Background and Aims: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor can enhance endothelial nitric oxide synthase expression and induce vasodilatation. The vasodilatory effect may be detrimental to portal-systemic collaterals due to aggravating the shunting degrees. The present study investigated the effects of pravastatin, a HMG-CoA reductase inhibitor, on the collateral vascular responsiveness to endothelin-1 (ET-1) and portal-systemic shunting in portal hypertensive rats. Methods: The partial portal vein-ligated (PVL) rats received either pravastatin (25 mg/kg per day) or distilled water since 2 days prior to until 7 days after ligation. On the 8(th) day following hemodynamic measurements, the collateral vascular responsiveness to ET-1 was evaluated by an in situ collateral perfusion model. The shunting degrees of collaterals were evaluated by constructing vascular flow-pressure curves and color microsphere study, respectively. PVL rats underwent pre-incubation with: (i) Krebs solution (control); or Krebs solution plus (ii) 2 x 10(-5) M pravastatin; (iii) pravastatin + N(omega)-nitro-L-arginine (10(-4) M); and (iv) pravastatin + indomethacin (10(-5) M), followed by ET-1 (10(-10)-10(-7) M) administration to evaluate the collateral vascular responsiveness. Results: In chronic study, pravastatin did not modify systemic and portal hemodynamics and collateral vascular responsiveness to ET-1. The resistances of flow-pressure curves and the microsphere study demonstrated similar shunting degrees between both groups. Furthermore, pravastatin pre-incubation didn't reduce collateral perfusion pressure to ET-1. Conclusion: Chronic pravastatin administration does not induce detrimental effects on hemodynamics and collaterals in PVL rats, nor does it influence the shunting degree. In addition, it does not modify the vasoconstrictive effect of ET-1 on the collaterals of PVL rats.

SUMMARY 1. Pravastatin is best known for its antilipidemic action. Recent studies have demonstrated that statins have immunomodulatory and anti-inflammatory effects. The present study aimed to determine whether or not pravastatin can attenuate acute lung injury and fibrosis in a mouse model. 2. Bleomycin was administrated to C57BL6 mice via intratracheal instillation. Pravastatin was administrated via intraperitoneal injection. To study the effect of pravastatin on the early inflammatory phase and the late fibrotic phase, mice were sacrificed on days 3, 7, 14 and 21. 3. Pravastatin attenuated the histopathologic change of bleomycin-induced lung injury and fibrosis. The accumulation of neutrophils and increased production of tumor necrosis factor-alpha in bronchoalveolar lavage fluid were inhibited in the early inflammatory phase. Pravastatin effectively inhibited the increase of lung hydroxyproline content induced by bleomycin. Moreover, pravastatin reduced the increased expression of transforming growth factor (TGF)-ss1, connective tissue growth factor (CTGF), RhoA, and CyclinD1. The increased levels of TGF-ss1 and CTGF mRNA expression were also significantly inhibited by pravastatin. 4. Pravastatin effectively attenuated bleomycin-induced lung injury and pulmonary fibrosis in mice. Our results provide evidence for the therapeutic potential of pravastatin in the treatment of acute lung injury and pulmonary fibrosis.

We investigated whether pravastatin ameliorates renal damage induced by cisplatin (CP). Forty-three male Wistar rats were divided into four groups: rats treated with a control diet for 19 days and saline injection on day 14 (group1), group 1 with pravastatin treatment with 19 days (group 2), group 1 with CP injection on day 14 (group 3), and group 2 with CP injection (group 4). Renal function and serum lipids, renal malondialdehyde (MDA) and glutathione (GSH) levels, glutathione peroxidase (GPx) mRNA expression and activity, and kidney triglyceride (TG) concentrations were measured. Histology was evaluated by light microscopy with immunohistochemistry for p53, p53-upregulated modulation of apoptosis (PUMA), and terminal deoxynucleotide transferase dUTP nick end-labeling (TUNEL) staining. CP induced renal tubular damage with a higher MDA level, increased PUMA expression, p53- and TUNEL-positive cells counts, elevation of serum lipids, and decreased GSH level, GPx mRNA expression, and activity. Pravastatin partially ameliorated CP-induced renal injury, based on suppression of the renal MDA and TG levels, decreased p53 expression, and apoptosis in CP-treated rats. These findings suggest that pravastatin has a partial protective effect against CP nephrotoxicity via antioxidant activity as well as attenuation of the p53 response, and lipid-lowering effects.

