Human carboxylesterase (CES) 1A is responsible for the biotransformation of angiotensin-converting enzyme (ACE) inhibitors such as imidapril and temocapril. Because antidiabetic or antihyperlipidemic drugs are often co-administered with ACE inhibitors in clinical pharmacotherapy, the inhibitory effect of these drugs on the CES1A1 enzyme activity was investigated. In addition, the inhibitory effect on the CES2 enzyme activity was evaluated to compare it with that on CES1A1. The inhibitory effects were evaluated with 11 antidiabetic and 12 antihyperlipidemic drugs. The imidapril hydrolase activity by recombinant CES1A1 was substantially inhibited by lactone ring-containing statins such as simvastatin and lovastatin, and thiazolidinediones such as troglitazone and rosiglitazone. The activity in human liver microsomes was also strongly inhibited by simvastatin and troglitazone (Ki = 0.8 +/- 0.1 muM and 5.6 +/- 0.2 muM, respectively). However, statins containing no lactone ring such as pravastatin and fluvastatin did not show strong inhibition. 7-Ethyl-10-[4-(1-piperidono)-1-piperidono]carbonyloxycamptothecin (CPT-11) hydrolase activity by recombinant human CES2 was substantially inhibited by fenofibrate (Ki = 0.04 +/- 0.01 muM) as well as by simvastatin (0.67 +/- 0.09 muM). Other fibrates such as clinofibrate and bezafibrate did not show strong inhibition. Thus, the inhibitory effects of the thiazolidinediones and fenofibrate on CES1A1 and CES2 were different. Some statins such as simvastatin and lovastatin, thiazolidinediones, and fenofibrate might attenuate the drug efficacy of prodrugs biotransformed by CES1A and CES2.

BACKGROUND.: Chronic graft-versus-host disease (CGVHD) is a serious and increasingly common complication after allogeneic (allo) hematopoietic stem-cell transplantation, but currently available therapies have demonstrated limited efficacy. Furthermore, the statins have been reported to be effective in various immune-mediated disease models, but their therapeutic potentials versus CGVHD have not been determined. METHODS.: We used a B10.D2-->BALB/c model of CGVHD, which differs at minor histocompatibility loci, to address the therapeutic effect of statins on the development of CGVHD. Pravastatin (PST, 30 mg/kg/day) was intraperitoneally injected for 5 days per week from the day of transplantation until 4 weeks after allo hematopoietic stem-cell transplantation. RESULTS.: The onset of clinical cutaneous GVHD was significantly slower in PST-treated recipients than in allo-controls (36 days vs. 25 days, respectively, P<0.05), and pathologic changes in skin disease confirmed this clinical result. Animals injected with PST showed less submucosal fibrosis in lungs than allo-controls. In addition, collagen deposition in skin and lungs was markedly attenuated by PST treatment. PST also significantly reduced protein concentrations and numbers of inflammatory and epithelial cells in bronchoalveolar lavage fluid. Significantly lower numbers of donor CD11b and CD4, but not CD8 cells, were observed in skin and bronchoalveolar lavage fluid after PST treatment. The protein concentrations of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) in skin and lungs were substantially reduced in PST-treated animals when compared with allo-controls. CONCLUSIONS.: This study suggests that the CGVHD-protecting effect of PST involves the down-regulation of chemokines and the reduction of collagen synthesis.

To facilitate comprehensive cardiometabolic risk assessment, we developed a simple 12-point checklist of traditional and emerging risk factors. We recently analyzed data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial of 4162 high-risk patients hospitalized with recent acute coronary syndrome, and found that an increasing cardiometabolic risk factor count was associated with increasing risk of cardiovascular events over the next 2 years. In addition, we observed that the average number of risk factors a given patient had was 5, with some risk factors like obesity having clustering of additional risk factors, suggesting the need to assess the full list of risk factors to be able to provide comprehensive risk factor assessment and modification. We now have developed a 1-page patient encounter sheet to facilitate rapid assessment of these 12 cardiometabolic risk factors in a busy clinical office setting. It is hoped that with the simple risk assessment tool provided, clinicians would be able to comprehensively screen for and treat these traditional and nontraditional risk markers. As such, this could motivate both patients and physicians to work jointly toward reducing global cardiometabolic risk.

