Inhibitory effect of fluvastatin on ileal ulcer formation in rats induced by nonsteroidal antiinflammatory drug

AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs)cause gastrointestinal damage as one of their side effects in humans and experimental animals. Lipid peroxidation plays an important role in NSAID-induced ulceration. The aim of this study was to investigate the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors on the ulceration in small intestines of rats.METHODS: The effects of three HMG-CoA reductase inhibitors, fluvastatin, pravastatin and atorvastatin on ileal ulcer formation in 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT)-treated rats were examined. Antioxidative activity of the inhibitors was measured by a redox-linked colorimetric method.RESULTS: Fluvastatin, which was reported to have antioxidative activity, repressed the ileal ulcer formation in rats treated with BFMeT an NSAIDs. However, the other HMG-CoA reductase inhibitors (pravastatin and atorvastatin)did not repress the ileal ulcer formation. Among these HMG-CoA reductase inhibitors, fluvastatin showed a significantly stronger reducing power than the others(pravastatin, atorvastatin).CONCLUSION: Fluvastatin having the antioxidaitive activity suppresses ulcer formation in rats induced by NSAIDs.

ABCA1基因R219K多态性对AMI患者他汀药物调脂效应的影响

目的:研究三磷酸腺苷结合盒转运子A1(ABCA1)R219K基因多态性和AMI患者血脂水平关系以及他汀药物调脂疗效与患者不同基因型的关系。方法:AMI患者(150例),其中ST段抬高型心肌梗死120例,非ST段抬高性心肌梗死30例,对照组(100例)为门诊健康体检者,均清晨空腹采血,测定血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、极低密度脂蛋白胆固醇(VLDL-C)。并采用聚合酶链式反应-限制性片段长度多态性(PCR-RFIP)方法对R219K基因多态性进行检测,AMI患者给与普伐他汀40 mg/d,12周后重复测定上述血脂水平。结果:ABCA1基因的R219K多态性基因型频率和等位基因频率在对照组和AMI组相似(P>0.05);AMI患者中RR基因型较KK基因型具有明显升高的血清TG水平和较低的HDL-C水平(P<0.05);KK基因型患者较RR基因型患者相比,普伐他汀治疗明显增加HDL-C水平(P<0.05)。结论:ABCA1基因的R219K多态性与血脂水平相关,并且可影响AMI患者HDL-C水平对普伐他汀的治疗效果。

Is there evidence for statins in the treatment of aortic valve stenosis?

Research revealed that the pathogenesis of aortic stenosis(AS) not merely comprises of a mechanical wear and tear process yet that active biological processes, similar to those of coronary artery disease are involved, a promising role for statins in disease-modifying therapy was suggested. However, recently, many prospective studies could not observe decreased progression nor regression of the disease. Here, we review the current knowledge on the pathomechanisms of AS and its similarities and differences with atherosclerosis. Moreover, we discuss whether there is still a place for statins in the treatment of particular AS patient subgroups.

Research progress of Statins

Statins are one of the most popular lipid-lowering drugs( LLDs). Upon oral administration,these drugs are well absorbed by the intestine and effectively used for the treatment of dyslipidemias. This manuscript aims to investigate the demographics of the data who used Statins,review the benefits and challenges of Statins and the future of the treatment.

Factors Related to Adherence with Treatment of Dyslipidemic Patients on Continuous Use of Oral Lipid-Lowering Drugs

Several studies have shown that regular prescribed statins may reduce cardiovascular events and decrease the overall mortality. The aim of this study was to analyze factors related to medication and patients with dyslipidemia, statin users in the city of Ribeir&atilde;o Preto, S&atilde;o Paulo, Brazil. It was an observational, descriptive, traverse character, relating to the year 2007. We included 332 individuals, randomly selected, of both sexes, referred to public health system and private clinics. The selected individuals were submitted to an interview and their medical files analyzed. Simvastatin was the most frequently used oral lipid-lowering drugs. 60% of patients showed forgetfulness as the main cause for treatment interruption, followed by the difficulty of finding of drugs in public pharmacies. Adherence to diet was the main conduct adopted by patients to help control lipid levels. The prevalent adverse events were muscle cramps, paresthesias of the limbs and muscle pains. Among the key factors that would discourage the correct follow-up treatment for lipid control were: long wait for office visits and the difficulties of finding of drugs in pharmacies (Clinical Hospital of the Faculty of Medicine of Ribeir&atilde;o Preto-USP and public health posts). The study allowed a reflection regarding the functioning of the Public Health System. The study allows a reflection regarding the functioning of the Public Health System for which we must constantly search for strategies that enable the same functionality, which has factors that discourage patient adherence to treatment.