Background and purpose: Statins (HMG CoA reductase inhibitors) have beneficial effects independent of reducing cholesterol synthesis and this includes their ability to acutely activate endothelial nitric oxide synthase (eNOS). The mechanism by which this occurs is largely unknown and thus we characterized the pathways by which statins activate NOS, including involvement of scavenger receptor-B1 (SR-B1), which is expressed in endothelial cells and maintains cholesterol concentrations. Experimental approach: Nitric oxide production was monitored in bovine aortic endothelial cells (BAECs) exposed to lovastatin (LOV) or pravastatin (PRA) for 10-20 min, alone or following pre-exposure to the end product of HMG-CoA reductase (mevalonate), G protein inhibitors (pertussis/cholera toxins), phospholipase C (PLC) inhibitor (U-73122), or intracellular and extracellular calcium chelators - BAPTA-AM and EGTA (respectively), or a function blocking antibody to SR-B1. Key results: Both statins increased NO production in a rapid, dose-dependent and HMG-CoA reductase-independent manner. Inhibiting Gi protein or PLC almost completely blocked statin-induced NO generation. Additionally, removing extracellular calcium inhibited statin-induced NO production. COS-7 cells co-transfected with eNOS and SR-B1 increased NO production when exposed to LOV or high-density lipoprotein (HDL), an agonist of SR-B1. These effects were not observed in COS-7 cells with eNOS alone or co-transfected with bradykinin receptor 2, indicating specificity for SR-B1. Further, pretreatment of BAEC with blocking antibody for SR-B1 blocked NO responses to statins and HDL. Conclusions and implications: LOV and PRA acutely activate eNOS through pathways that include the cell surface receptor SR-B1, Gi protein, phosholipase C and entry of extracellular calcium into endothelial cells.

Previous studies have demonstrated that benefits of intensive statin therapy compared to standard statin therapy begin shortly after an acute event and are continued up to 2 years of follow-up. However, whether efficacy and safety of intensive statin therapy in patients with a recent cardiac event are maintained in longer-term follow-up has not been evaluated. We conducted a post hoc analysis of a subgroup of 999 patients who had a first acute myocardial infarction (MI) <2 months before randomization in a prospective, open-label, blinded end-point evaluation trial of 8,888 patients with a history of MI that compared intensive statin therapy (atorvastatin 80 mg) to standard statin therapy (simvastatin 20 to 40 mg) over approximately 5 years of follow-up. We analyzed the same composite end point used in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial (death, MI, hospitalization for unstable angina, revascularization, and stroke). Rates of the composite end point were 44.7% (n = 226) in the simvastatin group and 37.9% (n = 187) in the atorvastatin group (hazard ratio 0.82, 95% confidence interval 0.67 to 0.99, p = 0.04). Although statistical power was smaller than that of the PROVE IT trial, the relative risk decrease observed at 5 years is consistent with that in the 2-year follow-up in PROVE IT. The 2 treatment regimens were well tolerated. In conclusion, our analysis provides support for the strategy of placing patients with recent MI on intensive statin therapy and maintaining the high dose over the long term, beyond 2 years.

Summary Randomised controlled trials evaluating the effect of statin use on maintenance of normal sinus rhythm (NSR) after electrical cardioversion (ECV) of persistent atrial fibrillation (AF) have demonstrated conflicting results. However, many of these trials were of relatively small size and thus underpowered to adequately evaluate this end-point. The aim of this study was to conduct a meta analysis evaluating the effect of statin use on maintenance of NSR after ECV of persistent AF. Randomised controlled trials evaluating the use of statins to maintain NSR after ECV of AF were identified through a systematic search including Medline (1950 through December 2009), the Cochrane CENTRAL Register (4th quarter, 2009) and a manual review of references without any language restrictions. Pooled estimates of effect are reported as relative risks (RRs) with accompanying 95% confidence intervals (CIs) using a random-effects model. Four trials (n = 424; range: 48-212) were identified and subject to meta analysis. Evaluated statins included atorvastatin 10 and 80 mg and pravastatin 40 mg/day. Over a mean of 2.1 months (range: 1-3 months) statins did not increase the likelihood of maintaining NSR following ECV (RR, 1.12; 95%CI, 0.85-1.46) compared with control. Current evidence does not suggest that statins are associated with an increased probability of maintaining NSR following ECV of persistent AF.