Background and Aims: Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Materials and Methods: Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Statistical Analysis: Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Results: Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Conclusion: Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.

BACKGROUND AND PURPOSE The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel. EXPERIMENTAL APPROACH Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP. KEY RESULTS Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 microM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 microM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC(50) values of 0.03 +/- 0.07 microM and 0.55 +/- 0.06 microM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 microM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations </=10 microM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation. CONCLUSIONS AND IMPLICATIONS At clopidogrel concentrations >10 microM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations </=10 microM. CYP2C19 inhibition by clopidogrel at concentrations >10 microM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.

PURPOSE: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma. METHODS: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6months (PFR(6months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0)=50%; P(1)=70%; alpha=0.05; beta=0.10). RESULTS: Thirty patients were enrolled. PFR(6months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6months and median OS was 6 and 8months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm. CONCLUSION: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.

BACKGROUND: The FDA revised the labels of amiodarone and simvastatin in 2002 to warn of increased risk of rhabdomyolysis, the most severe form of myopathy, when the 2 drugs are taken concomitantly in doses greater than 20 milligrams (mg) per day of simvastatin. The FDA reissued the warning in 2008 after receiving reports of 52 cases of rhabdomyolysis in the Adverse Event Reporting System (AERS) after the label changes in 2002 and suggested use of an alternative statin for patients receiving amiodarone who require more than 20 mg simvastatin to attain lipid goals. OBJECTIVES: To (a) assess the prevalence of concomitant amiodarone and simvastatin in doses greater than 20 mg per day and the frequency of additional risk factors for myopathy in these patients, and (b) implement and evaluate a protocol to convert patients receiving this combination to alternative statins. METHODS: A review was conducted of all patients with active prescriptions for both simvastatin at doses greater than 20 mg per day and amiodarone from a Veterans Affairs (VA) medical center as of November 1, 2008. Data collected included demographics, duration of therapy, baseline lipid and aminotransferase values, and risk factors for myopathy (i.e., aged 80 years or older; female sex; small body frame; hypothyroidism; hepatic or renal insufficiency; diabetes; alcohol abuse; and use of medications, such as gemfibrozil and nicotinic acid, that may increase the risk of myopathy). Patients were converted to either pravastatin or rosuvastatin based on baseline simvastatin dose, low-density lipoprotein cholesterol (LDL-C) level, and renal function. The conversion protocol was developed to maintain LDL-C lowering with potentially safer statins. Follow-up lipid and aminotransferase values were collected as customary clinical markers of efficacy and safety, respectively, for patients converted per the protocol. Because creatine kinase values are not routinely assessed in clinical practice, they were not available as part of the current protocol. RESULTS: Of the 48,612 patients who accessed the pharmacy in this VA medical center, 17,760 (36.5%) had an active order for simvastatin 40 mg or 80 mg per day, and 92 of these patients (0.52%) also had an active order for amiodarone. These patients were prescribed simvastatin primarily for secondary prevention (88 [95.7%] with coronary artery disease [CAD] as the indication for statin therapy), and were highly controlled with mean (SD) baseline LDL-C of 71 (21) mg per deciliter. The mean (median) duration of therapy on the combination of amiodarone plus simvastatin 40 mg or more per day was 43 (37) months. Of the 92 patients, 26 (28.3%), 35 (38.0%), and 18 (19.6%) patients had 1, 2, or 3 or more additional risk factors for myopathy, respectively. 16 patients were not converted per protocol to an alternate statin (4 were taken off amiodarone, 2 were taken off statin therapy, 6 had the simvastatin dose reduced to 20 mg per day or less, and 4 were converted to an alternate statin off-protocol), and 14 patients did not have follow-up laboratory values. For the 62 patients converted per protocol and with follow-up laboratory values, there were no statistically significant changes in mean lipid or aminotransferase values after conversion. One patient reported symptoms of myalgia after conversion to rosuvastatin; however, the conversion protocol did not require obtaining creatine kinase values. CONCLUSION: 0.19% of patients (n=92) with pharmacy dispensing records in this VA facility in 2008 received amiodarone in combination with simvastatin in doses greater than 20 mg per day, and the majority of patients had additional risk factors for myopathy. There were no significant changes in mean laboratory values for lipids or aminotransferase for the 62 patients (67%) who were converted and who had baseline and follow-up values; there was 1 case of self-reported myalgia in a patient converted to rosuvastatin.

