bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluvastatin, HMG‐CoA Reductase Inhibitor: Antiatherogenic Profiles Through Its Lipid‐Lowering–Dependent and ‐Independent Actions
Authors: Mitani Hironobu , Kimura Masaaki 
Published: August 2010

ABSTRACTFluvastatin, the first totally synthetic inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, has the unique structure of a mevalonolactone derivative of a fluorophenyl‐substituted indole ring. Fluvastatin markedly reduces plasma lipid levels in animals and humans by inhibiting the activity of HMG‐CoA reductase following the up‐regulation of low density lipoprotein receptors, as it occurs with other HMG‐CoA reductase inhibitors. Several lines of evidence indicate that the hypolipidemic action of fluvastatin results in antiatherosclerotic effects in hyperlipidemic animal models. Recent findings have shown, however, that fluvastatin inhibits the progression of atherosclerosis independent of its lipid‐lowering effects. In addition, fluvastatin inhibits key events or factors in the initiation or progression of atherosclerosis. These effects include antioxidant and antithrombotic properties, improvement of endothelial function, inhibition of activated monocyte‐endothelial cell interaction, and inhibition of activated macrophage and smooth muscle cell function.Recent large clinical trials with fluvastatin demonstrated its beneficial effects on the incidence of clinical events and on the progression of atherosclerotic plaques in patients with hyperlipidemia. Although angiographic changes (e.g., the decrease in minimum lumen diameter) in response to therapy were modest, the accompanying clinical benefit appeared to be significant. The lipid‐lowering therapy can not fully explain the results of clinical trials. The antiatherogenic profiles of fluvastatin might contribute to the decrease in the clinical events by directly inhibiting the atherosclerotic plaque progression and stabilizing the atherosclerotic plaque lesion.Elucidation of pleiotropic effects of fluvastatin other than lipid‐lowering properties encourages the clinical use of fluvastatin not only for the reduction of plasma cholesterol levels but also for the secondary prevention of coronary heart disease in patients with hypercholesterolemia.
Pharmacology of the Thromboxane Receptor Antagonist and Thromboxane Synthase Inhibitor BM‐531
Authors: Dogné Jean‐Michel , Rolin Stéphanie , de Leval Xavier , Benoit Patricia , Neven Philippe , Delarge Jacques , Kolh Philippe , Damas Jacques , David Jean‐Louis , Masereel Bernard 
Published: August 2010

ABSTRACTBM‐531 (N‐tert‐butyl‐N'‐[(2‐cyclohexylamino‐5‐nitrobenzene)sulfonyl]urea), a torasemide derivative, is a novel noncarboxylic thromboxane receptor antagonist and thromboxane synthase inhibitor. Indeed, its affinity for human washed platelet TXA2receptors labeled with [3H]SQ‐29548 (IC50= 0.0078 μM) is higher than sulotroban (IC50= 0.93 μM) and SQ‐29548 (IC50= 0.021 μM). Moreover, BM‐531 is characterized by a potent antiaggregatory property. Indeed, on one hand, in human citrated platelet‐rich plasma BM‐531 prevents platelet aggregation induced by arachidonic acid (600 μM) (ED100= 0.125 μM), U‐46619, a stable TXA2agonist (1 μM) (ED50= 0.482 μM) or collagen (1 μg/mL) (percentage of inhibition: 42.9% at 10 μM) and inhibits the second wave of ADP (2 μM)‐induced aggregation. On the other hand, when BM‐531 is incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA‐100®) is significantly prolonged. In addition, at the concentrations of 10 and 1 μM, BM‐531 totally prevents the production of TXB2by human platelets activated by arachidonic acid. Finally, at 10 μM, BM‐531 significantly prevents rat fundus contractions induced by U‐46619 but not by prostacyclin. These results suggest that BM‐531, which is devoid of the diuretic property of torasemide, can be regarded as a promising antiplatelet agent.
Ifetroban Sodium: An Effective TxA2/PGH2Receptor Antagonist
Authors: Rosenfeld Louis , Grover Gary J. , Stier Charles T. 
Published: August 2010

ABSTRACTThis review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2receptor antagonist. Thromboxane A2is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2– and prostaglandin H2‐mediated processes.
Sotalol: The Mechanism of Its Antiarrhythmic‐Defibrillating Effect
Authors: Manoach Mordechai , Tribulova Narcis 
Published: August 2010

ABSTRACTThis minireview deals with the role of intercellular communication and synchronization in the initiation and maintenance of ventricular fibrillation. It is proposed that myocardial cell junctions might represent a therapeutic substrate for the prevention of this fatal arrhythmia. This hypothesis is supported by the results of recent experimental studies involving elucidation of the mechanism of antiarrhythmic‐defibrillating effects of sotalol. Enhancement of intercellular communication and myocardial synchronization are thought to play critical role in the mechanism of action of this drug.
Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)
Authors: Delyani John A. , Rocha Ricardo , Cook Chyung S. , Tolbert Dwain S. , Levin Stuart , Roniker Barbara , Workman Diane L. , Sing Yuen‐lung L. , Whelihan Brian 
Published: August 2010

ABSTRACTAldosterone, the final product of the renin‐angiotensin‐aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin‐converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels — a phenomenon termed “aldosterone synthesis escape.” Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone — the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) — is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24‐h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.
Norbormide: a Calcium Entry Blocker with Selective Vasoconstrictor Activity in Rat Peripheral Arteries
Authors: Bova Sergio , Cima Lorenzo , Golovina Vera , Luciani Sisto , Cargnelli Gabriella 
Published: August 2010

ABSTRACTNorbormide is a unique vasoactive substance endowed with species‐ and tissue‐specific, endothelium independent, vasoconstrictor activity that is restricted to the peripheral arteries of rat. In rat aorta and in all tested arteries of other species norbormide exhibits vasorelaxant property presumably due to the blockade of calcium channels. A calcium entry blocker effect of norbormide has also been described in isolated, perfused guinea pig hearts. In these preparations norbormide produced coronary vasodilator, as well as negative inotropic and dromotropic effects. In single ventricular myocytes of guinea pigs norbormide reduces L‐type calcium current. The mechanism underlying the selective vasoconstrictor effect of norbormide is unknown. In rat caudal artery, a vessel contracted by norbormide, the drug activates phospholipase C (PLC) signal cascade which is the biochemical pathway involved in the contractile effect triggered by most receptor‐activating vasoactive agents. Therefore, norbormide‐ induced contraction of rat peripheral vessels is likely to be due to the activation of a PLC‐coupled receptor abundantly or selectively expressed in vascular smooth muscle cells. The identification of this putative receptor could facilitate the development of tissue‐selective pharmacological agents.
Cardiovascular Actions of Berberine
Authors: Lau Chi‐Wai , Yao Xiao‐Qiang , Chen Zhen‐Yu , Ko Wing‐Hung , Huang Yu 
Published: August 2010

ABSTRACTBerberine, is an alkaloid fromHydrastis canadensisL., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8‐oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some of cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+channels (delayed rectifier and KATP) and stimulation of Na+‐Ca2+exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.
Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake
Authors: Liu Yongge , Shakur Yasmin , Yoshitake Masuhiro , Kambayashi Jun‐ichi 
Published: August 2010

ABSTRACTCilostazol (Pletal®), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP‐elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting anti‐platelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3‐inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferationin vitroand has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL‐cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double‐blind randomized placebo‐controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double‐blinded, placebo‐controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well‐tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off‐label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.
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

ABSTRACTRaloxifene 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

ABSTRACTTissue 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

ABSTRACTOlprinone 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

ABSTRACTThe 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

ABSTRACTLipoprotein 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.