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Sample records for reductase inhibitors statins

  1. Benefit–risk assessment of HMG-CoA reductase inhibitors (statins): a discrete choice experiment

    PubMed Central

    Sornlertlumvanich, Korn; Ngorsuraches, Surachat

    2016-01-01

    Objectives To conduct the benefit–risk assessment of 3-hydroxy-3-methyl-glutaryl (HMG) coenzyme A reductase inhibitors (statins) using a discrete choice experiment, based on 3 major stakeholders’ perspectives including patients, experts and policymakers in Thailand. Design A discrete choice experiment questionnaire survey in three stakeholders’ perspectives. Setting Public hospitals in Thailand. Participants A total of 353 policymakers, experts and patients. Outcomes Stakeholders’ preferences for assessment criteria (stroke reduction, myocardial infarction reduction, myalgia and hepatotoxicity). Statins’ ranking and maximum acceptable risk in all perspectives were also calculated. Results For any perspective, the most and least important criteria were the risk of hepatotoxicity and the benefit of myocardial infarction reduction, respectively. Patients and experts agreed on the order of importance for myalgia and stroke reduction, but policymakers had different order of importance in these criteria. Overall, results showed that the highest and lowest chances of being chosen were atorvastatin and rosuvastatin, respectively. Only patients’ ranking order was different from others. Maximum acceptable risk of hepatotoxicity was lower than that of myalgia, reflecting the greater concern of all perspectives to statin consequence on liver. Conclusions The results of benefit–risk assessment from every perspective were somewhat consistent. This study demonstrated the feasibility of applying a discrete choice experiment in the benefit–risk assessment of drugs and encouraged the engagement of multiple stakeholders in the decision-making process. PMID:26916689

  2. Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

    SciTech Connect

    Sarver, Ronald W.; Bills, Elizabeth; Bolton, Gary; Bratton, Larry D.; Caspers, Nicole L.; Dunbar, James B.; Harris, Melissa S.; Hutchings, Richard H.; Kennedy, Robert M.; Larsen, Scott D.; Pavlovsky, Alexander; Pfefferkorn, Jeffrey A.; Bainbridge, Graeme

    2008-10-02

    Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2--7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC{sub 50} = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a {Delta}H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

  3. Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells

    PubMed Central

    Chiang, Kuang-Hsing; Cheng, Wan-Li; Shih, Chun-Ming; Lin, Yi-Wen; Tsao, Nai-Wen; Kao, Yung-Ta; Lin, Chih-Ting; Wu, Shinn-Chih; Huang, Chun-Yao; Lin, Feng-Yen

    2015-01-01

    Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved

  4. LDL Cholesterol, Statins And PCSK 9 Inhibitors

    PubMed Central

    Gupta, Sanjiv

    2015-01-01

    Reduction of low density lipoprotein cholesterol (LDLc) is of vital importance for the prevention of atherosclerotic cardiovascular disease (ASCVD). Statin is the most effective therapy today to lower LDLc by inhibiting HMG-CoA-reductase. However despite intensive statin therapy, there remains a residual risk of recurrent myocardial infarction in about 20–30% cases. Moreover a few patients develop statin intolerance. For severe hypercholesterolemia, statins alone or in combination of ezetimibe, niacin and fenofibrate have been advocated. For homozygous familial hypercholesterolemia (HOFH), a microsomal triglyceride transfer protein MTP inhibitor (Lopitamide) and antisense oligonucleotide (ASO) (Mipomersen) have recently been approved by FDA, USA through ‘Risk evaluation and Mitigation Strategy (REMS)’. Possible future therapies include PCSK-9 inhibitors which have excellent lipid lowering properties. Three monoclonal antibodies (PCSK 9 Inhibitors) alirocumab, evolocumab and Bococizumab are under advanced clinical stage IV trials and awaiting approval by FDA and European Medicines Agency. PMID:26432726

  5. LDL cholesterol, statins and PCSK 9 inhibitors.

    PubMed

    Gupta, Sanjiv

    2015-01-01

    Reduction of low density lipoprotein cholesterol (LDLc) is of vital importance for the prevention of atherosclerotic cardiovascular disease (ASCVD). Statin is the most effective therapy today to lower LDLc by inhibiting HMG-CoA-reductase. However despite intensive statin therapy, there remains a residual risk of recurrent myocardial infarction in about 20-30% cases. Moreover a few patients develop statin intolerance. For severe hypercholesterolemia, statins alone or in combination of ezetimibe, niacin and fenofibrate have been advocated. For homozygous familial hypercholesterolemia (HOFH), a microsomal triglyceride transfer protein MTP inhibitor (Lopitamide) and antisense oligonucleotide (ASO) (Mipomersen) have recently been approved by FDA, USA through 'Risk evaluation and Mitigation Strategy (REMS)'. Possible future therapies include PCSK-9 inhibitors which have excellent lipid lowering properties. Three monoclonal antibodies (PCSK 9 Inhibitors) alirocumab, evolocumab and Bococizumab are under advanced clinical stage IV trials and awaiting approval by FDA and European Medicines Agency. PMID:26432726

  6. Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

    PubMed

    Osaki, Yoshinori; Nakagawa, Yoshimi; Miyahara, Shoko; Iwasaki, Hitoshi; Ishii, Akiko; Matsuzaka, Takashi; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Sone, Hirohito; Ohashi, Ken; Ishibashi, Shun; Yamada, Nobuhiro; Shimano, Hitoshi

    2015-10-23

    HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.

  7. Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

    PubMed

    Koskinas, Konstantinos; Wilhelm, Matthias; Windecker, Stephan

    2016-01-01

    Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients. PMID:27400448

  8. Thioredoxin Reductase and its Inhibitors

    PubMed Central

    Saccoccia, Fulvio; Angelucci, Francesco; Boumis, Giovanna; Carotti, Daniela; Desiato, Gianni; Miele, Adriana E; Bellelli, Andrea

    2014-01-01

    Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis. PMID:24875642

  9. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins.

    PubMed

    Andrade, Chittaranjan

    2014-02-01

    Elderly patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular and cerebrovascular events. Elderly patients also commonly receive antidepressant drugs, usually selective serotonin reuptake inhibitors (SSRIs), for the treatment of depression, anxiety, or other conditions. SSRIs are associated with many pharmacokinetic drug interactions related to the inhibition of the cytochrome P450 (CYP) metabolic pathways. There is concern that drugs that inhibit statin metabolism can trigger statin adverse effects, especially myopathy (which can be potentially serious, if rhabdomyolysis occurs). However, a detailed literature review of statin metabolism and of SSRI effects on CYP enzymes suggests that escitalopram, citalopram, and paroxetine are almost certain to be safe with all statins, and rosuvastatin, pitavastatin, and pravastatin are almost certain to be safe with all SSRIs. Even though other SSRI-statin combinations may theoretically be associated with risks, the magnitude of the pharmacokinetic interaction is likely to be below the threshold for clinical significance. Risk, if at all, lies in combining fluvoxamine with atorvastatin, simvastatin, or lovastatin, and even this risk can be minimized by using lower statin doses and monitoring the patient.

  10. Is decreased libido associated with the use of HMG-CoA-reductase inhibitors?

    PubMed Central

    de Graaf, L; Brouwers, A H P M; Diemont, W L

    2004-01-01

    Aims and methods To describe patients with decreased libido during use of a HMG-CoA-reductase-inhibitor, and to discuss causality and pharmacological hypotheses for this association by analysis of the adverse drug reactions (ADR) database of the Netherlands Pharmacovigilance Centre Lareb. Results Eight patients were identified as having decreased libido during use of statins. In two of these cases testosterone levels were determined and appeared to be decreased. Conclusion Decreased libido is a probable adverse drug reaction of HMG-CoA-reductase-inhibitors and is reversible. The ADR may be caused by low serum testosterone levels, mainly due to intracellular cholesterol depletion. PMID:15327593

  11. Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

    PubMed Central

    Wang, Hye Jin; Park, Jae Yeo; Kwon, Obin; Choe, Eun Yeong; Kim, Chul Hoon; Hur, Kyu Yeon; Lee, Myung-Shik; Yun, Mijin; Cha, Bong Soo; Kim, Young-Bum; Lee, Hyangkyu; Kang, Eun Seok

    2015-01-01

    Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance. PMID:26389569

  12. Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

    PubMed Central

    Würtz, Peter; Wang, Qin; Soininen, Pasi; Kangas, Antti J.; Fatemifar, Ghazaleh; Tynkkynen, Tuulia; Tiainen, Mika; Perola, Markus; Tillin, Therese; Hughes, Alun D.; Mäntyselkä, Pekka; Kähönen, Mika; Lehtimäki, Terho; Sattar, Naveed; Hingorani, Aroon D.; Casas, Juan-Pablo; Salomaa, Veikko; Kivimäki, Mika; Järvelin, Marjo-Riitta; Davey Smith, George; Vanhala, Mauno; Lawlor, Debbie A.; Raitakari, Olli T.; Chaturvedi, Nish; Kettunen, Johannes; Ala-Korpela, Mika

    2016-01-01

    Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug

  13. Statins and cerebral hemodynamics

    PubMed Central

    Giannopoulos, Sotirios; Katsanos, Aristeidis H; Tsivgoulis, Georgios; Marshall, Randolph S

    2012-01-01

    HMG-CoA reductase inhibitors (statins) are associated with improved stroke outcome. This observation has been attributed in part to the palliative effect of statins on cerebral hemodynamics and cerebral autoregulation (CA), which are mediated mainly through the upregulation of endothelium nitric oxide synthase (eNOS). Several animal studies indicate that statin pretreatment enhances cerebral blood flow after ischemic stroke, although this finding is not further supported in clinical settings. Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA. PMID:22929438

  14. Statin-associated myopathy.

    PubMed

    Thompson, Paul D; Clarkson, Priscilla; Karas, Richard H

    2003-04-01

    Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia with and without elevated CK levels, muscle weakness, muscle cramps, and persistent myalgia and CK elevations after statin withdrawal. We performed a literature review to provide a clinical summary of statin-associated myopathy and discuss possible mediating mechanisms. We also update the US Food and Drug Administration (FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy were identified via a PubMed search through November 2002 and articles on statin clinical trials, case series, and review articles were identified via a PubMed search through January 2003. Adverse event reports of statin-associated rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature review found that reports of muscle problems during statin clinical trials are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. Cerivastatin was the most commonly implicated statin. Few data are available regarding the frequency of less-serious events such as muscle pain and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis and other adverse effects with statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications. Medications such as the fibrate gemfibrozil alter statin metabolism and increase statin plasma concentration. How statins injure skeletal muscle is not clear, although recent evidence suggests that statins reduce the production of small regulatory proteins that are important for myocyte maintenance.

  15. Statins and Myotoxic Effects Associated With Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies

    PubMed Central

    Watanabe, Yurika; Suzuki, Shigeaki; Nishimura, Hiroaki; Murata, Ken-ya; Kurashige, Takashi; Ikawa, Masamichi; Asahi, Masaru; Konishi, Hirofumi; Mitsuma, Satsuki; Kawabata, Satoshi; Suzuki, Norihiro; Nishino, Ichizo

    2015-01-01

    Abstract Statins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG. We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies. We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients’ serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of

  16. Cutaneous allergy to insulin: could statins and ACE inhibitors play a role? A case report.

    PubMed

    Pitrola, D; MacIver, C; Mallipedhi, A; Udiawar, M; Price, D E; Stephens, J W

    2014-04-01

    Insulin allergy is rare. Both statins and angiotensin converting enzyme (ACE) inhibitors may cause local urticarial skin reactions and have been implicated to precipitate local reactions to insulin. We describe a case of a localised urticarial allergic reaction related to insulin use in a patient co-prescribed an ACE inhibitor and statin. PMID:24534533

  17. Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs

    SciTech Connect

    Nishimoto, Tomoyuki; Ishikawa, Eiichiro; Anayama, Hisashi; Hamajyo, Hitomi; Nagai, Hirofumi; Hirakata, Masao; Tozawa, Ryuichi

    2007-08-15

    High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.

  18. Radical scavengers as ribonucleotide reductase inhibitors.

    PubMed

    Basu, Arijit; Sinha, Barij Nayan

    2012-01-01

    This paper compiled all the previous reports on radical scavengers, an interesting class of ribonucleotide reductase inhibitors. We have highlighted three key research areas: chemical classification of radical scavengers, structural and functional aspects of the radical site, and progress in drug designing for radical scavengers. Under the chemical classification section, we have recorded the discovery of hydroxyurea followed by discussions on hydroxamic acids, amidoximes, hydroxyguanidines, and phenolic compounds. In the next section, we have compiled the structural information for the radical site obtained from different crystallographic and theoretical studies. Finally, we have included the reported ligand based and structure based drug-designing studies.

  19. Statins can induce myasthenia gravis.

    PubMed

    Gale, Jesse; Danesh-Meyer, Helen V

    2014-02-01

    The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are commonly prescribed for prevention of cardiovascular morbidity. A rare side effect of statin medication is the induction of autoimmune illnesses, including myasthenia gravis (myasthenia). Here we present two patients with seropositive myasthenia that developed 4 weeks after initiation of atorvastatin, increasing the total reported patients to seven. Reviewing recent literature we highlight the connections between statins, auto-immunity and myasthenia. Statins may favour T-cell phenotypes that reduce cell-mediated immunity but could increase antibody-mediated humoral immunity.

  20. Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents.

    PubMed

    Kishta, Sara; Ei-Shenawy, Reem; Kishta, Sobhy

    2016-01-01

    Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs ( e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness. PMID:27583130

  1. Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

    PubMed Central

    Kishta, Sara; EI-Shenawy, Reem; Kishta, Sobhy

    2016-01-01

    Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs ( e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness. PMID:27583130

  2. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial.

    PubMed

    Bjarnadottir, Olöf; Romero, Quinci; Bendahl, Pär-Ola; Jirström, Karin; Rydén, Lisa; Loman, Niklas; Uhlén, Mathias; Johannesson, Henrik; Rose, Carsten; Grabau, Dorthe; Borgquist, Signe

    2013-04-01

    Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment.

  3. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial.

    PubMed

    Bjarnadottir, Olöf; Romero, Quinci; Bendahl, Pär-Ola; Jirström, Karin; Rydén, Lisa; Loman, Niklas; Uhlén, Mathias; Johannesson, Henrik; Rose, Carsten; Grabau, Dorthe; Borgquist, Signe

    2013-04-01

    Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment. PMID:23471651

  4. Statins, ACE inhibitors and ARBs in cardiovascular disease.

    PubMed

    Montecucco, Fabrizio; Mach, François

    2009-06-01

    Atherosclerotic cardiovascular disease (CVD) is the main cause of death in developed and developing countries. It is well accepted that several diseases - including hypertension, dyslipidemia and diabetes mellitus - increase CVD. More recently also chronic inflammatory diseases, such as rheumatoid arthritis, have been shown to accelerate CVD. This association further supports a responsible role for inflammatory processes in all stages of CVD pathophysiology. Clinically, CVD ranges through different acute and chronic syndromes with ischemic symptoms in distal tissues, including heart, cerebral region or peripheral arteries. Several treatments for reducing CVD are under investigation. In this review we focus on statins, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin-II receptor blockers (ARBs), updating therapeutic evidence from the last clinical trials with particular relevance to diabetic patients. PMID:19520311

  5. Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells.

    PubMed

    Sidaway, James E; Davidson, Robert G; McTaggart, Fergus; Orton, Terry C; Scott, Robert C; Smith, Graham J; Brunskill, Nigel J

    2004-09-01

    Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-beta(2)-microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption. PMID:15339975

  6. Statins and cancers.

    PubMed

    Stryjkowska-Góra, Aleksandra; Karczmarek-Borowska, Bożenna; Góra, Tomasz; Krawczak, Katarzyna

    2015-01-01

    Statins (inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) are a group of drugs used to treat lipid disorders. They inhibit cholesterol synthesis at an early stage of the biosynthesis pathway, thus eliminating numerous metabolites involved in the cycle. Numerous studies point to different possible effects of statins on cancer cells. Statins inhibit growth of a tumor, invasion and metastasis formation. They block the production of isoprenoids, which are necessary for post-translational modifications of many proteins, including those involved in normal cell signaling. They also contribute to the reduction in the expression of vascular endothelial growth factor, sensitize tumor cells to NK cell activity, and modify the body inflammatory response. Due to different pharmacokinetic properties of individual statins, they may have opposite effects on the risk of cancer. Currently, most information on the effects of statins on the risk of developing cancer is obtained from observational studies. The studies have different results depending on the location of cancer. The protective effect of statins was observed in the meta-analysis of numerous studies including prostate cancer, stomach cancer, esophagus cancer, and hepatocellular carcinoma; however, it has not yet been confirmed that statins influence the risk of developing colorectal cancer, breast cancer, or lung cancer. The protective effect of statins on the development of many kinds of cancer can be a valuable and easy way to reduce morbidity. However, further research is necessary to thoroughly determine the value of this group of drugs. PMID:26557755

  7. Proton pump inhibitors and statins: a possible interaction that favors low-density lipoprotein cholesterol reduction?

    PubMed Central

    Barkas, F; Elisaf, M; Rizos, CV; Klouras, E; Kostapanos, MS; Liberopoulos, E

    2015-01-01

    Background: Proton pump inhibitors (PPIs) might influence the metabolism of cholesterol and statins in the liver. Aim: The impact of PPIs on low-density lipoprotein cholesterol (LDL-C) levels in statin-treated patients. Methods: Retrospective observational study including consecutive statin-treated individuals followed for ≥3 years in a university hospital lipid clinic. Demographic characteristics as well as clinical and laboratory data were recorded at baseline and the most recent visit. High, moderate and low-intensity statin therapy was defined according to the expected LDL-C reduction (≥50%, 30-50%, and <30%, respectively). We compared the LDL-C reduction in subjects receiving statin + PPI with those on statin alone and assessed the overall effect of PPI administration on LDL-C lowering. Results: Of 648 statin-treated subjects, 7% were also taking a PPI. There was no difference between PPI vs. non-PPI group regarding baseline characteristics and intensity of lipid-lowering therapy. Stepwise linear regression analysis showed that PPI use was significantly associated with LDL-C reduction (b =0.104, p =0.005) along with baseline LDL-C levels (b =0.482, p <0.001), treatment with ezetimibe (b =0.198, p <0.001), presence of diabetes (b =0.168, p <0.001), compliance with treatment (b =0.205, p <0.001), intensity of statin treatment (b =0.101, p =0.005) and cardiovascular risk (b =0.082, p =0.049). Subjects receiving statin + PPI had a higher LDL-C reduction by 6.4% compared with those taking a statin alone (fully adjusted p =0.005). Conclusions: PPIs may modestly boost the statin-mediated LDL-C reduction. This effect should be confirmed by prospective clinical studies. Hippokratia 2015; 19 (4): 332-337.

  8. An overview on 5alpha-reductase inhibitors.

    PubMed

    Aggarwal, Saurabh; Thareja, Suresh; Verma, Abhilasha; Bhardwaj, Tilak Raj; Kumar, Manoj

    2010-02-01

    Benign prostatic hyperplasia (BPH) is the noncancerous proliferation of the prostate gland associated with benign prostatic obstruction and lower urinary tract symptoms (LUTS) such as frequency, hesitancy, urgency, etc. Its prevalence increases with age affecting around 70% by the age of 70 years. High activity of 5alpha-reductase enzyme in humans results in excessive dihydrotestosterone levels in peripheral tissues and hence suppression of androgen action by 5alpha-reductase inhibitors is a logical treatment for BPH as they inhibit the conversion of testosterone to dihydrotestosterone. Finasteride (13) was the first steroidal 5alpha-reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the prostatic DHT level by 70-90% and reduces the prostatic size. Dutasteride (27) another related analogue has been approved in 2002. Unlike Finasteride, Dutasteride is a competitive inhibitor of both 5alpha-reductase type I and type II isozymes, reduced DHT levels >90% following 1 year of oral administration. A number of classes of non-steroidal inhibitors of 5alpha-reductase have also been synthesized generally by removing one or more rings from the azasteroidal structure or by an early non-steroidal lead (ONO-3805) (261). In this review all categories of inhibitors of 5alpha-reductase have been covered. PMID:19879888

  9. HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice.

    PubMed

    Roy, Avik; Jana, Malabendu; Kundu, Madhuchhanda; Corbett, Grant T; Rangaswamy, Suresh B; Mishra, Rama K; Luan, Chi-Hao; Gonzalez, Frank J; Pahan, Kalipada

    2015-08-01

    Neurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARα and that Leu331 and Tyr 334 residues of PPARα are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARα-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARα, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARα. This study identifies statins as ligands of PPARα, describes neurotrophic function of statins via the PPARα-CREB pathway, and analyzes the importance of PPARα in the therapeutic success of simvastatin in an animal model of Alzheimer's disease.