OBJECTIVE: Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins. METHODS AND RESULTS: Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide (H2O2), as judged by senescence-associated beta-galactosidase assay and cell morphological appearance. Atorvastatin, pravastatin, and pitavastatin inhibited the oxidative stress induced-endothelial senescence. These statins phosphorylated Akt at Ser473 and subsequently led to increased expression of endothelial nitric oxide synthase (eNOS), SIRT1, and catalase. Treatment with LY294002 or Akt short interfering RNA decreased the eNOS activation, SIRT1 expression, and antisenescent property of atorvastatin. Moreover, in streptozotocin-diabetic mice, administration of pitavastatin increased eNOS, SIRT1, and catalase expression and decreased endothelial senescence, but levels remained unaltered in Sirt1 knockout mice. CONCLUSIONS: Our results indicate that treatment with statins inhibits endothelial senescence and that enhancement of SIRT1 plays a critical role in prevention of endothelial senescence through the Akt pathway, a direct target of statins.

Aim: A reduced risk of type 2 diabetes has been reported following treatment with pravastatin. Adiponectin is an adipocyte-derived protein that has an antidiabetic property. The objective of this study was to evaluate the effect of pravastatin on serum adiponectin concentration and other influencing factors.Methods: This study was a multicenter observational study: Dyslipidemia Open-labeled observa-tional study by Lipid-lowering therapy with Pravastatin of the effect on High-molecular weight adi-ponectin in Nippon Yokohama (DOLPHIN). The protocol was registered in the UMIN Clinical Trial Registry as UMIN000000791. All patients received pravastatin 10 mg/day for 6 months and the change in concentration of total and high molecular weight adiponectin was assessed before and after follow-up. The difference in the change in total adiponectin concentration by patient characteristics was analyzed by an unpaired t-test. Influences of continuous variable factors on the change in total adiponectin concentration were estimated by simple linear regression analyses. Finally, in order to estimate the influences of factors that potentially affect the change in total adiponectin concentration induced by pravastatin, multiple linear regression analysis was conducted.Results: After 6 months, total adiponectin concentration was increased significantly by 23.2% from 11.7+/-6.4 to 13.7+/-8.6 microg/mL (p=0.002). The use of thiazolidinedione as a concomitant medication was the only significant influencing factor (beta=0.580, p<0.001).Conclusion: Pravastatin increased the serum adiponectin concentration in Japanese dyslipidemic patients without previous coronary artery disease. Interestingly, this effect was seen synergistically in combination with thiazolidinedione.

Because of their good tolerability and their positive effect on lipid parameters and clinical outcomes, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become the drugs of first choice for the management of dyslipidemia. Pitavastatin is the newest member in the statin family and received Food and Drug Administration approval for oral use in August 2009. Compared to other statins such as atorvastatin, simvastatin and pravastatin at specific doses, pitavastatin dosed at 1 to 4 mg daily showed similar efficacy in lowering low-density lipoprotein cholesterol (LDL-C) and altering other lipid parameters according to a number of studies. In addition, pitavastatin demonstrated cholesterol-lowering efficacy in special populations such as the elderly, patients with diabetes, and patients with higher cardiovascular risk. Because pitavastatin is minimally metabolized by the cytochrome P-450 isoenzymes, it is associated with a lower frequency of drug-drug interactions, and this may be a desirable characteristic of pitavastatin. Beneficial effects, such as reductions of coronary plaque volume and fibrofatty composition, have also been observed with pitavastatin. Thus far, the safety profile of pitavastatin is favorable and appears to be similar to those of other statins. Given its encouraging pharmacokinetic and pharmacodynamic characteristics, pitavastatin is likely to be a good alternative to other more established statins. The pharmacologic and pharmacokinetic properties of pitavastatin are reviewed in this article.

