Low-dose Simvastatin Research Articles

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-inflammatory properties of statins. The purpose of this study was to evaluate the anti-inflammatory effect of simvastatin on bleomycin (BLM)-induced pulmonary fibrosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buffered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The effect of simvastatin on pulmonary fibrosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-p1 levels in bronchoalveolar lavage (BAL) fluid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused significant change in BAL fluid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no effect on cytokine levels, HD significantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no effect on a BLM-induced pulmonary fibrosis model, while the high dose caused partial improvement in profibrotic cytokine levels.

Effects of Grapefruit Juice Consumption on Pharmacokinetics of Low Dose Simvastatin: Cross-over Study with a Review of the Literature

The effects of consumption of grapefruit juice on the pharmacokinetics of conventional low-dose simvastatin in Japan were investigated. In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 400ml or water for 2 days. On day 3, a single 5mg dose of simvastatin was administered with grapefruit juice 200ml or water. Plasma concentrations of HMG-CoA reductase inhibitor were determined up to 8 h thereafter. Grapefruit juice increased the area under the plasma concentration-time curves from 0 to 8 h of total HMG-CoA reductase inhibitor 1.7- fold (p=0.002) and that of active HMG-CoA reductase inhibitor 1.7-fold (p=0.024). However, the peak concentrations (Cmax) and Tmax of total and active HMG-CoA reductase inhibitors were not significant influenced.Consumption of grapefruit juice with low-dose simvastatin thus resulted in mild increase of the plasma HMG-CoA reductase inhibitor, so that the pharmacokinetic interaction can be labeled as of weak CYP3A type.

Comparative effects of high and low-dose simvastatin on prostate epithelial cells: The role of LDL

Epidemiological studies have linked statin use with a decreased risk of advanced prostate cancer and an improved recurrence-free survival after radical therapy. It is unclear, however, whether statins could have direct effects against prostate cancer in a clinical setting, as their growth-inhibiting effects on prostate cancer cells have been demonstrated at drug concentrations which exceed the level in plasma during standard clinical dosing. We compared responses to high-dose and therapeutic-dose simvastatin in normal and cancerous prostate epithelial cells. Simvastatin was more effective at inhibiting the growth of normal prostate epithelial cells than of cancer cells. At therapeutic 100 nM concentration simvastatin had a cytostatic effect on normal cells: apoptosis was only slightly induced, but a decrease in cell cycle activity and an increase in senescence were observed. At therapeutic concentrations, lipophilic simvastatin caused a stronger growth inhibition than did hydrophilic rosuvastatin. In contrast, 10 μM simvastatin had a cytotoxic effect both on normal and cancer cells. Addition of LDL-cholesterol effectively reversed the cytostatic effect in all cell lines, but overcoming the cytotoxicity of 10 μM simvastatin required a combination of LDL-cholesterol and mevalonate. As LDL-cholesterol completely prevented the growth-inhibiting effect of therapeutic-dose simvastatin already at low, subphysiological concentrations it is unlikely that statins have direct effects on growth of prostate epithelial cells in vivo. Statins' possible benefits against prostate cancer could be due to systemic cholesterol-lowering, as suggested by epidemiological studies. Future clinical studies evaluating the effects of statins on prostate cancer prevention should monitor serum LDL and should probably administer statins at higher concentrations than those currently used in the treatment of hypercholesterolemia.

Cardioprotective effects of low-dose combination therapy with a statin and an angiotensin receptor blocker in a rat myocardial infarction model

Statins attenuate angiotensin II-induced myocyte hypertrophy and this might increase the cardioprotective effects of renin-angiotensin system inhibition in the ischemic heart. In this study, we investigated the cardioprotective effects of combination therapy with low-dose simvastatin and low-dose losartan using a rat myocardial infarction model. Myocardial infarction was created in rats by left anterior descending artery ligation, and the animals were randomly allocated to one of four groups: control (n=8), losartan 3 mg/kg/day (n=8), simvastatin 2 mg/kg/day (n=8), and losartan 3 mg/kg/day plus simvastatin 2 mg/kg/day (n=8). Each treatment was started on the day of coronary ligation, and hemodynamics, myocardial blood flow, and infarct size were measured after 28 days. Blood pressure, heart rate, and left ventricular systolic and end-diastolic pressures were not significantly different comparing the control group with the 3 other treatment groups. The peak positive first derivative of left ventricular pressure (peak LV dP/dt) was equivalent comparing the control group with the losartan and simvastatin groups. However, the peak LV dP/dt was greater in the losartan plus simvastatin group than in the control group (p<0.05). Myocardial blood flow, left ventricular weight, and infarct size were not significantly altered by the 3 treatments. Treatment with 3 mg/kg/day losartan plus 2 mg/kg/day simvastatin but not losartan or simvastatin alone improved left ventricular systolic function in a rat myocardial infarction model. The result suggests that statins given in combination with angiotensin receptor blockers might have beneficial cardioprotective effects, even at low-doses for each agent.

