bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efonidipine Hydrochloride: A Dual Blocker of L‐ and T‐Type Ca2+ Channels
Authors: Tanaka Hikaru , Shigenobu Koki 
Published: August 2010

ABSTRACTT‐type Ca2+ channels have properties different from those of the L‐type and are involved in cardiac pacemaking and regulation of blood flow, but not in myocardial contraction. Efonidipine is an antihypertensive and antianginal drug with dihydropyridine structure that was recently found to block both L‐ and T‐type Ca2+ channels. In isolated myocardial and vascular preparations, efonidipine has potent negative chronotropic and vasodilator effects but only a weak negative inotropic effect. In experimental animals and patients, reduction of blood pressure by the drug was accompanied by no or minimum reflex tachycardia leading to improvement of myocardial oxygen balance and maintenance of cardiac output. Efonidipine increased glomerular filtration rate without increasing intraglomerular pressure. By relaxing both the afferent and efferent arterioles, efonidipine markedly reduced proteinuria. Thus, efonidipine, an L‐ and T‐type dual Ca2+ channel blocker, appears to have an ideal profile as an antihypertensive and antianginal drug with organ‐protective effects in the heart and kidney.
Sitosterolemia
Authors: Salen Gerald , Patel Shailesh , Batta A. K. 
Published: August 2010

ABSTRACTSitosterolemia was first described 28 years ago in two sisters. They had tendon xanthomas, normal plasma cholesterol levels, and elevated plant sterol levels. The high plant sterol levels were shown to be due to the increased absorption and delayed removal of plant sterols from the body. The increased absorption of plant sterols does not affect cholesterol absorption in these patients. However, cholesterol biosynthesis pathway is downregulated and turnover rates are reduced. Bile acid binding resins and ileal bypass surgery are effective treatments for sitosterolemic patients, whereas statins are ineffective. Sitosterolemia is inherited as a recessive trait. Recent studies have shown that mutations in ABCG5 and ABCG8 genes contribute to sitosterolemia. Most likely, ABCG5 and ABCG8 proteins function as obligate heterodimers and play a role in the absorption of plant sterol or control their rate of absorption.
Update on Fenofibrate
Authors: Guay David R. P. 
Published: August 2010

ABSTRACTFenofibrate is a fibric acid derivative that has been marketed since the mid‐1970's (1998 in the United States). Its active metabolite, fenofibric acid, is responsible for the primary pharmacodynamic effects of the drug: reductions in total plasma cholesterol, lowdensity lipoprotein cholesterol, triglycerides, and very low‐density lipoprotein concentrations and increases in high‐density lipoprotein cholesterol and apolipoproteins AI and AII concentrations. These effects are mediated by activation of peroxisome proliferator‐activated receptor‐α (PPARα). The drug has broad spectrum utility, with documented efficacy in Fredrickson types IIa, IIb, III, IV, and V hyperlipidemias. Fenofibrate is well tolerated, with digestive and musculoskeletal side effects similar to those of other fibrates. Results of the initial cardiovascular morbidity/mortality outcomes study with fenofibrate (known as DAIS [Diabetes Atherosclerosis Intervention Study]) were encouraging vis‐à‐vis slowing of atherosclerotic progression in the coronary vasculature of type II diabetics. The results of other ongoing outcome trials are eagerly awaited. These results will help to establish the overall place of fenofibrate in the hypolipidemic armamentarium.
Rosuvastatin: A Highly Effective New HMG‐CoA Reductase Inhibitor
Authors: Olsson Anders G. , McTaggart Fergus , Raza Ali 
Published: August 2010

ABSTRACTRosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG‐CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome P450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug‐drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose‐ranging studies in hypercholesterolemic patients demonstrated dose‐dependent effects in reducing low‐density lipoprotein cholesterol (LDL‐C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1‐ to 40‐mg dose range and a significant 8.4% additional reduction in LDL‐C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL‐C, increasing high‐density lipo‐protein cholesterol (HDL‐C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL‐C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL‐C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride‐containing lipoproteins, non‐HDL‐C, and LDL‐C and increasing HDL‐C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL‐C and non‐HDL‐C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid‐lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended‐release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long‐term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.
Pioglitazone: Cardiovascular Effects in Prediabetic Patients
Authors: Mizushige Katsufumi , Tsuji Teppei , Noma Takahisa 
Published: August 2010

