bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pitavastatin: Efficacy and Safety Profiles of A Novel Synthetic HMG‐CoA Reductase Inhibitor
Authors: Kajinami Kouji , Takekoshi Noboru , Saito Yasushi 
Published: August 2010

ABSTRACTThe use of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis‐associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug‐drug interactions.Pitavastatin (NK‐104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol‐lowering action. The short‐term and long‐term lipid‐modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type‐2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid‐lowering drug seems to be similar, or potentially superior, to that of atorvastatin.According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4‐mediated metabolism of concomitantly administered drugs; P‐glycoprotein‐mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P‐glycoprotein activity.It could be concluded that pitavastatin could provide a new and potentially better thera‐peutic choice for lipid‐modifying therapy than do the currently available statins. The ef‐ficacy and safety of higher dose treatment, as well as its long‐term effects in the pre‐vention of coronary artery disease, should be further investigated.
KB130015, A New Amiodarone Derivative with Multiple Effects on Cardiac Ion Channels
Authors: Mubagwa Kanigula , Macianskiene Regina , Viappiani Serena , Gendviliene Vida , Carlsson Bo , Brandts Bodo 
Published: August 2010

ABSTRACTKB130015 (KB015), a new drug structurally related to amiodarone, has been proposed to have antiarrhythmic properties. In contrast to amiodarone, KB015 markedly slows the kinetics of inactivation of Na+channels by enhancing concentration‐dependently (K0.5# 2 μM) a slow‐inactivatingINacomponent (#slow# 50 ms) at the expense of the normal, fast‐inactivating component (#fast# 2 to 3 ms). However, like amiodarone, KB015 slows the recovery from inactivation and causes a shift (K0.5. # 6.9 μM) of the steady‐state voltage‐dependent inactivation to more negative potentials. Despite prolonging the opening of Na+channels KB015 does not lengthen but often shortens the action potential duration (APD) in pig myocytes or in multicellular preparations. Only short APDs in mouse are markedly prolonged by KB015, which frequently induces early afterdepolarizations. KB015 has also an effect on other ion channels. It decreases the amplitude of the L‐type Ca2+current (ICa‐L) without changing its time course, and it inhibits G‐protein gated and ATP‐gated K+channels. Both the receptor‐activatedIk(ACH)(induced in atrial myocytes by either ACh, adenosine or sphingosylphosphorylcholine) and the receptor‐independent (GTPγS‐induced or background)Ik(ACH)are concentration‐dependently (K0.5# 0.6 – 0.9 μM) inhibited by KB015.Ik(ATP), induced in atrial myocytes during metabolic inhibition with 2,4‐dinitrophenol (DNP), is equally suppressed. However, KB015 has no effect onIK1or onIto. Consistent with the effects in K+currents, KB015 does not depolarize the resting potential but antagonizes the APD shortening by muscarinic receptor activation or by DNP. Intracellular cell dialysis with KB015 has marginal or no effect on Na+or K+channels and does not prevent the effect of extracellularly applied drug, suggesting that KB015 interacts directly with channels at sites more easily accessible from the extracellular than the intracellular side of the membrane. At high concentrations KB015 exerts a positive inotropic action. It also interacts with thyroid hormone nuclear receptors. Its toxic effects remain largely unexplored, but it is well tolerated during chronic administration.
CVT‐510: A Selective A1Adenosine Receptor Agonist
Authors: Cheung Jim W. , Lerman Bruce B. 
Published: August 2010

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

ABSTRACTKC 12291 was designed as a voltage‐gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+current, and markedly reduces sustained (or slowly or non‐inactivating) Na+current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+current.In isolated atria and Langendorff‐perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activityin vivoin the absence of major hemodynamic effects.Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+current, represent, therefore, promising potential antiischemic and cardioprotective drugs.
Guinea Pigs as Models to Study the Hypocholesterolemic Effects of Drugs
Authors: West Kristy L. , Luz Fernandez Maria 
Published: August 2010

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

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

ABSTRACTPortal hypertension, a life threatening complication of liver cirrhosis, results from increased intrahepatic resistance and increased portal blood inflow through a hyperdynamic splanchnic system. The increased intrahepatic vascular tone is the result of an enhanced activity of endogenous vasoconstrictors and a deficiency of nitric oxide (NO) release by sinusoidal endothelial cells. These pathophysiological events provide the rational basis for using NO‐based therapies for the treatment of portal hypertension. Clinical studies have demonstrated that nitrate therapy results in a significant reduction of portal pressure as assessed by hepatic venous portal gradient but causes vasodilation in both systemic arterial and venous vascular beds, aggravating the progression of the vasodilatory syndrome of cirrhotic patients. For this reason, the ideal drug for the treatment of portal hypertension should act by decreasing intrahepatic vascular resistance, without worsening the splanchnic/systemic vasodilatation.NCX‐1000 is the prototype of a family of NO‐releasing derivatives of ursodeoxycholic acid (UDCA). These compounds are releasing selectively, from parenchymal and non‐parenchymal hepatic cells, biologically active NO into the liver microcirculation with no detectable effect on systemic circulation. Preclinical studies have shown that long‐ and short‐term administration of NCX‐1000 to rodents with chronic liver injury protects against the development of portal hypertension and reduces the intrahepatic hyperreactivity to α1‐adrenoceptor agonists. The finding of increased liver nitrite/nitrate content in NCX‐1000‐treated animals together with an increase in cGMP levels in their liver homogenates suggests that this nitro‐compound behaves as a liver‐selective NO donor. In contrast to conventional NO‐donors such as isosorbide mono‐ and di‐nitrate, which are also used for primary and secondary prevention of gastrointestinal bleeding, NCX‐1000 has no effect on mean arterial pressure in either normal or cirrhotic animals indicating the absence of adverse systemic effect. In summary, these data suggest that NCX‐1000 may provide a novel therapy for the treatment of patients with portal hypertension.
Prevention of Cardiovascular Complications of Diabetes Mellitus by Aspirin
Authors: Nobles‐James Candi , James Erskine A. , Sowers James R. 
Published: August 2010