Hyperlipidaemia and cardiovascular disease

Fibrates continue to be a viable treatment option for mixed atherogenic dyslipidemia, and recent reports from clinical studies have shed new light on the therapeutic utility of fibrates for the prevention of microvascular and macrovascular disease, especially in combination with statins. Data from randomized placebo-controlled trials have shown that fibrates reduce nonfatal coronary events but do not confer any benefit on mortality or other adverse cardiovascular outcomes. The ACCORD Lipid trial studied the additive effect of fenofibrate therapy along with low-dose simvastatin therapy in 5,518 patients with type 2 diabetes mellitus, and found that fenofibrate did not affect any of the adverse cardiovascular outcomes, either individually or as part of a composite outcome, after 4.7 years of follow-up. An a priori subgroup analysis showed a significant benefit from fenofibrate-simvastatin combination therapy over simvastatin alone in participants with moderate hypertriglyceridemia and low HDL-cholesterol on major cardiovascular events, consistent with post-hoc analyses of previous fibrate trials. The ACCORD-Eye study adds to the sparse clinical data on the effect of fenofibrate on diabetic retinopathy, and showed that fenofibrate may be used to reduce the risk of progression of diabetic retinopathy even in patients with established disease. The combination of statin and fibrate was well tolerated. Fibrate therapy does not reduce mortality but may reduce nonfatal coronary events in patients at risk for cardiovascular disease, including those with type 2 diabetes. The ACCORD Lipid study shows that the combination of low-dose simvastatin and fenofibrate is well tolerated, and is potentially cardioprotective in patients with atherogenic 'mixed' dyslipidemia.

Simvastatin augments the efficacy of therapeutic angiogenesis induced by bone marrow-derived mesenchymal stem cells in a murine model of hindlimb ischemia

Many studies showed beneficial effects of either statin or bone marrow-derived mesenchymal stem cells (MSC) treatment in ischemic disease. In an attempt to further improve postischemic tissue repair, we investigated the effect of a local administration of MSC, in the presence or not of low-dose simvastatin, on angiogenesis and functional recovery in a mouse model of hindlimb ischemia. In vitro, the proliferation, migration, apoptosis, and tube formation of bone marrow MSC derived from transgenic mice expressing green fluorescent protein (GFP) were detected in the presence or not of 0.01 μmol/l simvastatin, respectively. In vivo, immediately after hindlimb ischemia, the mice were divided into four groups, namely control, MSC, statin, and statin-MSC, and received a single local injection of MSC (2×10(6) cells) and/or a repeated gavages' administration of simvastatin (0.2 mg/kg) for 21 days. The blood flow was measured by laser Doppler imaging, the capillary density was detected by alkaline phosphatase staining and, the MSC differentiation was assessed by immunofluorescent staining at 21 days after the ischemia. In vitro, the MSC proliferation rate, migration ability and tube formation number were increased significantly in simvastatin group relative to control group. Whereas, the H2O2 induced-apoptosis was inhibited significantly in simvastatin group relative to control group. In vivo, hindlimb blood reperfusion was significantly improved (MSC 0.55±0.08, statin 0.57±0.05, vs. control 0.47±0.07, P<0.05) and capillary density was obviously higher at day 21 post-ischemia by Laser Doppler Imaging in the MSC group and the Statin group when compared with control group. The combined use of statin and MSC further improved revascularization (perfusion ratio of 0.70±0.09; P<0.001 verse other groups) and resulted in the highest capillary density (P<0.05 vs. all other groups). GFP-labeled transplanted cells were more frequently observed in the Statin-MSC group than in the MSC group (6.8±0.5-3.1±0.7, P<0.05). Low-dose simvastatin could act in a synergistic way with MSC to potentiate the functional neovascularization in a mouse model of hind limb ischemia.

E0043 Effects of simvastatin on angiogenesis and the expression of Ang1 after myocardial infarction in rats

ObjectiveTo investigate the effects of simvastatin on myocardial angiogenesis and the expression of angiopoietin-1 after experimental myocardial infarction (MI) in rats.Methods60 healthy adult SD rats were randomly divided into the...

