bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ezetimibe: A First‐in‐Class, Novel Cholesterol Absorption Inhibitor
Authors: Lipka Leslie J. 
Published: August 2010

ABSTRACTSignificant 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

ABSTRACTProtease 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

ABSTRACTCoronary 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

ABSTRACTIt 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

ABSTRACTThe 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

ABSTRACTNebivolol 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

ABSTRACTGlaucoma 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

ABSTRACTCandesartan 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

ABSTRACTThe 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

ABSTRACTBM‐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

ABSTRACTTolvaptan 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

ABSTRACTH11 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.