Review of the Mechanisms of Action of the Statins and Their Pleiotropic Effects in the Treatment of Hypercholesterolemia and Atherosclerosis

Statins are lipid-lowering agents widely used in the treatment of hypercholesterolemia and atherosclerosis. They act by inhibiting of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme responsible for the conversion of HMG-CoA to mevalonate in cholesterol biosynthesis. Due to their ability to reduce low-density lipoproteins (LDL) levels more than other cholesterol-lowering drugs, they have become the drugs most often prescribed in the treatment of atherosclerosis.

Long-term effects of various types of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on changes in glomerular filtration rate in Korea

Few long-term follow-up studies have compared the changes in renal function according to the type of statin used in Korea.We compared the long-term effects of statin intensity and type on the changes in the glomerular filtration rate(GFR).We extracted data of patients who took statin for the first time.We analyzed whether or not different statins affect the changes in GFR at 3 months after baseline and 4 years after.We included 3678 patients and analyzed the changes in GFR.The GFR decreased by 3.2%±0.4%on average 4 years after the first statin prescription,indicating statistically significant deterioration(from 83.5±0.4 mL/min/1.73 m2 to 79.9±0.4 mL/min/1.73 m2,P<0.001).When comparing the GFR among different statins,significant differences were observed between atorvastatin and fluvastatin(−5.3%±0.7%vs.1.2%±2.2%,P<0.05)and between atorvastatin and simvastatin(−5.3%±0.7%vs.−0.7%±0.8%,P<0.05).In pitavastatin(odds ratio[OR]=0.64,95%confidence interval[CI]=0.46-0.87,P<0.005)and simvastatin(OR=0.69,95%CI=0.53-0.91,P<0.008),the GFR rate that decreased by<60 mL/min/1.73 m2 was significantly lower than that of atorvastatin.Regarding long-term statin intake,GFR changed with the type of statin.This work is the first in Korea to compare each statin in terms of changes in the GFR after the statin prescription.

Fluvastatin attenuates myocardial interstitial fibrosis and cardiac dysfunction in diabetic rats by inhibiting over-expression of connective tissue growth factor

Background Diabetic myocardiopathy is characterized by myocardial interstitial fibrosis and cardiac dysfunction. Statins were found to exert protective effects on cardiovascular disease by suppressing activation of small G proteins, independently of their lipid-lowering effect. The study investigated the effect of fluvastatin on myocardial interstitial fibrosis, cardiac function and mechanism of its action in diabetic rats. Methods Twenty-four male SD rats were randomly assigned to 3 groups： control rats （n=-8）, streptozotocin （STZ）-induced diabetic rats （n=8）, and diabetic rats treated with fluvastatin （administered fluvastatin orally, 10 mg/kg body weight per day, n=-8）. Twelve weeks later, miniature cardiac catheter was inserted into the left ventricle to conduct hemodynamic examination. Then myocardium tissues were collected, collagen content was detected by picro-sirius red staining, real-time quantitative reverse transcription polymerase chain reaction （RT-PCR） was used to detect the mRNA expression of connective tissue growth factor （CTGF）, and Western blotting was used to detect the protein expression of CTGF. Rho activity was determined by pull-down assay. Results After 12 weeks, the left ventricular systolic pressure （LVSP） and maximum rate of left ventricular （LV） pressure rise and fall （＋dP/dt max and -dP/dt max） were significantly lower and left ventricular end diastolic pressure （LVEDP） was higher in the diabetic rats than those in the control rats （P 〈0.01）. Moreover, in LV myocardial tissue of diabetic rats the collagen content, fibronectin, mRNA and protein expression of CTGF and the activity of RhoA were all significantly increased compared with the control rats （P 〈0.01）. Administration of fluvastain obviously improved the cardiac function of diabetic rats, attenuated fibronectin expression, mRNA and protein expression of CTGF and the activity of RhoA in LV myocardium of diabetic rats. Conclusions Fluvastatin attenuates cardiac dysfunction and myocardial interstitial fibrosis of diabetic rat by inhibiting activity of RhoA to down-regulate the overexpression of CTGF, and Rho/Rho-kinase pathway may be an important target in the treatment of diabetic cardiomyopathy.

