the pharmacological profile of SEA0400, as presented in the published literature, and discusses the therapeutic potential of this compound in attenuating myocardial ischemia/reperfusion injury.
Pharmacological Profile and Therapeutic Potential of BM‐573, a Combined Thromboxane Receptor Antagonist and Synthase Inhibitor
Authors: Ghuysen Alexandre , Dogné Jean‐Michel , Chiap Patrice , Rolin Stéphanie , Masereel Bernard , Lambermont Bernard , Kolh Philippe , Tchana‐Sato Vincent , Hanson Julien , D'Orio Vincent
Published: August 2010

BM‐573 (N‐terbutyl‐N′‐[2‐(4′‐methylphenylamino)‐5‐nitro‐benzenesulfonyl]urea), a torsemide derivative, is a novel non‐carboxylic dual TXA2 synthase inhibitor and receptor antagonist. The pharmacological profile of the drug is characterized by a higher affinity for the thromboxane receptor than that of SQ‐29548, one of the most powerful antagonists described to date, by a complete prevention of human platelet aggregation induced by arachidonic acid at a lower dose than either torsemide or sulotroban, and by a significantly prolonged closure time measured by the platelet function analyser (PFA‐100®). Moreover, at the concentrations of 1 and 10 μM, BM‐573 completely prevented production of TXB2 by human platelets activated by 0.6 mM of arachidonic acid. BM‐573 prevents rat fundus contraction induced by U‐46619 but not by prostacyclin or other prostaglandins. Despite possessing a chemical structure very similar to that of a diuretic torsemide, BM‐573 has no diuretic activity. BM‐573 does not prolong bleeding time and, unlike some of the other sulfonylureas, has no effect on blood glucose levels. In vivo, BM‐573 appears to have antiplatelet and antithrombotic activities since it reduced thrombus weight and prolonged the time to abdominal aorta occlusion induced by ferric chloride. BM‐573 also relaxed rat aorta and guinea pig trachea precontracted with U‐46619. In pigs, BM‐573 completely antagonized pulmonary hypertensive effects of U‐46619 and reduced the early phase of pulmonary hypertension in models of endotoxic shock and pulmonary embolism. Finally, BM‐573 protected pigs from myocardial infarction induced by coronary thrombosis.

These results suggest that BM‐573 should be viewed as a promising therapeutic agent in the treatment of pulmonary hypertension and syndromes associated with platelet activation.
Tolvaptan, an Orally Active Vasopressin V2‐Receptor Antagonist—Pharmacology and Clinical Trials
Authors: Miyazaki Toshiki , Fujiki Hiroyuki , Yamamura Yoshitaka , Nakamura Shigeki , Mori Toyoki
Published: August 2010

Tolvaptan is an orally effective nonpeptide arginine vasopressin (AVP) V2‐receptor antagonist synthesized by Otsuka Pharmaceutical Co., Ltd. Inin vitroreceptor‐binding studies, tolvaptan blocked the binding of [3H]AVP to human V2receptors with 29‐fold greater selectivity than that for V1areceptors, and showed no inhibition of V1breceptors. Tolvaptan inhibited not only the binding of [3H]AVP but also the AVP‐induced production of cyclic AMP in human V2‐receptor–expressing HeLa cells. In addition, tolvaptan has no intrinsic V2receptor agonistic effect.

Inin vivostudies, tolvaptan showed marked aquaresis in healthy and diseased animals. In rat models with acute and chronic hyponatremia, tolvaptan improved hyponatremia, resulting in the prevention of death, and improved organ water retention. Tolvaptan reduced cardiac preload without unfavorable effects on renal functions, systemic hemodynamics, or circulating neurohormones in dogs with heart failure (HF). Furthermore, in animal models of human polycystic kidney disease (PKD), tolvaptan showed a decrease in kidney weight as well as in cyst and fibrosis volume.

