Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolaemia with simvastatin

Summary Thirty-six patients with total serum cholesterol levels above 6.5 mmol/l and Lipoprotein(a) levels above 100 mg · 1^–1 were evaluated in a 24 week double-blind, placebo controlled, cross-over study to assess the possible changes in Lp(a) during treatment with the HMG CoA reductase inhibitor simvastatin.The median plasma Lp(a) increased from 359 to 464 mg·l^–1 during simvastin treatment as compared to placebo (not significant). Individual changes in Lp(a) varied. In a multivariate linear regression analysis the individual change in Lp(a) was correlated with the baseline Lp(a) (r = 0.64), the change in serum triglycerides (r = 0.48) and the baseline apolipoprotein B (r = 0.36). Differences between the Lp(a) phenotypes may explain some of the varied Lp(a) responses. It appears that the effect of simvastatin on the Lp(a) level in individuals is usually insignificant, but in patients with a high Lp(a) simvastatin may further increase it.     

Anti-inflammatory and hypolipemic effects in vitro of simvastatin comparing to epicatechin in patients with type-2 hypercholesterolemia

Objective

The study involved 25 patients with type-2 hypercholesterolemia (mean age 49.3 ± 11.3). The control group consisted of 28 healthy individuals (mean age 50.7 ± 7.2).

Methods

The cholesterol concentrations in plasma membranes of erythrocytes were measured by means of Liebermann-Burchard reagent. The membrane lipid peroxidation in whole erythrocytes was determined. The membrane fluidity was estimated by spin labelled method.

Results

The in vitro study shows that the cholesterol concentration in membranes incubated with simvastatin and epicatechin decreases; in healthy donors there are no changes. Simvastatin does not lead to changes in the lipid peroxidation in the in vitro data. Epicatechin decreases the level of membrane lipid peroxidation in patients with hypercholesterolemia and in healthy donors. Simvastatin and epicatechin cause an increase in the fluidity of plasma membranes of erythrocytes.

Conclusions

Simvastatin causes the decrease in cholesterol concentration in erythrocytes membranes not only in the in vivo but also the in vitro experiments. Flavonoids have antioxidant properties in vitro. Simvastatin influences the lipid peroxidation only in vivo, not in vitro systems. This observation is an additional contribution to the statins’ pleiotropic effect.     

The potential of cholesteryl ester transfer protein as a therapeutic target

Introduction: Over recent decades, attempts to ascertain the pro-atherogenic nature of plasma cholesteryl ester transfer protein (CETP) and to establish the relevance of its pharmacological blockade as a promising high density lipoproteins-raising and anti-atherogenic therapy have been disappointing.

Areas covered: The current review focuses on CETP as a multifaceted protein, on genetic variations at the CETP gene and on their possible consequences for cardiovascular risk in human populations. Specific attention is given to physiological modulation of endogenous CETP activity by the apoC1 inhibitor. Finally, the rationale behind the need for selection of patients to treat is discussed in the light of recent studies.

Expert opinion: At this stage one can only speculate on the clinical outcome of pharmacological CETP inhibitors in high-risk populations, but recent advances give cause to adjust the expectations from now on. The CETP effect is probably largely influenced by the overall metabolic state, and whether CETP blockade may be relevant or not in promoting cholesterol disposal is still questioned. The possible need for a careful stratification of patients to treat with CETP inhibitors is outlined. Finally, manipulation of CETP activity should be considered with caution in the context of sepsis and infectious diseases.     

Short-term effects of treatment with simvastatin on testicular function in patients with heterozygous familial hypercholesterolaemia

Summary The effects of simvastatin 40 mg per day for 14 weeks on the pituitary-testis axis of 19 men with familial hypercholesterolaemia have been examined in a single-blind study.Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol and triglycerides by 45% and 30%, respectively, and significantly increased high density lipoprotein (HDL) cholesterol by 15%.The alterations, which were stable 4 weeks after the start of treatment, were not associated with any significant change in sperm quality, the seminal plasma concentrations of various sex gland products (prostate-specific acid phosphatase, polyamines, citrate, fructose, -glucosidase), or the serum concentrations of cortisol, testosterone, LH, FSH, or prolactin.It is concluded that a short-term reduction in circulating LDL-cholesterol has no marked effect on testicular function or sperm quality.     