  10. Statins and Renin Angiotensin System Inhibitors Dose-Dependently Protect Hypertensive Patients against Dialysis Risk

    PubMed Central

    Wu, Szu-Yuan

    2016-01-01

    Background Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28–90, 91–365, and >365 cumulative defined daily doses (cDDDs). Results In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis

  11. Biochemistry of Statins.

    PubMed

    Egom, Emmanuel Eroume A; Hafeez, Hafsa

    2016-01-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Elevated blood lipids may be a major risk factor for CVD. Due to consistent and robust association of higher low-density lipoprotein (LDL)-cholesterol levels with CVD across experimental and epidemiologic studies, therapeutic strategies to decrease risk have focused on LDL-cholesterol reduction as the primary goal. Current medication options for lipid-lowering therapy include statins, bile acid sequestrants, a cholesterol-absorption inhibitor, fibrates, nicotinic acid, and omega-3 fatty acids, which all have various mechanisms of action and pharmacokinetic properties. The most widely prescribed lipid-lowering agents are the HMG-CoA reductase inhibitors, or statins. Since their introduction in the 1980s, statins have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes (Kapur and Musunuru, 2008 [1]). The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia. This chapter focuses on the biochemistry of statins including their structures, pharmacokinetics, and mechanism of actions as well as the potential adverse reactions linked to their clinical uses. PMID:26975972

  12. Pharmacogenetics of Response to Statins

    PubMed Central

    Zineh, Issam

    2016-01-01

    The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) are among the most commonly prescribed drugs worldwide. On average, statins improve lipid profiles and have been shown to have ancillary beneficial effects on inflammation, platelet activity, and endothelial function. However, variability in drug response exists regardless of the measured phenotype, and genetic variability may be a contributing factor. Recently, there has been an interesting shift in statin pharmacogenetic studies. Novel study designs have been employed and nontraditional candidate genes have been investigated in relation to both lipid and nonlipid responses to statins. This review outlines earlier pharmacogenetic studies and highlights newly published findings that expand on previous work. Furthermore, a framework is provided in which the necessary next steps in research are described, with the ultimate goal of translating pharmacogenetic findings into clinically meaningful changes in patient care. PMID:18241612

  13. A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro.

    PubMed

    Wasko, Brian M; Smits, Jacqueline P; Shull, Larry W; Wiemer, David F; Hohl, Raymond J

    2011-11-01

    Statins and nitrogenous bisphosphonates (NBP) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) and farnesyl diphosphate synthase (FDPS), respectively, leading to depletion of farnesyl diphosphate (FPP) and disruption of protein prenylation. Squalene synthase (SQS) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis. Herein, we have identified novel bisphosphonates as potent and specific inhibitors of SQS, including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid (compound 5). Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells. At high concentrations, lovastatin and zoledronate impaired protein prenylation and decreased cell viability, which limits their potential use for cholesterol depletion. When combined with lovastatin, compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation. Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation. Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with an HMGCR or FDPS inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion.

  14. Multitasking of the 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor: beyond cardiovascular diseases.

    PubMed

    Calabro, Paolo; Yeh, Edward T H

    2004-01-01

    Statins can profoundly affect cellular metabolism by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the rate-limiting enzyme responsible for cholesterol synthesis. Many physicians prescribe statins to lower plasma cholesterol levels, which has beneficial effects in both the primary and secondary prevention of coronary artery disease. However, in vitro, in vivo, animal, and clinical studies have all shown that statins may also have important pleiotropic properties. In fact, a number of clinical studies have suggested that statins are involved in modulating diseases such as cancer, osteoporosis, and dementia (including Alzheimer's disease). However, because these studies have been only preliminary and observational in nature, large randomized, placebo-controlled studies are needed to confirm the modulatory role of statins in these important diseases.

  15. Co-medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

    PubMed Central

    Devold, Helene M; Molden, Espen; Skurtveit, Svetlana; Furu, Kari

    2009-01-01

    AIMS To assess the prevalence of co-medication of statins and CYP3A4 inhibitors before and after introduction of a new Norwegian reimbursement policy, which states that all patients should be prescribed simvastatin as first-line lipid-lowering therapy. METHODS Data from patients receiving simvastatin, lovastatin, pravastatin, fluvastatin or atorvastatin in 2004 and 2006, including co-medication of potent CYP3A4 inhibitors, were retrieved from the Norwegian Prescription Database covering the total population of Norway. Key measurements were prevalence of continuous statin use (two or more prescriptions on one statin) and proportions of different statin types among all patients and those co-medicated with CYP3A4 inhibitors. RESULTS In 2004, 5.9% (n = 272 342) of the Norwegian population received two or more prescriptions on one statin compared with 7.0% (n = 324 267) in 2006. The relative number of simvastatin users increased from 39.7% (n = 112 122) in 2004 to 63.1% (n = 226 672) in 2006. A parallel increase was observed within the subpopulation co-medicated with statins and CYP3A4 inhibitors, i.e. from 42.9% (n = 7706) in 2004 to 63.6% (n = 13 367) in 2006. For all other statins the number of overall users decreased to a similar extent to those co-medicated with CYP3A4 inhibitors. CONCLUSIONS In both 2004 and 2006, the choice of statin type did not depend on whether the patient used a CYP3A4 inhibitor or not. Considering the pronounced interaction potential of simvastatin with CYP3A4 inhibitors, a negative influence of the new policy on overall statin safety seems likely. PMID:19220274

  16. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control?

    PubMed Central

    Zimmerman, Marj P.

    2015-01-01

    Despite advances in the approach toward treating hypercholesterolemia and widespread access to statin medications, not all people are able to reach target low-density lipoprotein cholesterol (LDL-C) levels to reduce their cardiovascular risk. Some of the reasons include the inability to tolerate statin therapy, LDL-C levels that remain high even in the presence of statin therapy, and a familial disorder that is characterized by extremely high levels of LDL-C. A new therapeutic class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, represents a novel and promising approach to reducing LDL-C levels using a mechanism at the LDL receptor level. The recent approval of the first 2 PCSK9 inhibitors and the anticipated approval of the third agent in this class within approximately 1 year may provide clinicians powerful new weapons to lower LDL-C levels in patients who are not satisfactorily managed with statins. However, the results of long-term studies of the ability of these new medications to influence cardiovascular outcomes will not be known for several years. PMID:26702335

  17. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control?

    PubMed

    Zimmerman, Marj P

    2015-11-01

    Despite advances in the approach toward treating hypercholesterolemia and widespread access to statin medications, not all people are able to reach target low-density lipoprotein cholesterol (LDL-C) levels to reduce their cardiovascular risk. Some of the reasons include the inability to tolerate statin therapy, LDL-C levels that remain high even in the presence of statin therapy, and a familial disorder that is characterized by extremely high levels of LDL-C. A new therapeutic class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, represents a novel and promising approach to reducing LDL-C levels using a mechanism at the LDL receptor level. The recent approval of the first 2 PCSK9 inhibitors and the anticipated approval of the third agent in this class within approximately 1 year may provide clinicians powerful new weapons to lower LDL-C levels in patients who are not satisfactorily managed with statins. However, the results of long-term studies of the ability of these new medications to influence cardiovascular outcomes will not be known for several years. PMID:26702335

  18. Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element

    PubMed Central

    Stanley, Frederick M.; Linder, Kathryn M.; Cardozo, Timothy J.

    2015-01-01

    Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein that has important roles in inflammation and wound healing. Its aberrant regulation may contribute to many disease processes such as heart disease. The PAI-1 promoter is responsive to multiple inputs including cytokines, growth factors, steroids and oxidative stress. The statin drugs, atorvastatin, mevastatin and rosuvastatin, increased basal and stimulated expression of the PAI-1 promoter 3-fold. A statin-responsive, nuclear hormone response element was previously identified in the PAI-1 promoter, but it was incompletely characterized. We characterized this direct repeat (DR) of AGGTCA with a 3-nucleotide spacer at -269/-255 using deletion and directed mutagenesis. Deletion or mutation of this element increased basal transcription from the promoter suggesting that it repressed PAI-1 transcription in the unliganded state. The half-site spacing and the ligand specificity suggested that this might be a pregnane X receptor (PXR) responsive element. Computational molecular docking showed that atorvastatin, mevastatin and rosuvastatin were structurally compatible with the PXR ligand-binding pocket in its agonist conformation. Experiments with Gal4 DNA binding domain fusion proteins showed that Gal4-PXR was activated by statins while other DR + 3 binding nuclear receptor fusions were not. Overexpression of PXR further enhanced PAI-1 transcription in response to statins. Finally, ChIP experiments using Halo-tagged PXR and RXR demonstrated that both components of the PXR-RXR heterodimer bound to this region of the PAI-1 promoter. PMID:26379245

  19. Statin Use in Prostate Cancer: An Update.

    PubMed

    Babcook, Melissa A; Joshi, Aditya; Montellano, Jeniece A; Shankar, Eswar; Gupta, Sanjay

    2016-01-01

    3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are commonly prescribed for the treatment of hypercholesterolemia and cardiovascular disease. A systematic review was conducted using the keywords "statin and prostate cancer" within the title search engines including PubMed, Web of Science, and the Cochrane Library for relevant research work published between 2004 and December 2015. Although still premature, accumulating clinical evidence suggests that statin use may be beneficial in the prevention and/or treatment of prostate cancer. These human studies consist of meta-analyses of secondary endpoints obtained from randomized, controlled cardiovascular disease clinical trials of statins, patient database, observational studies, and a few, small case-control studies, directly addressing statin use on prostate cancer pathology and recurrence. This review summarizes and discusses the recent clinical literature on statins and prostate cancer with a recommendation to move forward with randomized, placebo-controlled clinical trials, investigating the use of statins. Additional preclinical testing of statins on prostate cancer cell lines and in vivo models is needed to elucidate pathways and determine its efficacy for prevention and/or treatment of prostate cancer, more specifically, the difference in the effectiveness of lipophilic versus hydrophilic statins in prostate cancer. PMID:27441003

  20. Statin Use in Prostate Cancer: An Update

    PubMed Central

    Babcook, Melissa A.; Joshi, Aditya; Montellano, Jeniece A.; Shankar, Eswar; Gupta, Sanjay

    2016-01-01

    3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are commonly prescribed for the treatment of hypercholesterolemia and cardiovascular disease. A systematic review was conducted using the keywords “statin and prostate cancer” within the title search engines including PubMed, Web of Science, and the Cochrane Library for relevant research work published between 2004 and December 2015. Although still premature, accumulating clinical evidence suggests that statin use may be beneficial in the prevention and/or treatment of prostate cancer. These human studies consist of meta-analyses of secondary endpoints obtained from randomized, controlled cardiovascular disease clinical trials of statins, patient database, observational studies, and a few, small case–control studies, directly addressing statin use on prostate cancer pathology and recurrence. This review summarizes and discusses the recent clinical literature on statins and prostate cancer with a recommendation to move forward with randomized, placebo-controlled clinical trials, investigating the use of statins. Additional preclinical testing of statins on prostate cancer cell lines and in vivo models is needed to elucidate pathways and determine its efficacy for prevention and/or treatment of prostate cancer, more specifically, the difference in the effectiveness of lipophilic versus hydrophilic statins in prostate cancer. PMID:27441003

  1. Effect of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor on Disease Activity in Patients With Rheumatoid Arthritis

    PubMed Central

    Xing, Bin; Yin, Yu-Feng; Zhao, Li-Dan; Wang, Li; Zheng, Wen-Jie; Chen, Hua; Wu, Qing-Jun; Tang, Fu-Lin; Zhang, Feng-Chun; Shan, Guangliang; Zhang, Xuan

    2015-01-01

    Abstract HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid-lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk. However, whether they have an effect on RA disease activity is controversial. This study aimed to investigate the effect of statins on disease activity in RA patients. A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases. Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included. The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP. The Jadad score was used for quality assessment. The inverse variance method was used to analyze continuous outcomes. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used. For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis. Publication bias was assessed using Egger test. A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP. The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was −0.55 (95% CI [−0.83, −0.26], P = 0.0002), with an I2 value of 68%. Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD −0.73, P = 0.01) than patients with moderate or low disease activity (SMD −0.38, P = 0.03). Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not

  2. Synthesis and metabolism of inhibitors of ribonucleotide reductase

    SciTech Connect

    Smith, F.T.

    1985-01-01

    In an effort to prepare more effective inhibitors of ribo-nucleotide reductase a series of 2-substituted-4,6-dihydroxypyrimidines was prepared via the appropriately substituted benzamidine. None of the compounds exhibited in vivo activity against L1210 leukemia. No further testing was performed. In order to investigate the metabolism of 3,4-dihydroxybenzohydroxamic acid, a known inhibitor of ribonucleotide reductase, radiolabeled 3,4-dihydroxybenzohydroxamic acid was synthesized by a modification of the procedure of Pichat and Tostain. /sup 14/C-3,4-Dihydroxybenzoic acid was converted to the methyl ester and subsequently reacted with hydroxylamine to give the hydroxamic acid. /sup 14/C-3,4-Dihydroxybenzohydroxamic acid was given i.p. to Sprague-Dawley rats. Excretion occurred mainly (72%) via the urine. HPLC coupled with GC/MS analyses showed that the compound was excreted mainly unchanged. The compound was metabolized to 3,4-dihydroxybenzamide, 4-methoxy-3-hydroxybenzohydroxamic acid, and 4-hydroxy-3-methoxybenzohydroxamic acid. HPLC analysis also showed the lack of formation of any glucuronide or sulfate conjugates through either the hydroxamic acid or catechol functionalities.

  3. Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statins.

    PubMed

    Lahaye, Clément; Beaufrére, Anne Marie; Boyer, Olivier; Drouot, Laurent; Soubrier, Martin; Tournadre, Anne

    2014-01-01

    Immune-mediated necrotizing myopathy (IMNM) associated with statin use and anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody is a new and emerging entity that supports a link between statin use and IMNM and raises the questions of distinct clinical phenotypes and treatment strategy. We describe the clinical and histopathological characteristics of a patient and discuss the spectrum of IMNM and statin-induced myopathies. A 65-year-old man was suffering from proximal muscle weakness and elevated CK levels, following exposure to statin therapy. The symptoms worsened despite discontinuation of the drug. At that point, no myositis-specific or -associated antibodies were detected. Malignancy screening did not reveal abnormalities. Muscle biopsy demonstrated a predominantly necrotizing myopathy with minimal lymphocytic infiltrates, MHC class I expression in necrotic muscle fibers, and complement deposition on scattered non-necrotic muscle fibers. Muscle protein analysis by western blot was normal. The patient did not improve with steroid and methotrexate and required monthly intravenous immunoglobulin (IVIG) therapy. Muscle strength gradually improved, CK levels normalized and IVIG were stopped 1 year later. Screening for anti-HMGCR antibodies, not available at the time of presentation, was highly positive. Identification of anti-HMGCR antibodies in statin-exposed patients with myopathy appears to be helpful both for differential diagnosis and for treatment strategy. In patients who did not improve after discontinuation of the statin treatment, a muscle biopsy should be performed as well as screening for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment.

  4. Molecular mechanisms underlying the effects of statins in the central nervous system.

    PubMed

    McFarland, Amelia J; Anoopkumar-Dukie, Shailendra; Arora, Devinder S; Grant, Gary D; McDermott, Catherine M; Perkins, Anthony V; Davey, Andrew K

    2014-11-10

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins' effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins' effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins' possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed.

  5. 5 alpha-reductase inhibitors and prostatic disease.

    PubMed

    Schröder, F H

    1994-08-01

    5 alpha-Reductase inhibitors are a new class of substances with very specific effects on type I and type II 5 alpha R which may be of use in the treatment of skin disease, such as male pattern baldness, male acne and hirsutism, as well as prostatic hyperplasia and prostate cancer. At least two types of 5 alpha R inhibitors with a different pH optimum have been described. cDNA encoding for both the type I and the type II enzyme has been cloned. Most of the orally effective 5 alpha R inhibitors belong to the class of 4-azasteroids. The radical substituted in the 17 position of the steroid ring seems to be related to species specific variations and to the types of 5 alpha R enzymes in different species and organ systems. 5 alpha R inhibitors lead to a decrease of plasma DHT by about 65% while there is a slight rise in plasma testosterone. The decrease of tissue DHT in the ventral prostate of the intact rat, the dog and in humans is more pronounced and amounts to about 85%. There is a reciprocal rise of tissue T in these systems. The application of an inhibitor of 5 alpha R type II leads to a shrinkage of BPH in men by about 30%. In the rat a similar shrinkage accompanied by a significant decrease of total organ DNA occurs. This decrease, however, is not as pronounced as can be achieved with castration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7522999

  6. 5-Alpha-Reductase Inhibitors and Combination Therapy.

    PubMed

    Füllhase, Claudius; Schneider, Marc P

    2016-08-01

    By inhibiting the conversion from testosterone to dihydrotestosterone 5-Alpha reductase inhibitors (5ARIs) are able to hinder prostatic growth, shrink prostate volumes, and improve BPH-related LUTS. 5ARIs are particularly beneficial for patients with larger prostates (>30-40ml). Generally the side effects of 5ARI treatment are mild, and according to the FORTA classification 5ARIs are suitable for frail elderly. 5ARI / alpha-blocker (AB) combination therapy showed the best symptomatic outcome and risk reduction for clinical progression. Combining Phosphodieseterase type 5 inhbibitors (PDE5Is) with 5ARIs counteracts the negative androgenic sexual side effects of 5ARIs, and simultaneously combines their synergistic effects on LUTS. PMID:27476125

  7. Metabolism of the aldose reductase inhibitor ALO1567 in man.

    PubMed Central

    Park, Y H; Hudson, J E; Barker, R C; York, B M; Brazzell, R K

    1991-01-01

    1. The metabolism of the aldose reductase inhibitor, ALO1567, was studied in man. The major biotransformation pathway was aromatic hydroxylation followed by glucuronide conjugation. 2. Hydroxylation occurred at several positions on the fluorene ring. The major metabolite was identified as the 7-hydroxy analogue of ALO1567 and three minor metabolites were characterized as positional isomers of the 7-hydroxy metabolite. 3. Oxidative defluorination and metabolism on the hydantoin ring were also indicated as minor pathways. 4. The capacity of normal subjects to oxidize ALO1567 was indicated by the urinary ratio of the parent drug to the 7-hydroxy metabolite after daily oral administration of 100 mg and 200 mg of ALO1567. Most subjects having higher ALO1567 plasma concentrations showed higher ratios. PMID:1931471

  8. Diuretic and natriuretic effects of sorbinil, an aldose reductase inhibitor.

    PubMed

    Springate, J E; Feld, L G; Van Liew, J B; Fildes, R D; Acara, M A

    1991-04-01

    The renal effects of sorbinil, an aldose reductase inhibitor that interferes with the conversion of glucose to sorbitol, were studied in rats and rabbits before and after fluid deprivation. The intracellular osmolar solute, sorbitol, is found in increasing concentrations from cortex to medulla in the kidney and may be involved in the urinary concentrating mechanism. Oral administration of sorbinil in the rabbit resulted in significant increases in urine flow rate and sodium excretion with a tendency toward decreased urine osmolality and increased potassium excretion both before and after water deprivation. When fluid intake was controlled in the rat study, significant increases in urine flow rate and sodium and potassium excretion and a significant decrease in urine osmolality occurred only in response to fluid deprivation. Thus, sorbinil has diuretic and natriuretic properties and may prevent the normal concentration of urine in the antidiuretic animal.

  9. Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening

    PubMed Central

    Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

    2015-01-01

    Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening. PMID:26170618

  10. Statins and progressive renal disease.

    PubMed

    Buemi, Michele; Senatore, Massimino; Corica, Francesco; Aloisi, Carmela; Romeo, Adolfo; Cavallaro, Emanuela; Floccari, Fulvio; Tramontana, Domenico; Frisina, Nicola

    2002-01-01

    Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.

  11. Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.

    SciTech Connect

    El-Kabbani, O.; Old, S. E.; Ginell, S. L.; Carper, D. A.; Biosciences Division; Monash Univ.; NIH

    1999-09-03

    PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 in aldose reductase contributes to the tight binding of NADPH.

  12. Statins and angiogenesis: Is it about connections?

    SciTech Connect

    Khaidakov, Magomed; Wang, Wenze; Khan, Junaid A.; Kang, Bum-Yong; Hermonat, Paul L.; Mehta, Jawahar L.

    2009-09-25

    Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, have been shown to induce both angiogenic and angiostatic responses. We attempted to resolve this controversy by studying the effects of two different statins, rosuvastatin and simvastatin, in two different assay systems. In the matrigel angiogenesis assay, both statins enhanced tube formation by human umbilical vein endothelial cells (HUVECs, p < 0.01 vs. control). In the ex vivo mouse aortic ring sprouting assay, both statins virtually abolished new vessel formation (p < 0.01). As a basic difference between the two models of angiogenesis is dispersed state of endothelial cells vs. compact monolayer, we analyzed influence of statins on endothelial junction proteins. RT-PCR analysis and cytoimmunostaining of HUVECs treated with simvastatin revealed increased expression of VE-cadherin (p < 0.05). The blockade of VE-cadherin with a specific antibody reversed simvastatin-induced tube formation (p < 0.002). These data suggest that statins through VE-cadherin stimulation modulate cell-cell adhesion and diminish the ability of cells to proliferate and migrate. The observations of reduced angiogenesis in the intact vessel may relate to anti-atherosclerotic and anti-cancer effects of statins, and provide a feasible explanation for conflicting data under different experimental conditions.