Effects of simvastatin on expression of CTGF and α-SMA in renal tubulointerstitium of rats with diabetic nephropathy

To investigate the effects of low-dose simvastatin on the expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in the renal tubulointerstitium of rats with diabetic nephropathy. Sixty male SD rats were randomly divided into three groups: Group C (control group), Group D, in which diabetes was induced by stroptozotocin (STZ) and Group DS, in which STZ-induced diabetic rats were treated with low-dose (no cholesterol-lowering effect) simvastatin. The following parameters were measured after 6 weeks and 12 weeks in each groups, respectively: body weight and kidney weight, 24-h urinary albumin excretion (UAE), biochemical indexes including blood glucose (GLU), low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG) and serum creatinine (SCr). The expression of CTGF and α-SMA in renal tubulointerstitium was assessed by immunohistochemical method. After 6 and 12 weeks, there were no significant differences in SCr, LDL, HDL and TG levels among all three groups. The expression levels of CTGF and α-SMA in the tubulointerstitium of Group DS were significantly decreased compared with those of Group D at week 6 (P<0.05); there were no significant differences compared with Group C (P>0.05). After 12 weeks, CTGF and α-SMA expressions in Group DS were also lower than those in Group D (P<0.05); while higher than those in Group C (P<0.05). Simvastatin with a under cholesterol-lowering dose, can decrease the expression levels of CTGF and α-SMA in renal tubulointerstitium of rats with diabetic nephropathy, by which the progression of the tubulointerstitial fibrosis would be delayed.

The research of effect of Low-dose simvastatin on vascular endothelial function in patients with hypertensives and its safety

Objective To explore the low-dose simvastatin (5 mg)on vascular endothelial function in hypertensives and safety of low-dose.Methods 204 hypertensives were randomly divided into 3 groups: conventional control group( conventional antihypertensive treatment alone without oral simvastatin),5 mg group (simvastatin 5 mg/d),20 mg group( simvastatin 20 mg/d)respectively 68 cases were treated for 12 weeks,and blood lipid,hepatic and rena function,muscle enzymes,blood cells were detected before treatment and two weeks after treatment,during the the patients with adverse drug reaction of simvastatin will withdraw from the study,Before and after treatment brachial artery endothelial FMD ( flow-mediated dilation) and NMD ( nitroglycerin-mediated dilation) were detected using color Doppler ultrasound,the changes in level of lipid of 3 groups were observed before and after treatment and changes in endothelial function and lipid levels in each group before and after treatment and incidence of adverse reactions of simvastatin each group were compared.Results ①The incidence of adverse drug reactions of simvastatin in 5 mg and 20 mg group Group were respectively 4.41%,25% and the incidence of adverse drug reactions of simvastatin in 5 ng was was significantly lower than in 20 mg group ( P ＜ 0.05 ).②The level of TC,LDL-C after treatment in 20 mg group than before treatment decreased significantly(P ＜0.05);FMD in 5 mg and 20 mg groups were significantly improved pre-treatment(P ＜0.05),Changes in the value of FMD were no difference in 5 mg and 20 mg groups( P ＞ 0.05).Conclusion The incidence of adverse drug reactions in Low-dose simvastatin is fewer,both low-dose and conventional-dose simvastatin can significantly improve vascular endothelial function in hypertensives.These patients which need long-term use of statins and whose lipid levels are not too high or low may use low doses statins drugs,which could play a role improving vascular endothelial function but not a role of regulation of lipid levels and reduce incidence of adverse cardiovascular and cerebrovascular events,ultimately reduce the complications of hypertension. Key words: Low-dose simvastatin; Hypertension; Vascular endothelial function; Security; Serum lipid

The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients

Background/aim Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. Method A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia–myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5 mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. Results The reached simvastatin dose ranged from 0.825 to 8.75 mg/day with a mean dose of 4 mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% ( p < 0.001). Eleven percent of the patients reached LDL-cholesterol target levels (< 2.6 mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. Conclusion Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients.