The treatment of opportunistic fungal infections is often difficult as the number of available antifungal agents is limited. Nowadays, there is increasing interest in the investigation of the antifungal activity of nonantifungal drugs, and in the development of efficient antifungal combination therapy. In this study, the in vitro interactions of the effects of various statins (lovastatin, simvastatin, fluvastatin, atorvastatin (ATO), rosuvastatin (ROS) and pravastatin) and various azole antifungals [miconazole, ketoconazole, itraconazole and fluconazole (FLU)] against different opportunistic pathogenic fungi were investigated using a standard chequerboard broth microdilution method. When the investigated strains were sensitive to both compounds of the combination, additive interactions were frequently noticed. Synergistic interactions were observed in many cases when a strain was sensitive only to the azole compound (as in certain combinations with ATO or ROS) or the statin compound (as in certain combinations with FLU). In many combinations with an additive effect, the concentrations of drugs needed for total growth inhibition could be decreased by several dilution steps. Similar interactions were observed when the variability of the within-species sensitivities to some selected drug combinations was investigated.

Aims Small GTPases RhoA and Rac1 play crucial roles in endothelial dysfunction and reactive oxygen species (ROS) generation. We reported evidence that in thrombin-stimulated endothelial cells, rapid geranylgeranylation is an essential process for full activation of unprocessed RhoA, which is blocked by statin. In this study, we examined the effects of intravenous administration of pravastatin on thrombin-triggered vascular responses in vivo, as well as on the lipid modification of unprocessed forms of RhoA and Rac1 and their activation induced by thrombin. Methods and Results Thrombin (50 U/kg) was intravenously injected with or without 0.3 mg/kg pravastatin into Wistar and spontaneously hypertensive rats. Coadministration of pravastatin prevented thrombin-induced impaired endothelium-dependent coronary vasodilation and down-regulated Akt/endothelial nitric oxide synthase (eNOS) phosphorylation within 1 hour, as well as the down-regulation of eNOS protein expression within 4 hours. In addition, thrombin increased Rac1/p47(phox)-dependent NAD(P)H oxidase activities of rat aortas within 1 hour, resulting in ROS generation, which was prevented by the coadministration of pravastatin. Furthermore, the coadministration of pravastatin prevented thrombin-induced conversion of unprocessed RhoA and Rac1 into the geranylgeranylated forms as well as GTP-loading and membrane translocation within 1 hour. Conclusion Intravenous injection of pravastatin prevents impaired NO-dependent vasodilation and Rac1/NAD(P)H oxidase mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways and the full activation of unprocessed RhoA and Rac1 in vivo.

Glomerular hyperfiltration is associated with mesangial cell hypocontractility. How 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) influence mesangial cell contraction is unclear. We investigated the effect of statins on mesangial cell hypocontractility and identified candidate proteins and filamentous/globular (F/G)-actin involved in this process. A high-glucose-induced mouse mesangial cell hypocontractility model was treated with fungal statins, simvastatin (Sim), lovastatin (Lov), and pravastatin (Pra). The optimum statin dose was determined by an 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and then applied to a cell model. A 2-dimensional gel/matrix-assisted laser desorption/ionization time-of-flight mass spectrometer analysis was used to evaluate protein expression cells incubated in the presence of a normal level of glucose (N), a high level of glucose (H), and a high level of glucose plus Sim (H + S). Candidate proteins were analyzed. Finally, the ratio of F/G actin in groups N, H, and H+S was evaluated. The MTT assay showed that Sim and Lov exerted dose- and time-related inhibition of proliferation of mesangial cells at N, but Pra had no effect. The optimum doses selected for Sim was 1 muM and for Lov was 3 muM, which were 1 increment before significant proliferation inhibition. Both doses reversed cell hypocontractility significantly, but Sim was chosen for further proteomic and F/G actin analyses. Proteomic analysis of groups N, H, and H + S showed that 18 proteins were involved in hypocontractility. These proteins were grouped and analyzed based on their known functions. Two selected proteins, TCP-1beta and GRP78, that were upregulated and downregulated, respectively, were confirmed by Western blot and immunohistochemistry. In regard to the F/G actin, group H had a significantly lower ratio than that of group N, and group H + S returned to a level similar to that of group N. In conclusion, Sim and Lov both seem to reverse mesangial cell hypocontractility. The process of Sim reversal of mesangial cell hypocontractility may involve F-actin, TCP-1beta, and GRP78.