ABSTRACTPioglitazone is the second thiazolidine derivative used clinically in the type 2 diabetes mellitus (DM). In the prediabetic stage, hyperinsulinemia or insulin resistance has been suggested to be closely associated with the oxidative stress. The first thiazolidine derivative used to treat DM, troglitazone, is chemically related to α‐tocopherol, a known anti‐oxidant. Troglitazone prevents tissue damage, but has been reported to produce hepatotoxicity. Pioglitazone strongly increases insulin sensitivity, improves glucose and lipid metabolism and showed no evidence of hepatotoxicity. The mechanism of the antidiabetic action of pioglitazone involves activation of insulin receptors and /or high affinity for peroxisome proliferator‐activated receptor γ (PPARγ). Hydroxylation of the phenyl and pyridine rings in the chemical structure of pioglitazone may facilitate the scavenging of hydro‐xyl radicals. The direct antioxidant effect of pioglitazone may contribute to its effect on insulin resistance. The hypoglycemic and hypolipidemic effects of pioglitazone are likely to reduce the expression of TNFα. The reduction in the oxidative stress may lead to the suppression of TGFβ and of collagen accumulation. A decrease in collagen content is likely to improve left ventricular diastolic function and distensibility of the aortic wall. Reduction in the oxidative stress may prevent the proliferation of vascular smooth muscle cells and contribute to the decrease in the aortic wall stiffness.
Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)
Authors: Llaverías Gemma , Laguna Juan C. , Alegret Marta 
Published: August 2010

ABSTRACTAvasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration‐dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B‐containing lipoproteins into plasma. Avasimibe induced cholesterol 7α‐hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol‐fed as well as in non‐cholesterol‐fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non‐HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50–500 mg/day, significantly reduced plasma total triglyceride and VLDL‐cholesterol. Although total cholesterol, LDL‐cholesterol, and HDL‐cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol‐lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.
The P2Y1Receptor as a Target for New Antithrombotic Drugs: A Review of the P2Y1Antagonist MRS‐2179
Authors: Baurand Anthony , Gachet Christian 
Published: August 2010

ABSTRACTMRS‐2179 is a selective P2Y1receptor antagonist, a strong inhibitor of ADP‐induced platelet aggregationin vitroandex vivo.By i.v. administration to mice MRS‐2179 increases resistance to thromboembolism induced by a mixture of collagen and epinephrine or by a tissue factor. Likewise, it significantly increases the time to thrombus formation in a ferric chloride‐induced model of localized arterial thrombosis. MRS‐2179 also confers resistance to localized venous thrombosis, which is dependent on thrombin generation and in which platelets play a relatively minor role as compared to stasis or activation of coagulation. These data provide considerable encouragement for the development of new P2Y1receptor antagonists. Nevertheless, the properties of MRS‐2179 indicate that new compounds should be optimized in order to increase the half‐life of the moleculein vivoand its selectivity and potency at the P2Y1receptor. Further directions include the synthesis of molecules with modifications of the nucleotide structure which replace the fragile moiety by a stable bond and should lead to a non‐hydrolysable structure. In conclusion, P2Y1antagonists have been shown to be efficient antithrombotic agents. MRS‐2179 is the first P2Y1antagonist with antithrombotic action. Its effectiveness demonstrates that the P2Y1receptor is a potentially promising target for drugs designed to treat thrombotic syndromes.
Bucillamine: A Potent Thiol Donor with Multiple Clinical Applications
Authors: Horwitz Lawrence D. 
Published: August 2010