In clinical trials including the “ACTIV in CHF” study, tolvaptan in addition to standard therapy increased fluid loss resulting in decreased body weight, and improved edema and serum sodium without affecting blood pressure, heart rate, or renal functions in patients with HF. In patients with hyponatremia, treatment with tolvaptan without fluid restriction appeared to be more effective than fluid restriction alone at correcting hyponatremia without an increase in adverse events. A phase III trial EVEREST is currently being conducted to evaluate the long‐term efficacy and safety of tolvaptan in hospitalized patients with severe HF.

In conclusion, tolvaptan offers the possibility of a useful therapy in hyponatremia, congestive heart failure, and various other diseases that are associated with volume overload. Furthermore, tolvaptan is also expected to be effective in the treatment of PKD.
Therapeutic Potential of H11 Kinase for the Ischemic Heart
Authors: Danan Ilan J. , Rashed Eman R. , Depre Christophe
Published: August 2010

H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac‐specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol‐3‐kinase/Akt pathway, the AMP‐dependent protein kinase, the PKCε pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage.
Inhibiting Metalloproteases with PD 166793 in Heart Failure: Impact on Cardiac Remodeling and Beyond
Authors: Kaludercic Nina , Lindsey Merry L. , Tavazzi Barbara , Lazzarino Giuseppe , Paolocci Nazareno
Published: August 2010

Metalloproteinases (MMPs, also called matrixins) are extracellular proteolytic enzymes involved in the degradation of both matrix and nonmatrix proteins. Currently, 25 MMPs have been identified in humans, and the overexpression of one or more MMPs has been implicated in several pathologies, spanning from cancer to rheumathoid arthritis to cardiovascular disease. While research over the past 20 years has focused on understanding MMP biology and selectively inhibiting MMP activity, key issues that remain to be addressed include MMP roles in the context of normal versus pathological conditions and whether globally inhibiting MMPs improves or deteriorates overall organ function. In terms of cardiovascular disease, increased MMP expression has been demonstrated in the setting of myocardial ischemia, reperfusion injury, and during the progression to congestive heart failure. MMPs are also major contributors to the progression of atherosclerotic lesions. In this review, we focus on cardiovascular effects produced by PD 166793, a wide‐broad spectrum MMP inhibitor, originally developed by Parke‐Davis (now Pfizer). We will briefly review its structure, mechanism of action, and inhibitory capacity. Finally, we will illustrate the cardiac contexts, bothin vivoandin vitro, in which PD166793 administration has proven beneficial.
Inhibitors of Advanced Glycation End Products (AGEs): Potential Utility for the Treatment of Cardiovascular Disease
Authors: Yamagishi Sho‐ichi , Nakamura Kazuo , Matsui Takanori , Ueda So , Noda Yoshihiro , Imaizumi Tsutomu
Published: August 2010

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, stroke, blindness, and end‐stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Recent clinical studies have substantiated the concept of “hyperglycemic memory” in the pathogenesis of cardiovascular disease (CVD) in diabetes. Indeed, the Diabetes Control and Complications Trial‐Epidemiology of Diabetes Interventions and Complications (DCCT‐EDIC) Research, has revealed that intensive therapy during the DCCT reduces the risk of cardiovascular events by about 50% in type 1 diabetic patients 11 years after the end of the trial. Among various biochemical pathways activated under diabetic conditions, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory “hyperglycemic memory.” Further, there is a growing body of evidence that AGEs play an important role in CVD in diabetes. These observations suggest that the inhibition of AGEs formation may be a promising target for therapeutic intervention in diabetic vascular complications. Therefore, in this article, we review several agents with inhibitory effects on AGEs formation and their therapeutic implications in CVD in diabetes.
Cardioprotective Effect of Vanadyl Sulfate on Ischemia/Reperfusion‐Induced Injury in Rat HeartIn vivoIs Mediated by Activation of Protein Kinase B and Induction of FLICE‐Inhibitory Protein
Authors: Bhuiyan Md. Shenuarin , Takada Yoko , Shioda Norifumi , Moriguchi Shigeki , Kasahara Jiro , Fukunaga Kohji
Published: August 2010