We report two cases of systemic photosensitivity induced by simvastatin and pravastatin that presented as photodistributed erythema multiforme. One of them occurred in a 75-year-old woman who had been suffering recurrent eruptions following sun exposures over a period of 12 years. The other patient was a 54-year-old man who had a 1-week history of pruritic lesions on the face and the hands. They had no history of herpes simplex virus infection. In both cases, the close temporal relationship between drug ingestion and onset of the conditions suggested statin-induced photosensitivity. The diagnosis was confirmed by the marked reduction of UVB-MED or both UVA and UVB-MED while taking the drug and its normalization after discontinuing the statin intake.

Several Thai spices/dietary ingredients were previously shown to have hypocholesterolaemic effects. These studies were mostly conducted in animal models in which the mechanisms of action were not yet well-established. Therefore, this study aimed to investigate the potential mechanism of hypocholesterolaemic action of 12 selected plants, namely Hibiscus sabdariffa L., Moringa oleifera Lam., Cucurbita moschata Duchesne, Ananas comosus (L.) Merr., Zingiber officinale, Morus alba L., Camellia sinensis (L.) Kuntze, Piper nigrum L., Alpinia galanga (L.) Willd., Curcuma zedoaria Rose, Bacopa monnieri (L.) Wettst. and Piper retrofractum Vahl., widely used as spices and ingredients in various types of Thai food. The extract of P. nigrum at 100 microg mL(-1) was found to be the most effective cholesterol uptake inhibitor whereas those of A. galanga and C. sinensis effectively inhibited pancreatic lipase activity with IC(50) values of 8.99 +/- 3.41 and 12.36 +/- 1.23 microg mL(-1), respectively. The potency of extracts from H. sabdariffa, M. oleifera and C. moschata at 100 microg mL(-1) were found to be similar to 0.4 microg mL(-1) pravastatin in inhibiting HMG-CoA reductase and possibly reduced cholesterol biosynthesis. This study also demonstrated that several of the tested plants possessed multiple sites of action that were possibly responsible for their cholesterol-lowering effect in the in vivo model.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids. Because pravastatin is a water-soluble organic anion, it cannot easily penetrate the lipid bilayer of the cell membrane. As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified, we examined the roles of the organic anion transporter family on pravastatin-treated islet and adipocyte functions. Rat oatp1/slco1a1, oatp2/slco1a4 and oatp3/slco1a5 were expressed in the pancreas, and rat oatp3/slco1a5 was also detected in rat insulinoma cell line INS-1e. Pravastatin was transported not only by oatp1/slco1a1 and oatp2/slco1a4, but also by rat oatp3/slco1a5. Pravastatin uptake into INS-1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin, both of which are known to inhibit oatp family-mediated uptake. In addition, pravastatin enhanced the glucose-stimulated insulin secretion from INS-1e cells. When fat-loaded db/db mice were treated with pravastatin, glucose intolerance and insulin resistance were prevented. In addition, insulin secretion from isolated islets was enhanced by pravastatin. These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat/glucose conditions.