Lifibrol is a potent lipid-lowering drug with an unknown mechanism of action. We investigated its effects on lipoprotein and sterol metabolism in normocholesterolemic male participants. Seven participants were treated for 4 weeks with 600 mg/d lifibrol and 9 with 40 mg/d pravastatin in a double-blind randomized parallel-group trial. Kinetic studies were performed at baseline and under acute and chronic treatment. Turnover of apolipoprotein B-100 was investigated with endogenous stable-isotope labeling, and kinetic parameters were derived by multicompartmental modeling. Lathosterol and cholesterol metabolism were investigated using mass isotopomer distribution analysis (MIDA) after [1-(13)C]acetate labeling. Carbon metabolism was investigated by calculating the total isotope incorporation into newly formed sterols and measuring the disposal of acetate by (13)CO2 breath analysis. Total- and low-density lipoprotein (LDL) cholesterol decreased by 18% and 27% under lifibrol and by 17% and 28% under pravastatin, respectively, whereas very-low-density lipoprotein (VLDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol did not change. Very-low-density lipoprotein apoB fractional synthesis and production increased under lifibrol but remained unchanged under pravastatin. Low-density lipoprotein apoB fractional synthesis and production increased under pravastatin but remained unchanged under lifibrol. Mass isotopomer distribution analysis indicated that both drugs decrease endogenous sterol synthesis after acute administration, but pravastatin had more powerful effects. Carbon-13 appearance in breath was higher during pravastatin than during lifibrol treatment. Mass isotopomer distribution analysis and carbon metabolism analysis indicated compartmentalization at the site of sterol synthesis, thus suggesting differential effects of the 2 drugs. Although having comparable lipid-lowering properties, lifibrol seems to have a mechanism of action distinct from that of statins. Lifibrol could serve as a model compound for the development of new lipid-lowering agents.

The cardiovascular risk reduction associated with different statins for the prevention of cardiovascular disease and the cardiovascular risk increase associated with excess dietary intake of fat have been quantified. However, these relative risks have never been directly juxtaposed to determine whether an increase in relative risk by 1 activity could be neutralized by an opposing change in relative risk from a second activity. The investigators compared the increase in relative risk for cardiovascular disease associated with the total fat and trans fat content of fast foods against the relative risk decrease provided by daily statin consumption from a meta-analysis of statins in primary prevention of coronary artery disease (7 randomized controlled trials including 42,848 patients). The risk reduction associated with the daily consumption of most statins, with the exception of pravastatin, is more powerful than the risk increase caused by the daily extra fat intake associated with a 7-oz hamburger (Quarter Pounder(R)) with cheese and a small milkshake. In conclusion, statin therapy can neutralize the cardiovascular risk caused by harmful diet choices. In other spheres of human activity, individuals choosing risky pursuits (motorcycling, smoking, driving) are advised or compelled to use measures to minimize the risk (safety equipment, filters, seatbelts). Likewise, some individuals eat unhealthily. Routine accessibility of statins in establishments providing unhealthy food might be a rational modern means to offset the cardiovascular risk. Fast food outlets already offer free condiments to supplement meals. A free statin-containing accompaniment would offer cardiovascular benefits, opposite to the effects of equally available salt, sugar, and high-fat condiments. Although no substitute for systematic lifestyle improvements, including healthy diet, regular exercise, weight loss, and smoking cessation, complimentary statin packets would add, at little cost, 1 positive choice to a panoply of negative ones.