Here we explored the mechanism of cardioprotective action of a tyrosine phosphatase inhibitor vanadyl sulfate on myocardial infarction and cardiac functional recovery in rats subjected to myocardial ischemia/reperfusion (MI/R)in vivo. Male Sprague‐Dawley rats underwent 30 min heart ischemia by left coronary artery occlusion followed by 24‐h reperfusion. Rats were randomized to receive either vehicle or vanadyl sulfate (1 and 5 mg/kg) intraperitoneally 0 min and 30 min after the start of reperfusion. Posttreatment with vanadyl sulfate significantly reduced the infarct size and significantly decreased the elevated left ventricular end diastolic pressure, improved left ventricular developed pressure, and left ventricular contractility (± dP/dt) after 72‐h reperfusion in a dose‐dependent manner. Moreover, treatment with vanadyl sulfate also significantly inhibited the apoptosis‐related Caspase‐3 and Caspase‐9 processing, thereby elicited the antiapoptotic effect. The cardioprotective effect of vanadyl sulfate was closely associated with restoration of reduced protein kinase B (Akt) activity following MI/R injury. The recovered Akt activity correlated with increased phosphorylation of forkhead transcription factors, FKHR and FKHRL‐1, thereby inhibiting apoptotic signaling. Furthermore, treatment with vanadyl sulfate significantly increased FLICE‐inhibitory protein (FLIP) expression, and decreased expression of Fas ligand and Bim in cardiomyocytes. Taken together, rescue of cardiomyocytes by posttreatment with vanadyl sulfate from MI/R injury was mediated by increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt. These results demonstrate that treatment with vanadyl sulfate exerts significant cardioprotective effects along with cardiac functional recovery.
Postponing or eliminating red blood cell transfusions of very low birth weight neonates by obtaining all baseline laboratory blood tests from otherwise discarded fetal blood in the placenta
Authors: Christensen Robert D. , Lambert Diane K. , Baer Vickie L. , Montgomery Dianne P. , Barney Cindy K. , Coulter David M. , Ilstrup Sarah , Bennett Sterling T.
Published: August 2010

BACKGROUND: Safely reducing the proportion of very low birth weight neonates (<1500 g) that receive a red blood cell (RBC) transfusion would be an advance in transfusion practice.

STUDY DESIGN AND METHODS: We performed a prospective, single‐centered, case‐control, feasibility analysis, preparatory to designing a definitive trial. Specifically, we sought to determine whether we could obtain all baseline neonatal intensive care unit blood tests from the placenta, after placental delivery, thereby initially drawing no blood from the neonate.

RESULTS: Ten cases where all baseline blood tests were drawn from the placenta, and 10 controls where all tests were drawn from the neonate, were closely matched for birth weight, gestational age, sex, and race. Early cord clamping was used for all 20. Over the first 18 hours the hemoglobin increased in nine cases versus two controls (p = 0.005). During the first 72 hours one case versus five controls qualified for and received an RBC transfusion. In the first week the cases received four transfusions and the controls received 16 (p = 0.02). None of the cases had an intraventricular hemorrhage (IVH) but four of the controls had a Grade 1 and two had a Grade 3 (p = 0.01).

CONCLUSION: We speculate that this method is feasible and generally postpones the first RBC transfusion until beyond the period of peak vulnerability to IVH.
CLASS IA AND CLASS IB ANTIARRHYTHMIC DRUGS — A Review of Their Pharmacokinetics, Electrophysiology, Efficacy, and Toxicity
Authors: SALERNO DAVID M.
Published: August 2010

Class 1A agents share the electrophysiologic property of slmuing of Vmaxof phase 0 of the action potential and moderate prolongation of the action potential duration and refractoriness. Their electrocardiographic effect in therapeutic doses is to prolong the QTc. interval due to prolongation of the JTcinterval. The PR and QRS intervals are not prolonged in therapeutic doses. This group of agents contains the standard antiarrhythmic agents released prior to 1984. The older drugs in this group wilt be reviewed only briefly in this report. Their effect on suppression of ventricular ectopic depolarizations will be reviewed for comparison with the newer agents.
Intravenous Flecainide in the Management of Acute Supraventricular Tachyarrhythmias*
Authors: LACOMBE PIERRE , COINTE ROLAND , METGE MARC , BRU PAUL , BRU RAYMOND , GERARD RAYMOND , LEVY SAMUEL
Published: August 2010