  13. Strategies to overcome statin intolerance.

    PubMed

    Agouridis, Aris P; Nair, Devaki R; Mikhailidis, Dimitri P

    2015-06-01

    This editorial discusses several options to overcome statin intolerance in clinical practice. For example, switching to a different statin, changing statin dosing, using lipid-lowering drugs other than statins (e.g., ezetimibe, bile acid sequestrants and fibrates, alone or in combination), or combining statins with other lipid-lowering drugs. The authors focus on the potential mechanisms involved in statin-related myopathy. New lipid-lowering drugs currently in development (e.g., cholesterol ester transfer protein inhibitors [anacetrapib] and proprotein convertase subtilisin/kexin 9 inhibitors) inhibitors may help in the management of statin intolerance while achieving low-density lipoprotein cholesterol targets as set out by the guidelines.

  14. The use of 5-alpha reductase inhibitors for the prevention of prostate cancer.

    PubMed

    Yu, Eun-mi; El-Ayass, Walid; Aragon-Ching, Jeanny B

    2010-07-01

    The use of 5-alpha-reductase inhibitors has been studied not only in benign prostatic hyperplasia, but as a chemopreventive strategy in prostate cancer. Both finasteride and dutasteride, 5 alpha-reductase inhibitors (5ARI), have been shown to decrease the risk of prostate cancer. The results of the REDUCE trial using the dual alpha-reductase isoenzyme inhibitor dutasteride, has recently been published by Andriole et al. in the New England Journal of Medicine. Certain considerations regarding its use and applicability to men with high risk of developing prostate cancer are herein discussed. PMID:20574153

  15. Finasteride: the first 5 alpha-reductase inhibitor.

    PubMed

    Sudduth, S L; Koronkowski, M J

    1993-01-01

    Finasteride is a synthetic 4-azasteroid that is a specific competitive inhibitor of 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT). It has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. It is well absorbed after oral administration, with absolute bioavailability in humans of 63% (range 34-108%). The mean time to maximum concentration is 1-2 hours, and it is approximately 90% plasma protein bound. The elimination half-life averages 6-8 hours. The agent is metabolized to a series of five metabolites, of which two are active and possess less than 20% of the 5 alpha-reductase activity of finasteride. Little is known about potential drug interactions, although they appear to be minimal and not clinically relevant. The drug is indicated for the treatment of symptomatic benign prostatic hyperplasia. Its efficacy in regression of prostate gland enlargement is rapid and predictable, although correlation with subsequent improvement in urinary flow and symptoms is highly variable. Dosages of 0.5-100 mg/day regress prostate enlargement; the recommended dosage is 5 mg once/day. Finasteride may hold promise for other DHT-mediated disorders such as acne, facial hirsutism, frontal lobe alopecia, and prostate cancer, but its use in these conditions remains investigational. The frequency of adverse drug events is low, with the most common side effects being impotence, decreased libido, and decreased volume of ejaculate. No reports of intentional overdose have been reported, and dosages of up to 80 mg/day for 3 months have been taken without adverse effect. PMID:7689728

  16. Prostates, pates, and pimples. The potential medical uses of steroid 5 alpha-reductase inhibitors.

    PubMed

    Tenover, J S

    1991-12-01

    The steroid 5 alpha-reductase enzyme is responsible for the formation of DHT from testosterone. DHT has been the major androgen implicated in the pathogenesis of benign prostatic hyperplasia, male pattern baldness, acne, and idiopathic female hirsutism. Although specific inhibitors of 5 alpha-reductase are not yet generally available for human use, it is expected that they will become available within the next several years. Based on biochemical, histologic, and anatomic information from animals given 5 alpha-reductase inhibitors, preliminary data on their use in humans, and knowledge gained from men with the inherited 5 alpha-reductase deficiency, it is expected that these 5 alpha-reductase inhibitors may have a major role in the medical management of benign prostatic hyperplasia. In addition, it is possible that these compounds will hold promise for the prevention of male pattern baldness and for the treatment of resistant acne and idiopathic hirsutism. PMID:1723383

  17. Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism.

    PubMed

    Tomita, Y; Maeda, K; Sugiyama, Y

    2013-07-01

    Because the plasma exposure levels of rosuvastatin in Asians are generally twice those in Caucasians, the starting dose for Asians in the United States is set to half of that for non-Asians. However, the precise role of ethnicity in the clearance of rosuvastatin has not yet been clarified. This review focuses on ethnic variability in the clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) and angiotensin II receptor antagonists. The mechanisms of such variability are discussed quantitatively, with building a hypothetical model for pravastatin, and validated against other statins. Our analyses suggest that the ethnic variability in the plasma exposure of statins cannot be explained only by the difference in the allele frequencies of organic anion-transporting polypeptide (OATP)1B1 and breast cancer resistance protein (BCRP), and the intrinsic ethnic variability in the activity of OATP1B1 (the ratio of Japanese/Caucasians is 0.584) must be considered. Further work and validation with additional data will clarify the applicability of this model to other OATP1B1 substrates.

  18. 20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng.

    PubMed

    Fatmawati, Sri; Ersam, Taslim; Yu, Hongshan; Zhang, Chunzhi; Jin, Fengxie; Shimizu, Kuniyoshi

    2014-09-15

    The root of Panax ginseng C. A. Meyer (Araliaceae) is a well-known herbal medicine in East Asia. The major bioactive metabolites in this root are commonly identified as ginsenosides. A series of ginsenosides were determined for in vitro human recombinant aldose reductase. This Letter aims to clarify the structural requirement for aldose reductase inhibition. We discovered that only ginsenoside 20(S)-Rh2 showed potent against aldose reductase, with an IC50 of 147.3 μM. These results implied that the stereochemistry of the hydroxyl group at C-20 may play an important role in aldose reductase inhibition. An understanding of these requirements is considered necessary in order to develop a new type of aldose reductase inhibitor. Furthermore, P. ginseng might be an important herbal medicine in preventing diabetic complications.

  19. Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections

    PubMed Central

    Lorenzo-Morales, Jacob; Machin, Rubén P.; López-Arencibia, Atteneri; García-Castellano, José Manuel; de Fuentes, Isabel; Loftus, Brendan; Maciver, Sutherland K.; Valladares, Basilio; Piñero, José E.

    2013-01-01

    Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease. PMID:23114753

  20. Statin therapy, myopathy and exercise--a case report.

    PubMed

    Semple, Stuart J

    2012-01-01

    In a bid to reduce the morbidity and mortality associated with coronary artery disease, statin therapy has become a cornerstone treatment for patients with dyslipideamia. Statins, or HMG-CoA reductase inhibitors, are effective in blocking hepatic synthesis of cholesterol and are generally regarded as safe. Although rare, severe adverse side effects such as rhabdomyolysis have been reported, however, the more common complaint from patients is that related to myopathy. There is also mounting evidence that exercise may exacerbate these side effects, however the mechanisms are yet to be fully defined and there is controversy regarding the role that inflammation may play in the myopathy. This paper reports a patients experience during 6 months of simvastatin therapy and provides some insight into the white cell count (inflammation) following two bouts of moderate intensity exercise before and during statin therapy. It also highlights the need for rehabilitation practitioners to be aware of the adverse effects of statins in exercising patients. PMID:22420409

  1. Potential Autonomic Nervous System Effects of Statins in Heart Failure

    PubMed Central

    Horwich, Tamara; Middlekauff, Holly

    2008-01-01

    Synopsis Sympathetic nervous system activation in heart failure, as indexed by elevated norepinephrine levels, higher muscle sympathetic nerve activity and reduced heart rate variability, is associated with pathologic ventricular remodeling, increased arrhythmias, sudden death, and increased mortality. Recent evidence suggests that HMG-CoA reductase inhibitor (statin) therapy may provide survival benefit in heart failure of both ischemic and non-ischemic etiology, and one potential mechanism of benefit of statins in heart failure is modulation of the autonomic nervous system. Animal models of heart failure demonstrate reduced sympathetic activation and improved sympathovagal balance with statin therapy. Initial human studies have reported mixed results. Ongoing translational studies and outcomes trials will help delineate the potentially beneficial effects of statins on the autonomic nervous system in heart failure. PMID:18433696

  2. Three's company: regulation of cell fate by statins.

    PubMed

    Vamvakopoulos, Joannis E

    2005-04-01

    Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (statins), the rate-limiting enzyme of the mevalonate biosynthetic pathway, are currently the leading prescription drugs worldwide. Programmed cell death (apoptosis) is a powerful physiological regulator of cellular development, function and dynamics. Statins are known to induce cellular apoptosis in vitro; however, the clinical relevance of this action remains controversial. This paper draws from 15 years' worth of research to explore the impact of statin treatment on cell fate, as represented by the interlinked processes of cellular growth, differentiation and apoptosis. In particular, I outline our current understanding of the pertinent molecular mechanisms; and discuss the evidence for clinical relevance of statin-induced apoptosis.

  3. Studies on WF-3681, a novel aldose reductase inhibitor. I. Taxonomy, fermentation, isolation and characterization.

    PubMed

    Nishikawa, M; Tsurumi, Y; Namiki, T; Yoshida, K; Okuhara, M

    1987-10-01

    WF-3681 was isolated from a cultured filtrate of Chaetomella raphigera as a novel inhibitor of aldose reductase. It was extracted with ethyl acetate and then purified with silica gel chromatography. Its molecular formula was determined to be C13H12O5 by elemental analysis and high resolution electron impact mass spectrometry. IC50 of WF-3681 was 2.5 X 10(-7) M for partially purified aldose reductase of rabbit lens. PMID:3119547

  4. [Progress in research of aldose reductase inhibitors in traditional medicinal herbs].

    PubMed

    Feng, Chang-Gen; Zhang, Lin-Xia; Liu, Xia

    2005-10-01

    The traditional medicinal herbs are natural product, and have no obviously toxic action and side effect, and their resources are extensive. The adverse effects produced by aldose reductase inhibitors in traditional medicinal herbs are less than those from chemical synthesis and micro-organism, they can effectively prevent and delay diabetic complication, such as diabetic nephropathy, vasculopathy, retinopathy, peripheral neuropathy, and so on. They will have a wonderful respect. Flavonoid compounds and their derivates from traditional medicinal herbs are active inhibitors to aldose reductase, such as quercetin, silymarin, puerarin, baicalim, berberine and so on. In addition, some compound preparations show more strongly activity in inhibiting aldose reductase and degrading sorbitol contents, such as Shendan in traditional medicinal herbs being active inhibitors and Jianyi capsule, Jinmaitong composita, Liuwei Di-huang pill, et al. The progresses definite functions of treating diabetes complications have been reviewed.

  5. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review

    PubMed Central

    Hirshburg, Jason M.; Kelsey, Petra A.; Therrien, Chelsea A.; Gavino, A. Carlo; Reichenberg, Jason S.

    2016-01-01

    Finasteride and dutasteride, both 5-alpha reductase inhibitors, are considered first-line treatment for androgenetic hair loss in men and used increasingly in women. In each case, patients are expected to take the medications indefinitely despite the lack of research regarding long-term adverse effects. Concerns regarding the adverse effects of these medications has led the United States National Institutes of Health to add a link for post-finasteride syndrome to its Genetic and Rare Disease Information Center. Herein, the authors report the results of a literature search reviewing adverse events of 5-alpha reductase inhibitors as they relate to prostate cancer, psychological effects, sexual health, and use in women. Several large studies found no increase in incidence of prostate cancer, a possible increase of high-grade cancer when detected, and no change in survival rate with 5-alpha reductase inhibitor use. Currently, there is no direct link between 5-alpha reductase inhibitor use and depression; however, several small studies have led to depression being listed as a side effect on the medication packaging. Sexual effects including erectile dysfunction and decreased libido and ejaculate were reported in as many as 3.4 to 15.8 percent of men. To date, there are very few studies evaluating 5-alpha reductase inhibitor use in women. Risks include birth defects in male fetuses if used in pregnancy, decreased libido, headache, gastrointestinal discomfort, and isolated reports of changes in menstruation, acne, and dizziness. Overall, 5-alpha reductase inhibitors were well-tolerated in both men and women, but not without risk, highlighting the importance of patient education prior to treatment. PMID:27672412

  6. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review

    PubMed Central

    Hirshburg, Jason M.; Kelsey, Petra A.; Therrien, Chelsea A.; Gavino, A. Carlo; Reichenberg, Jason S.

    2016-01-01

    Finasteride and dutasteride, both 5-alpha reductase inhibitors, are considered first-line treatment for androgenetic hair loss in men and used increasingly in women. In each case, patients are expected to take the medications indefinitely despite the lack of research regarding long-term adverse effects. Concerns regarding the adverse effects of these medications has led the United States National Institutes of Health to add a link for post-finasteride syndrome to its Genetic and Rare Disease Information Center. Herein, the authors report the results of a literature search reviewing adverse events of 5-alpha reductase inhibitors as they relate to prostate cancer, psychological effects, sexual health, and use in women. Several large studies found no increase in incidence of prostate cancer, a possible increase of high-grade cancer when detected, and no change in survival rate with 5-alpha reductase inhibitor use. Currently, there is no direct link between 5-alpha reductase inhibitor use and depression; however, several small studies have led to depression being listed as a side effect on the medication packaging. Sexual effects including erectile dysfunction and decreased libido and ejaculate were reported in as many as 3.4 to 15.8 percent of men. To date, there are very few studies evaluating 5-alpha reductase inhibitor use in women. Risks include birth defects in male fetuses if used in pregnancy, decreased libido, headache, gastrointestinal discomfort, and isolated reports of changes in menstruation, acne, and dizziness. Overall, 5-alpha reductase inhibitors were well-tolerated in both men and women, but not without risk, highlighting the importance of patient education prior to treatment.

  7. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review.

    PubMed

    Hirshburg, Jason M; Kelsey, Petra A; Therrien, Chelsea A; Gavino, A Carlo; Reichenberg, Jason S

    2016-07-01

    Finasteride and dutasteride, both 5-alpha reductase inhibitors, are considered first-line treatment for androgenetic hair loss in men and used increasingly in women. In each case, patients are expected to take the medications indefinitely despite the lack of research regarding long-term adverse effects. Concerns regarding the adverse effects of these medications has led the United States National Institutes of Health to add a link for post-finasteride syndrome to its Genetic and Rare Disease Information Center. Herein, the authors report the results of a literature search reviewing adverse events of 5-alpha reductase inhibitors as they relate to prostate cancer, psychological effects, sexual health, and use in women. Several large studies found no increase in incidence of prostate cancer, a possible increase of high-grade cancer when detected, and no change in survival rate with 5-alpha reductase inhibitor use. Currently, there is no direct link between 5-alpha reductase inhibitor use and depression; however, several small studies have led to depression being listed as a side effect on the medication packaging. Sexual effects including erectile dysfunction and decreased libido and ejaculate were reported in as many as 3.4 to 15.8 percent of men. To date, there are very few studies evaluating 5-alpha reductase inhibitor use in women. Risks include birth defects in male fetuses if used in pregnancy, decreased libido, headache, gastrointestinal discomfort, and isolated reports of changes in menstruation, acne, and dizziness. Overall, 5-alpha reductase inhibitors were well-tolerated in both men and women, but not without risk, highlighting the importance of patient education prior to treatment. PMID:27672412

  8. Statin Exposure Is Associated with Decreased Asthma-related Emergency Department Visits and Oral Corticosteroid Use

    PubMed Central

    Li, Lingling; Butler, Melissa G.; Fung, Vicki; Kharbanda, Elyse O.; Larkin, Emma K.; Vollmer, William M.; Miroshnik, Irina; Rusinak, Donna; Weiss, Scott T.; Lieu, Tracy; Wu, Ann Chen

    2013-01-01

    Rationale: Statins, or HMG-CoA reductase inhibitors, may aid in the treatment of asthma through their pleiotropic antiinflammatory effects. Objectives: To examine the effect of statin therapy on asthma-related exacerbations using a large population-based cohort. Methods: Statin users aged 31 years or greater with asthma were identified from the Population-Based Effectiveness in Asthma and Lung population, which includes data from five health plans. Statin exposure and asthma exacerbations were assessed over a 24-month observation period. Statin users with a statin medication possession ratio greater than or equal to 80% were matched to non–statin users by age, baseline asthma therapy, site of enrollment, season at baseline, and propensity score, which was calculated based on patient demographics and Deyo-Charlson conditions. Asthma exacerbations were defined as two or more oral corticosteroid dispensings, asthma-related emergency department visits, or asthma-related hospitalizations. The association between statin exposure and each of the three outcome measures was assessed using conditional logistic regression. Measurements and Main Results: Of the 14,566 statin users, 8,349 statin users were matched to a nonuser. After adjusting for Deyo-Charlson conditions that remained unbalanced after matching, among statin users, statin exposure was associated with decreased odds of having asthma-related emergency department visits (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53–0.77; P < 0.0001) and two or more oral corticosteroid dispensings (OR, 0.90; 95% CI, 0.81–0.99; P = 0.04). There were no differences in asthma-related hospitalizations (OR, 0.91; 95% CI, 0.66–1.24; P = 0.52). Conclusions: Among statin users with asthma, statin exposure was associated with decreased odds of asthma-related emergency department visits and oral corticosteroid dispensings. PMID:24093599

  9. The C-terminal loop of aldehyde reductase determines the substrate and inhibitor specificity.

    PubMed

    Barski, O A; Gabbay, K H; Bohren, K M

    1996-11-12

    Human aldehyde reductase has a preference for carboxyl group-containing negatively charged substrates. It belongs to the NADPH-dependent aldo-keto reductase superfamily whose members are in part distinguished by unique C-terminal loops. To probe the role of the C-terminal loops in determining substrate specificities in these enzymes, two arginine residues, Arg308 and Arg311, located in the C-terminal loop of aldehyde reductase, and not found in any other C-terminal loop, were replaced with alanine residues. The catalytic efficiency of the R311A mutant for aldehydes containing a carboxyl group is reduced 150-250-fold in comparison to that of the wild-type enzyme, while substrates not containing a negative charge are unaffected. The R311A mutant is also significantly less sensitive to inhibition by dicarboxylic acids, indicating that Arg311 interacts with one of the carboxyl groups. The inhibition pattern indicates that the other carboxyl group binds to the anion binding site formed by Tyr49, His112, and the nicotinamide moiety of NADP+. The correlation between inhibitor potency and the length of the dicarboxylic acid molecules suggests a distance of approximately 10 A between the amino group of Arg311 and the anion binding site in the aldehyde reductase molecule. The sensitivity of inhibition of the R311A mutant by several commercially available aldose reductase inhibitors (ARIs) was variable, with tolrestat and zopolrestat becoming more potent inhibitors (30- and 5-fold, respectively), while others remained the same or became less potent. The catalytic properties, substrate specificity, and susceptibility to inhibition of the R308A mutant remained similar to that of the wild-type enzyme. The data provide direct evidence for C-terminal loop participation in determining substrate and inhibitor specificity of aldo-keto reductases and specifically identifies Arg311 as the basis for the carboxyl-containing substrate preference of aldehyde reductase. PMID:8916913

  10. Statins and bone formation.

    PubMed

    Garrett, I R; Gutierrez, G; Mundy, G R

    2001-05-01

    The main therapy needed most in the bone field is an anabolic agent for the treatment of osteoporosis. Current drugs on the market, which included bisphosphonates, calcitonin, estrogen and related compounds, vitamin D analogues trabecular microarchitecture. Therefore, it would be desirable to have a satisfactory and universally and iprifalvone, are essentially bone resorption inhibitors that mainly act to stabilize bone mass. Patients with established osteoporosis have lost more than 50% of their bone mass at critical sites in the skeleton, and more over have marked disruption of acceptable drug that would stimulate new bone formation and correct this disturbance of trabecular microarchitecture characteristic of established osteoporosis. Recently inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which controls the first step in the biosynthesis of cholesterol, have been shown to stimulate bone formation in rodents both in vitro and in vivo. The effect is associated with an increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. These statins drugs are widely used agents for lowering cholesterol and reducing heart attacks, however they are also known to elicit numerous pleiotropic effects including inhibition of proliferation and migration of smooth muscle cells, inhibition of tumor growth and anti-inflammatory activity. Some of these effects have been attributed to not only to the reduction of cholesterol synthesis by inhibition of the HMG-CoA reductase enzyme but also by the concurrent reduction in downstream metabolites of the mevalonate pathway such as mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. The findings that statins are capable of increasing bone formation and bone mass in rodents suggests a potential new action for the statins, which may be beneficial in patients with established osteoporosis where marked bone loss has occurred. Recent clinical data suggests that they

  11. Cuminaldehyde: Aldose Reductase and alpha-Glucosidase Inhibitor Derived from Cuminum cyminum L. Seeds.

    PubMed

    Lee, Hoi-Seon

    2005-04-01

    The inhibitory activity of Cuminum cyminum seed-isolated component was evaluated against lens aldose reductase and alpha-glucosidase isolated from Sprague-Dawley male rats and compared to that of 11 commercially available components derived from C. cyminum seed oil, as well as quercitrin as an aldose reductase inhibitor and acarbose as an alpha-glucosidase inhibitor. The biologically active constituent of C. cyminum seed oil was characterized as cuminaldehyde by various spectral analyses. The IC(50) value of cuminaldehyde is 0.00085 mg/mL against aldose reductase and 0.5 mg/mL against alpha-glucosidase, respectively. Cuminaldehyde was about 1.8 and 1.6 times less in inhibitory activity than acarbose and quercitin, respectively. Nonetheless, cuminaldehyde may be useful as a lead compound and a new agent for antidiabetic therapeutics.

