MP2, density functional theory,and semi-empirical calculations of the interaction energies between a series of statin-drug-like molecules and the HMG-CoA reductase active site

In previous work [E.A. Kee, M.C. Livengood, E.E. Carter, M.L. McKenna, M. Cafiero, J. Phys. Chem. B 113 (2009) 14810] it has been shown that the residue Tyr479 in the active site of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase exerts a strong attraction on ligands. Statin drugs moderate blood cholesterol levels by acting as competitive inhibitors for this enzyme, blocking the biosynthesis of cholesterol early in the synthesis pathway. In this work a novel molecular fragment that binds strongly to Tyr479 has been developed using abinitio correlated methods and attached to known statin drugs (which bind well to other important residues in the active site) to create novel drug candidates that interact more strongly with the entire enzyme active site than the original drugs. Interaction energies between small molecule ligands and the target enzyme active site are calculated with all-electron density functional theory and semi-empirical methods, showing that the novel drug molecules will likely bind strongly in the active site. Solvation energies are also calculated to confirm behavior of the novel drug candidate molecules invivo.     

Effect of atorvastatin on plasma levels of asymmetric dimethylarginine in patients with non-ischaemic heart failure

BACKGROUND: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endothelial nitric oxide synthase (eNOS) inhibitor, may contribute to endothelial dysfunction in chronic heart failure (CHF). Since statins upregulate eNOS and ameliorate endothelial dysfunction in non-ischaemic CHF, we hypothesized that this may be in part through modification of ADMA. AIM: To evaluate the effect of atorvastatin on the relationship between ADMA and endothelial function in non-ischaemic CHF. METHODS: Twenty-four patients with CHF (ejection fraction <40%, New York Heart Association Functional Classes II and III) were randomised to atorvastatin treatment (40 mg) or placebo once daily for 6 weeks in a double-blinded, placebo-controlled crossover study. Plasma ADMA and l-arginine levels were measured by HPLC. Endothelial function was assessed by flow-mediated dilatation and invasive forearm plethysmography. RESULTS: Post-statin therapy, endothelial function was improved (p<0.05) independent of LDL-cholesterol reductions, but no changes were observed in ADMA levels or the l-arginine to ADMA ratio. There was a trend for ADMA to inversely correlate with endothelial function at baseline. CONCLUSIONS: Short-term atorvastatin treatment in non-ischaemic CHF improves endothelial function but has no effect on ADMA or the l-arginine to ADMA ratio. Our finding suggests that the observed statin-induced improvements in endothelial function are likely mediated via alternative pathways.     

Statins in the first-line therapy of acute coronary syndrome – similar to aspirin?

Statins are cholesterol-lowering drugs, highly effective in the primary and secondary prevention of coronary artery disease. It has been found, however, that statins also have nonlipid effects; they can influence different pathways, which have been described to participate in the pathogenesis of acute coronary syndrome (ACS). Inflammation or decreased production of nitric oxide are obvious targets for statin therapy. Recently, several large clinical trials have been published, showing safety and, in some areas, efficacy of administration of statins early after ACS. Furthermore, there is growing evidence from both experimental and small clinical studies that statin therapy may have favourable effects when started as soon as possible after the development of ACS. Confirmation of this approach by large randomized trials is needed; however, based on currently available data, statins have high chance of achieving a similar place in the first-line therapy of ACS as the pillar of contemporary therapeutic strategy, aspirin.     

Effects of amlodipine,atorvastatin and combination of both on advanced atherosclerotic plaque in APOE*3-Leiden transgenic mice

Combined treatment of statins and calcium channel blockers has been suggested to be superior to statin therapy alone. We quantified the anti-atherosclerotic potential of amlodipine, atorvastatin and their combination on existing atherosclerotic plaques in the aorta of APOE*3-Leiden transgenic mice. Sixty-two mice were fed a high cholesterol containing diet for 18 weeks. A subgroup of 10 mice was then killed. All other mice received the diet for another 18 weeks, alone (late control group), along with 0.01% atorvastatin, 0.002% w/w amlodipine, or their combination (all groups, n = 13). Atherosclerotic lesions, collagen content and monocyte adherence were quantified using standard histology (aortic root). Raman spectroscopy was used to quantify the content of cholesterol and calcification (aortic arch). Compared to the late control group, treatment with amlodipine, atorvastatin or the combination, reduced atherosclerostic lesion area by, respectively, 25%, 39% and 46% in the aortic root (P < 0.01) and by 53%, 55% and 60% in the aortic arch (P < 0.05). Atorvastatin, but not amlodipine reduced the adherence of monocytes in the intima. Lesion severity and plaque contents of collagen, cholesterol and calcification were equal for all treatment groups. Neither treatment resulted in regression of atherosclerotic plaque size. In conclusion, both atorvastatin and amlodipine significantly retard the progression of existing atherosclerotic lesions. No additive effect of the combination of amlodipine and atorvastatin could be observed in this study.     

