cerivastatin and pitavastatin

Pitavastatin is the newest statin on the market, and the dose-related magnitude of effect of pitavastatin on blood lipids is not known.. Primary objective To quantify the effects of various doses of pitavastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in participants with and without cardiovascular disease. To compare the effect of pitavastatin on surrogate markers with other statins.  Secondary objectives To quantify the effect of various doses of pitavastatin on withdrawals due to adverse effects.  SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for trials up to March 2019: the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2019), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.. RCT and controlled before-and-after studies evaluating the dose response of different fixed doses of pitavastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without cardiovascular disease.. Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered data from RCT and controlled before-and-after studies into Review Manager 5 as continuous and generic inverse variance data, respectively. Withdrawals due to adverse effects (WDAE) information was collected from the RCTs. We assessed all included trials using the Cochrane 'Risk of bias' tool under the categories of allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other potential sources of bias.. Forty-seven studies (five RCTs and 42 before-and-after studies) evaluated the dose-related efficacy of pitavastatin in 5436 participants. The participants were of any age with and without cardiovascular disease, and pitavastatin effects were studied within a treatment period of three to 12 weeks. Log dose-response data over doses of 1 mg to 16 mg revealed strong linear dose-related effects on blood total cholesterol and LDL cholesterol and triglycerides. There was no dose-related effect of pitavastatin on blood HDL cholesterol, which was increased by 4% on average by pitavastatin. Pitavastatin 1 mg/day to 16 mg/day reduced LDL cholesterol by 33.3% to 54.7%, total cholesterol by 23.3% to 39.0% and triglycerides by 13.0% to 28.1%. For every two-fold dose increase, there was a 5.35% (95% CI 3.32 to 7.38) decrease in blood LDL cholesterol, a 3.93% (95% CI 2.35 to 5.50) decrease in blood total cholesterol and a 3.76% (95% CI 1.03 to 6.48) decrease in blood triglycerides. The certainty of evidence for these effects was judged to be high. When compared to other statins for its effect to reduce LDL cholesterol, pitavastatin is about 6-fold more potent than atorvastatin, 1.7-fold more potent than rosuvastatin, 77-fold more potent than fluvastatin and 3.3-fold less potent than cerivastatin. For the placebo group, there were no participants who withdrew due to an adverse effect per 109 subjects and for all doses of pitavastatin, there were three participants who withdrew due to an adverse effect per 262 subjects.. Pitavastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. Based on the effect on LDL cholesterol, pitavastatin is about 6-fold more potent than atorvastatin, 1.7-fold more potent than rosuvastatin, 77-fold more potent than fluvastatin and 3.3-fold less potent than cerivastatin. There were not enough data to determine risk of withdrawal due to adverse effects due to pitavastatin.

Topics: Atorvastatin; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Controlled Before-After Studies; Drug Administration Schedule; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Pyridines; Quinolines; Randomized Controlled Trials as Topic; Rosuvastatin Calcium; Sex Factors; Triglycerides

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Topics: Animals; Atorvastatin; Bone and Bones; Clinical Trials as Topic; Drug Delivery Systems; Fatty Acids, Monounsaturated; Fluorobenzenes; Fluvastatin; Fractures, Bone; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Lovastatin; Osteogenesis; Osteoporosis; Pharmacokinetics; Pravastatin; Pyridines; Pyrimidines; Pyrroles; Quinolines; Rosuvastatin Calcium; Simvastatin; Sulfonamides

Primary Amoebic Encephalitis due to Naegleria fowleri species is a fatal infection of the Central Nervous System mostly affecting children and young adults. Infections often occur after performance of risk activities in aquatic habitats such as swimming and splashing. PAḾs therapy remain a key issue to be solved which needs an urgent development. Recently, statins have been highlighted as possible novel compounds to treat PAM. Furthermore, type 2 statins due to improved pharmacological properties and lower toxicity could be use in the future. In the present work, three type 2 statins were checked for their activity against two type strains of N. fowleri. In addition, the effects at the cellular level triggered in treated amoebae were checked in order to evaluate if programmed cell death was induced. The obtained results showed that the tested statins, rosuvastatin, pitavastatin and cerivastatin were able to eliminate N. fowleri trophozoites and also induced PCD. Therefore, type 2 statins could be used in the near future for the treatment of PAM.