  12. Steroid 5 α-reductase inhibitors targeting BPH and prostate cancer.

    PubMed

    Schmidt, Lucy J; Tindall, Donald J

    2011-05-01

    Steroid 5 alpha-reductase inhibitors (5ARIs) have been approved for use clinically in treatment of benign prostate hyperplasia (BPH) and accompanying lower urinary tract symptoms (LUTS) and have also been evaluated in clinical trials for prevention and treatment of prostate cancer. There are currently two steroidal inhibitors in use, finasteride and dutasteride, both with distinct pharmacokinetic properties. This review will examine the evidence presented by various studies supporting the use of these steroidal inhibitors in the prevention and treatment of prostate disease. Article from the Special issue on Targeted Inhibitors. PMID:20883781

  13. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

    SciTech Connect

    Fukuda, Kazuki; Matsumura, Takeshi; Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko; Nakao, Saya; Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji; Kawada, Teruo; Nishikawa, Takeshi; Araki, Eiichi

    2015-01-30

    Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects

  14. Benefit versus risk in statin treatment.

    PubMed

    Guyton, John R

    2006-04-17

    The Statin Safety Assessment Conference of the National Lipid Association (NLA), reported in this supplement to The American Journal of Cardiology, provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. To place these in context, one can express both the risk of side effects and the benefits for cardiovascular disease in terms of events per person-year of statin treatment. The mortality risk from fatal rhabdomyolysis is approximately 0.3 per 100,000 person-years, and the risks of nonfatal rhabdomyolysis and of putative statin-attributable peripheral neuropathy are approximately 3 and 12 events, respectively, per 100,000 person-years. Reports of acute liver failure and acute or chronic kidney disease give lower rate estimates that, even when corrected for underreporting, are approximately equal to the background rates of these conditions in the general population, lending scant support for statin-attributable etiology. In contrast, the benefit of statin use is to avert several hundred deaths and several hundred cases each of heart and brain infarction per 100,000 person-years in appropriately treated high-risk patients. Although population estimates such as these are useful, they must be translated repeatedly to individual patient-provider encounters, where clinical skill and art must combine with scientific evidence. The continued publication of individual case reports and small randomized trials among groups of patients with potential side effects should be encouraged. Statins should not be used in situations where minimal benefit is expected, as safety data and risk-benefit analysis must be meshed with guidelines that help the clinician decide whom to treat and how aggressively to treat.

  15. Benefit versus risk in statin treatment.

    PubMed

    Guyton, John R

    2006-04-17

    The Statin Safety Assessment Conference of the National Lipid Association (NLA), reported in this supplement to The American Journal of Cardiology, provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. To place these in context, one can express both the risk of side effects and the benefits for cardiovascular disease in terms of events per person-year of statin treatment. The mortality risk from fatal rhabdomyolysis is approximately 0.3 per 100,000 person-years, and the risks of nonfatal rhabdomyolysis and of putative statin-attributable peripheral neuropathy are approximately 3 and 12 events, respectively, per 100,000 person-years. Reports of acute liver failure and acute or chronic kidney disease give lower rate estimates that, even when corrected for underreporting, are approximately equal to the background rates of these conditions in the general population, lending scant support for statin-attributable etiology. In contrast, the benefit of statin use is to avert several hundred deaths and several hundred cases each of heart and brain infarction per 100,000 person-years in appropriately treated high-risk patients. Although population estimates such as these are useful, they must be translated repeatedly to individual patient-provider encounters, where clinical skill and art must combine with scientific evidence. The continued publication of individual case reports and small randomized trials among groups of patients with potential side effects should be encouraged. Statins should not be used in situations where minimal benefit is expected, as safety data and risk-benefit analysis must be meshed with guidelines that help the clinician decide whom to treat and how aggressively to treat. PMID:16581337

  16. [Liver damage in a patient treated with a vitamin K antagonist, a statin and an ACE inhibitor].

    PubMed

    Bruggisser, M; Terraciano, L; Rätz Bravo, A; Haschke, M

    2010-10-20

    We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors. PMID:20960395

  17. Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.

    PubMed

    Schonewille, Marleen; Freark de Boer, Jan; Mele, Laura; Wolters, Henk; Bloks, Vincent W; Wolters, Justina C; Kuivenhoven, Jan A; Tietge, Uwe J F; Brufau, Gemma; Groen, Albert K

    2016-08-01

    Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins.

  18. Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.

    PubMed

    Schonewille, Marleen; Freark de Boer, Jan; Mele, Laura; Wolters, Henk; Bloks, Vincent W; Wolters, Justina C; Kuivenhoven, Jan A; Tietge, Uwe J F; Brufau, Gemma; Groen, Albert K

    2016-08-01

    Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins. PMID:27313057

  19. Identifying statin-associated autoimmune necrotizing myopathy.

    PubMed

    Albayda, Jemima; Christopher-Stine, Lisa

    2014-12-01

    Statins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity.

  20. Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

    PubMed Central

    Beierlein, Jennifer M.; Frey, Kathleen M.; Bolstad, David B.; Pelphrey, Phillip M.; Joska, Tammy M.; Smith, Adrienne E.; Priestley, Nigel D.; Wright, Dennis L.; Anderson, Amy C.

    2008-01-01

    Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 Å resolution. The structure reveals several features that can be exploited for further development of this lead series. PMID:19007108

  1. Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

    SciTech Connect

    Beierlein, J.; Frey, K; Bolstad, D; Pelphrey, P; Joska, T; Smith, A; Priestley, N; Wright, D; Anderson, A

    2008-01-01

    Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 A resolution. The structure reveals several features that can be exploited for further development of this lead series.

  2. Cheminformatics Models for Inhibitors of Schistosoma mansoni Thioredoxin Glutathione Reductase

    PubMed Central

    Gaba, Sonam; Jamal, Salma; Open Source Drug Discovery Consortium

    2014-01-01

    Schistosomiasis is a neglected tropical disease caused by a parasite Schistosoma mansoni and affects over 200 million annually. There is an urgent need to discover novel therapeutic options to control the disease with the recent emergence of drug resistance. The multifunctional protein, thioredoxin glutathione reductase (TGR), an essential enzyme for the survival of the pathogen in the redox environment has been actively explored as a potential drug target. The recent availability of small-molecule screening datasets against this target provides a unique opportunity to learn molecular properties and apply computational models for discovery of activities in large molecular libraries. Such a prioritisation approach could have the potential to reduce the cost of failures in lead discovery. A supervised learning approach was employed to develop a cost sensitive classification model to evaluate the biological activity of the molecules. Random forest was identified to be the best classifier among all the classifiers with an accuracy of around 80 percent. Independent analysis using a maximally occurring substructure analysis revealed 10 highly enriched scaffolds in the actives dataset and their docking against was also performed. We show that a combined approach of machine learning and other cheminformatics approaches such as substructure comparison and molecular docking is efficient to prioritise molecules from large molecular datasets. PMID:25629082

  3. 5alpha-Reductase inhibitor treatment of prostatic diseases: background and practical implications.

    PubMed

    Dörsam, J; Altwein, J

    2009-01-01

    This literature review discusses the theoretical background of 5alpha-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5alpha-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time. PMID:19030020

  4. Effects of aldose reductase inhibitor treatment in diabetic polyneuropathy - a clinical and neurophysiological study.

    PubMed Central

    Fagius, J; Jameson, S

    1981-01-01

    The efficacy of treatment with an aldose reductase inhibitor (1,3-dioxo-1 H-benz-de-isoquinoline-2(3H)-acetic acid, AY-22,284, Alrestatin) on peripheral nerve function in diabetic polyneuropathy was assessed. Thirty patients with long-standing diabetes and slight to moderate neuropathy participated in the double-blind placebo trial. Clinical examination, sensory threshold determinations for vibratory, tactile and thermal stimuli, conduction velocity measurements and studies of automatic function were performed to evaluate the treatment. Significant differences favouring Alrestatin over placebo were found for many of the measured variables, whereas no changes occurred on placebo. The apparent improvement of neuropathy occurred despite persisting hyperglycaemia. The results indicate that aldose reductase inhibitor treatment may be of value in diabetic polyneuropathy, and provide support for the sorbitol pathway hypothesis of diabetic polyneuropathy. PMID:6801211

  5. Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors.

    PubMed

    Shelke, Rupesh U; Degani, Mariam S; Raju, Archana; Ray, Mukti Kanta; Rajan, Mysore G R

    2016-08-01

    Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.

  6. Inhibition of Rab prenylation by statins induces cellular glycosphingolipid remodeling.

    PubMed

    Binnington, Beth; Nguyen, Long; Kamani, Mustafa; Hossain, Delowar; Marks, David L; Budani, Monique; Lingwood, Clifford A

    2016-02-01

    Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol and cardiac risk, but many other effects are seen. We now show an effect of these drugs to induce profound changes in the step-wise synthesis of glycosphingolipids (GSLs) in the Golgi. Glucosylceramide (GlcCer) was increased several-fold in all cell lines tested, demonstrating a widespread effect. Additionally, de novo or elevated lactotriaosylceramide (Lc3Cer; GlcNAcβ1-3Galβ1-4GlcCer) synthesis was observed in 70%. Western blot showed that GlcCer synthase (GCS) was elevated by statins, and GCS and Lc3Cer synthase (Lc3S) activities were increased; however, transcript was elevated for Lc3S only. Supplementation with the isoprenoid precursor, geranylgeranyl pyrophosphate (GGPP), a downstream product of HMG Co-A reductase, reversed statin-induced glycosyltransferase and GSL elevation. The Rab geranylgeranyl transferase inhibitor 3-PEHPC, but not specific inhibitors of farnesyl transferase, or geranylgeranyl transferase I, was sufficient to replicate statin-induced GlcCer and Lc3Cer synthesis, supporting a Rab prenylation-dependent mechanism. While total cholesterol was unaffected, the trans-Golgi network (TGN) cholesterol pool was dissipated and medial Golgi GCS partially relocated by statins. GSL-dependent vesicular retrograde transport of Verotoxin and cholera toxin to the Golgi/endoplasmic reticulum were blocked after statin or 3-PEHPC treatment, suggesting aberrant, prenylation-dependent vesicular traffic as a basis of glycosyltransferase increase and GSL remodeling. These in vitro studies indicate a previously unreported link between Rab prenylation and regulation of GCS activity and GlcCer metabolism. PMID:26405105

  7. Screening for inhibitors of dihydrofolate reductase using pulsed ultrafiltration mass spectrometry.

    PubMed

    Nikolic, D; van Breemen, R B

    1998-04-01

    A method of screening combinatorial libraries for inhibitors of eukaryotic dihydrofolate reductase has been developed using pulsed ultra-filtration electrospray mass spectrometry, which is a continuous-flow affinity separation system for extracting and identifying high affinity ligands in combinatorial libraries. In this application, pulsed ultrafiltration conditions were optimized for the isolation and identification of inhibitors of dihydrofolate reductase from a 22 compound library containing six known inhibitors of the enzyme including trimethoprim, aminopterin, methotrexate, pyrimethamine, folic acid, and folinic acid, and 16 compounds without known affinity. In order to optimize the screening method, sources of non-specific binding were identified and minimized. A significant source of non-specific binding for this set of library compounds was hydrophobic interaction with the surfaces of the ultrafiltration chamber. After affinity separation of bound (high affinity) versus free (low affinity) library compounds during pulsed ultrafiltration, receptor-bound ligands were released and eluted using either organic solvent or acidified mobile phase. Although 80% methanol easily disrupted the receptor-ligand complexes, organic solvent had the undesirable effect of releasing non-specifically bound compounds from the chamber and thereby increasing the background noise. Interference from non-specific binding was minimized by releasing bound ligands using a low pH mobile phase eluent instead of organic solvent. Under the conditions used, pulsed ultrafiltration mass spectrometry selectively identified the two library compounds with the highest affinity for dihydrofolate reductase, methotrexate and aminopterin.

  8. Statin Pharmacogenomics: Opportunities to Improve Patient Outcomes and Healthcare Costs with Genetic Testing

    PubMed Central

    Canestaro, William J.; Brooks, David G.; Chaplin, Donald; Choudhry, Niteesh K.; Lawler, Elizabeth; Martell, Lori; Brennan, Troyen; Wassman, E. Robert

    2012-01-01

    HMG-CoA reductase inhibitors, commonly known as statins, are some of the most widely prescribed medications worldwide and have been shown to be effective at lowering cholesterol in numerous long-term prospective trials, yet there are significant limitations to their use. First, patients receiving statin therapy have relatively low levels of medication adherence compared with other drug classes. Next, numerous statin formulations are available, each with its own unique safety and efficacy profile, and it may be unclear to prescribers which treatment is optimal for their patients. Finally, statins have class-wide side effects of myopathy and rhabdomyolysis that have resulted in a product recall and dosage limitations. Recent evidence suggests that two genomic markers, KIF6 and SLCO1B1, may inform the therapy choice of patients initiating statins. Given the prevalence of statin usage, their potential health advantages and their overall cost to the healthcare system, there could be significant clinical benefit from creating personalized treatment regimens. Ultimately, if this approach is effective it may encourage higher adoption of generic statins when appropriate, promote adherence, lower rates of myopathy, and overall achieve higher value cardiovascular care. This paper will review the evidence for personalized prescribing of statins via KIF6 and SLCO1B1 and consider some of the implications for testing these markers as part of routine clinical care. PMID:25562358

  9. Antihormonal activities of 5 alpha-reductase and aromatase inhibitors.

    PubMed

    Zoppi, S; Cocconi, M; Lechuga, M J; Messi, E; Zanisi, M; Motta, M

    1988-10-01

    The problem of developing androgen antagonists has been tackled so far only by synthesizing steroids able to displace testosterone and other androgens from their specific receptor sites. The observation that testosterone has to be converted intracellularly either to 5 alpha-reduced metabolites (DHT, 3 alpha-diol, etc.) or to estrogens, in order to become fully active on androgen-dependent structures (both central and peripheral), has opened the possibility of creating molecules which prevent these conversions, and which could then block the actions of testosterone. The availability of these new compounds has allowed a better understanding of the selective physiological role of each of the metabolites of testosterone, and to provide the basis for the development of new hormone antagonists to be used in those clinical conditions for which an inhibition of the actions of testosterone is foreseen. The usefulness of these enzyme inhibitors is underlined by some examples described in this paper. The results obtained may permit the formulation of the following conclusions: (1) The conversion of testosterone to its 5 alpha-reduced metabolites occurring in the neuroendocrine structures may represent an essential step for the appearance of the inhibitory feedback effect testosterone exerts on LH secretion; (2) Testosterone exhibits its negative feedback effect on FSH secretion as such and not following the local aromatization to estrogens; (3) Testosterone exerts its effect on the intrahypothalamic stores of LHRH acting as such and not following its local conversion either to 5 alpha-reduced metabolites or to estrogenic molecules; (4) Some of the new enzyme inhibitors (e.g. 4-OH-A) may represent an interesting tool for the treatment and/or the prevention of BPH and possibly of other androgen-dependent diseases (prostate carcinoma, acne etc.), as shown by their ability to prevent the in vitro conversion of testosterone to its 5 alpha-reduced metabolites both in the normal

  10. Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase inhibitory effect of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas.

    PubMed

    Terashima, S; Shimizu, M; Horie, S; Morita, N

    1991-12-01

    The hot water extracts of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas, were found to have potent inhibitory activity towards lens aldose reductase (AR). Ellagic acid (4) was isolated from C. morifolium and I. batatas, isoscutellarein (7) from B. orellana and 3,5-dicaffeoylquinic acid (10) from I. batatas, respectively, as potent inhibitors. PMID:1814628

  11. Approach to clinical and genetic characterization of statin-induced myopathy.

    PubMed

    Feng, QiPing

    2014-01-01

    HMG CoA reductase inhibitors (statins) are among the most commonly prescribed medications in the industrialized world. They are generally regarded as safe. Mild myalgias can occur in up to 10 % of patients exposed to statins, but skeletal muscle damage (accompanied by an increase in circulating creatine kinase levels) occurs much less frequently. Clinical predictors of statin-induced rhabdomyolysis (severe muscle damage with end organ failure) include female gender, advanced age, and concomitant medications known to interact with critical pharmacokinetic and pharmacodynamic processes. The influence of genetic variations has been investigated by candidate gene association studies, genome-wide association studies, and whole-genome sequencing. This chapter summarizes current available approaches to clinical and genetic characterization of statin-related adverse effect.

  12. Statins in the prevention of cardiovascular events in patients with renal failure.

    PubMed

    Buemi, Michele; Floccari, Fulvio; Nostro, Lorena; Campo, Susanna; Caccamo, Chiara; Sturiale, Alessio; Aloisi, Carmela; Giacobbe, Maria Stella; Frisina, Nicola

    2007-03-01

    HMG-CoA reductase inhibitors (statins) are among the most widely used hypolypemizing drugs with a pleiotropic activity. Numerous clinical trials have demonstrated that statins can have a significant effect in the prevention of cardiovascular diseases in the general population. In patients with renal failure, this drug preserves the hypolypemizing efficacy found in the general population without increasing their unwanted side-effects. The re-analysis of data from epidemiological studies conducted on the general population has confirmed that statins provide cardiovascular protection also in subjects with renal failure. These data have been partly confirmed by the findings made by 4D (Die Deutsche Diabetes Dialyse Studie) and Alert studies, conducted on diabetic patients on dialysis and patients with renal transplants, respectively. The results of other studies, such as AURORA, SHARP, REnal and Vascular End stage Disease, and ESPLANADE, clearly indicate that statins prevent cardiovascular disease in patients with renal insufficiency, just as they do in the general population.

  13. Discovering Echinococcus granulosus thioredoxin glutathione reductase inhibitors through site-specific dynamic combinatorial chemistry.

    PubMed

    Saiz, Cecilia; Castillo, Valerie; Fontán, Pablo; Bonilla, Mariana; Salinas, Gustavo; Rodríguez-Haralambides, Alejandra; Mahler, S Graciela

    2014-02-01

    In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine (2af) was identified, upon library analysis by HPLC (IC50 = 24 μM). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure-activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine (2aj) as the best enzyme inhibitor in these series, with an IC50 = 24 μM. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases.

  14. [Role of Monocarboxylate Transporter in Statin-induced Cytotoxicity].

    PubMed

    Kobayashi, Masaki

    2015-01-01

    Although exercise and drug therapy are important to prevent progression of arteriosclerotic disease, exercise leads to an increase in muscular disorder induced by HMG-CoA reductase inhibitors (statins). Elucidation of this mechanism is needed to prevent the occurrence of muscular disorders. Since exercise induces expression of monocarboxylate transporter (MCT) 4, we focused on the association between MCT4 function and statin-induced muscle injury. First, we examined the transport of L-lactate via MCT4 using MCT4 cRNA-injected Xenopus laevis oocytes. L-lactate uptake by MCT4-expressing oocytes was markedly reduced by alkalizing the buffer pH and saturated at higher L-lactate concentrations. On the other hand, AMP-activated protein kinase (AMPK) and protein kinase C (PKC) are activated by exercise. We next examined whether AMPK and PKC activation affects the expression and function of MCT4 in rat skeletal muscle and RD cells as an in vitro skeletal muscle model. AMPK and PKC activation increased MCT4 expression level and lactate efflux by MCT4. Finally, we examined the association between MCT4 function and statin-induced cytotoxicity. Statins inhibited transport of L-lactate via MCT4 in a concentration-dependent manner. Statin-induced cytotoxicity was associated with intracellular acidification and caspase-3/7 activation. On the other hand, bicarbonate suppressed statin-induced pH alteration, caspase activation, and morphological change. The results suggest that statin-induced muscle injury exacerbated by exercise is associated with intracellular acidification and that the effects of statins on L-lactate transport are mediated by MCT4.

  15. Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

    PubMed Central

    Golomb, Beatrice A.; Evans, Marcella A.

    2009-01-01

    HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity. PMID:19159124

  16. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.

    PubMed Central

    Hernández-Perera, O; Pérez-Sala, D; Navarro-Antolín, J; Sánchez-Pascuala, R; Hernández, G; Díaz, C; Lamas, S

    1998-01-01

    Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 microg/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able to prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors. PMID:9637705

  17. Impact of Statins on Gene Expression in Human Lung Tissues

    PubMed Central

    Lane, Jérôme; van Eeden, Stephan F.; Obeidat, Ma’en; Sin, Don D.; Tebbutt, Scott J.; Timens, Wim; Postma, Dirkje S.; Laviolette, Michel; Paré, Peter D.; Bossé, Yohan

    2015-01-01

    Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin

  18. Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

    SciTech Connect

    Schormann, Norbert; Velu, Sadanandan E.; Murugesan, Srinivasan; Senkovich, Olga; Walker, Kiera; Chenna, Bala C.; Shinkre, Bidhan; Desai, Amar; Chattopadhyay, Debasish

    2010-09-17

    Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.