Enhancement of antioxidant defense mechanism by pitavastatin and rosuvastatin on obesity-induced oxidative stress in Wistar rats

Context: There has been a steady increase in the epidemiology of obesity over the last 30 years with developed countries leading the way. Oxidative stress was believed to be the principle contributor to the development of cardiovascular disorders that linked with obesity.

Objective: To evaluate the enhancement of antioxidant defense mechanism by Pitavastatin (PTV) and Rosuvastatin (RSV) on obesity-induced oxidative stress in Wistar rats.

Methods: Fifty Wistar albino rats were divided into five groups. High fat diet (HFD, 20?g/day/rat) pellets were given for 28 days to produce obesity-induced oxidative stress in Wistar rats. Oral administration of HFD along with PTV, RSV and Orlistat [(HFD for 28 days + from 8th day PTV (1?mg/kg), RSV (5?mg/kg) and Orlistat (10?mg/kg) to 28th day] were given respectively.

Results: Both PTV and RSV produced significant (p?<?0.01) reduction in serum apolipoprotein-B (Apo-B), total cholesterol (TC), triglycerides (TGs), cardiac-lipid peroxides (TBARS) levels and elevation in serum high density lipoprotein (HDL-C), cardiac antioxidant enzymes [glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catase (CAT)] levels.

Discussion and conclusion: Results were comparable with Orlistat, a standard antiobesity drug and present initial evidence that Pitavastatin and Rosuvastatin are useful for the treatment of obesity by enhancing the antioxidant defense mechanism. However, the effects of PTV were more prominent than RSV. The present findings of Pitavastatin and Rosuvastatin raise the possibility of a new application as an antiobesity therapeutic modality.     

中药调脂液和血脂康、辛伐他汀对中老年人高脂血症调脂作用的比较

目的 研究中药调脂液对中老年高脂血症病人的调脂作用并与血脂康、辛伐他汀比较。方法117例高脂血症病人随机分为三组,服药前及服药后第6周测定血脂。结果 三组治疗前后比较,三组间TC差异无显著意义(P>0.05),TG差异有极显著意义(P<0.01)。结论 中药调脂液、血脂康和辛伐他汀调TC作用基本相符,均适用于治疗Ⅱa、Ⅲb型高胆固醇血症;调TG作用,中药调脂液优于血脂康,血脂康优于辛伐他汀,因此中药调脂液和血脂康也适用于治疗其他类型的高脂血症。     

The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects

AIMS: Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. METHODS: The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). RESULTS: Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. CONCLUSIONS: The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.     

Prediction of therapeutic response to pregabalin in subjects with neuropathic pain

Objective: To evaluate four models based on potential predictors for achieving a response to pregabalin treatment for neuropathic pain (NeP).

Methods: In total, 46 pain studies were screened, of which 27 NeP studies met the criteria for inclusion in this analysis. Data were pooled from these 27 placebo-controlled randomized trials to assess if baseline characteristics (including mean pain and pain-related sleep interference [PRSI] scores), early clinical response during weeks 1–3 of treatment (change from baseline in pain and PRSI scores), and presence of treatment-emergent adverse events (AEs) were predictive of therapeutic response. Therapeutic response was defined as a ≥30% reduction from baseline in either pain and/or PRSI scores at week 5 with supplemental analyses to predict pain outcomes at weeks 8 and 12. Predictors of Patient Global Impression of Change (PGIC) were also evaluated. Four models were assessed: Random Forest, Logistic Regression, Naïve Bayes, and Partial Least Squares.

Results: The number of pregabalin-treated subjects in the training/test datasets, respectively, were 2818/1407 (30% pain analysis), 2812/1405 (30% sleep analysis), and 2693/1345 (PGIC analysis). All four models demonstrated consistent results, and the most important predictors of treatment outcomes at week 5 and pain outcomes at weeks 8 and 12 were the reduction in pain score and sleep score in the first 1–3 weeks. The presence or absence of the most common AEs in the first 1–3 weeks was not correlated with any treatment outcome.