ABSTRACTBucillamine has potential to attenuate or prevent damage during myocardial infarction, cardiac surgery and organ transplantation. Bucillamine, a cysteine derivative that contains two donatable thiol groups, is capable of replenishing the thiol group in glutathione, thereby reactivating this endogenous defense against oxidant injury. Bucillamine rapidly enters cells by the same mechanism that normally transports the amino acid cysteine. Bucillamine is a more potent thiol donor than other cysteine derivatives: approximately 16‐fold more potent than N‐acetylcysteine (Mucomyst®) in vivo. In addition bucillamine appears to have additional anti‐inflammatory effects unrelated to its antioxidant effect. Oral bucillamine is used clinically in Asia for treatment of rheumatoid arthritis. There is a strong preclinical evidence that parenteral infusion of this agent is efficacious in acute settings characterized by inflammation and oxidative stress. In an investigator‐blinded, rigorous intact dog model, consisting of 90 min of coronary artery occlusion and 48 h of reperfusion, bucillamine, given i.v. during the first 3 h of reperfusion, substantially reduced myocardial infarct size. Livers exposed to 24 h of cold ischemia were markedly protected by bucillamine in several transplantation models. In Phase I human studies in normal volunteers, bucillamine at doses up to 25 mg/kg/h i.v. for 3 h elicited no serious toxicity. On the basis of pharmacokinetic analyses of blood levels during these studies it was concluded that bucillamine, infused at i.v. doses ≥10 mg/kg/h for 3 h to humans could be expected to be therapeutically effective in myocardial infarction, organ transplantation and other acute inflammatory syndromes.
Calcium Antagonists in Patients with Type 2 Diabetes and Hypertension
Authors: McFarlane Samy I. , Farag Amal , Sowers James 
Published: August 2010

ABSTRACTHypertension is twice as common in patients with diabetes compared to those without diabetes. It accounts for up to 75% of cardiovascular disease risk leading to the substantial increase in morbidity and mortality. Control of blood pressure in people with diabetes has been shown in randomized controlled trials to decrease cardiovascular risk and improve outcome especially in preventing stroke.A target blood pressure goal of <130/80 mm Hg is currently recommended for patients with diabetes. However, less than 1/3 of these patients achieve such a goal. This is in part due to the inherent difficulty in controlling blood pressure in these patients where hypertension is usually associated with increased salt sensitivity, volume expansion and isolated systolic hypertension. Therefore, patients with diabetes usually require multiple medications for optimal blood pressure control. Calcium channel antagonists have been shown in large clinical trials to be both safe and effective in controlling blood pressure in diabetic patients and will continue to play a major role in the management of hypertension in this population, particularly in the combination therapy that these patients usually require.
Pharmacology of KB‐R7943: A Na+–Ca2+exchange inhibitor
Authors: Amran Md. Shah , Homma Nobuo , Hashimoto Keitaro 
Published: August 2010

ABSTRACTThe Na+–Ca2+exchange (NCX) system plays a pivotal role in regulating intracellular Ca2+concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca2+‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.
Phosphomannopentaose Sulfate (PI‐88): Heparan Sulfate Mimetic with Clinical Potential in Multiple Vascular Pathologies
Authors: Khachigian Levon M. , Parish Christopher R. 
Published: August 2010

ABSTRACTThe sulfated oligosaccharide PI‐88 is a potent antiangiogenic, antitumor and anti‐metastatic agent derived from yeast. It is primarily composed of sulfated phosphomannopentaose and phosphomannotetraose oligosaccharide units and is presently under evaluation in Phase II clinical trials for anticancer efficacy. PI‐88 inhibits the heparan sulfate‐degrading enzyme heparanase, exhibits antiangiogenic activity and has anticoagulant properties mediated by heparin cofactor II. It also inhibits vascular smooth muscle cell proliferation, kinase signalling and arterial intimal thickening following balloon injury. Many heparan sulfate‐binding growth factors require heparan sulfate as a co‐receptor in order to effectively deliver growth signals to cells. Thus, the antiangiogenic and antirestenotic activity of PI‐88 may be at least partially due to this highly sulfated oligosaccharide competing with the interaction of growth factors, such as FGF‐2 and VEGF, with cell surface heparan sulfate. This heparan sulfate mimetic has, therefore, multiple functions and therapeutic potential in a variety of vascular disorders.
Agmatine Signaling: Odds and Threads
Authors: Berkels Reinhard , Taubert Dirk , Gründemann Dirk , Schömig Edgar 
Published: August 2010