  19. Selective non-steroidal inhibitors of 5 alpha-reductase type 1.

    PubMed

    Occhiato, Ernesto G; Guarna, Antonio; Danza, Giovanna; Serio, Mario

    2004-01-01

    The enzyme 5 alpha-reductase (5 alpha R) catalyses the reduction of testosterone (T) into the more potent androgen dihydrotestosterone (DHT). The abnormal production of DHT is associated to pathologies of the main target organs of this hormone: the prostate and the skin. Benign prostatic hyperplasia (BPH), prostate cancer, acne, androgenetic alopecia in men, and hirsutism in women appear related to the DHT production. Two isozymes of 5 alpha-reductase have been cloned, expressed and characterized (5 alpha R-1 and 5 alpha R-2). They share a poor homology, have different chromosomal localization, enzyme kinetic parameters, and tissue expression patterns. Since 5 alpha R-1 and 5 alpha R-2 are differently distributed in the androgen target organs, a different involvement of the two isozymes in the pathogenesis of prostate and skin disorders can be hypothesized. High interest has been paid to the synthesis of inhibitors of 5 alpha-reductase for the treatment of DHT related pathologies, and the selective inhibition of any single isozyme represents a great challenge for medical and pharmaceutical research in order to have more specific drugs. At present, no 5 alpha R-1 inhibitor is marketed for the treatment of 5 alpha R-1 related pathologies but pharmaceutical research is very active in this field. This paper will review the major classes of 5 alpha R inhibitors focusing in particular on non-steroidal inhibitors and on structural features that enhance the selectivity versus the type 1 isozyme. Biological tests to assess the inhibitory activity towards the two 5 alpha R isozymes will be also discussed. PMID:15026079

  20. The flavin inhibitor diphenyleneiodonium renders Trichomonas vaginalis resistant to metronidazole, inhibits thioredoxin reductase and flavin reductase, and shuts off hydrogenosomal enzymatic pathways.

    PubMed

    Leitsch, David; Kolarich, Daniel; Duchêne, Michael

    2010-05-01

    Infections with the microaerophilic protozoan parasite Trichomonas vaginalis are commonly treated with metronidazole, a 5-nitroimidazole drug. Metronidazole is selectively toxic to microaerophiles and anaerobes because reduction at the drug's nitro group, which is a precondition for toxicity, occurs only quantitatively in these organisms. In our previous work we identified the flavin enzyme thioredoxin reductase as an electron donor to 5-nitroimidazole drugs in T. vaginalis and observed that highly metronidazole-resistant cell lines lack thioredoxin reductase and flavin reductase activities. In this study we added the flavin inhibitor diphenyleneiodonium (DPI) to T. vaginalis cultures in order to test our hypothesis that metronidazole reduction is catalyzed by flavin enzymes, e.g. thioredoxin reductase, and intracellular free flavins. Indeed, within hours, DPI rendered T. vaginalis insensitive to metronidazole concentrations as high as 1mM and prevented the formation of metronidazole adducts with proteins. Thioredoxin reductase activity was absent from DPI-treated cells and flavin reductase activity was sharply decreased. In addition, DPI-treated cells also upregulated the expression of antioxidant enzymes, i.e. thioredoxin peroxidases and superoxide dismutases, and displayed a fundamentally altered metabolism caused by inactivation of pyruvate:ferredoxin oxidoreductase (PFOR) and concomitant upregulation of lactate dehydrogenase (LDH) activity. Thus, the disruption of the cellular flavin metabolism by DPI mediated metabolic steps which are similar to that of cells with metronidazole resistance induced in vitro. Finally, we present direct evidence that the increased expression of antioxidant enzymes is dispensable for acquiring resistance to metronidazole. PMID:20093143

  1. Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue.

    PubMed

    Yoshimura, Koichi; Nagasawa, Ayako; Kudo, Junichi; Onoda, Masahiko; Morikage, Noriyasu; Furutani, Akira; Aoki, Hiroki; Hamano, Kimikazu

    2015-05-18

    HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) have been suggested to attenuate abdominal aortic aneurysm (AAA) growth. However, the effects of statins in human AAA tissues are not fully elucidated. The aim of this study was to investigate the direct effects of statins on proinflammatory molecules in human AAA walls in ex vivo culture. Simvastatin strongly inhibited the activation of nuclear factor (NF)-κB induced by tumor necrosis factor (TNF)-α in human AAA walls, but showed little effect on c-jun N-terminal kinase (JNK) activation. Simvastatin, as well as pitavastatin significantly reduced the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and epithelial neutrophil-activating peptide (CXCL5) under both basal and TNF-α-stimulated conditions. Similar to statins, the Rac1 inhibitor NSC23766 significantly inhibited the activation of NF-κB, accompanied by a decreased secretion of MMP-9, MCP-2 and CXCL5. Moreover, the effect of simvastatin and the JNK inhibitor SP600125 was additive in inhibiting the secretion of MMP-9, MCP-2 and CXCL5. These findings indicate that statins preferentially inhibit the Rac1/NF-κB pathway to suppress MMP-9 and chemokine secretion in human AAA, suggesting a mechanism for the potential effect of statins in attenuating AAA progression.

  2. New 5alpha-reductase inhibitors: in vitro and in vivo effects.

    PubMed

    Pérez-Ornelas, Víctor; Cabeza, Marisa; Bratoeff, Eugene; Heuze, Ivonne; Sánchez, Mauricio; Ramírez, Elena; Naranjo-Rodríguez, Elia

    2005-03-01

    The enzyme 5alpha-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5alpha-reductase enzyme offers a potentially useful treatment for these diseases. In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments. In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT. The results of this study carried out with 5alpha-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5alpha-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride). The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5alpha-reductase enzyme. PMID:15763601

  3. Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase.

    PubMed

    Persch, Elke; Bryson, Steve; Todoroff, Nickolay K; Eberle, Christian; Thelemann, Jonas; Dirdjaja, Natalie; Kaiser, Marcel; Weber, Maria; Derbani, Hassan; Brun, Reto; Schneider, Gisbert; Pai, Emil F; Krauth-Siegel, R Luise; Diederich, François

    2014-08-01

    The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.

  4. Role of 5α-reductase inhibitors in prostate cancer prevention and treatment.

    PubMed

    Azzouni, Faris; Mohler, James

    2012-06-01

    Although testosterone is the most abundant serum androgen, dihydrotestosterone is the main prostatic androgen. Testosterone is converted to dihydrotestosterone by the enzyme 5α-reductase (5α-R). Dihydrotestosterone plays an important role in several human diseases, including benign prostate enlargement and prostate cancer. The observation that males born with 5α-R 2 deficiency have never been reported to develop prostate cancer stimulated interest in development of 5α-R inhibitors. Thus far, 2 5α-R inhibitors are approved for clinical use. Several trials evaluated the use of 5α-R inhibitors in prostate cancer prevention and treatment and will be reviewed in this article. PMID:22446342

  5. Role of 5α-reductase inhibitors in androgen-stimulated skin disorders.

    PubMed

    Azzouni, Faris; Zeitouni, Nathalie; Mohler, James

    2013-02-01

    5α-reductase (5α-R) isozymes are ubiquitously expressed in human tissues. This enzyme family is composed of 3 members that perform several important biologic functions. 5α-R isozymes play an important role in benign prostate hyperplasia, prostate cancer, and androgen-stimulated skin disorders, which include androgenic alopecia, acne, and hirsutism. Discovery of 5α-R type 2 deficiency in 1974 sparked interest in development of pharmaceutical agents to inhibit 5α-R isozymes, and 2 such inhibitors are currently available for clinical use: finasteride and dutasteride. 5α-R inhibitors are US Food and Drug Administration (FDA)-approved for the treatment of benign prostate hyperplasia. Only finasteride is FDA-approved for treatment of male androgenic alopecia. This article reviews the pathophysiology of androgen-stimulated skin disorders and the key clinical trials using 5α-R inhibitors in the treatment of androgen-stimulated skin disorders. PMID:23377402

  6. Statin intolerance.

    PubMed

    Ahmad, Zahid

    2014-05-15

    The term statin intolerance refers to an inability to use statins because of muscle symptoms or elevated creatine kinase, and the major diagnostic challenge is to unambiguously link these to statin use. Roughly 5% to 10% of statin users develop statin intolerance, and because statin use is expected to increase--especially after recent updated guidelines have expanded the statin benefit groups--adverse effects from statins will become a growing issue. Unfortunately, the pathophysiology--and even the terminology--of statin-related muscle injury lacks clarity. Several risk factors have been identified, including advanced age, family history of myopathy and statin dose; many cases manifest only after patients are administered an interacting medication (e.g., azole antifungals, cimetidine, clarithromycin, erythromycin and cyclosporine). The diagnosis of myopathy remains challenging, especially because some patients can have normal serum creatine kinase levels despite demonstrable weakness and muscle biopsy-proven statin-induced myopathy. A statin withdrawal and rechallenge helps patients distinguish whether their myalgia symptoms are because of statins, but, in at least 1 clinical trial, even 5% of placebo-treated patients developed myalgias during a controlled withdrawal and rechallenge. No consensus exists for management of patients with statin intolerance. Many patients can eventually tolerate a statin but often at suboptimal doses. A subset of patients do well with nondaily regimens such as every other day or once weekly dosing. Some patients cannot tolerate statins at all, requiring nonstatin lipid-lowering medications--the benefit of which remains unclear with regard to preventing atherosclerotic events. Ultimately, statin intolerance undermines the drug adherence that is critical for achieving the benefits of lifelong lipid-lowering therapy. In conclusion, statin myopathy is a common challenge in lipid management, and further work is needed to establish a

  7. A structural account of substrate and inhibitor specificity differences between two Naphthol reductases

    SciTech Connect

    Liao, D.-I.; Thompson, J.E.; Fahnestock, S.; Valent, B.; Jordan, D.B.

    2010-03-08

    Two short chain dehydrogenase/reductases mediate naphthol reduction reactions in fungal melanin biosynthesis. An X-ray structure of 1,3,6,8-tetrahydroxynaphthalene reductase (4HNR) complexed with NADPH and pyroquilon was determined for examining substrate and inhibitor specificities that differ from those of 1,3,8-trihydroxynaphthalene reductase (3HNR). The 1.5 {angstrom} resolution structure allows for comparisons with the 1.7 {angstrom} resolution structure of 3HNR complexed with the same ligands. The sequences of the two proteins are 46% identical, and they have the same fold. The 30-fold lower affinity of the 4HNR-NADPH complex for pyroquilon (a commercial fungicide that targets 3HNR) in comparison to that of the 3HNR-NADPH complex can be explained by unfavorable interactions between the anionic carboxyl group of the C-terminal Ile282 of 4HNR and CH and CH{sub 2} groups of the inhibitor that are countered by favorable inhibitor interactions with 3HNR. 1,3,8-Trihydroxynaphthalene (3HN) and 1,3,6,8-tetrahydroxynaphthalene (4HN) were modeled onto the cyclic structure of pyroquilon in the 4HNR-NADPH-pyroquilon complex to examine the 300-fold preference of the enzyme for 4HN over 3HN. The models suggest that the C-terminal carboxyl group of Ile282 has a favorable hydrogen bonding interaction with the C6 hydroxyl group of 4HN and an unfavorable interaction with the C6 CH group of 3HN. Models of 3HN and 4HN in the 3HNR active site suggest a favorable interaction of the sulfur atom of the C-terminal Met283 with the C6 CH group of 3HN and an unfavorable one with the C6 hydroxyl group of 4HN, accounting for the 4-fold difference in substrate specificities. Thus, the C-terminal residues of the two naphthol reductase are determinants of inhibitor and substrate specificities.

  8. Biological evaluation of some uracil derivatives as potent glutathione reductase inhibitors

    NASA Astrophysics Data System (ADS)

    Güney, Murat; Ekinci, Deniz; Ćavdar, Huseyin; Şentürk, Murat; Zilbeyaz, Kani

    2016-04-01

    Discovery of glutathione reductase (GR) inhibitors has become very popular recently due to antimalarial and anticancer activities. In this study, GR inhibitory capacities of some uracil derivatives (UDCs) (1-4) were reported. Some commercially available molecules (5-6) were also tested for comparison reasons. The novel UDCs were obtained in high yields using simple chemical procedures and exhibited much potent inhibitory activities against GR at low nanomolar concentrations with IC50 values ranging from 2.68 to 166.6 nM as compared with well-known agents.

  9. Aldose reductase inhibitors from the leaves of Myrciaria dubia (H. B. & K.) McVaugh.

    PubMed

    Ueda, H; Kuroiwa, E; Tachibana, Y; Kawanishi, K; Ayala, F; Moriyasu, M

    2004-11-01

    Ellagic acid (1) and its two derivatives, 4-O-methylellagic acid (2) and 4-(alpha-rhamnopyranosyl)ellagic acid (3) were isolated as inhibitors of aldose reductase (AR) from Myrciaria dubia (H. B. & K.) McVaugh. Compound 2 was the first isolated from the nature. Compound 3 showed the strongest inhibition against human recombinant AR (HRAR) and rat lens AR (RLAR). Inhibitory activity of compound 3 against HRAR (IC50 value = 4.1 x 10(-8) M) was 60 times more than that of quercetin (2.5 x 10(-6) M). The type of inhibition against HRAR was uncompetitive. PMID:15636180

  10. Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors.

    PubMed

    Shelke, Rupesh U; Degani, Mariam S; Raju, Archana; Ray, Mukti Kanta; Rajan, Mysore G R

    2016-08-01

    Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design. PMID:27320965

  11. Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review.

    PubMed

    Canestaro, William J; Austin, Melissa A; Thummel, Kenneth E

    2014-11-01

    Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.

  12. Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review

    PubMed Central

    Canestaro, William J.; Austin, Melissa A.; Thummel, Kenneth E.

    2015-01-01

    Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1. PMID:24810685

  13. The New Face of Hyperlipidemia Management: Proprotein Convertase Subtilisin/Kexin Inhibitors (PCSK-9) and Their Emergent Role As An Alternative To Statin Therapy.

    PubMed

    Smith, Lillian; Mosley, Juan; Yates, Jarah; Caswell, Luke

    2016-01-01

    This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha). This article will overview this medication class, describe their pathophysiology, and analyze the clinical data from the numerous studies and trials done on both of these medications for their efficacy and safety outcomes. Data compiled on this new class of medications support the research that PCSK-9 inhibitors are both a safe and effective means of lowering the LDL levels of resistant or otherwise currently unmanaged hypercholesterolemia patients. PMID:27096698

  14. Essential Role of TGF-β/Smad Pathway on Statin Dependent Vascular Smooth Muscle Cell Regulation

    PubMed Central

    Rodríguez-Vita, Juan; Sánchez-Galán, Eva; Santamaría, Beatriz; Sánchez-López, Elsa; Rodrigues-Díez, Raquel; Blanco-Colio, Luís Miguel; Egido, Jesús; Ortiz, Alberto; Ruiz-Ortega, Marta

    2008-01-01

    Background The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-β (TGF-β) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-β/Smad pathway in atherosclerosis and vascular cells. Methodology In cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-β. In addition, statins upregulated TGF-β receptor type II (TRII), and increased TGF-β synthesis and TGF-β/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-β induced apoptosis and increased TGF-β-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-β/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected. Conclusions Statins enhance TGF-β/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-β/Smad pathway is essential for statins-dependent actions in VSMCs. PMID:19088845

  15. How to take statins

    MedlinePlus

    ... Pravastatin (Pravachol®); Rosuvastatin (Crestor®); Fluvastatin (Lescol®); Hyperlipidemia - statins; Hardening of the arteries statins; Cholesterol - statins; Hypercholesterolemia - statins; ...

  16. Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

    PubMed Central

    Cheng, Gang; Muench, Stephen P.; Zhou, Ying; Afanador, Gustavo A.; Mui, Ernest J.; Fomovska, Alina; Lai, Bo Shiun; Prigge, Sean T.; Woods, Stuart; Roberts, Craig W.; Hickman, Mark R.; Lee, Patty J.; Leed, Susan E.; Auschwitz, Jennifer M.; Rice, David W.; McLeod, Rima

    2013-01-01

    Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan’s poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the Bring modifications have additional interactions with the strongly conserved Asn130. PMID:23453069

  17. Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2.

    PubMed

    St John, Sarah E; Jensen, Katherine C; Kang, Soosung; Chen, Yafang; Calamini, Barbara; Mesecar, Andrew D; Lipton, Mark A

    2013-10-01

    Resveratrol (3,5,4'-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.

  18. Combination therapy with statins and omega-3 fatty acids.

    PubMed

    Nambi, Vijay; Ballantyne, Christie M

    2006-08-21

    Combined dyslipidemia is the concurrent presence of multiple abnormalities in various lipid subfractions, including elevated concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides (TGs), as well as decreased concentrations of high-density lipoprotein (HDL) cholesterol. The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of TG levels, established non-HDL cholesterol levels as a secondary target of therapy in patients with TGs of >or=2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated LDL cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to offset the secondary increase in levels of LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for combined dyslipidemia. Patients with recent myocardial infarction may also benefit from this combination. When considering risks and benefits of adding a second agent to statins for treatment of combined dyslipidemia, omega-3 fatty acids provide additional lipid improvements without requiring additional laboratory tests and do not increase risk for adverse muscle or liver effects. PMID:16919515

  19. Statins in nephrotic syndrome: a new weapon against tissue injury.

    PubMed

    Buemi, Michele; Nostro, Lorena; Crascì, Eleonora; Barillà, Antonio; Cosentini, Vincenzo; Aloisi, Carmela; Sofi, Tito; Campo, Susanna; Frisina, Nicola

    2005-11-01

    The nephrotic syndrome is characterized by metabolic disorders leading to an increase in circulating lipoproteins levels. Hypertriglyceridemia and hypercholesterolemia in this case may depend on a reduction in triglyceride-rich lipoproteins catabolism and on an increase in hepatic synthesis of Apo B-containing lipoproteins. These alterations are the starting point of a self-maintaining mechanism, which can accelerate the progression of chronic renal failure. Indeed, hyperlipidemia can affect renal function, increase proteinuria and speed glomerulosclerosis, thus determining a higher risk of progression to dialysis. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in cholesterol synthesis from mevalonate and its inhibitors, or statins, can therefore interfere with the above-mentioned consequences of hyperlipidemia. Statins are already well known for their effectiveness on primary cardiovascular prevention, which cannot be explained only through their hypolipemic effect. As far as kidney diseases are concerned, statin therapy has been shown to prevent creatinine clearance decline and to slow renal function loss, particularly in case of proteinuria, and its favorable effect may depend only partially on the attenuation of hyperlipidemia. Statins may therefore confer tissue protection through lipid-independent mechanisms, which can be triggered by other mediators, such as angiotensin receptor blockers. Possible pathways for the protective action of statins, other than any hypocholesterolemic effect, are: cellular apoptosis/proliferation balance, inflammatory cytokines production, and signal transduction regulation. Statins also play a role in the regulation of the inflammatory and immune response, coagulation process, bone turnover, neovascularization, vascular tone, and arterial pressure. In this study, we would like to provide scientific evidences for the pleiotropic effects of statins, which could be the starting point for the

  20. [Autoimmune myopathy associated with statin use].

    PubMed

    Ljøstad, Unn; Mygland, Åse

    2016-09-01

    It is well known that statins can have a toxic effect on musculature, but less widely known that they can also trigger progressive autoimmune myopathy. Statin-associated autoimmune myopathy is characterised by proximal muscle weakness, antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in serum, and necrosis without lymphocytic infiltration on muscle biopsy. PMID:27637055

  1. Identification of Cryptosporidium parvum Dihydrofolate Reductase Inhibitors by Complementation in Saccharomyces cerevisiae

    PubMed Central

    Brophy, Victoria Hertle; Vasquez, John; Nelson, Richard G.; Forney, John R.; Rosowsky, Andre; Sibley, Carol Hopkins

    2000-01-01

    There is a pressing need for drugs effective against the opportunistic protozoan pathogen Cryptosporidium parvum. Folate metabolic enzymes and enzymes of the thymidylate cycle, particularly dihydrofolate reductase (DHFR), have been widely exploited as chemotherapeutic targets. Although many DHFR inhibitors have been synthesized, only a few have been tested against C. parvum. To expedite and facilitate the discovery of effective anti-Cryptosporidium antifolates, we have developed a rapid and facile method to screen potential inhibitors of C. parvum DHFR using the model eukaryote, Saccharomyces cerevisiae. We expressed the DHFR genes of C. parvum, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, and humans in the same DHFR-deficient yeast strain and observed that each heterologous enzyme complemented the yeast DHFR deficiency. In this work we describe our use of the complementation system to screen known DHFR inhibitors and our discovery of several compounds that inhibited the growth of yeast reliant on the C. parvum enzyme. These same compounds were also potent or selective inhibitors of the purified recombinant C. parvum DHFR enzyme. Six novel lipophilic DHFR inhibitors potently inhibited the growth of yeast expressing C. parvum DHFR. However, the inhibition was nonselective, as these compounds also strongly inhibited the growth of yeast dependent on the human enzyme. Conversely, the antibacterial DHFR inhibitor trimethoprim and two close structural analogs were highly selective, but weak, inhibitors of yeast complemented by the C. parvum enzyme. Future chemical refinement of the potent and selective lead compounds identified in this study may allow the design of an efficacious antifolate drug for the treatment of cryptosporidiosis. PMID:10722506

  2. Design, synthesis and evaluation of 2,4-diaminoquinazolines as inhibitors of trypanosomal and leishmanial dihydrofolate reductase.