Conclusions: Subjects with an early response to pregabalin are more likely to experience an end-of-treatment response.     

辛伐他汀对实验性高脂血症小鼠高密度脂蛋白的影响

目的:探讨辛伐他汀对动脉粥样硬化(As)形成过程中高密度脂蛋白(HDL)性质及其相关酶活性的影响。方法:喂食高脂饲料建立C57BL/6小鼠高脂血症模型,利用辛伐他汀(20mg.kg-1)给予小鼠灌胃8周,血浆经快速蛋白液相色谱(FPLC)分离后酶法检测各脂蛋白的胆固醇水平,酶法测定HDL相关抗氧化酶对氧磷酯酶1(PON1)和血小板活化因子-乙酰水解酶(PAF-AH)活性。结果:辛伐他汀使C57BL/6高脂模型鼠血清总胆固醇水平降低了34.4%,甘油三酯水平下降60.2%,HDL-C水平仅增高7.8%,但HDL相关的PON1和PAF-AH酶活性明显升高。结论:辛伐他汀不仅能显著改善血脂水平,同时能有效增强HDL的抗氧化能力,表现出较强的抗As作用。     

Phospholipid hydrolysis in serum lipoproteins by a basic phospholipase A2 from Naja nigricollis snake venom and an acidic phospholipase A2 from Naja naja atra snake venom

Apparent Km and Vmax values for PC and PE hydrolysis were determined following exposure of HDL, LDL, and VLDL to a basic phospholipase A2 from N. nigricollis snake venom and an acidic phospholipase A2 from N. nigricollis snake venom and an acidic phospholipase A2 from N. n. atra snake venom. Both enzymes hydrolyzed the lipoprotein phospholipids approximately as fast as they hydrolyzed pure phospholipids in mixed micelles, however, the N. nigricollis enzyme, which has a much stronger anticoagulant effect than the N. n. atra enzyme, had lower apparent Vmax values. These values were highest for phospholipids in VLDL and lowest for HDL, however, the differences between the lipoproteins were relatively small with the N. nigricollis enzyme while the differences were much larger with the N. n. atra enzyme. Fractions of the two enzymes in which varying numbers of lysines were carbamylated showed much larger differences in relative rates of phospholipid hydrolysis in HDL, LDL and VLDL. Triton X-100 eliminates these differences in rates of hydrolysis. These results are discussed in terms of the differences in the organized structure of the lipoprotein classes and in the penetration ability of the phospholipases.     

Effects of ethyl-CPIB (clofibrate) on tissue lipoprotein lipase and plasma post-heparin lipolytic activity in rats

The role of LPL in reducing the serum triacylglycerol concentration was investigated in rats fed a high sucrose diet containing 0.25% (w/w) ethyl-CPIB. Compared with sucrose-fed controls, drug treatment resulted in a fall in adipose tissue LPL activity and a rise in enzyme activity in thigh and heart muscle. Serum post-heparin lipoprotein lipase activity after a high dose of heparin was lower in ethyl-CPIB-treated rats than controls, but after a low dose of heparin the values were similar. The amount of LPL activator was decreased by the drug. Thus, the low serum triacylglycerol concentration observed in the ethyl-CPIB-treated rats cannot be explained by changes in functional LPL activity. The plasma triacylglycerol-lowering effect of the drug could be explained by the observed decrease in triacylglyerol output by the liver.     