Fluvastatin prevents renal injury and expression of lactin-like exidized low-density lipoprotein receptor-1 in rabbits with hypercholesterolemia

Background Lipid abnormalities are often complicated by renal dysfunction. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line choice for lowering cholesterol levels. The present study was designed to investigate whether statins could prevent and invert the development of renal injury in cholesterol-fed rabbits and to find the possible mechanism of their effects by detecting gene and protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the renal artery.Methods Twenty-four male New Zealand white rabbits were divided into three groups: (1) control group, regular granules chow; (2) HC-diet group, granules chow with 1% cholesterol and 5% lard oil; and (3) fluvastatin group, 1% cholesterol and 5% lard oil diet plus fluvastatin (10 mg·kg -1 ·d -1 ) . After 16 weeks, serum total cholesterol (TC), low-density lipoprotein(LDL) and creatinine (Cr) levels were measured. Renal hemodynamics and function, mainly including glomerular filtration rate (GFR) in vivo were quantified using 99m Tc-DTPA single photon emission computed tomograph ( 99m Tc-DTPA SPECT). The thickness of the renal artery intima was quantitated in HE-stained segments by histomorphometry. Gene expression of LOX-1 in the renal artery was examined by semi-quantitative RT-PCR and its protein expression was evaluated by immunohistochemistry.Results High cholesterol diet induced hypercholesterolemia (HC) complicated by renal dysfunction with increased levels of serum lipid and Cr, decreased GFR and delayed excretion and extensively thickened renal arterial intima in the HC-diet group. Rabbits in the control group showed a minimal LOX-1 expression (mRNA and protein) in the endothelium and neointima of the renal artery. Intimal proliferation of the renal artery in the HC-diet group was associated with a marked increase of LOX-1 expression (protein and mRNA). Treatment with fluvastatin improved renal function, attenuated intimal proliferation of the renal artery and markedly decreased the enhanced LOX-1 expression in the endothelium and neointima of the renal artery in rabbits. Conclusions Fuvastatin treatment could prevent the development of renal injury in patients with HC and early atherosclerosis (AS). This beneficial effect might be mediated by its pleiotropic effects including a decrease in total cholesterol exposure level and prevention of LOX-1 expression in atherosclerotic arteries.

Pravastatin activates platelet nitric oxide synthase (NOS) in patients with type 2 diabetes mellitus and NOS activation is accompanied by serine phosphorylation

Statins cause reductions in myocardial infarction and also morbidity and mortality of type 2diabetes related to atheromatous disease and its thrombotic complications beyond those predicted by reductions in low density lipoprotein cholesterol （LDL） It has been suggested that the protective mechanism （s） may relate to improved endothelial function and/or antithrombotic effects, but the mechanism is not clear.

Synthesis of 1,3,5-Trisubstituted [4-tert-Butyl 2-（5,5-difluoro- 2,2-dimethyl-6-vinyl-l,3-dioxan-4-yl）acetate]pyrazoles via a Pd-Catalyzed C--H Activation

The gem-difluoromethylenated acetonide 2 was efficiently synthesized as new precursor of HMG-CoA reduc- tase inhibitor. Straightforward olefination via Pd-catalyzed C4-H activation of 1,3,5-trisubstituted pyrazoles 1 was proceeded smoothly in the presence of Pd（OAc）2 and AgCO3. This protocol has merits in terms of the improved atomic economy and prevention from the generation of by-products.