Although cholesteryl ester transfer protein (CETP) plays an important role in human lipoprotein metabolism, its relation to coronary artery disease remains controversial. The present study evaluated the relation between on-statin CETP mass and recurrent coronary events. The plasma CETP mass, measured after 4 months of statin therapy, was quantified in 3,218 patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study. Of the 3,218 patients, 150 experienced the combined end point of recurrent myocardial infarction or death from coronary causes during a mean follow-up of 1.8 years. An increasing on-statin CETP mass was inversely related to the risk of coronary events in both unadjusted (hazard ratio [HR] per SD increase 0.77, 95% confidence interval 0.65 to 0.92, p = 0.005) and fully adjusted (HR per SD increase 0.81, 95% confidence interval 0.67 to 0.98, p = 0.027) analyses that included traditional cardiovascular risk factors. A similar trend was observed across increasing CETP mass quartiles (p trend = 0.07). A significant interaction between the CETP mass and on-treatment low-density lipoprotein (LDL) cholesterol was noted (p interaction = 0.007). A CETP mass greater than the median was associated with a decreased risk in patients with LDL cholesterol less than the median of 80 mg/dl (HR 0.52, 95% confidence interval 0.31 to 0.89, p = 0.02), but not in patients with LDL cholesterol greater than the median. In conclusion, an increasing on-statin CETP mass was inversely related to the coronary outcomes in this large clinical trial-based cohort, particularly among those with low LDL cholesterol levels. This finding is consistent with CETP facilitating reverse cholesterol transport in the setting of robust LDL clearance and might have important implications for efforts to optimally target patients with pharmacologic CETP inhibition.

Please cite this paper as: Di Filippo, Monopoli, Ongini, Perretti and D'Amico (2010). The Cardio-Protective Properties of Ncx-6550, a Nitric Oxide Donating Pravastatin, in the Mouse. Microcirculation17(6), 417-426. Abstract Objective: Determine the cardio-protective properties of a nitric oxide-releasing pravastatin (Ncx-6550), in comparison to pravastatin. Methods: A mouse model of myocardial infarct was used assessing tissue damage both at 2 and 24 hour post-reperfusion, administering compounds both prophylactically and therapeutically. Results: Ncx-6550 induced a significant dose-dependent (2.24-22.4 mumol/kg i.p.) cardioprotection in the two hour reperfusion protocol. In vehicle-treated mice, infarct size (expressed as fraction of area at risk; IS/AR) was 41.2 +/- 1%, and it was reduced to 22.2 +/- 0.9% and 32.6 +/- 0.9% following 22.4 and 6.72 mumol/kg Ncx-6550 (p < 0.05). 22.4 mumol/kg Ncx-6550 also increased cardiac levels of the enzyme heme oxygenase-1. Treatment of mice with pravastatin induced significant reduction of myocardial injury only at 22.4 mumol/kg (IS/AR value: 33.7 +/- 0.9%). In a 24 hour reperfusion protocol, Ncx-6550 and pravastatin were tested only at 22.4 mumol/kg i.p. being given either one hour prior to ischemia (prophylactic protocol) or one hour into reperfusion (therapeutic protocol). With either treatment scheme, Ncx-6550 produced higher cardioprotection compared to pravastatin, as reflected also by a reduction in the incidence of lethality as well as in circulating troponin I and interleukin-1beta levels. Conclusions: These results indicate Ncx-6550 as a novel therapeutic agent with a potential for the treatment of myocardial infarct.

PURPOSE: The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. METHODS: OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. RESULTS: Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC (50) value of 30.4 muM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 muM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. CONCLUSION: Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.