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

ABSTRACTClevidipine is an ultrashort‐acting vasoselective calcium antagonist under development for short‐term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4‐dihydropyridine that inhibits L‐type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg). and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half‐life in patients undergoing cardiac surgery is less than one min.Unlike sodium nitroprusside, a drug commonly used for the short‐term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate.In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min‐long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside.
The Preclinical Pharmacology of BIBN4096BS, a CGRP Antagonist
Authors: Hay Debbie L. , Poyner David 
Published: August 2010

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

ABSTRACTBunazosin hydrochloride is a potent and selective α1‐adrenoceptor antagonist that has been clinically used both as a systemic antihypertensive as well as an ocular hypotensive drug. In a number of studies, we have examined some effects of bunazosin hydrochloride that might indicate its potential as an anti‐glaucoma drug. In normal rabbit eyes, topically instilled bunazosin hydrochloride reached the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine‐ or endothelin‐1 (ET‐1)‐induced constriction of retinal arteries. Furthermore, bunazosin hydrochloride improved the impairment of optic nerve head (ONH) blood flow, the prolongation of visual‐evoked potentials (VEP) implicit time, the enlargement of the optic disk cup, and the decrease in the number of retinal ganglion cell layer cells induced by repeated injections of ET‐1 in rabbits. Topically instilled bunazosin hydrochloride improved the reductions in ONH capillary blood flow and VEP amplitude induced in rabbit eyes by nitric oxide synthase inhibition. In rat primary retinal cultures, bunazosin hydrochloride reduced glutamate‐induced neuronal cell death, presumably through a Na+channel blocking effect. In healthy humans, topically instilled bunazosin hydrochloride reportedly increases blood velocity in the ONH, retina and choroid, without significantly altering either blood pressure or heart rate. These results indicate that bunazosin hydrochloride exerts both an improvement effect within the ocular circulation and a direct neuroprotective effect. Hence, bunazosin hydrochloride may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that are associated with disturbances of the ocular circulation.
Efficacy and Safety of Sitosterol in the Management of Blood Cholesterol Levels
Authors: Luz Fernandez Maria , Vega‐López Sonia 
Published: August 2010

ABSTRACTElevated levels of plasma LDL cholesterol (LDL‐C) represent a major risk factor for cardiovascular disease. Treatments aimed at reducing levels of circulating LDL are regarded, therefore, as cardioprotective. The cholesterol lowering properties of plant sterols have been known for some time and many clinical studies have confirmed the efficacy of sitosterol in lowering plasma LDL‐C concentrations. Animal studies have also shown reductions in LDL by sitosterol. The use of animal models has been useful in facilitating the elucidation of specific mechanisms by which this sterol exerts its hypocholesterolemic action. It is well known that plant sterols compete with cholesterol for space within bile salt micelles in the intestinal lumen thereby reducing cholesterol absorption. The understanding of the function of plant sterols in impeding cholesterol absorption has been clarified with the discovery of the adenosine binding cassette transporters, ABCG5/8, involved in the regulation of sterol absorption and secretion into the enterocyte and hepatocyte. Compared to cholesterol and other sterols, sitosterol is preferentially pumped out to the intestinal lumen by the ABCG5/8 transporters. This selective binding of sitosterol to the transporters ultimately results in significant lowering of plasma cholesterol. However, some findings support the hypothesis that plant sterols might be an additional risk factor for coronary heart disease. From the review of these studies, it is apparent that sitosterol is a useful dietary supplement for the lowering of plasma cholesterol. Nevertheless, this plant sterol should be used with caution in certain individuals who have a higher absorption rate of sitosterol.
Pharmacological Mechanisms Contributing to the Clinical Efficacy of Levosimendan
Authors: Papp Zoltán , Csapó Kálmán , Pollesello Piero , Haikala Heimo , Édes István 
Published: August 2010

ABSTRACTAcute decompensation of chronic heart failure is a direct life‐threatening situation with short‐term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+‐sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+‐sensitization through binding to troponin C in the myocardium, and the opening of ATP‐sensitive K+channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long‐term benefits on mortality following short‐term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of pre‐clinical and clinical investigations suggest that the combination of levosimendan‐induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+‐sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP‐sensitive K+channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.