LDL-C Goal Attainment in Patients who Remain on Atorvastatin or Switch to Equivalent or Non-equivalent Doses of Simvastatin: A Retrospective Matched Cohort Study in Clinical Practice

Background: As clinical trials have shown the benefits of more intensive cholesterol control, treatment targets for low-density lipoprotein cholesterol (LDL-C) have decreased progressively. At the same time, physicians have been encouraged to contain costs by prescribing cheaper, generic statins for cholesterol management. To determine how these possibly conflicting goals are managed in clinical practice, we examined LDL-C control in patients switched from a potent, branded statin (atorvastatin) to a less potent, generic statin (simvastatin). Methods: Patients who switched from atorvastatin to simvastatin between July 2006 and January 2008 were retrospectively identified from a US medical and pharmacy claims database, and matched with controls remaining on atorvastatin. Outcomes measured were the number of switched patients receiving a simvastatin milligram dose ≥ 2 times their previous atorvastatin dose, changes in LDL-C levels, and percentage of patients achieving recommended LDL-C targets. All study variables were analyzed descriptively. Results: After applying exclusion and inclusion criteria, 1048 patients who switched from atorvastatin to simvastatin and 1048 matched controls who remained on atorvastatin were included. Among the switchers, 379 (36%) received an inappropriately low dose of simvastatin (< 2 times atorvastatin dose). In patients remaining on atorvastatin, mean LDL-C decreased from 105.7 mg/dL to 102.3 mg/dL after 44 weeks, whereas in switched patients, LDL-C remained similar, at 105.9 mg/dL on atorvastatin and 105.8 mg/dL on simvastatin. Before switching, when all patients were receiving atorvastatin, 67.4% of switchers and 69.9% of controls achieved recommended LDL-C targets. After switching, significantly fewer switchers than controls met LDL-C targets (69.1% vs 74.6%; P = 0.005). However, among patients who switched to an equivalent dose of simvastatin (≥ 2 times prior atorvastatin dose), similar proportions met LDL-C targets (72.8% vs 74.6% of controls; P = 0.402), whereas among patients who switched to inappropriate non-equivalent dose of simvastatin, a significantly lower proportion met LDL-C targets (62.5% vs 74.6% of controls; P = 0.001). Conclusions: Continuing atorvastatin was associated with lower LDL-C levels and better LDL-C target attainment compared with switching to simvastatin. Patients switched to an equivalent simvastatin dose had lower LDL-C levels and were more likely to achieve LDL-C targets than patients switched to a non-equivalent dose, suggesting physicians must consider dosage equivalence when switching statins, and should measure LDL-C and titrate statins as necessary to achieve LDL-C control.

Simvastatin Protects Against the Development of Endometriosis in a Nude Mouse Model

Previous studies have demonstrated that proliferation of endometrial stroma (ES) in vitro is inhibited by a number of statins in a concentration-dependent manner. An in vitro model of endometriosis found that lovastatin also abolished angiogenesis. Another study using a rat autotransplantation model reported that the size of surgically induced experimental endometriosis was reduced by atorvastatin. These actions of statins in preventing the development of endometriosis may involve their anti-inflammatory properties. A number of studies have shown that inhibition of matrix metalloproteinase-3 (MMP-3) in mice and tissues results in a marked reduction in the establishment of experimental endometriosis. The present study investigated the effects of simvastatin on development of endometriosis using a nude mouse model. The effects of simvastatin on MMP-3 were also evaluated in the presence and absence of an inflammatory challenge induced by interleukin (IL)-1α. Normal endometrial tissues were obtained by biopsy from 11 healthy volunteers. The tissues were used to isolate ES cells or to establish organ cultures. All tissues were maintained in culture in the presence of 1 nM 17β-estradiol for 24 hour before injection into mice. Ovariectomized female nude mice were implanted with a SILASTIC capsule implant containing 8 mg 17β-estradiol for 24 hours before receiving subperitoneal injections of human endometrial tissues. Twenty-four hours after tissue injection, mice were randomly assigned to receive by gavage either 5 mg/kg or 25 mg/kg of simvastatin, or a placebo vehicle daily for 10 days. At various times after treatment, the mice were killed and examined for the presence, number, and size of lesions. To evaluate the in vitro effect of simvastatin on MMP-3, isolated human ES cells were cultured for 24 hours in medium containing 1 nM estradiol, in the absence (control) or the presence of simvastatin (1 and 10 μM). Some cells were exposed to an inflammatory challenge by addition of IL-1α (200 ng/mL) for the last 6 hour of culture. Simvastatin reduced both the number and the volume of endometriotic lesions in nude mice in a dose-dependent manner. About 85% of the mice receiving vehicle alone (control) developed lesions, whereas 58% of the mice receiving low-dose simvastatin (P = 0.2) and only 17% (P = 0.001) of those given high-dose simvastatin had lesions. In cultured ES cells, simvastatin induced a concentration-dependent decrease in MMP-3 expression, even after a challenge with IL-1α. These findings demonstrating a marked simvastatin-induced inhibition of both endometriosis development in the nude mouse model and reduced MMP-3 expression in cultures of ES cells suggest that the use of statins for the treatment of endometriosis is promising.