辛伐他汀对急性冠脉综合征早期C反应蛋白和血脂的影响

目的　观察急性冠脉综合征的早期应用辛伐他汀后C反应蛋白和血脂的变化。方法　70例急性冠脉综合征患者随机分为对照组(无服用任何调脂药物,34例)和治疗组(辛伐他汀10mg/d ,36例) ,测定治疗前后C反应蛋白和血脂的变化。结果　治疗组治疗5d后C反应蛋白水平下降35 % ,与治疗前比较差异有显著意义(P <0 . 0 5 ) ;治疗4周后TC、LDL C分别下降30 %、4 0 % ,与治疗前比较差异有显著意义;而且随访期间治疗组的心肌梗死发生率、再住院率均明显低于对照组。结论　在急性冠脉综合征早期予以辛伐他汀治疗是可行及有效的,可明显降低血脂和血浆炎症因子的水平,可能有利于动脉粥样斑块的稳定。     

Increase or decrease of HDL-cholesterol concentrations during pravastatin treatment depending on the pre-treatment HDL cholesterol levels

Objective: The effect of pravastatin was evaluated using patient data accumulated in the data base of a hospital information system (HIS). Methods: We selected 130 patients treated with pravastatin 10 mg per day, for a minimum period of 4 weeks. Results: In the t test analysis, the reduction rates of total cholesterol (TC) and low-density lipoprotein (LDL) levels for pravastatin administration were 18%, and 27%, respectively. These values were similar to previous reports. The high-density lipoprotein (HDL) level, however, did not change significantly, although previous reports have shown an elevation of HDL levels. In an attempt to explain the origin of this difference, we studied the pretreatment value dependence of the cholesterol change using regression analysis. We found that pravastatin raised the HDL level in those cases where pretreatment values were lower than 58 mg · dl⁻¹ and reduced it for higher values. We also showed that the reductions of TC, LDL and triglyceride (TG) levels correlated positively with their pretreatment values. Received: 22 August 1995 / Accepted in revised form: 31 January 1997     

Activation of membrane outward currents by human low density lipoprotein in mouse peritoneal macrophages

Summary The aim of the present study was to search for electrophysiological effects of human lipoproteins on membrane currents in mouse peritoneal macrophages which had been cultured for 5 to 20 days. Whole-cell currents were recorded by using a voltage-clamp technique.Low density lipoprotein (LDL, 100 g/ml) increased a slowly activating nonspecific cation current (i_so) in the positive potential range to 244 ± 23% of the reference (test potential + 55 mV, n = 13, P < 0.005). Augmentation of current resulted out of a negative shift of the activation curve along the voltage axis (–22 mV) and an increase of maximally available current.Furthermore, LDL increased a rapidly activating outward current (i_fo) at test potentials positive to the potassium equilibrium potential. At +55 mV i_fo-amplitude increasedto 165 ± 14% ofreference (n = 16, P < 0.005). LDL-induced effects on i_fo-current could be mimicked by application of the calcium ionophore A 23187 (1 mol/l) which led to an increase of i_fo-current to 161 ± 25% of the reference (test potential + 55 mV, n = 11, P < 0.005).Acetylated-LDL (100 g/ml, 5–15 min) produced no significant effect on the membrane currents under investigation. Correspondence to U. Borchard at the above address     

Effects of Low and High Density Lipoproteins on Renal Cyclosporine A and Cyclosporine G Disposition in the Isolated Perfused Rat Kidney

Purpose. This study investigated the effects of low (LDL) and high density lipoproteins (HDL) on renal cyclosporine A (CsA) and cyclosporine G (CsG) disposition in the isolated perfused rat kidney model. Methods. Kidneys were perfused with CsA or CsG in perfusion medium containing 6% protein, bovine serum albumin only (BSA) (Control), LDL (200 mg/dl) and BSA, or HDL (200 mg/dl) and BSA. In vitro protein binding studies were conducted with CsA and CsG in the same media. Results. The unbound fractions (f_u) of CsA and CsG were significantly reduced with LDL and HDL in the perfusion media. In the presence of LDL, f_u for CsA and CsG was 3.9% and 5.9%, respectively. With HDL, f_u was 2.1% for CsA and 1.8% for CsG. f_u for the controls was 14.7% for CsA and 11.9% for CsG. Renal clearance (CL_R) of CsA and CsG was significantly reduced when perfused with perfusion medium containing LDL and HDL. LDL and HDL had similar effects on reducing CsA and CsG CL_R, and were four-fold lower when compared to controls (0.006 Vs. 0.023 ml/min). Renal CsA and CsG tissue (whole organ, cortex and medulla) concentrations were lower than corresponding controls when perfused with LDL or HDL. Conclusions. The interaction of CsA and CsG with LDL and HDL significantly reduced the CL_R and extent of renal tissue distribution of both compounds.     