Abstract Pravastatin increases the plasma adiponectin level. We examined whether this is a statins' class effect or specific to pravastatin. Of 50 patients undergoing cardiac surgery for coronary artery disease (CAD, n = 36) and valvular heart disease (VHD, n = 14), 23 with CAD and serum LDL-cholesterol level >100 mg/dL were randomized to pravastatin at 10 mg/day (PRAVA, n = 12) or rosuvastatin at 2.5 mg/day (ROSUVA, n = 11) for 2 months, and the other 13 with CAD and LDL-cholesterol </=100 mg/dL were not treated with statin (Non-statin, n = 13). Patients with VHD did not have CAD and were not treated with statin. Blood was sampled at baseline and surgery. Visceral (VIS) and subcutaneous (SC) adipose tissues were harvested during surgery. At baseline, the plasma adiponectin level was low in patients with CAD compared with that of patients with VHD. At surgery, adiponectin level in PRAVA was increased to the level in VHD, whereas those in ROSUVA and Non-statin were unchanged. VIS contents and gene expressions of adiponectin in PRAVA and VHD were similar to each other and were both higher than those in Non-statin and ROSUVA. SC content and gene expression of adiponectin were similar among 4 groups. Protein carbonyl (PC) level, an indicator of oxidative stress, in VIS was lower in PRAVA and VHD than in ROSUVA and Non-statin. There was a negative correlation between the plasma adiponectin and VIS PC levels (r = -0.41, P < 0.05). Thus, pravastatin increases adiponectin generation, whereas rosuvastatin does not.

Abstract Cholesteryl ester rich apolipoprotein B100 (apoB100) lipoproteins accumulate in Bruch's membrane before the development of age-related macular degeneration. It is not known if these lipoproteins come from the circulation or local ocular tissue. Emerging, but incomplete evidence suggests that the retinal pigmented epithelium (RPE) can secrete lipoproteins. The purpose of this investigation was to determine 1) whether human RPE cells synthesize and secrete apoB100, and 2) whether this secretion is driven by cellular cholesterol, and if so, 3) whether statins inhibit this response. The established, human derived ARPE-19 cells challenged with 0-0.8mM oleic acid accumulated cellular cholesterol, but not triglycerides. Oleic acid increased the amount of apoB100 protein recovered from the medium by both Western blot analysis and (35)S-radiolabeled immunoprecipitation while negative stain electron microscopy showed lipoprotein-like particles. Of nine statins evaluated, lipophilic statins induced HMG-CoA reductase mRNA expression the most. The lipophilic Cerivastatin (5muM) reduced cellular cholesterol by 39% and abrogated apoB100 secretion by 3-fold. In contrast, the hydrophilic statin Pravastatin had minimal effect on apoB100 secretion. These data suggest that ARPE-19 cells synthesize and secrete apoB100 lipoproteins, that this secretion is driven by cellular cholesterol, and that statins can inhibit apoB100 secretion by reducing cellular cholesterol.

Background: Remnant lipoproteinemia is a strong risk factor for cardiovascular (CV) diseases. This study examined which of 2 common lipid-lowering drugs (fibrates and statins) is more effective in patients with remnant lipoproteinemia and if lowering remnant lipoprotein levels can reduce CV risk. Methods and Results: Remnant lipoprotein levels were measured by an immunoseparation method (remnant-like lipoprotein particles cholesterol: RLP-C) in 274 patients with coronary artery disease and high RLP-C levels (>/=5.0 mg/dl). They were randomly assigned to receive bezafibrate (200-400 mg/day) or pravastatin (10-20 mg/day), and were prospectively followed-up for 1 year or until the occurrence of CV events. Complete follow-up data were obtained in 180 patients. RLP-C levels at 1 year of treatment were reduced more by bezafibrate than pravastatin (37% and 25% from baseline, respectively). During follow-up, bezafibrate-treated patients had 3 CV events, compared with 12 events in pravastatin-treated patients (P<0.01). In multivariate logistic regression analysis, a decrease in RLP-C level was significantly associated with a reduction in CV events after adjustment for treatment group and changes in levels of other lipids. Conclusions: Bezafibrate therapy decreased RLP-C levels to a greater extent than pravastatin and a decrease in RLP-C level may be associated with a reduction in CV events in patients with high RLP-C levels.