Effects of Low-Dose Simvastatin on the Distribution of Plasma Cholesterol and Oxidized Low-Density Lipoprotein in Three Ultra-centrifugally Separated Low-Density Lipoprotein Subfractions: 12- Month, Open-Label Trial

The effects of statins on the distribution of oxidized LDL in plasma LDL subfractions have not been well defined. Effects of 12-month treatment with low-dose simvastatin on the distribution of cholesterol and oxidized LDL in 3 ultracentrifugally separated plasma LDL subfractions were compared in patients with hypercholesterolemia. Simvastatin was administered to 30 hypercholesterolemic subjects for 12 months at an initial dose of 5 mg/day, which was increased to 20 mg/day via 10mg/day to decrease plasma LDL-cholesterol (C) lower than 130 mg/dL. Simvastatin dose was fixed after 3 months of treatment. The amounts of cholesterol and oxidized LDL in 3 ultracentrifugally separated plasma LDL subfractions were compared between 0 and 12 months of treatment. The distribution of ox-LDL skewed to denser LDL fractions, compared with cholesterol in plasma LDL subfractions. Plasma cholesterol in low-density LDL, medium-density LDL and high-density LDL decreased significantly by 31%, 30%, and 25%, respectively (p<0.0001) after 12 months of simvastatin treatment. Plasma oxidized LDL was decreased from 70 U/L to 56 U/L in medium-density LDL (p=0.042). Oxidized LDL in low-density LDL and high-density LDL did not change significantly after 12 months of treatment. Treatment with low-dose simvastatin decreased plasma cholesterol in 3 LDL subfractions and oxidized LDL in medium-density LDL. The decrease of oxidized LDL seemed to be not due to the decrease of cholesterol in plasma LDL subfractions because the decreasing patterns of cholesterol and ox-LDL were different in 3 LDL subfractions.

Obesity as a Risk Factor for Coronary Events in Japanese Patients with Hypercholesterolemia on Low-Dose Simvastatin Therapy

We previously reported that obesity (defined as a body mass index (BMI) >or=25 kg/m(2)) was not an independent risk factor for coronary heart disease (CHD) in hypercholesterolemic patients without a history of CHD from the Japan Lipid Intervention Trial (J-LIT). In this study, the obese J-LIT subgroup was further analyzed to assess CHD risk. In the J-LIT study, patients received simvastatin treatment (usually at 5 mg/day) for 6 years. A total of 38,385 patients (mean age: 57.7+/-7.9, 12,111 men) without prior CHD and/or stroke were analyzed. In this cohort, 181 CHD (acute myocardial infarction or sudden cardiac death) were observed. Obesity (n=12,929) was not an independent risk factor for CHD (relative risk; 1.18, 95% confidence interval; 0.87?1.59) after adjustment for the major risk known factors, such as age, sex, hypertension, diabetes mellitus (DM), and smoking. However, blood pressure, triglycerides, and fasting plasma glucose all increased, while high-density lipoprotein-cholesterol decreased, with increased BMI. The percentage of patients having two or three risk factors (such as dyslipidemia, hypertension, and DM) also increased with increased BMI. Obesity was not an independent risk factor for CHD in hypercholesterolemic patients on statin therapy; however, it is important to control obesity, a condition in which CHD risks accumulate, in order to improve associated risk factors along with the treatment of each risk factor, thus further reducing the risk of CHD.

Low dose simvastatin induces compositional, structural and dynamic changes in rat skeletal extensor digitorum longus muscle tissue

Statins are commonly used drugs in the treatment of hypercholesterolaemia. There are many adverse effects of statins on skeletal muscle, but the underlying mechanisms remain unclear. In the present study, the effects of low dose (20 mg/kg) simvastatin, a lipophilic statin, on rat EDL muscle (extensor digitorum longus muscle) were investigated at the molecular level using FTIR (Fourier-transform infrared) spectroscopy. FTIR spectroscopy allows us rapid and sensitive determination of functional groups belonging to proteins, lipids, carbohydrates and nucleic acids simultaneously. The results revealed that simvastatin treatment induces a significant decrease in lipid, nucleic acid, protein and glycogen content. A significant increase in the lipid/protein and nucleic acid/protein ratios was also obtained with simvastatin treatment. Furthermore, an increase in lipid order and membrane fluidity was detected. A decrease in the bandwidth of the amide I band and shifting of the position of this band to higher frequency values in treated muscle indicates structural changes in proteins. Detailed secondary structure analysis of the amide I band revealed a significant increase in antiparallel and aggregated beta-sheet, random coil structure and a significant decrease in beta-sheet structure, which indicates protein denaturation.

Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Aβ) levels and the number of Aβ plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Aβ plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.

Impact of Apolipoprotein A5 Variants on Statin Treatment Efficacy

Despite the fact that statin treatment efficacy is very high, there are substantial differences in treatment effectiveness among individuals. It is supposed that genetic predisposition plays an important role in these differences, but the contribution of individual polymorphisms is poorly understood. So far, more than 30 genes have been examined with ambiguous results. Apolipoprotein A5 is an important determinant of plasma lipid concentrations and its genetic variation could account for some of the observed differences in the response to statin therapy. However, this has not been analyzed before. We examined the putative association between APOA5 SNPs (c.-1131T>C, c.56C>G and c.457G>A) and efficacy during 3 months of statin treatment in 187 adult Caucasians. Patients were treated with low-dose (10 or 20 mg per day) simvastatin (46.3%), atorvastatin (40.5%) and lovastatin (13.2%). The decrease in cholesterol was not significantly associated with the type or dose of statin. Carriers of the APOA5 genotype TT-1131 (n = 154) benefited more from statin treatment when compared with the C-1131 allele carriers (n = 33) (Delta low-density lipoprotein cholesterol: -36.3 +/- 15.1% vs Delta low-density lipoprotein cholesterol: -29.9 +/- 12.5%; p < 0.005, Mann-Whitney test). This result was independent of sex, age, BMI and APOE polymorphism. Our results suggest that the APOA5 gene variants may play an important role in the pharmacogenetics of statin treatment.

Conversion to Tacrolimus and Atorvastatin in Cyclosporine-treated Heart Transplant Recipients With Dyslipidemia Refractory to Fluvastatin

Lipid-lowering therapy with statins has been associated with decreased mortality and morbidity in heart transplant recipients. Among the available drugs, pravastatin, fluvastatin or low-dose simvastatin have been recommended due to the low risk of pharmacokinetic interaction. However, these first-line statins possess a rather modest lipid-lowering effect and selection of alternative statins is limited due to interactions with cyclosporine (CsA). The aim of this prospective study was to evaluate the safety and efficacy of conversion to tacrolimus and atorvastatin in CsA-treated heart transplant recipients and dyslipidemia refractory to fluvastatin. Thirty heart transplant recipients taking CsA and fluvastatin 40 to 80 mg/day, with total cholesterol levels of >211 mg/dl, were recruited. After baseline assessment, they were converted to tacrolimus and atorvastatin at a starting dose of 20 mg/day and underwent clinical and laboratory follow-up at 1, 4, 7, 10 and 13 months. During 13 months of follow-up, treatment with tacrolimus and atorvastatin was tolerated in 24 patients (80%). No case of myotoxicity, liver toxicity or new-onset diabetes was observed. After conversion, the mean cholesterol level (as averaged from levels at 1, 4, 7, 10 and 13 months) was lower than before conversion (183 +/- 24 vs 231 +/- 33 mg/dl, p < 0.0001). When compared with baseline values, conversion also resulted in lower mean LDL-cholesterol levels (92 +/- 25 vs 130 +/- 38 mg/dl, p < 0.0001) and lower mean triglyceride levels (166 +/- 60 vs 220 +/- 101 mg/dl, p < 0.0001). Conversion to tacrolimus and atorvastatin appears to be a safe and effective lipid-lowering therapy in CsA-treated heart transplant recipients with dyslipidemia refractory to fluvastatin.

SEARCHing for JUPITER: starry-eyed optimism is not warranted

November 2008 saw the release of the last words in cardiovascular prevention so far as statins are concerned. Two major trials were presented at the American Heart Association in New Orleans - the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocy-steine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH) study in secondary prevention of low-dose vs. high-dose simvastatin (1) and the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial in primary prevention of patients with moderate lipid levels and an elevated C-reactive protein (2). Unfortunately, both trials have been confounded by the spin attached to them. Their implementation will be a challenge in the light of the financial constraints, operating within health services following the crash of 2008.