Topics: Animals; Apoptosis; Cell Line; Dose-Response Relationship, Drug; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Meningoencephalitis; Mice; Molecular Structure; Naegleria fowleri; Pyridines; Quinolines; Rosuvastatin Calcium; Structure-Activity Relationship

In the present study, we examined effects of pitavastatin and cerivastatin on NO production and their mechanisms in EC.. HUVEC cells (1x10(4) cells/well) were seeded into 96-well plates in 100 microl of culture medium for overnight, and then treated with various concentrations of pitavastatin or cerivastatin for 48 h. The cytotoxicity was evaluated using a WST-8 assay; The cells were cultured for 6 h in 200 microl of fresh medium containing increasing doses of pitavastatin or cerivastatin at 37 degrees C for 6 h, the NO production was detected by diaminofluoresceins (DAFs) assay; Simultaneously, The cells (1 x 10(5) cells/well) were seeded into 96-well plates in medium for overnight, and then treated with reagents at 37 degrees C for 30 min, cGMP level was measured by enzyme-immunoassay. The cells were cultured in 2 ml of fresh medium containing increasing doses of pitavastatin or cerivastatin at 37 degrees C for 30 min, the phosphorylations of eNOS and Akt were detected by Western blotting.. We found that pitavastatin not only induced NO production, but also increased cGMP level in HUVECs. Furthermore, EC were incubated with pitavastatin or cerivastatin for 30 min, Western blot analysis showed that pitavastatin (0.1 microM) significantly upregulated the phosphorylation of eNOS and Akt about 1.4-fold or 1.3-fold compared with control, however, cerivastatin (0.1 microM) did not have any effects on them.. Low dose of pitavastatin (0.1 microM) involves Akt pathway, activates eNOS activity, increases cGMP level and produces NO in EC, which is higher than that of cerivastatin.

Topics: Analysis of Variance; Blotting, Western; Cells, Cultured; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nitric Oxide Synthase Type III; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridines; Quinolines; Umbilical Veins

It has been reported that 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors (statins) produce a variety of cardiovascular protective effects independent of their ability to lower total and low-density lipoprotein cholesterol. Recent studies have also reported that statins produce pleiotropic effects through improved endothelial function, enhanced fibrinolysis, and antithrombotic actions. In the present study, we examined the effects of pitavastatin, pravastatin, atorvastatin, and cerivastatin on endothelin (ET)-1 production in cultured porcine aortic endothelial cells (PAECs). Treatment with cerivastatin but not pitavastatin, pravastatin, or atorvastatin decreased basal and TNF-alpha-stimulated ET-1 release from PAECs in a dose-dependent manner (1-10 microM). Northern blot analysis showed that cerivastatin markedly suppressed prepro ET-1 mRNA expression in both conditions. In addition, these inhibitory effects of cerivastatin on ET-1 release and prepro ET-1 mRNA expression were completely abolished by simultaneous treatment with 200 microM mevalonate. Furthermore, cerivastatin did not have any effects on endothelial nitric oxide synthase (eNOS) protein levels, but induced eNOS phosphorylation at Ser1177. From these findings, it is most likely that cerivastatin suppresses ET-1 production, possibly through an increase in eNOS activity and the subsequent nitric oxide production in PAECs. These findings also suggest that cerivastatin may have beneficial effects on ET-1-related diseases.

Topics: Animals; Aorta; Atorvastatin; Cells, Cultured; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nitric Oxide Synthase Type III; Phosphorylation; Pravastatin; Pyridines; Pyrroles; Quinolines; RNA, Messenger; Swine

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most effective drugs for hypercholesteloremia. However, a significant side effect of statin treatment is rhabdomyolysis. In order to study the effect of statins in skeletal muscle cells, we used a DNA microarray analysis to investigate the changes in gene expression profiles brought about by statins in two skeletal muscle cell lines, namely, differentiated rat L6 myotubes and a human skeletal muscle cell line (hSkMC). In both cell lines, the statins (atorvastatin, cerivastatin and pitavastatin) induced the expression of four genes, which relate to cholesterol metabolism, namely, HMG-CoA synthase 1, HMG-CoA reductase, farnesyl diphosphate synthase and isopentenyl-diphosphate delta isomerase. Statin inhibited the synthesis of cholesterol at least five times more effectively in hSkMCs than in the hepatocytes. In addition, unlike in osteoblasts or coronary artery smooth muscle cells, statins upregulated the mRNA expression of cholesterol-associated enzymes in hSkMCs. These results provide basic information on skeletal muscle cells treated with statins and indicate that the cells are sensitive to the inhibition of HMG-CoA reductase, which may be related to the pathogenesis of muscle damage in statin therapy.