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats

OBJECTIVES: The aim of the present study was to determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have preventive effects on the development of cardiac hypertrophy and heart failure. BACKGROUND: Statins have been reported to have various pleiotropic effects, such as inhibition of inflammation and cell proliferation. METHODS: Dahl rats were divided into three groups: LS, the rats fed the low-salt diet (0.3% NaCl); HS, the rats fed the high-salt diet (8% NaCl) from the age of 6 weeks; and CERI, the rats fed the high-salt diet with cerivastatin 1 mg/kg/d by gavage from the age of 6 weeks. RESULTS: In HS rats, cardiac function was markedly impaired and all rats showed the signs of heart failure within 17 weeks of age. In CERI rats, cardiac function was better than that of HS and no rats were dead up to 17 weeks of age. The development of cardiac hypertrophy and fibrosis was attenuated, and the number of apoptotic cells and expression of proinflammatory cytokine interleukin (IL)-1beta gene were less as compared with HS rats. Pretreatment of cerivastatin suppressed the adriamycin-induced apoptosis of cultured cardiomyocytes of neonatal rats. CONCLUSIONS: These results suggest that statins have a protective effect on cardiac myocytes and may be useful to prevent the development of hypertensive heart failure.     

胆固醇酯转移蛋白与氟伐他汀降脂疗效的关系

目的:研究胆固醇酯转移蛋白(CETP)基因单核苷酸多态性(SNPs)与氟伐他汀调脂疗效的关系。方法:选取中国上海汉族人群中血脂异常患者121例,男49例,女72例,平均年龄(61.13±11.05)岁。在饮食控制4周后,予氟伐他汀40 mg/d,共随访8周。采用聚合酶链式反应扩增DNA后,以四色荧光法标记的双脱氧终止法对CETP基因外显子及其上下游100~200 bp区域进行测序,用以发现SNP位点并进行基因分型,研究其与氟伐他汀调脂疗效的关系。结果:(1)CETP基因共检出SNP位点10个,其中包括3个新的SNP:①位于第7内含子区的新发现的SNP1,序列为CTGGTGAGTG[C/T]GTTTCTGTCT;②位于第9内含子区的新的SNP2,与rs11076176是紧密连锁,序列为GCTGCTAGGG[A/G]ATCCAGATGG;③位于第12内含子区发现新的SNP3:序列为ATTATCCATCG[C/T]TTTTTTATTT。NCBI dbSNP未见报道。(2)CETP基因多态性与调脂疗效:①SNP1:治疗后TT基因型个体HDL-C水平升高,而CC CT基因型的个体的HDL-C水平反而降低,治疗前后HDL-C水平变化分别为(16.65±14.35)%和(-2.49±20.77)%,P<0.05;②rs289741:GG基因型基础TC水平与AA GA基因型的个体相比较低,分别为(5.93±0.82)mmol/L和(6.87±1.86)mmol/L,P<0.01。治疗后GG基因型个体HDL-C水平升高,而AA GA基因型的个体的HDL-C水平反而降低,治疗前后HDL-C水平改变分别为(10.25±19.03)%和(-2.22±20.03)%,P<0.05。结论:CETP基因的SNP与氟伐他汀的调脂疗效相关。     

Impact of combined pharmacologic treatment with clopidogrel and a statin on outcomes of patients with non-ST-segment elevation acute coronary syndromes: perspectives from a large multinational registry.

AIMS: To evaluate clinical outcomes associated with the combined use of clopidogrel and statins vs. clopidogrel alone on a background of aspirin therapy in patients with the spectrum of acute coronary syndromes (ACS). METHODS AND RESULTS: Utilizing data from the Global Registry of Acute Coronary Events, we studied 15 693 patients admitted with non-ST-segment elevation myocardial infarction (MI) or unstable angina, dividing them according to discharge medications: aspirin alone (group I); aspirin + clopidogrel (group II); aspirin + statin (group III); aspirin + clopidogrel + statin (group IV). Among the groups of patients in whom clopidogrel was used (groups II and IV), group II patients were older, more likely to have prior MI, but less likely to have a history of prior revascularization. In-hospital cardiac catheterization and revascularization rates were similar between groups II and IV. Importantly, Kaplan-Meier analysis showed that the 6 month mortality rate was lower in group IV (log-rank test 22.8, P<0.0001). The hazard ratio for the 6 month mortality rate was adjusted using the Cox proportional hazard model for confounding variables and for propensity score, and the 6 month mortality rate for patients in group IV remained lower compared with those in group II [0.59 (0.41-0.86), P<0.0001]. CONCLUSION: Our data suggest that the combination of clopidogrel with a statin has synergistic effects on the clinical outcomes of patients with non-ST-segment elevation ACS.     

Comparison of the 2017 Taiwan lipid guidelines and the Western lipid guidelines for high risk patients

Dyslipidemia is a major contributor in initiation, development and progression of atherosclerotic cardiovascular disease (ASCVD). Most lipid guidelines are from Europe and America and centered on the reduction of atherogenic lipids levels through lifestyle intervention and pharmacotherapy. Recently, the 2017 Taiwan lipid guidelines for high risk patients was published to facilitate the control of dyslipidemia in patients that are highly susceptible to ASCVD, including patients with preexisting ASCVD, diabetes, chronic kidney disease and familial hypercholesterolemia. Most recommendations outlined in the 2017 Taiwan lipid guidelines for high risk patients are in concordance with those of Western guidelines. However, based on evidence from the studies originating from Asia and local expert opinions, there are some recommendations different from the other guidelines. The purpose of the current review is to compare the similarities and differences between the perspectives of the 2017 Taiwan lipid guidelines for high risk patients and other Western guidelines in individuals at high risk of ASCVD. The definitions of high risk groups and treatment goals defined to achieve ASCVD risk reduction are specifically compared.