ABSTRACTAgmatine is a metabolite of L‐arginine. It is formed by the decarboxylation of L‐arginine via arginine decarboxylase in bacteria, plants and mammals. It is becoming clear that it has multiple physiological functions as a potential transmitter. Agmatine binds to α2‐adrenoceptors and to imidazoline binding sites. It blocks NMDA receptors and other ligand‐gated cation channels. It also inhibits nitric oxide synthase, induces release of peptide hormones and antizyme and plays a role during cell proliferation by interacting with the generation and transport of polyamines. Although the precise function of endogenously released agmatine is presently still unclear, this review will summarize several aspects concerning the biological function of agmatine.
Therapeutic Potentials of Sarpogrelate in Cardiovascular Disease*
Authors: Saini Harjot K. , Takeda Nobuakira , Goyal Ramesh K. , Kumamoto Hideo , Arneja Amarjit S. , Dhalla Naranjan S. 
Published: August 2010

ABSTRACTIn view of the pivotal role of serotonin (5‐HT) in a wide variety of cardiovascular disorders, extensive effort has been made to develop different types of 5‐HT receptor antagonists for therapeutic use. On the basis of experimental studies, this article is focused on the potentials of sarpogrelate, a specific 5‐HT2Areceptor antagonist as an antiplatelet, antithrombotic, antiatherosclerotic and antianginal agent. The major effects of sarpogrelate are due to the inhibition of 5‐HT‐induced platelet aggregation and smooth muscle cell proliferation. This agent was found to attenuate the 5‐HT‐mediated increase in intracellular Ca2+and ischemia‐reperfusion injury in the heart. Sarpogrelate has been found to have beneficial effects in peripheral vascular disease, restenosis after coronary stenting, pulmonary hypertension, acute and chronic myocardial infarction.
Low‐Molecular‐Weight Heparins in Thrombosis and Cancer: Emerging Links
Authors: Mousa Shaker A. 
Published: August 2010

ABSTRACTHeparin as well as low‐molecular‐weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti‐Xa and anti‐IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix‐degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH‐releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix‐degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non‐anticoagulant LMWH derivatives was shown to be reversed by anti‐TFPI. Thus, modulation of tissue factor/Vila noncoagulant activities by LMWH‐releasable TFPI and the inhibitory effects on matrix‐degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis‐associated disorders, including human tumor growth and metastasis.
Cardiovascular Protective Effects of Resveratrol
Authors: Bradamante Silvia , Barenghi Livia , Villa Alessandro 
Published: August 2010

ABSTRACTResveratrol (3,4′,5‐trihydroxy‐trans‐stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia‐reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans.
Pharmacological and Clinical Studies with Temocapril, an Angiotensin Converting Enzyme Inhibitor that is Excreted in the Bile
Authors: Yasunari Kenichi , Maeda Kensaku , Nakamura Munehiro , Watanabe Takanori , Yoshikawa Junichi , Asada Akira 
Published: August 2010

ABSTRACTTemocapril is an angiotensin converting enzyme inhibitor (ACEI), a prodrug with a thiazepine ring. Its active form, temocaprilat, is slightly more potent than enalaprilat in inhibiting ACE isolated from rabbit lung. The inhibitory potency of temocaprilat on isolated rat aorta is 3 times that of enalaprilat. Temocapril is excreted in the bile and urine and can be used in patients with renal insufficiency. It reduces blood pressure without causing any significant change in heart rate or cardiac output. Temocapril has been reported to improve endothelial dysfunction in vitro by suppressing increased oxidative stress. In vivo it improves reactive hyperemia in patients with essential hypertension. It has been reported to prevent coronary vascular remodeling in vivo by suppressing local ACE and increased oxidative stress. In humans temocapril has been found to improve insulin resistance partly by increasing adiponectin levels. Cardiac remodeling was improved by temocapril not only in experiment animals but also in humans. It improves renal function and decreases urinary albumin excretion in diabetics as well as in hypertensive patients. Temocapril is currently marketed only in Japan. Considering its beneficial effects and unique pharmaco‐kinetics, temocapril, is likely to be introduced in other countries as well.