    PubMed

    Khabnadideh, Soghra; Pez, Didier; Musso, Alexander; Brun, Reto; Pérez, Luis M Ruiz; González-Pacanowska, Dolores; Gilbert, Ian H

    2005-04-01

    This paper describes the design, synthesis and evaluation of a series of 2,4-diaminoquinazolines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were designed by a generating virtual library of compounds and docking them into the enzyme active site. Following their synthesis, they were found to be potent and selective inhibitors of leishmanial dihydrofolate reductase. The compounds were also found to have potent activity against Trypanosoma brucei rhodesiense, a causative organism of African trypanosomiasis and also against Trypanosoma cruzi, the causative organism of Chagas disease. There was significantly lower activity against Leishmania donovani, one of the causative organisms of leishmaniasis. PMID:15755663

  3. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies.

    PubMed

    Mohassel, Payam; Mammen, Andrew L

    2013-10-01

    Statins are among the most commonly prescribed medications that significantly reduce cardiovascular risk in selected individuals. However, these drugs can also be associated with muscle symptoms ranging from mild myalgias to severe rhabdomyolysis. Although statin myotoxicity is usually self-limited, in some instances statin-exposed subjects can develop an autoimmune myopathy typically characterized by progressive weakness, muscle enzyme elevations, a necrotizing myopathy on muscle biopsy, and autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacologic target of statins. These antibodies are also found in some autoimmune myopathy patients without statin exposure. Importantly, anti-HMGCR antibodies are not found in the vast majority of statin-exposed subjects without autoimmune myopathy, including those with self-limited statin intolerance. Thus, testing for these antibodies may help differentiate those with self-limited statin myopathy who recover after statin discontinuation from those with a progressive statin-associated autoimmune myopathy who typically require immunosuppressive therapy.

  4. Prospective Screening of Novel Antibacterial Inhibitors of Dihydrofolate Reductase for Mutational Resistance

    PubMed Central

    Frey, Kathleen M.; Viswanathan, Kishore; Wright, Dennis L.

    2012-01-01

    Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphlococcus aureus (MRSA). For the past several years we have used structure-based design to create propargyl-linked antifolates that are highly potent antibacterial agents. In order to focus priority on the development of lead compounds with a low propensity to induce resistance, we prospectively evaluated resistance profiles for two of these inhibitors in an MRSA strain. By selection with the lead inhibitors, we generated resistant strains that contain single point mutations F98Y and H30N associated with TMP resistance and one novel mutation, F98I, in DHFR. Encouragingly, the pyridyl propargyl-linked inhibitor selects mutants at low frequency (6.85 × 10−10 to 1.65 × 10−9) and maintains a low MIC (2.5 μg/ml) and a low mutant prevention concentration (1.25 μg/ml), strongly supporting its position as a lead compound. Results from this prospective screening method inform the continued design of antifolates effective against mutations at the Phe 98 position. Furthermore, the method can be used broadly to incorporate ideas for overcoming resistance early in the development process. PMID:22491688

  5. Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase.

    PubMed

    Rawson, Jonathan M O; Roth, Megan E; Xie, Jiashu; Daly, Michele B; Clouser, Christine L; Landman, Sean R; Reilly, Cavan S; Bonnac, Laurent; Kim, Baek; Patterson, Steven E; Mansky, Louis M

    2016-06-01

    Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2'-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity. PMID:27117260

  6. Intensive statin therapy for Indians: Part-I. Benefits.

    PubMed

    Enas, Enas A; Pazhoor, Hancy Chennikkara; Kuruvila, Arun; Vijayaraghavan, Krishnaswami

    2011-01-01

    The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an

  7. Effects of HMG-CoA reductase inhibitors on learning and memory in the guinea pig.

    PubMed

    Maggo, Simran; Ashton, John C

    2014-01-15

    Statins reduce the risk of death from cardiovascular disease in millions of people worldwide. Recent pharmacovigilance data has suggested that people taking statins have an increased risk of psychiatric adverse events such as amnesia and anxiety. This study aimed to investigate the possibility of statin-induced amnesia through animal models of memory and learning. We conducted extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices to examine the effects of acute cholesterol lowering with lipid lowering drugs. We also assessed the effect of six weeks of simvastatin (2mg/kg/d) and atorvastatin (1mg/kg/d) treatment using the Morris water maze. Long Term Potentiation (LTP) was significantly diminished in the presence of 3µM atorvastatin or simvastatin and by the cholesterol sequestering agent methyl-β-cyclodextrin (MBCD). The effects were reversed in the MBCD but not the statin treated slices by the addition of cholesterol. In the water maze, statin treatment did not cause any deficits in the first five days of reference memory testing, but statin treated guinea pigs preformed significantly worse than control animals in a working memory test. The deficits observed in our experiments in water maze performance and hippocampal LTP are suggestive of statin induced changes in hippocampal plasticity. The effects on LTP are independent of cholesterol regulation, and occur at concentrations that may be relevant to clinical use. Our results may help to explain some of the behavioural changes reported in some people after beginning statin treatment. PMID:24296319

  8. Targeting Inflammation and Oxidative Stress in Atrial Fibrillation: Role of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibition with Statins

    PubMed Central

    Pinho-Gomes, Ana Catarina; Reilly, Svetlana; Brandes, Ralf P.

    2014-01-01

    Abstract Significance: Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF. Recent Advances: Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF. Critical Issues: Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty. Future Directions: A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention. Antioxid. Redox Signal. 20, 1268–1285. PMID:23924190

  9. GP-1447, an inhibitor of aldose reductase, prevents the progression of diabetic cataract in rats.

    PubMed

    Kawakubo, Ken; Mori, Asami; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2012-01-01

    We examined the effects of GP-1447 (3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenyl acetic acid) on existing cataracts and sorbitol content in the lens in rats with streptozotocin-induced diabetes. GP-1447 is an inhibitor of aldose reductase, which is the first enzyme in the polyol pathway. Cataracts in the central region of the lens were observed in 7 of 14 eyes (50%) by the fifth week after induction of diabetes, and development of mature cataracts was observed in most lenses by the ninth week. In diabetic rats that received GP-1447 treatment beginning in the fifth week after induction of diabetes, progression of cataracts was observed for 1 week after initiation of treatment. Thereafter, the severity of cataracts did not change substantially. Sorbitol levels in the lens peaked during the first week of diabetes, and this increase was maintained during the 9-week observation period. Elevated sorbitol levels in the lenses of diabetic rats gradually declined after GP-1447 treatment was started on the fifth week after induction of diabetes. Cataracts and sorbitol elevation were not observed in the lenses of controls or diabetic rats treated with GP-1447 immediately after induction of diabetes. These results suggest that the polyol pathway plays an important role in both the appearance and progression of cataracts in diabetic rats. Inhibition of aldose reductase could significantly prevent progression of existing cataracts. PMID:22687477

  10. The REDUCE trial: chemoprevention in prostate cancer using a dual 5alpha-reductase inhibitor, dutasteride.

    PubMed

    Musquera, Mireia; Fleshner, Neil E; Finelli, Antonio; Zlotta, Alexandre R

    2008-07-01

    Dutasteride, a dual 5alpha-reductase inhibitor, is used in the treatment of benign prostatic hyperplasia (BPH). It reduces serum prostate-specific antigen levels by approximately 50% at 6 months and total prostate volume by 25% after 2 years. Randomized placebo-controlled trials in BPH patients have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate. Side effects occurring with dutasteride are decreased libido, erectile dysfunction, ejaculation disorders and gynecomastia. Preliminary data from placebo-controlled BPH trials have shown a decrease in the detection of prostate cancer in patients treated with dutasteride, although these studies were not designed to look at this issue. Dutasteride differs from finasteride in that it inhibits both isoenzymes of 5alpha-reductase, type I and type II. The landmark Prostate Cancer Prevention Trial at the end of the 7-year study demonstrated a 24.8% reduction in the incidence of prostate cancer in the finasteride group compared with placebo. However, a 25.5% increase in the prevalence of high-grade Gleason tumors has been observed, the clinical significance of which has been debated. Preliminary data suggest a decrease in prostate cancer incidence in dutasteride-treated patients and demonstrate type I alphareductase enzyme expression in prostate cancer. As a result, dutasteride is being investigated for prostate cancer prevention in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which is discussed here. PMID:18588452

  11. Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors.

    PubMed

    Wang, Qi-Qin; Cheng, Ning; Zheng, Xiao-Wei; Peng, Sheng-Ming; Zou, Xiao-Qing

    2013-07-15

    Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.

  12. Pleiotropic effects of statins on the treatment of chronic periodontitis – a systematic review

    PubMed Central

    Estanislau, Ilanna Mara Gomes; Terceiro, Icrólio Ribeiro Colares; Lisboa, Mario Roberto Pontes; Teles, Patrícia de Barros; Carvalho, Rosimary de Sousa; Martins, Ricardo Souza; Moreira, Maria Mônica Studart Mendes

    2015-01-01

    Aim Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss. Methods In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected. Results Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts. Conclusion Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis. PMID:25444240

  13. Design, Synthesis and Evaluation of Fe-S Targeted Adenosine 5′-Phosphosulfate Reductase Inhibitors

    PubMed Central

    Paritala, Hanumantharao; Suzuki, Yuta; Carroll, Kate S.

    2015-01-01

    Adenosine 5′-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5′-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N6-substituted adenosine analogues and their 5′-phosphates as well as adenosine 5′-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5′-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors. PMID:25710356

  14. 2,4-Diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase.

    PubMed

    Pez, Didier; Leal, Isabel; Zuccotto, Fabio; Boussard, Cyrille; Brun, Reto; Croft, Simon L; Yardley, Vanessa; Ruiz Perez, Luis M; Gonzalez Pacanowska, Dolores; Gilbert, Ian H

    2003-11-01

    This paper describes the synthesis of 4'-substituted and 3',4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. PMID:14556785

  15. Statins and aspirin: do they really work in women?

    PubMed

    Desai, Hemal; Hollingsworth, Paula W; Chugh, Atul R

    2015-06-01

    Cardiovascular disease continues to be the most common cause of mortality in women in the USA. As a result, greater emphasis has been placed on preventive measures. Studies examining the role of aspirin and HMG-CoA reductase inhibitors (statins) have shown important clinical differences in men versus women in the preventive realm. This has led to inconsistent recommendations by guideline committees and clinicians alike. This review presents a summary of the past and current guidelines. In addition, important clinical trials influencing current era practice are also discussed. Both strengths and limitations of these studies are described in detail, along with recommendations regarding future directions and the scope of aspirin and statin use for primary and secondary prevention of cardiovascular disease. PMID:25812803

  16. Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4.

    PubMed

    Banerjee, Deb Ranjan; Dutta, Debajyoti; Saha, Baisakhee; Bhattacharyya, Sudipta; Senapati, Kalyan; Das, Amit K; Basak, Amit

    2014-01-01

    We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 μM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 μM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure-activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes. PMID:24129589

  17. Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management.

    PubMed

    Tuccori, Marco; Montagnani, Sabrina; Mantarro, Stefania; Capogrosso-Sansone, Alice; Ruggiero, Elisa; Saporiti, Alessandra; Antonioli, Luca; Fornai, Matteo; Blandizzi, Corrado

    2014-03-01

    Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, are cholesterol-lowering drugs used in clinical practice to prevent coronary heart disease. These drugs are generally well tolerated and have been rarely associated with severe adverse effects (e.g. rhabdomyolysis). Over the years, case series and data from national registries of spontaneous adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; use of ω-3 fatty acids or coenzyme Q10 supplements; and treatment with psychotropic drugs. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients. Additional data are required, and further clinical studies are needed. PMID:24435290

  18. [In vitro study over statins effects on cellular growth curves and its reversibility with mevalonate].

    PubMed

    Millan Núñez-Cortés, Jesús; Alvarez Rodriguez, Ysmael; Alvarez Novés, Granada; Recarte Garcia-Andrade, Carlos; Alvarez-Sala Walther, Luis

    2014-01-01

    HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have heavy anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL-c reduction or via a direct effect on cellular functions. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. So, although statins typically have similar effects on LDL-c levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects. In this paper we analize the in vitro effects of different statins over different cell lines from cells implicated in atherosclerotic process: endothelial cells, fibroblasts, and vascular muscular cells. In relation with our results we can proof that the effects of different dosis of different statins provides singular effects over growth curves of different cellular lines, a despite of a class-dependent effects. So, pleiotropic effects and its reversibility with mevalonate are different according with the molecule and the dosis. PMID:24126321

  19. Statin induced necrotizing autoimmune myopathy.

    PubMed

    Babu, Suma; Li, Yuebing

    2015-04-15

    Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management.

  20. Herbicidal effects of statin pharmaceuticals in Lemna gibba.

    PubMed

    Brain, Richard A; Reitsma, Tamara S; Lissemore, Linda I; Bestari, Ketut; Sibley, Paul K; Solomon, Keith R

    2006-08-15

    Statin pharmaceuticals, heavily prescribed in the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR). In plants, these compounds also inhibit HMGR, which regulates cytosolic isoprenoid biosynthesis in the mevalonic acid (MVA) pathway. Phytotoxicity was evaluated in the higher aquatic plant Lemna gibba exposed to atorvastatin and lovastatin for 7-days by measuring the concentrations of sterols and ubiquinone; products downstream in the MVA pathway. The efficiency of the parallel and unaffected methylerythritol phosphate pathway (MEP) was also evaluated by measuring the end product, plastoquinone. Statin treatment caused an accumulation of plastoquinone, and unexpectedly, ubiquinone, an artifact likely due to metabolite sharing from the plastidial MEP pathway. Statins were, however, highly phytotoxic to L. gibba and HPLC-UV analysis of plant extracts showed significantly decreased concentrations of both stigmasterol and beta-sitosterol, which are critical components of plant membranes and regulate morphogenesis and development. EC10 values for atorvastatin and lovastatin were as small as 26.1 and 32.8 microg/L, respectively. However, hazard quotients indicated that statins present little risk to the model higher aquatic plant Lemna gibba at environmentally relevant concentrations, even though pathway-specific endpoints were 2-3 times more sensitive than traditional gross morphological endpoints typically used in risk assessment. PMID:16955916

  1. Statins: Cardiovascular Risk Reduction in Percutaneous Coronary Intervention—Basic and Clinical Evidence of Hyperacute Use of Statins

    PubMed Central

    Morales-Villegas, Enrique C.; Di Sciascio, Germano; Briguori, Carlo

    2011-01-01

    Reduction of LDL-cholesterol concentration in serum, blocking the isoprenylation of GTPases and the activation of myocyte-protective enzyme systems are three mechanisms that currently explain the lipid and non-lipid effects of statins. However, the decrease of LDL-cholesterol, the reduction of inflammation biomarkers and even the atheroregresion, as surrogate effects to the mechanisms of action of statins would be irrelevant if not accompanied by a significant decrease in the incidence of cardiovascular events. Statins like no other pharmacological group have proven to reduce the incidence of cardiovascular events and prolong life in any clinical scenario. This article review the basic and clinical evidence that support a new indication for HMG-CoA reductase inhibitors “pharmacological myocardial preconditioning before anticipated ischemia” or hyperacute use of statins in subjects with any coronary syndrome eligible for elective, semi-urgent or primary percutaneous coronary intervention: ARMYDA-Original, NAPLES I-II, ARMYDA-ACS, ARMYDA-RECAPTURE, Non-STEMI-Korean, Korean-STEMI trials. PMID:21461336

  2. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

    PubMed

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors. PMID:26384019

  3. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

    PubMed Central

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors. PMID:26384019

  4. Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.

    PubMed

    Qin, Xiangyu; Hao, Xin; Han, Hui; Zhu, Shaojuan; Yang, Yanchun; Wu, Bobin; Hussain, Saghir; Parveen, Shagufta; Jing, Chaojun; Ma, Bing; Zhu, Changjin

    2015-02-12

    Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032-0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants. PMID:25602762

  5. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

    PubMed

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

  6. Effect on short- and long-term major adverse cardiac events of statin treatment in patients with acute myocardial infarction and renal dysfunction.

    PubMed

    Lim, Sang Yup; Bae, Eun Hui; Choi, Joon Seok; Kim, Chang Seong; Park, Jeong Woo; Ma, Seong Kwon; Jeong, Myung Ho; Kim, Soo Wan

    2012-05-15

    The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduce major adverse cardiac events (MACE) and mortality in patients with acute coronary syndrome. We investigated the effectiveness of statin therapy in reducing MACE in patients with acute myocardial infarction (AMI) and renal dysfunction (RD). In the present retrospective study of 12,853 patients with AMI, the patients were categorized into 4 groups: group I, statin therapy and no RD (estimated glomerular filtration rate ≥60 ml/min/1.73 m(2)); group II, neither statin therapy nor RD; group III, statin therapy and RD; group IV, no statin therapy but RD. The primary end points were death and complications during the hospital course. The secondary end points were MACE during 1 year of follow-up after AMI. Significant differences in the composite MACE during 12 months of follow-up were observed among the 4 groups (group I, 11.7%; group II, 19.0%; group III, 26.7%; and group IV, 45.5%; p <0.001). In a Cox proportional hazards model, mortality at 12 months increased stepwise from group II to IV compared to group I. Moreover, MACE-free survival in the severe RD group (estimated glomerular filtration rate <30 mL/min/1.73 m(2)) was also greater in the statin-treated group. In conclusion, statin therapy reduced MACE at 1 year of follow-up in patients with AMI regardless of RD.

  7. Aldo-keto reductases in retinoid metabolism: search for substrate specificity and inhibitor selectivity.

    PubMed

    Porté, Sergio; Xavier Ruiz, F; Giménez, Joan; Molist, Iago; Alvarez, Susana; Domínguez, Marta; Alvarez, Rosana; de Lera, Angel R; Parés, Xavier; Farrés, Jaume

    2013-02-25

    Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldo-keto reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARβ/γ agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket. PMID

  8. Advance in dietary polyphenols as aldose reductases inhibitors: structure-activity relationship aspect.

    PubMed

    Xiao, Jianbo; Ni, Xiaoling; Kai, Guoyin; Chen, Xiaoqing

    2015-01-01

    The dietary polyphenols as aldose reductases inhibitors (ARIs) have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure-activity relationship of dietary polyphenols inhibiting aldose reductases (AR). The molecular structures influence the inhibition of the following: (1) The methylation and methoxylation of the hydroxyl group at C3, C3', and C4' of flavonoids decreased or little affected the inhibitory potency. However, the methylation and methoxylation of the hydroxyl group at C5, C6, and C8 significantly enhanced the inhibition. Moreover, the methylation and methoxylation of C7-OH influence the inhibitory activity depending on the substitutes on rings A and B of flavonoids. (2) The glycosylation on 3-OH of flavonoids significantly increased or little affected the inhibition. However, the glycosylation on 7-OH and 4'-OH of flavonoids significantly decreased the inhibition. (3) The hydroxylation on A-ring of flavones and isoflavones, especially at positions 5 and 7, significantly improved the inhibition and the hydroxylation on C3' and C4' of B-ring of flavonoids remarkably enhanced the inhibition; however, the hydroxylation on the ring C of flavones significantly weakened the inhibition. (4) The hydrogenation of the C2=C3 double bond of flavones reduced the inhibition. (5) The hydrogenation of α=β double bond of stilbenes hardly affected the inhibition and the hydroxylation on C3' of stilbenes decreased the inhibition. Moreover, the methylation of the hydroxyl group of stilbenes obviously reduced the activity. (6) The hydroxylation on C4 of chalcone significantly increased the inhibition and the methylation on C4 of chalcone remarkably weakened the inhibition.

  9. Does African American Race Impact Statin Efficacy in Renal Transplant Outcomes?

    PubMed Central

    Ozieh, Mukoso N.; Taber, David J.; Egede, Leonard E.