Intravenous flecainide (1.5 mg/kg) was given to 30 patients with acute supraventricular tachyarrhythmias: atrial fibrillation (12 patients), atrial flutter (7 patients), and reciprocating tachycardia due to reentry through an accessory pathway (5 patients). The total rate of conversion to sinus rhythm was 18 out of 30 patients (60%), 11 out of 11 patients (100%) with reciprocating tachycardia and 7 out of 19 patients (37%) with atrial flutter or fibrillation. In those patients not converted to sinus rhythm, the mean ventricular rate significantly (P < 0.1) slowed from 140 ± 15 beats/min with slowing of ventricular rate below 100 beats/min in 2 patients. Tolerable side effects occurred in 5 patients (17%) and included transient moderate hypotension (1 patient), blurred vision (1 patient), and transient conduction defects (3 patients). We conclude that intravenous flecainide is a safe and effective antiarrhythmic agent for the termination of acute reciprocating tachycardias and moderately useful for the management of atrial flutter or fibrillation.
Long‐term Reproducibility of Response to Noninvasive Programmed Cardiac Stimulation in Spontaneous, Sustained Ventricular Tachycardia Treated with Amiodarone Therapy
Authors: MENOZZI CARLO , BRIGNOLE MICHELE , LOLLI GINO , BACCHI MIRKA , MONDUCCI IGOR , SARTORE BRUNO , BARRA MAURO
Published: August 2010

A total of 73 noninvasive serial electrophysiological studies were carried out in 12 patients with spontaneous sustained ventricular tachycardia, inducible in spite of chronic treatment with amiodarone, in order to verify the effect of this drug on the long‐term reproducibility of the test. A ventricular tachycardia was induced in 72 of 73 times; in 59% of cases, the clinical form was induced. In 8 of 12 patients, two or more types or morphologies of ventricular tachycardia could be induced. The induction modes (driving rate and number of extrastimuli) changed considerably in different studies. During a follow‐up of 12 ± 6 months, 5 out of 12 patients had spontaneous relapses. We observed no differences between these patients and the others regarding inducibility, types and morphologies of the induced tachycardias, or induction modes. Therefore, when ventricular tachycardia is inducible in spite of chronic amiodarone therapy, it is always inducible during follow‐up, even if a great intrapatient change of type and the morphology of induced tachycardias and induction modes is observed. However, since similar electrophysiological features are present in patients with and without spontaneous recurrence of ventricular tachycardia, serial electrophysiological studies are of little value in predicting the clinical outcome.
Arrhythmia Profile and Sudden Death After Myocardial Infarction and Cardiac Arrest
Authors: TRAPPE HANS‐JOACHIM , KLEIN HELMUT , WENZLAFF PAUL , LICHTLEN PAUL R.
Published: August 2010

Incidence of sudden death and arrhythmia pattern were studied using ambulatory monitoring in 40 patients resuscitated < 24 hours (n = 26, Group I) or 4–12 weeks (n = 14, Group II) after myocardial infarction. Forty patients with myocardial infarction and no resuscitation served as controls (Group III). Ambulatory ECGs were recorded with an average of 2 months (Recording 1) and 28 months (Recording 2) after myocardial infarction. Incidence of sudden death was significantly higher in Group II (43%) than in Group I (15%) or Group III (8%) (p < 0.01). In Recording 1, there were no significant differences in the incidence of premature ventricular beats and complex arrhythmias (couplets or salvos) between survivors and sudden death patients in Groups I, II and III, whereas in Recording 2 the mean incidence of premature ventricular beats and complex arrhythmias was significantly higher in survivors in Group II than in Group I or Group III (p < 0.05). In addition, in survivors in Group II, incidence of premature ventricular beats and complex arrhythmias was significantly higher in Recording 2 than in Recording 1 (p < 0.05). Our data show that the risk of sudden death is high in patients with cardiac arrest 4–12 weeks after myocardial infarction. Repeated studies using ambulatory monitoring are helpful in estimating the risk of sudden death in patients with myocardial infarction and cardiac arrest.
Clinical Course and Implantable Cardioverter Defibrillator Therapy in Postinfarction Women with Severe Left Ventricular Dysfunction
Authors: ZAREBA WOJCIECH , MOSS ARTHUR J. , JACKSON HALL W. , WILBER DAVID J. , RUSKIN JEREMY N. , MCNITT SCOTT , BROWN MARY , WANG HONGYUE ,   MADIT II Investigators
Published: August 2010