Topics: Animals; Atorvastatin; Cell Culture Techniques; Cholesterol; Gene Expression Profiling; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle Fibers, Skeletal; Myoblasts, Skeletal; Pyridines; Pyrroles; Quinolines; Rats; RNA, Messenger

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Fatty Acids, Monounsaturated; Femoral Artery; Fluvastatin; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pyridines; Quinolines

Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation.. Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site.. PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

Topics: Alitretinoin; Animals; Atorvastatin; Base Sequence; Cell Line; Cholesterol; Consensus Sequence; DNA-Binding Proteins; Gene Expression Regulation; Hepatocytes; Heptanoic Acids; Homeostasis; Humans; Hydroxycholesterols; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Lovastatin; Mevalonic Acid; Mice; Orphan Nuclear Receptors; Promoter Regions, Genetic; Proprotein Convertase 9; Proprotein Convertases; Pyridines; Pyrroles; Quinolines; Rats; Receptors, Cytoplasmic and Nuclear; Regulatory Sequences, Nucleic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Alignment; Sequence Homology, Nucleic Acid; Serine Endopeptidases; Simvastatin; Sp1 Transcription Factor; Species Specificity; Sterol Regulatory Element Binding Protein 2; Transcription Factors; Tretinoin

Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model.. Dogs were subjected to coronary occlusion (90 minutes) and reperfusion (6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 microg/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5'-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5'-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5'-nucleotidase showed activation in parallel, and this activation was completely abolished by wortmannin, a PI3-K inhibitor. The magnitude of the infarct-limiting effect paralleled the increase in Akt and ecto-5'-nucleotidase activity and was blunted by administration of wortmannin, alpha,beta-methyleneadenosine-5'-diphosphate, or 8-sulfophenyltheophylline during reperfusion. Both collateral flow and the area at risk were comparable for all groups.. Activation of ecto-5'-nucleotidase after ischemia by PI3-K activation may be crucial for immediate infarct-size limitation by statins. There seems to be an optimal dose for each statin that is independent of its clinical cholesterol-lowering effect.

Topics: 5'-Nucleotidase; Adenosine Triphosphate; Androstadienes; Animals; Cardiotonic Agents; Chromones; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Enzyme Activation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Morpholines; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pravastatin; Pyridines; Quinolines; Signal Transduction; Theophylline; Wortmannin

An in vitro study was carried out in order to examine the metabolic basis of the interaction between fibrates and statins. Metabolic inhibition of statins was noted in the presence of gemfibrozil. However, increase in the unchanged form was fairly small for pitavastatin, compared with other statins. Several CYP enzymes were shown to be principally responsible for the metabolism of gemfibrozil in contrast to other fibrates. In the presence of gemfibrozil, a focal point was obtained in Dixon plots, demonstrating that there was inhibition of CYP2C8-, CYP2C9- and CYP3A4-mediated metabolism. We propose that the increase of plasma concentration caused by co-administration of gemfibrozil and statins is at least partially due to CYP-mediated inhibition.

Topics: Atorvastatin; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Gemfibrozil; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Microsomes, Liver; Pyridines; Pyrroles; Quinolines

In this study, we used a coactivator-dependent receptor-ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARalpha, delta, and gamma). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARalpha, delta, and gamma in the CARLA and that bezafibrate induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma/RXRalpha. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin, fluvastatin, and pitavastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma2/RXRalpha. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARalpha/RXRalpha induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARalpha/RXRalpha was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreased the transactivation of nuclear factor kappaB (NFkappaB) and the activation of NFkappaB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARalpha/RXRalpha.

Topics: Anticholesteremic Agents; Bezafibrate; Blotting, Western; CCAAT-Enhancer-Binding Proteins; Cell Nucleus; DNA-Binding Proteins; DNA, Complementary; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Fluvastatin; Gene Library; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Ligands; Liver; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Muscle, Skeletal; NF-kappa B; Nuclear Proteins; Protein Structure, Tertiary; Pyridines; Quinolines; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Sequence Analysis, DNA; Sterol Regulatory Element Binding Protein 1; Trans-Activators; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection

Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.

Topics: Animals; Anticholesteremic Agents; Apolipoprotein A-I; Cell Line; Culture Media, Serum-Free; Cyclic N-Oxides; DNA-Binding Proteins; Enzyme Inhibitors; Fenofibrate; Gene Expression Regulation; Genes, Reporter; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, HDL; Mercaptoethanol; Phosphorylation; Promoter Regions, Genetic; Pyridines; Quinolines; Rats; Receptors, Cytoplasmic and Nuclear; Recombinant Fusion Proteins; rho GTP-Binding Proteins; Signal Transduction; Transcription Factors