    2015-01-01

    Abstract There is a lack of studies assessing if race impacts the efficacy of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor (“statin”) therapy on renal transplantation (RTx) outcomes. We examined the association between statin therapy and RTx outcomes, while concurrently quantifying the effect modification African American (AA) race has on statin efficacy. This was a retrospective longitudinal cohort study of solitary adult RTx (n = 1176) between June 2005 and May 2013. The Cox proportional hazard model was used to examine the impact of statin therapy on graft loss, death, and acute rejection and determine if significant interactions exist between statin therapy and race. Models were adjusted for demographics, socioeconomic status, cardiovascular history, medication use, and transplant characteristics. AAs (n = 624) and non-African Americans (n = 552) were equally likely to receive statin therapy (P = 0.922). Mean LDL and TGs in AA were 94 mg/dL and 133 mg/dL compared to 90 mg/dL and 163 mg/dL in non-AA, respectively. After adjusting for confounders, high statin users had 52% lower risk of developing graft loss (HR 0.48, 95% CI 0.29–0.80) and a nonstatistically significant reduction in death (HR 0.50, 95% CI 0.23–1.06) compared to low statin users. Acute rejection was not significantly influenced by statin use (HR 0.77 95% CI 0.46–1.27). There was a significant interaction between race and statin therapy for death (P = 0.007), but not for graft loss (P = 0.121) or rejection (P = 0.605). After stratifying by race, high statin use reduced the risk of death in AAs (HR 0.43, 95% CI 0.20–0.94), but not in non-AAs (HR 1.09, 95% CI 0.49–2.44). High statin use reduces the risk of graft loss in RTx, with a mortality benefit in AAs compared to non-AA, despite similar LDL levels. These results suggest a compelling reason to optimize statin therapy in renal transplant recipients (RTR), especially in AAs. PMID

  10. Side Effects Related to 5 α-Reductase Inhibitor Treatment of Hair Loss in Women: A Review.

    PubMed

    Seale, Lauren R; Eglini, Ariana N; McMichael, Amy J

    2016-04-01

    5 α-reductase inhibitors such as finasteride and dutasteride have been studied for the treatment of hair loss in men, with finasteride being the only Food and Drug Administration-approved treatment. Increasingly, in recent years, off-label use of these drugs has been employed in the treatment of female pattern hair loss (FPHL) and frontal fibrosing alopecia (FFA) in women. Side effects with 5 α-reductase inhibitors can include changes in sexual function, and recent publications have characterized an increasing prevalence of these in men. A review of 20 peer-reviewed articles found that very few side effects, or adverse events, related to sexual function have been reported in studies in which dutasteride or finasteride has been used to treat hair loss in women. Future publications should investigate not only the efficacy of these drugs in treating FPHL and FFA, but the side effect profile in patients as well. PMID:27050696

  11. Discovery of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor suitable for antistaphylococcal agent.

    PubMed

    Kim, Yun Gyeong; Seo, Jae Hong; Kwak, Jin Hwan; Shin, Kye Jung

    2015-10-15

    We report the discovery, synthesis, and biological activities of phenoxy-4-pyrone and phenoxy-4-pyridone derivatives as novel inhibitors of enoyl-acyl carrier protein reductase (FabI). Pyridone derivatives showed better activities than pyrone derivatives against FabI and Staphylococcus aureus strains, including methicillin-resistant Staphylococcus aureus (MRSA). Among the pyridone derivatives, compound 16l especially exhibited promising activities against the MRSA strain and good pharmacokinetic profiles. PMID:26343826

  12. Probenecid Treatment Enhances Retinal and Brain Delivery of N-4-Benzoylaminophenylsulfonylglycine, An Anionic Aldose Reductase Inhibitor

    PubMed Central

    Sunkara, Gangadhar; Ayalasomayajula, Surya P.; DeRuiter, Jack; Kompella, Uday B.

    2009-01-01

    Anion efflux transporters are expected to minimize target tissue delivery of N-[4-(benzoylaminophenyl)sulfonyl]glycine (BAPSG), a novel carboxylic acid aldose reductase inhibitor, which exists as a monocarboxylate anion at physiological conditions. Therefore, the objective of this study was to determine whether BAPSG delivery to various eye tissues including the retina and the brain can be enhanced by probenecid, a competitive inhibitor of anion transporters. To determine the influence of probenecid on eye and brain distribution of BAPSG, probenecid was administered intraperitoneally (120 mg/kg body weight; i.p.) 20 minutes prior to BAPSG (50 mg/kg; i.p.) administration. Drug disposition in various eye tissues including the retina and the brain was determined at 15 min, 1, 2 and 4 hr after BAPSG dose in male Sprauge-Dawley rats. To determine whether probenecid alters plasma clearance of BAPSG, influence of probenecid (120 mg/kg; i.p.) on the plasma pharmacokinetics of intravenously administered BAPSG (15 mg/kg) was studied as well. Finally, the effect of probenecid co-administration on the ocular tissue distribution of BAPSG was assessed in rabbits following topical (eye drop) administration. Following pretreatment with probenecid in the rat study, retinal delivery at 1 hr was increased by about 11 fold (2580 vs 244 ng/gm; p<0.05). Further, following probenecid pretreatment, significant BAPSG levels were detectable in the brain (45 ± 20 ng/gm) at 1 hr, unlike controls where the drug was not detectable. Plasma concentrations, plasma elimination half-life, and total body clearance of intravenously administered BAPSG were not altered by i.p. probenecid pretreatment. In the topical dosing study, a significant decline in BAPSG delivery was observed in the iris-ciliary body but no significant changes were observed in other tissues of the anterior segment of the eye including tears. Thus, inhibition of anion transporters is a useful approach to elevate retinal and brain

  13. Battling prostate cancer with 5-alpha-reductase inhibitors: a pyrrhic victory?

    PubMed

    Hoffman, Richard M; Roberts, Richard G; Barry, Michael J

    2011-07-01

    Given the relatively small impact of prostate cancer screening on cancer mortality, experts are now suggesting that chemoprevention with 5-alpha-reductase inhibitors (5-ARI) may be a more effective strategy for cancer control. Two large placebo-controlled randomized trials found that men receiving 5-ARI were about 25% less likely than controls to be detected with cancer. However, most cancers were detected on routine biopsies required by study protocols. The benefit from receiving 5-ARI was minimal among men who underwent biopsy for clinical indications. Additionally, men receiving 5-ARI were more likely than controls to be diagnosed with high-grade cancers, though post-hoc analyses adjusting for biases accounted for the excess risk in one of the studies. A recent guideline recommended that men considering prostate cancer screening also consider chemoprevention. The rationale is that reducing cancer incidence, given the known risks for overdiagnosis and subsequent overtreatment, is sufficient justification for chemoprevention. However, a large randomized controlled trial found that screening was associated with a 70% increase in prostate cancer diagnosis--which chemoprevention would then reduce by 25%. This does not seem an acceptable trade-off especially because the potential increased risk for high-grade cancers could lead to higher cancer mortality. PMID:21222171

  14. Current status of 5α-reductase inhibitors in prostate disease management.

    PubMed

    Kang, Dong Il; Chung, Jae Il

    2013-04-01

    The key enzyme in the androgen synthesis and androgen receptor pathways is 5α-reductase (5-AR), which occurs as three isoenzymes. Types I and II 5-ARs the most important clinically, and two different 5-AR inhibitors (5-ARIs), finasteride and dutasteride, have been developed. Several urology associations have recommended and upgraded the use of 5-ARIs for an enlarged prostate with lower urinary tract symptoms. In the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events Trial, 5-ARIs reduced the incidence of low-grade prostate cancer. However, despite the documented reductions in the overall incidence of prostate cancer, 5-ARIs are at the center of a dispute. The American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA) presented clinical guidelines for the use of 5-ARIs for chemoprevention of prostate cancer in 2008. However, ASCO/AUA has eliminated these from the main "Clinical Guidelines" in 2012, because the U.S. Food and Drug Administration denied a supplemental New Drug Application for the use of dutasteride for prostate cancer chemoprevention. The 5-ARIs can also be used to manage hemospermia and prostatic hematuria, and to prevent intraoperative bleeding, although there is insufficient evidence for a standard strategy. This review summarizes the current use of 5-ARIs for prostate disease, including benign prostate hyperplasia, prostate cancer, prostate-related bleeding, and hemospermia. PMID:23614056

  15. 5-α reductase inhibitors and prostate cancer prevention: where do we turn now?

    PubMed

    Hamilton, Robert J; Freedland, Stephen J

    2011-01-01

    With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research. PMID:21920036

  16. Arsenic and cadmium are inhibitors of cyanobacterial dinitrogenase reductase (nifH1) gene.

    PubMed

    Singh, Shilpi; Shrivastava, A K; Singh, V K

    2014-09-01

    The enzyme nitrogenase complex is a key component conferring nitrogen fixation in all known diazotrophs. This study for the first time examines the impact of As, Na, Cd, Cu and butachlor on component II (dinitrogenase reductase, nifH1) of nitrogenase from diazotrophic cyanobacterium Anabaena sp. PCC7120 using in silico and wet lab approaches. The nifH1 of Anabaena is a glycine-rich stable protein having DNA-binding properties and shows close similarity with free living compared with symbiotic diazotrophs. Phylogenetic tree revealed an adverse effect of the selected stresses on close homologs across the diazotroph community. The protein interaction network demonstrated the presence of nirA, glnA, glnB, alr4255 and alr2485 proteins besides nif proteins, suggesting their involvement in nitrogen fixation along with nifH1. Homology modelling and docking under As, Na, Cd, Cu and butachlor revealed an interaction between stressors and nifH1 protein which was further validated by a transcript of the gene through quantitative real-time PCR (qRT-PCR). Presence of binding sites for As, Na, Cd and Cu on oxyR promoter attested their adverse affects on nifH1. Maximum down-regulation of nifH1 in Cd and As followed by salt, copper and butachlor revealed that arsenic and cadmium were most potential inhibitors of nitrogenase of diazotrophic community, which might negatively affect crop yield.

  17. The nitrate reductase inhibitor, tungsten, disrupts actin microfilaments in Zea mays L.

    PubMed

    Adamakis, Ioannis-Dimosthenis S; Panteris, Emmanuel; Eleftheriou, Eleftherios P

    2014-05-01

    Tungsten is a widely used inhibitor of nitrate reductase, applied to diminish the nitric oxide levels in plants. It was recently shown that tungsten also has heavy metal attributes. Since information about the toxic effects of tungsten on actin is limited, and considering that actin microfilaments are involved in the entry of tungsten inside plant cells, the effects of tungsten on them were studied in Zea mays seedlings. Treatments with sodium tungstate for 3, 6, 12 or 24 h were performed on intact seedlings and seedlings with truncated roots. Afterwards, actin microfilaments in meristematic root and leaf tissues were stained with fluorescent phalloidin, and the specimens were examined by confocal laser scanning microscopy. While the actin microfilament network was well organized in untreated seedlings, in tungstate-treated ones it was disrupted in a time-dependent manner. In protodermal root cells, the effects of tungsten were stronger as cortical microfilaments were almost completely depolymerized and the intracellular ones appeared highly bundled. Fluorescence intensity measurements confirmed the above results. In the meristematic leaf tissue of intact seedlings, no depolymerization of actin microfilaments was noticed. However, when root tips were severed prior to tungstate application, both cortical and endoplasmic actin networks of leaf cells were disrupted and bundled after 24 h of treatment. The differential response of root and leaf tissues to tungsten toxicity may be due to differential penetration and absorption, while the effects on actin microfilaments could not be attributed to the nitric oxide depletion by tungsten.

  18. Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

    DOE PAGES

    Wang, Hui; Lu, Yang; Liu, Li; Kim, Sung Won; Hooker, Jacob M.; Fowler, Joanna S.; Tonge, Peter J.

    2014-09-06

    Here we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a Ki value of 0.01 nM and a residence time of 750 min on the enzyme target in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU’s in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthymore » and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ~1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.« less

  19. Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

    SciTech Connect

    Wang, Hui; Lu, Yang; Liu, Li; Kim, Sung Won; Hooker, Jacob M.; Fowler, Joanna S.; Tonge, Peter J.

    2014-09-06

    Here we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a Ki value of 0.01 nM and a residence time of 750 min on the enzyme target in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU’s in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ~1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.

  20. Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Inhibitor Sml1 in Response to Iron Deficiency

    PubMed Central

    Sanvisens, Nerea; Romero, Antonia M.; An, Xiuxiang; Zhang, Caiguo; de Llanos, Rosa; Martínez-Pastor, María Teresa; Bañó, M. Carmen

    2014-01-01

    Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox-active cofactor in many biological processes, including DNA replication and repair. Eukaryotic ribonucleotide reductases (RNRs) are Fe-dependent enzymes that catalyze deoxyribonucleoside diphosphate (dNDP) synthesis. We show here that the levels of the Sml1 protein, a yeast RNR large-subunit inhibitor, specifically decrease in response to both nutritional and genetic Fe deficiencies in a Dun1-dependent but Mec1/Rad53- and Aft1-independent manner. The decline of Sml1 protein levels upon Fe starvation depends on Dun1 forkhead-associated and kinase domains, the 26S proteasome, and the vacuolar proteolytic pathway. Depletion of core components of the mitochondrial iron-sulfur cluster assembly leads to a Dun1-dependent diminution of Sml1 protein levels. The physiological relevance of Sml1 downregulation by Dun1 under low-Fe conditions is highlighted by the synthetic growth defect observed between dun1Δ and fet3Δ fet4Δ mutants, which is rescued by SML1 deletion. Consistent with an increase in RNR function, Rnr1 protein levels are upregulated upon Fe deficiency. Finally, dun1Δ mutants display defects in deoxyribonucleoside triphosphate (dNTP) biosynthesis under low-Fe conditions. Taken together, these results reveal that the Dun1 checkpoint kinase promotes RNR function in response to Fe starvation by stimulating Sml1 protein degradation. PMID:24958100

  1. Improved Biochemical Outcomes With Statin Use in Patients With High-Risk Localized Prostate Cancer Treated With Radiotherapy

    SciTech Connect

    Kollmeier, Marisa A.; Katz, Matthew S.; Mak, Kimberley; Yamada, Yoshiya; Feder, David J.; Zhang Zhigang; Jia Xiaoyu; Shi Weiji; Zelefsky, Michael J.

    2011-03-01

    Purpose: To investigate the association between 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and biochemical and survival outcomes after high-dose radiotherapy (RT) for prostate cancer. Methods and Materials: A total of 1711 men with clinical stage T1-T3 prostate cancer were treated with conformal RT to a median dose of 81 Gy during 1995-2007. Preradiotherapy medication data were available for 1681 patients. Three hundred eighty-two patients (23%) were taking a statin medication at diagnosis and throughout RT. Nine hundred forty-seven patients received a short-course of neoadjuvant and concurrent androgen-deprivation therapy (ADT) with RT. The median follow-up was 5.9 years. Results: The 5- and 8-year PSA relapse-free survival (PRFS) rates for statin patients were 89% and 80%, compared with 83% and 74% for those not taking statins (p = 0.002). In a multivariate analysis, statin use (hazard ratio [HR]0.69, p = 0.03), National Comprehensive Cancer Network (NCCN) low-risk group, and ADT use were associated with improved PRFS. Only high-risk patients in the statin group demonstrated improvement in PRFS (HR 0.52, p = 0.02). Across all groups, statin use was not associated with improved distant metastasis-free survival (DMFS) (p = 0.51). On multivariate analysis, lower NCCN risk group (p = 0.01) and ADT use (p = 0.005) predicted improved DMFS. Conclusions: Statin use during high-dose RT for clinically localized prostate cancer was associated with a significant improvement in PRFS in high-risk patients. These data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with RT in the treatment of prostate cancer.

  2. Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies.

    PubMed

    Gallwitz, H; Bonse, S; Martinez-Cruz, A; Schlichting, I; Schumacher, K; Krauth-Siegel, R L

    1999-02-11

    Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), a garlic-derived natural compound, is a covalent inhibitor as well as a substrate of human glutathione reductase (GR) and Trypanosoma cruzi trypanothione reductase (TR). The 2.1-A resolution crystal structure of GR inhibited by (E)-ajoene revealed a mixed disulfide between the active site Cys58 and the CH2=CH-CH2-SO-CH2-CH=CH-S moiety of ajoene. The modified enzyme has a markedly increased oxidase activity when compared to free GR. GR reduces (Z)-ajoene with a kcat/Km of 6.8 x 10(3) M-1 s-1 yielding 4,5,9-trithiadodeca-1, 6,11-triene (deoxyajoene) and 4,8,9,13-tetrathiahexadeca-1,6,10, 15-tetraene as stable reaction products. The reaction leads also to the formation of single-electron reduced products and concomitantly superoxide anion radicals as shown by coupling the reaction to the reduction of cytochrome c. The interactions between the flavoenzymes and ajoene are expected to increase the oxidative stress of the respective cell. The antiparasitic and cytostatic actions of ajoene may at least in part be due to the multiple effects on key enzymes of the antioxidant thiol metabolism.

  3. Modulating effect of synthetic statins against damage induced by doxorubicin in somatic cells of Drosophila melanogaster.

    PubMed

    Orsolin, P C; Silva-Oliveira, R G; Nepomuceno, J C

    2015-07-01

    The competitive inhibitors of HMG-CoA reductase, popularly known as statins, exert pleiotropic effects, which result from the ability of statins to inhibit the synthesis of isoprenoids, which are fundamental for the functioning of proteins responsible for intracellular signaling. Some recent studies suggest an important role associated with the use of antineoplastic atorvastatin and rosuvastatin, the statins most widely used today. In this study, the Drosophila wing spot test was used to evaluate possible protective effects of atorvastatin and rosuvastatin against damage induced by DXR. Larvae were chronically treated with negative control (ethanol 5%), positive control (DXR 0.125 mg/mL) and five different concentrations of atorvastatin and rosuvastatin. The results demonstrated absence of a mutagenic effect for the two statins tested. The analysis of the descendants co-treated with DXR and atorvastatin/rosuvastatin revealed a modulatory effect of these statins on damage induced by DXR. This effect was verified in all concentrations tested in the descendants of the ST and HB crosses treated with rosuvastatin, and only in descendants of the HB cross treated with atorvastatin. Induction of apoptosis and antioxidant activity appear to be the main mechanisms involved in reducing the frequency of mutant spots and consequent modulation of the damage induced by DXR. PMID:25846503

  4. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins.

    PubMed

    Caso, Giuseppe; Kelly, Patricia; McNurlan, Margaret A; Lawson, William E

    2007-05-15

    Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.

  5. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-01-01

    A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD. PMID:20696189

  6. Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients.

    PubMed

    Al-Muhanna, Fahad; Al-Mueilo, Samir; Al-Ali, Amein; Larbi, Emmanuel; Rubaish, Abdullah; Abdulmohsen, Mohammed Fakhry; Al-Zahrani, Alhussain; Al-Ateeq, Suad

    2008-11-01

    The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, apolipoprotein E (apo epsilon4) gene polymorphism and polymorphism of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with end-stage renal disease (ESRD). To determine the prevalence of these mutations in Saudi patients with ESRD on hemodialysis, we studied the allelic frequency and genotype distribution in patients receiving hemodialysis and in a control group, all residing in the Eastern Province of Saudi Arabia. The genotypes were determined using allele specific hybridization procedures and were confirmed by restriction fragment length polymorphism. The T allele frequency and homozygous genotype of MTHFR in ESRD patients were 14% and 2.4%, respectively compared to 13.4% and 0%, respectively in the control group. The allele frequency and homozygous genotype of 4G/4G PAI-1 gene polymorphism were 46.4% and 4.8% respectively in ESRD patients compared to 57.1% and 32% respectively in the control group. The apo s4 allele frequency and homozygous genotype distribution in hemodialysis patients were 7% and 2.4%, respectively compared to 13% and 2% in the control group. Although allele frequency of C677T of MTHFR was statistically similar in the hemodialysis patients and in the control group, the homozygotes T allele genotype was over represented in the hemodialysis group compared to normal. The prevalence of PAI-1 4G/4G polymorphism in ESRD patients was lower when compared to the control group. The prevalence of apo s4 allele did not differ significantly between the two groups. The present results demonstrate that all three studied polymorphic mutations are present in our population and that they may contribute to the etiology of the disease in our area. PMID:18974580

  7. Determination of triapine, a ribonucleotide reductase inhibitor, in human plasma by liquid chromatography tandem mass spectrometry.

    PubMed

    Feng, Ye; Kunos, Charles A; Xu, Yan

    2015-09-01

    Triapine is an inhibitor of ribonucleotide reductase (RNR). Studies have shown that triapine significantly decreases the activity of RNR and enhanced the radiation-mediated cytotoxicity in cervical and colon cancer. In this work, we have developed and validated a selective and sensitive LC-MS/MS method for the determination of triapine in human plasma. In this method, 2-[(3-fluoro-2-pyridinyl)methylene] hydrazinecarbothioamide (NSC 266749) was used as the internal standard (IS); plasma samples were prepared by deproteinization with acetonitrile; tripaine and the IS were separated on a Waters Xbridge Shield RP18 column (3.5 µm; 2.1 × 50 mm) using a mobile phase containing 25.0% methanol and 75.0% ammonium bicarbonate buffer (10.0 mM, pH 8.50; v/v); column eluate was monitored by positive turbo-ionspray tandem mass spectrometry; and quantitation of triapine was carried out in multiple-reaction-monitoring mode. The method developed had a linear calibration range of 0.250-50.0 ng/mL with correlation coefficient of 0.999 for triapine in human plasma. The IS-normalized recovery and the IS-normalized matrix factor of triapine were 101-104% and 0.89-1.05, respectively. The accuracy expressed as percentage error and precision expressed as coefficient of variation were ≤±6 and ≤8%, respectively. The validated LC-MS/MS method was applied to the measurement of triapine in patient samples from a phase I clinical trial. PMID:25677991

  8. 5-Alpha reductase inhibitor use and prostate cancer survival in the Finnish Prostate Cancer Screening Trial.