Role of oxidatively modified low density lipoproteins and anti-oxidants in atherothrombosis

Retrospective studies have demonstrated an association between coronary artery disease (CAD) and increased plasma levels of oxidised low density lipoproteins (LDL). A very recent prospective study in heart transplant patients has demonstrated that oxidised LDL is an independent risk factor for transplant CAD, thus further supporting the hypothesis that oxidised LDL is actively involved in the development of CAD. The increase of circulating oxidised LDL is most probably caused by back-diffusion from the atherosclerotic arterial wall in the blood, independent of plaque rupture. Indeed, plasma levels of oxidised LDL were very similar in patients with stable CAD and in patients with acute coronary syndromes. These were, however, associated with increased release of malondialdehyde (MDA)-modified LDL. Oxidised LDL may be generated by radical-mediated or by lipoxygenase or phospholipase catalysed lipid oxidation, and by myeloperoxidase catalysed protein and lipid oxidation. Prostaglandin synthesis by endothelial cells under oxidative stress and platelet activation are associated with the release of aldehydes; these induce the oxidative modification of the apolipoprotein B-100 moiety of LDL in the absence of lipid peroxidation, and thus generate MDA-modified LDL. Efficient prevention of in vivo oxidation may involve efficient cholesterol lowering, improving the anti-oxidative status of LDL by increasing the anti-oxidant content and increasing the oleate content of LDL, and by shifting the LDL away from phenotype B (characterised by small dense LDL particles). Anti-oxidative and anti-inflammatory enzymes associated with HDL may inhibit the oxidation of LDL or reverse the atherothrombotic effects of LDL.     

辛伐他汀治疗120例冠心病的疗效观察

目的探究不同剂量的辛伐他汀对冠心病的治疗效果。方法将我院于2010年收治的120例冠心病患者随机分为两组,A组运用辛伐他汀60mg/d,B组运用辛伐他汀20mg/d,两组运用的其他治疗方法相同。观察两组患者的血清胆固醇、低密度脂蛋白、高密度脂蛋白、三酰甘油等的情况变化,密切监测不良反应的发生情况。结果运用剂量为20mg/d的B组,对患者的血脂调节较好,且不良反应发生的较少,很好的控制了冠心病患者的血脂水平。总的用药费用减少,患者满意率升高。结论运用20mg/d的辛伐他汀在冠心病诊治过程中能取得令人满意的疗效,值得临床大力推广使用。     

Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects*

ABSTRACT

Background: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simvastatin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. Therefore, this study was conducted to determine the potential for pharmacokinetic drug–drug interaction between vildagliptin and simvastatin at steady-state.

Methods: An open label, single center, multiple dose, three period, crossover study was conducted in 24?healthy subjects. All subjects received once daily doses of either vildagliptin 100?mg or simvastatin 80?mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin β-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively.

Results: The 90% confidence intervals of C_max and AUC_τ of vildagliptin, simvastatin, and simvastatin β-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were administered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study.

Conclusions: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.     

高效液相色谱法测定复方辛伐他汀烟酸缓释片的有关物质

目的 建立复方辛伐他汀烟酸缓释片有关物质检查的HPLC方法.方法 采用C18柱,以乙腈-0.1%磷酸溶液(50∶50)为流动相A,0.1%磷酸的乙腈溶液为流动相B,梯度洗脱,对辛伐他汀的有关物质进行检测;以乙腈-0.05mol·L-1磷酸二氢钠溶液(磷酸调pH至2.5)(1∶99)为流动相,对烟酸进行检测.结果 在建立的色谱条件下,辛伐他汀、烟酸峰与其相关杂质峰均能完全分离.结论 本法简便、准确、专属性强,可用于本品的有关物质检查.