The role of archaeal membrane and its lipid constituents was investigated in bioenergetic functions of Methanothermobacter thermautotrophicus. The effects were determined of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, pravastatin, on lipid composition, and its impact on some bioenergetic functions of treated cells. Pravastatin remarkably inhibited the growth of M. thermautotrophicus. On membrane level, pravastatin treatment modulated the composition of the mixture of squalene and hydrosqualene derivatives as well as the activities of ATPase, A(1)A(o)-ATP synthase and Na(+)/H(+) antiporter. SDS-PAGE of chloroform-methanol extracts of membranes from control and pravastatin-treated cells revealed changes in the amount of AtpK proteolipids, which suggests that pravastatin modifies cell-membrane composition, hereby modulating the properties of some membrane-bound enzymes participating in energy transformation in methanoarchaea.

Since both statins and lycopene exert immunomodulatory activities following incubation with human peripheral blood mononuclear cells (PBMC), the present work was designed to examine whether they may induce a synergistic or antagonistic effect on cytokine production while applied together. Peripheral blood mononuclear cells isolated from 15 healthy subjects were incubated for 24 h as follows: (1) without and with 0.125 or 0.25 muM lycopene, (2) without and with 10 or 50 mM pravastatin or simvastatin, and (3) with lycopene and with one of the statins together at the respective doses. The production of the following cytokines was assessed: interleukin (IL)-1beta, IL-1ra, IL-2, and IL-10, as well as tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma). The results showed that lycopene and simvastatin applied together reduced TNFalpha and IFNgamma secretion, and abolished the increased production of the proinflammatory cytokine IL-1gamma caused by incubation with simvastatin only, an observation suggesting that simultaneous administration of both substances may reduce inflammatory responses.

Previous studies have shown that NCX 6550 (NCX), a nitric oxide (NO)-donating pravastatin, induces anti-inflammatory effects in murine macrophage cell lines. Here, we have studied its activity in human monocyte/macrophages, by investigating cytokine release, NF-kappaB translocation and Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) expression and function. For comparison, pravastatin, isosorbide-5-mononitrate (ISMN), sodium nitroprusside (SNP) and the PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ) were also tested. Monocytes and macrophages (MDM: monocyte-derived macrophages) were isolated from healthy donors; cytokine release was measured by ELISA, NF-kappaB by Electrophoretic Mobility Shift Assay and PPARgamma by Western blot and Real-Time PCR. NCX (1nM - 50muM) dose-dependently inhibited phorbol 12-myristate 13-acetate (PMA)-induced TNF-alpha release from monocytes (IC(50)= 240nM) and MDM (IC(50)= 52nM). At 50muM, it was more effective than pravastatin, ISMN and SNP (P<0.05), but less efficient than PGJ. Similar results were obtained for IL-6. Likewise, NCX was more effective than pravastatin and the other NO donors in inhibiting PMA-induced NF-kappaB translocation in both cell types, and, at the highest concentration, significantly (P <0.05) enhanced PPARgamma protein expression in monocytes. We conclude that NCX 6550 exerts a significant anti-inflammatory activity in human monocyte/macrophages, that is also contributed by its NO donating properties, as the effects exerted by NCX are significantly higher than those evoked by pravastatin in many experimental assays. These data further indicate that the incorporation of a NO-donating moiety into a statin structure confers pharmacological properties which may translate into useful therapeutic benefits.

Pitavastatin is a new, synthetic member of the statin class of lipid-lowering drugs. Compared with other available statins, it has a unique cyclopropyl group on its base structure that is believed to increase 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by a factor of five and to significantly increase the transcription and activity of LDL receptors. Pitavastatin is primarily metabolized via glucuronidation and is not a substrate for the cytochrome P450 3A4 enzyme, thus avoiding the potential for cytochrome P450-mediated drug-drug interactions. Clinical trials have shown that pitavastatin is comparable to atorvastatin and simvastatin in improving lipid measures, and more potent than pravastatin. Pitavastatin is effective in reducing triglycerides and increasing HDL-cholesterol, so it will be particularly beneficial in treating patients with mixed dyslipidemia. Its safety and adverse event profile is similar to that of other available statins, and it has an established history of use in Asia indicating tolerability and safety for treatment lasting up to 7 years.