Background:There are limited data regarding implantable cardioverter defibrillator (ICD) therapy in postinfarction women with severe left ventricular dysfunction. The aim of this study was to evaluate the risk of cardiac events and effects of ICD therapy in women as compared to men enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II).

Methods and Results:Among 1,232 patients enrolled in MADIT II, there were 192 (16%) women and 1,040 (84%) men. When compared to men, women had an increased frequency of NYHA class ≥II (70 vs 63%; P = 0.067), hypertension (60% vs 52%; P = 0.047), diabetes (42% vs 34%; P = 0.027), and LBBB (25% vs 17%; P = 0.011), and less frequent CABG surgery (42% vs 60%; P < 0.001). The 2‐year cumulative mortality in patients randomized to conventional therapy was not significantly different in women and men (30% and 20%, respectively; P = 0.19). Adjusting for relevant clinical covariates, the hazard ratios for ICD effectiveness were similar in women (0.57; 95% CI = 0.28–1.18; P = 0.132) and men (0.66; 95% CI = 0.48–0.91; P = 0.011). The risk of appropriate ICD therapy for VT/VF was lower in women than in men (hazard ratio = 0.60 for female vs male gender; 95% CI = 0.37–0.98; P = 0.039).

Conclusions:MADIT II women had similar mortality and similar ICD effectiveness when compared to men. MADIT II women with ICDs had a lower risk of arrhythmic events with fewer episodes of ventricular tachycardia than men.
Successful Radiofrequency Catheter Ablation of Epicardial Left Ventricular Outflow Tract Tachycardia from the Anterior Interventricular Coronary Vein
Authors: HIRASAWA YASUHIRO , MIYAUCHI YASUSHI , IWASAKI YU‐KI , KOBAYASHI YOSHINORI
Published: August 2010

We report a case of idiopathic left ventricular outflow tract (LVOT) tachycardia that was eliminated by a radiofrequency application from the anterior interventricular coronary vein (AIV). The ECG exhibited QRS complexes with an inferior axis and atypical left bundle branch block pattern with an early transition of the precordial R waves at V3. Several radiofrequency applications from the coronary cusps and endocardial LVOT were not effective. Radiofrequency applications in the AIV, where the activation preceded the onset of the QRS by 30 msec, successfully eliminated the tachycardia. The AIV may be an optional site for radiofrequency ablation of idiopathic epicardial LVOT tachycardia.
The Shield of Defense or the Sword of Prosecution? How Self‐Regulatory Focus Relates to Responses to Crime
Authors: O'Brien Barbara , Oyserman Daphna
Published: August 2010

People can strive to attain goals in one of two ways: They can be tolerant of risk and focus on attaining successes, or they can be intolerant of risk and focus on avoiding pitfalls and failures. These differences, termed promotion focus and prevention focus, respectively, have been related to differences in how personal goals are understood, but not yet applied to policy issues. Two studies examine the implications of chronic (Study 1) and experimentally induced (Study 2) promotion vs. prevention goals for a law‐and‐order mind set. Participants high in promotion focus assigned more punishment to a criminal (Study 1). Compared to prevention‐focused participants, experimentally induced promotion focus increased the likelihood of arresting a suspect and justifying this choice (Study 2).