OBJECTIVE:: To estimate the effects of pravastatin on the altered vascular function in a mouse model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase-1 (sFlt-1). METHODS:: Pregnant CD1 mice, at day 8 of gestation, were randomly allocated to injection using the tail vein of the adenovirus carrying sFlt-1 (10 plaque-forming units in 100 microliters; sFlt-1 group) or mFc (10 plaque-forming units) as virus control, and then to receive pravastatin (Pra; 5 mg/kg/d) dissolved in drinking water or control. The mice in four groups (sFlt-1, sFlt-1-pravastatin, mFc, and mFc-pravastatin; n=4-6 per group) were killed at day 18 of gestation and 2-mm segments of carotid artery were used for vascular reactivity studies. Serum sFlt-1 levels were also measured by enzyme-linked immunosorbent assay. RESULTS:: Mice in the sFlt-1 group had the highest responses to phenylephrine. Treatment with pravastatin decreased the contractile responses to phenylephrine (maximal effect [mean+/-standard error of the mean] 137.35+/- 27.70 compared with 42.24+/-8.76; P=.006) for sFlt-1 compared with sFlt-1-pravastatin, respectively. There were no differences in the contractile responses to thromboxane A2. The vasorelaxant responses to acetylcholine were significantly highest in the mFc-pravastatin group, with a maximal effect of 108.37+/-5.25 compared with 89.77+/-3.96 in the mFc group (P=.008), and those with sodium nitroprusside were not different across the four groups. Serum sFlt-1 levels were not different at baseline (day 8) but were significantly lower in sFlt-1-pravastatin compared with sFlt-1 at day 18 (59.42+/-5.31 compared with 102.59+/-15.15 ng/mL; P=.01). CONCLUSION:: Pravastatin improved the vascular reactivity in this murine model of preeclampsia by decreasing sFlt-1 levels. Statins should be evaluated for the prevention of the vascular abnormalities of preeclampsia.

Statins are potent inhibitors of cholesterol synthesis. Several statins are available with different molecular and pharmacokinetic properties. Simvastatin is more lipophilic than pravastatin and has a higher affinity to phospholipid membranes than atorvastatin allowing its passive diffusion through the cell membrane. In vitro studies on bone marrow stromal cells, osteoblast-like cells, and embryonic stem cells have shown statins to have cholesterol-independent anabolic effects on bone metabolism; alas statins were supplemented in osteogenic media which does not facilitate the elucidation of their potential osteoinductive properties. Embryonic stem cells (ESC), derived from the inner cell mass of the blastocyst, have the unique properties of perpetual self-proliferation as well as being pluripotent and able to differentiate towards all the cellular lineages composing the body, including the osteogenic lineage. Consequently, ESCs represent a potentially potent cell source for future clinical cellular therapies of various bone diseases, even though there are several hurdles that still need to be overcome. Herein, we demonstrate, for the first time to our knowledge, that simvastatin induces murine ESC (mESC) differentiation towards the osteogenic lineage in the absence of osteoinductive supplements. Specifically, we found that a simvastatin concentration in the microM range and higher was toxic to the cells and that effective concentration for osteoinduction was 0.1 nM as shown by increased alizarin red staining as well as increased osteocalcin and osetrix gene expression. These results suggest that lipophylic simvastatin may in the future provide a novel pharmacological agent for bone tissue engineering applications. (c) 2010 American Society for Bone and Mineral Research.

Human hepatocytes in primary culture are a very useful model to directly assess induction of gene expression by xenobiotics. We developed a novel cytochrome P450 (CYP) activity cocktail assay using model substrates for the seven important CYPs 1A2 (phenacetin), 2B6 (bupropion), 2C8 (amodiaquine), 2C9 (tolbutamide), 2C19 (S-mephenytoin), 2D6 (propafenone), and 3A4 (atorvastatin). Metabolite formation was determined by LC-MS/MS in hepatocyte culture supernatants. Atorvastatin has not been previously assessed as CYP3A probe drug. We demonstrate highly selective atorvastatin ortho-hydroxylation by CYP3A4 by recombinant CYPs. In human liver microsomes ortho-OH-atorvastatin formation was highly correlated to CYP3A4 protein content (rs=0.78, p<0.0001, n=150). We profiled induction of these CYP activities in primary human hepatocytes following treatment with 30 muM of atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin for 24 to 72 hours. Except for pravastatin, all statins induced CYP activities to various degrees, approximately in the order atorvastatin > simvastatin > lovastatin > rosuvastatin. Inducibility of CYPs followed the order CYP2C8 > CYP3A4 > CYP2C9 > CYP2B6 > CYP2C19 ~ CYP2D6 > CYP1A2. The strongest induction was observed for amodiaquine N-desalkylation, which was induced approximately 20-fold. Quantitative RT-PCR confirmed corresponding changes on the mRNA level with even more dramatic induction up to almost 100-fold. These data suggest a broader inducing effect of statins on cytochrome P450s and possibly other ADME genes than previously known, thus further emphasizing their drug-drug interaction potential. Our cocktail assay should be useful for economical use of human hepatocytes in the assessment of P450 induction by drugs and drug candidates.

Aims: To evaluate the relationship between low-density lipoprotein cholesterol (LDL-C) change and reduction of cardiovascular disease in the Management of Elevated cholesterol in the primary prevention Group of Adult Japanese (MEGA) study.Methods: Patients in the diet plus pravastatin group were divided into tertiles by their on-treatment LDL-C level, and the hazard ratios (HRs) in each tertile were compared with the diet group at 5 years using the Cox proportional hazards model. In addition, the treatment groups were combined and divided into quintiles according to the on-treatment LDL-C level during follow-up, and the incidence of cardiovascular events was compared among the 5 groups.Results: In the tertiles of the diet plus pravastatin group, HR was lowest in the second tertile against the diet group (HR 0.57, p=0.01) with on-treatment LDL-C range of 119.8-133.4 mg/dL. In the analysis of quintiles of the total population, a significant risk reduction of CVD was found in the fourth quintile (HR 0.48, p=0.0015) with an on-treatment LDL-C range of 120.9-133.3 mg/dL, and in the fifth quintile (HR 0.64, p=0.048) with an on-treatment LDL-C range of 56.7-120.8 mg/dL against tertile 1 with an on-treatment LDL-C range of 157.5-206.2 mg/dL.Conclusions: The usual Japanese dose of pravastatin therapy is sufficient in this low-risk patient population to reduce cardiovascular risk, with an achieved LDL-C level <133.4 mg/dL. Further risk reduction was not found with an achieved LDL <120 mg/dL.

BACKGROUND: In line with current guideline recommendations, patients at high cardiovascular risk are usually treated with statins for secondary as well as for primary prevention. While many studies investigated treatment goal achievement with regards to low-density lipoprotein (LDL-C) and total cholesterol (TC) there is paucity of data regarding high density lipoprotein (HDL-C), and/or triglycerides (TG). SETTING: Prospective, cross-sectional study (Dyslipidemia International Survey, DYSIS) with data provided by 748 office-based physicians throughout Germany. METHODS: Consecutive patients were eligible for participation, if they were at least 45 years old, currently treated with a statin and had had a documented lipid profile (at least 1 parameter) within the last 6 months. Besides descriptive analyses, logistic regression was performed with backward selection to assess predictors for lipid abnormalities (non-attainment of goals for TC, LDL-C, low HDL-C or elevated TG) classified according to current European Society of Cardiology guidelines. RESULTS: The 4,282 documented patients (98.6% Caucasian, 56.4% male; 86.6% at high cardiovascular risk) were predominantly treated with simvastatin (83.9%), pravastatin (7.7%) or atorvastatin (3.9%), usually with doses equivalent to simvastatin 20-40 mg daily. Non-statins were used in at most 12% of patients. No lipid abnormalities were found in 21.0% of patients, one abnormality in 38.5%, two in 31.9%, and all three in 8.5%. LDL-C goals were not attained in 58.1%, elevated TC was found in 66.6%, low HDL-C in 22.7%, and elevated TG in 47.3%. In the multivariate logistic regression model, non-attainment of LDL-C levels was predicted by hypertension (odds ratio, OR 1.4), current smoking (OR 1.3), sedentary lifestyle (OR 1.3), and female gender (OR 1.3). On the other hand, a reduced risk for missing LDL-C targets was noted in the presence of ischemic heart disease (OR 0.6), diabetes (0.5), higher statin doses, ezetimibe treatment, or specialist care, respectively. CONCLUSION: A substantial proportion of statin-treated patients not only missed targets for LDL-C, but also did not attain the normal levels for HDL-C and/or TG. There is a large disconnect between high prevalence of HDL and/or TG disorders, with or without elevated LDL-C, and utilization of therapies targeting these lipids. Particularly in high-risk patients, additional efforts should be made to improve their lipid profile.