    PubMed

    Murtola, Teemu J; Karppa, Elina K; Taari, Kimmo; Talala, Kirsi; Tammela, Teuvo L J; Auvinen, Anssi

    2016-06-15

    Randomized clinical trials have shown that use of 5α-reductase inhibitors (5-ARIs) lowers overall prostate cancer (PCa) risk compared to placebo, while the proportion of Gleason 8-10 tumors is elevated. It is unknown whether this affects PCa-specific survival. We studied disease-specific survival by 5-ARI usage in a cohort of 6,537 prostate cancer cases diagnosed in the Finnish Prostate Cancer Screening Trial and linked to the national prescription database for information on medication use. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for prostate cancer-specific deaths. For comparison, survival among alpha-blocker users was also evaluated. During the median follow-up of 7.5 years after diagnosis a total of 2,478 men died; 617 due to prostate cancer and 1,861 due to other causes. The risk of prostate cancer death did not differ between 5-ARI users and nonusers (multivariable adjusted HR 0.94, 95% CI 0.72-1.24 and HR 0.98, 95% CI 0.69-1.41 for usage before and after the diagnosis, respectively). Alpha-blocker usage both before and after diagnosis was associated with increased risk of prostate cancer death (HR 1.29, 95% CI 1.08-1.54 and HR 1.56, 95% CI 1.30-1.86, respectively). The risk increase vanished in long-term alpha-blocker usage. Use of 5-ARIs does not appear to affect prostate cancer mortality when used in management of benign prostatic hyperplasia. Increased risk associated with alpha-blocker usage should prompt further exploration on the prognostic role of lower urinary tract symptoms.

  9. Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma brucei *

    PubMed Central

    Lu, Jun; Vodnala, Suman K.; Gustavsson, Anna-Lena; Gustafsson, Tomas N.; Sjöberg, Birger; Johansson, Henrik A.; Kumar, Sangit; Tjernberg, Agneta; Engman, Lars; Rottenberg, Martin E.; Holmgren, Arne

    2013-01-01

    Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis. PMID:23900839

  10. Coumarin-thiazole and -oxadiazole derivatives: Synthesis, bioactivity and docking studies for aldose/aldehyde reductase inhibitors.

    PubMed

    Ibrar, Aliya; Tehseen, Yildiz; Khan, Imtiaz; Hameed, Abdul; Saeed, Aamer; Furtmann, Norbert; Bajorath, Jürgen; Iqbal, Jamshed

    2016-10-01

    In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a-o) and coumarin-oxadiazole 11(a-h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC50 value of 0.16±0.06μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC50=2.94±1.23μM for ARL1 and 0.12±0.05μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC50=1.71±0.01μM for ARL1 and 0.11±0.001μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC50=0.459±0.001μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors.

  11. Structure-Based Approach to the Development of Potent and Selective Inhibitors of Dihydrofolate Reductase from Cryptosporidium

    PubMed Central

    Bolstad, David B.; Bolstad, Erin S. D.; Frey, Kathleen M.; Wright, Dennis L.; Anderson, Amy C.

    2008-01-01

    Cryptosporidiosis is an emerging infectious disease that can be life-threatening in an immune-compromised individual and causes gastrointestinal distress lasting up to 2 weeks in an immune-competent individual. There are few therapeutics available for effectively treating this disease. We have been exploring dihydrofolate reductase (DHFR) as a potential target in Cryptosporidium. On the basis of the structure of the DHFR enzyme from C. hominis, we have developed a novel scaffold that led to the discovery of potent (38 nM) and efficient inhibitors of this enzyme. Recently, we have advanced these inhibitors to the next stage of development. Using the structures of both the protozoal and human enzymes, we have developed inhibitors with nanomolar potency (1.1 nM) against the pathogenic enzyme and high levels (1273-fold) of selectivity over the human enzyme. PMID:18834108

  12. Statins activate GATA-6 and induce differentiated vascular smooth muscle cells

    SciTech Connect

    Wada, Hiromichi Abe, Mitsuru; Ono, Koh; Morimoto, Tatsuya; Kawamura, Teruhisa; Takaya, Tomohide; Satoh, Noriko; Fujita, Masatoshi; Kita, Toru; Shimatsu, Akira; Hasegawa, Koji

    2008-10-03

    The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) beyond cholesterol lowering involve their direct actions on vascular smooth muscle cells (VSMCs). However, the effects of statins on phenotypic modulation of VSMCs are unknown. We herein show that simvastatin (Sm) and atorvastatin (At) inhibited DNA synthesis in human aortic VSMCs dose-dependently, while cell toxicity was not observed below the concentration of 1 {mu}M of Sm or 100 nM of At. Stimulating proliferative VSMCs with Sm or At induced the expression of SM-{alpha}-actin and SM-MHC, highly specific markers of differentiated phenotype. Sm up-regulated the binding activity of GATA-6 to SM-MHC GATA site and activated the transfected SM-MHC promoter in proliferative VSMCs, while mutating the GATA-6 binding site abolished this activation. Geranylgeranylpyrophosphate (10 {mu}M), an inhibitor of Rho family proteins, abolished the statin-mediated induction of the differentiated phenotype in VSMCs. These findings suggest that statins activate GATA-6 and induce differentiated VSMCs.

  13. Statins potently reduce the cytokine-mediated IL-6 release in SMC/MNC cocultures.

    PubMed

    Loppnow, Harald; Zhang, Li; Buerke, Michael; Lautenschläger, Michael; Chen, Li; Frister, Adrian; Schlitt, Axel; Luther, Tanja; Song, Nan; Hofmann, Britt; Rose-John, Stefan; Silber, Rolf-Edgar; Müller-Werdan, Ursula; Werdan, Karl

    2011-04-01

    Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall.

  14. Probing the Active Site of Candida Glabrata Dihydrofolate Reductase with High Resolution Crystal Structures and the Synthesis of New Inhibitors

    SciTech Connect

    Liu, J.; Bolstad, D; Smith, A; Priestley, N; Wright, D; Anderson, A

    2009-01-01

    Candida glabrata, a fungal strain resistant to many commonly administered antifungal agents, has become an emerging threat to human health. In previous work, we validated that the essential enzyme, dihydrofolate reductase, is a drug target in C. glabrata. Using a crystal structure of dihydrofolate reductase from C. glabrata bound to an initial lead compound, we designed a class of biphenyl antifolates that potently and selectively inhibit both the enzyme and the growth of the fungal culture. In this work, we explore the structure-activity relationships of this class of antifolates with four new high resolution crystal structures of enzyme:inhibitor complexes and the synthesis of four new inhibitors. The designed inhibitors are intended to probe key hydrophobic pockets visible in the crystal structure. The crystal structures and an evaluation of the new compounds reveal that methyl groups at the meta and para positions of the distal phenyl ring achieve the greatest number of interactions with the pathogenic enzyme and the greatest degree of selectivity over the human enzyme. Additionally, antifungal activity can be tuned with substitution patterns at the propargyl and para-phenyl positions.

  15. Bioactivity Focus of α-Cyano-4-hydroxycinnamic acid (CHCA) Leads to Effective Multifunctional Aldose Reductase Inhibitors

    PubMed Central

    Zhang, Laitao; Li, Yi-Fang; Yuan, Sheng; Zhang, Shijie; Zheng, Huanhuan; Liu, Jie; Sun, Pinghua; Gu, Yijun; Kurihara, Hiroshi; He, Rong-Rong; Chen, Heru

    2016-01-01

    Bioactivity focus on α-cyano-4-hydroxycinnamic acid (CHCA) scaffold results in a small library of novel multifunctional aldose reductase (ALR2) inhibitors. All the entities displayed good to excellent inhibition with IC50 72–405 nM. (R,E)-N-(3-(2-acetamido-3-(benzyloxy)propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide (5f) was confirmed as the most active inhibitor (IC50 72.7 ± 1.6 nM), and the best antioxidant. 5f bound to ALR2 with new mode without affecting the aldehyde reductase (ALR1) activity, implicating high selectivity to ALR2. 5f was demonstrated as both an effective ALR2 inhibitor (ARI) and antioxidant in a chick embryo model of hyperglycemia. It attenuated hyperglycemia-induced incidence of neural tube defects (NTD) and death rate, and significantly improved the body weight and morphology of the embryos. 5f restored the expression of paired box type 3 transcription factor (Pax3), and reduced the hyperglycemia-induced increase of ALR2 activity, sorbitol accumulation, and the generation of ROS and MDA to normal levels. All the evidences support that 5f may be a potential agent to treat diabetic complications. PMID:27109517

  16. Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial.

    PubMed

    Nissen, Steven E; Dent-Acosta, Ricardo E; Rosenson, Robert S; Stroes, Erik; Sattar, Naveed; Preiss, David; Mancini, G B John; Ballantyne, Christie M; Catapano, Alberico; Gouni-Berthold, Ioanna; Stein, Evan A; Xue, Allen; Wasserman, Scott M; Scott, Rob; Thompson, Paul D

    2016-03-01

    Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014. PMID:26946077

  17. Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial.

    PubMed

    Nissen, Steven E; Dent-Acosta, Ricardo E; Rosenson, Robert S; Stroes, Erik; Sattar, Naveed; Preiss, David; Mancini, G B John; Ballantyne, Christie M; Catapano, Alberico; Gouni-Berthold, Ioanna; Stein, Evan A; Xue, Allen; Wasserman, Scott M; Scott, Rob; Thompson, Paul D

    2016-03-01

    Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.

  18. Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir

    PubMed Central

    Bhave, Sukhada; Elford, Howard; McVoy, Michael A.

    2013-01-01

    Ganciclovir (GCV) is a deoxyguanosine analog that is effective in inhibiting human cytomegalovirus (HCMV) replication. In infected cells GCV is converted to GCV-triphosphate which competes with dGTP for incorporation into the growing DNA strand by the viral DNA polymerase. Incorporated GCV promotes chain termination as it is an inefficient substrate for elongation. Because viral DNA synthesis also relies on cellular ribonucleotide reductase (RR) to synthesize deoxynucleotides, RR inhibitors are predicted to inhibit HCMV replication. Moreover, as dGTP competes with GCV-triphosphate for incorporation, RR inhibitors may also synergize with GCV by reducing intracellular dGTP levels and there by promoting increased GCV-triphosphate utilization by DNA polymerase. To investigate potential of RR inhibitors as anti-HCMV agents both alone and in combination with GCV, HCMV-inhibitory activities of three RR inhibitors, hydroxyurea, didox, and trimidox, were determined. In both spread inhibition and yield reduction assays RR inhibitors had modest anti-HCMV activity with 50% inhibitory concentrations ranging from 36 ± 1.7 to 221 ± 52 µM. However, all three showed significant synergy with GCV at concentrations below their 50% inhibitory and 50% toxic concentrations. These results suggest that combining GCV with relatively low doses of RR inhibitors could significantly potentiate the anti-HCMV activity of GCV in vivo and could improve clinical response to therapy. PMID:23933116

  19. Cholesterol suppresses antimicrobial effect of statins

    PubMed Central

    Haeri, Mohammad Reza; White, Kenneth; Qharebeglou, Mohammad; Ansar, Malek Moein

    2015-01-01

    Objective(s): Isoprenoid biosynthesis is a key metabolic pathway to produce a wide variety of biomolecules such as cholesterol and carotenoids, which target cell membranes. On the other hand, it has been reported that statins known as inhibitors of isoprenoid biosynthesis and cholesterol lowering agents, may have a direct antimicrobial effect on the some bacteria. The exact action of statins in microbial metabolism is not clearly understood. It is possible that statins inhibit synthesis or utilization of some sterol precursor necessary for bacterial membrane integrity. Accordingly, this study was designed in order to examine if statins inhibit the production of a compound, which can be used in the membrane, and whether cholesterol would replace it and rescue bacteria from toxic effects of statins. Materials and Methods: To examine the possibility we assessed antibacterial effect of statins with different classes; lovastatin, simvastatin, and atorvastatin, alone and in combination with cholesterol on two Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and two Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria using gel diffusion assay. Results: Our results showed that all of the statins except for lovastatin had significant antibacterial property in S. aureus, E. coli, and Enter. faecalis. Surprisingly, cholesterol nullified the antimicrobial action of effective statins in statin-sensitive bacteria. Conclusion: It is concluded that statins may deprive bacteria from a metabolite responsible for membrane stability, which is effectively substituted by cholesterol. PMID:26877857

  20. Effect of cytochrome P450 and aldo-keto reductase inhibitors on progesterone inactivation in primary bovine hepatic cell cultures.

    PubMed

    Lemley, C O; Wilson, M E

    2010-10-01

    Progesterone is required for maintenance of pregnancy, and peripheral concentrations of progesterone are affected by both production and inactivation. Hepatic cytochrome P450 (EC 1.14.14.1) and aldo-keto reductase (EC 1.1.1.145-151) enzymes play a pivotal role in the first step of steroid inactivation, which involves the addition of hydroxyl groups to various sites of the cyclopentanoperhydrophenanthrene nucleus. The current objective was to discern the proportional involvement of hepatic progesterone inactivating enzymes on progesterone decay using specific enzyme inhibitors. Ticlopidine, diltiazem, curcumin, dicumarol, and naproxen were used because of their selective inhibition of cytochrome P450s, aldo-keto reductases, and glucuronosyltransferases. Liver biopsies were collected from 6 lactating Holstein dairy cows, and cells were dissociated using a nonperfusion technique. Confluent wells were preincubated for 4 h with enzyme inhibitor and then challenged with progesterone for 1 h. Cell viability was unaffected by inhibitor treatment and averaged 84±1%. In control wells, 50% of the progesterone had been inactivated after a 1-h challenge with 5 ng/mL of progesterone. Preincubation with curcumin, ticlopidine, or naproxen caused the greatest reduction in progesterone inactivation compared with controls and averaged 77, 39, or 37%, respectively. Hydroxylation of 4-nitrophenol to 4-nitrocatechol in intact cells was inhibited by approximately 65% after treatment with curcumin or ticlopidine. Glucuronidation of phenol red or 4-nitrocatechol in intact cells was inhibited by treatment with curcumin, dicumarol, or naproxen. In cytoplasmic preparations, aldo-keto reductase 1C activity was inhibited by curcumin, dicumarol, or naproxen treatment. Microsomal cytochrome P450 2C activity was inhibited by treatment with curcumin or ticlopidine, whereas cytochrome P450 3A activity was inhibited by treatment with curcumin or diltiazem. The contribution of cytochrome P450 2C and

  1. Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

    SciTech Connect

    Katz, Matthew S.; Minsky, Bruce D. . E-mail: minskyb@mskcc.org; Saltz, Leonard B.; Riedel, Elyn; Chessin, David B.; Guillem, Jose G.

    2005-08-01

    Purpose: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. Methods and Materials: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-flurouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. Results: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. Conclusion: In multivariate analysis, statin use is associated with an improved p

  2. Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors.

    PubMed

    Capasso, Clemente; Supuran, Claudiu T

    2014-06-01

    Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.

  3. Clinical use of statins in hematopoietic stem cell transplantation: Old drugs and new horizons.

    PubMed

    Mohammadi, Mehdi; Vaezi, Mohammad; Mirrahimi, Bahador; Hadjibabaie, Molouk

    2016-01-01

    Hydroxymethylglutaryl Co-enzyme A reductase inhibitors, also known as statins, are a class of anti-hyperlipidemic agents. These drugs have been employed vastly to reduce the morbidity and mortality of cardiovascular disorders. Soon after their introduction, benefits other than their primary actions were discovered. Along with these pleiotropic properties, a series of mainly favorable effects has been proposed in patients intended to undergo hematopoietic stem cell transplantation. These actions address some complications encountered by this special population such as graft-versus-host disease, efficacy of chemotherapy, infections, etc. This review presents the current evidence surrounding these issues. PMID:27047650

  4. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus.

    PubMed

    Judge, Eoin P; Phelan, D; O'Shea, Donal

    2010-09-01

    Total cholesterol and low-density lipoprotein (LDL) cholesterol exhibit an independent, strong, continuous correlation with cardiovascular events. The effectiveness of hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in the treatment and prevention of atherosclerosis is well-established. However, despite the lowering of LDL targets and the increased use of statins, patients with type 2 diabetes mellitus (DM) continue to experience a higher proportion of adverse coronary artery disease events. This is as a result of an atherogenic dyslipidaemia, characterized by low levels of high-density lipoprotein and elevated plasma triglyceride concentrations, often with high levels of cholesterol-rich remnant particles. This article will review dyslipidaemia and its role in DM, and will discuss available treatment modalities that address residual cardiovascular risk in this disease.

  5. Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor, Fidarestat

    PubMed Central

    Takahashi, Kazunori; Mizukami, Hiroki; Kamata, Kosuke; Inaba, Wataru; Kato, Noriaki; Hibi, Chihiro; Yagihashi, Soroku

    2012-01-01

    Background Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Methods Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Results Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. Conclusion AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality. PMID:22253906

  6. Dual effects of statins therapy in systemic lupus erythematosus and SLE-related atherosclerosis: the potential role for regulatory T cells.

    PubMed

    Tu, Haiyan; Li, Qi; Xiang, Shilong; Jiang, Hong; Mao, Youying; Shou, Zhangfei; Chen, Jianghua

    2012-05-01

    Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease associated with accelerated atherosclerosis independent of traditional risk factors. Statins, the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been widely prescribed for hyperlipidemia, which could slow the atherosclerosis progression, and reduce cardiovascular disease events. Nonetheless, accumulated evidences suggested that statins exert immunomodulatory and anti-inflammatory functions independent of their lipid-lowering effects. By the virtue of pleiotropic immunomodulatory property, statins may be applied for the treatment of both autoimmunity and atherosclerosis in patients with SLE. Interestingly, it has been well documented that regulatory T cells (Tregs) are involved in the pathogenesis of SLE as well as atherosclerosis. Meanwhile, studies have shown that statins could induce augmented number of Tregs with increased functional inhibitory properties. Thus, we hypothesized that the effect of statins ameliorating lupus disease manifestations and lupus-mediated atherogenesis might be mediated, at least partly, via the activation of Tregs. To our knowledge, this is the first hypothesis focused on that Tregs might be involved in the immunomodulatory effect of statins on SLE and SLE-related atherosclerosis.

  7. [Statins in the management of dyslipidemias].

    PubMed

    Scheen, André J

    2011-10-01

    Statins, combined with life-style advices, have a key position in the prevention of cardiovascular diseases. By inhibiting HMG-CoA reductase enzyme, these medications reduce total and LDL cholesterol levels in a dose-dependent manner. They also exert various pleiotropic effects that may contribute to the cardiovascular protection. Although some differences exist between available statins, a class effect seems predominant. Statins have proven their efficacy in numerous controlled randomized trials (recently pooled in meta-analyses), both in primary and secondary prevention, including various specific populations, among them patients with diabetes. Tolerance and safety profile is rather good even if muscular and hepatic adverse events may occur. The prescription of statins should target high-risk individuals and both therapeutic inertia and drug non-compliance should be avoided.

  8. 5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer

    PubMed Central

    Preston, Mark A.; Wilson, Kathryn; Markt, Sarah C.; Ge, Rongbin; Morash, Christopher; Stampfer, Meir J.; Loda, Massimo F.; Giovannucci, Edward; Mucci, Lorelei A.; Olumi, Aria F.

    2014-01-01

    Importance 5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. Objective To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. Design, Setting, and Participants Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study. Exposure Use of 5ARIs between 1996–2010. Main Outcome Measures Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. Results During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease. Conclusions and

  9. Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: A possible role in statin-induced hepatotoxicity?

    SciTech Connect

    Tavintharan, S. Ong, C.N.; Jeyaseelan, K.; Sivakumar, M.; Lim, S.C.; Sum, C.F.

    2007-09-01

    Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ{sub 10}). In HepG2 cells, simvastatin decreased mitochondrial CoQ{sub 10} levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ{sub 10}, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ{sub 10} deficiency plays an important role in statin-induced hepatopathy, and that CoQ{sub 10} supplementation protects HepG2 cells from this complication.

  10. Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans.

    PubMed

    Farooqui, Akhlaq A; Ong, Wei-Yi; Horrocks, Lloyd A; Chen, Peng; Farooqui, Tahira

    2007-12-01

    Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that

  11. Discovery of an Allosteric Inhibitor Binding Site in 3-Oxo-acyl-ACP Reductase from Pseudomonas aeruginosa

    PubMed Central

    2013-01-01

    3-Oxo-acyl-acyl carrier protein (ACP) reductase (FabG) plays a key role in the bacterial fatty acid synthesis II system in pathogenic microorganisms, which has been recognized as a potential drug target. FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the elongation cycle of fatty acid biosynthesis. Here, we report gene deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small molecule FabG inhibitors with IC50 values in the nanomolar to low micromolar range and good physicochemical properties. Structural characterization of 16 FabG-inhibitor complexes by X-ray crystallography revealed that the compounds bind at a novel allosteric site located at the FabG subunit–subunit interface. Inhibitor binding relies primarily on hydrophobic interactions, but specific hydrogen bonds are also observed. Importantly, the binding cavity is formed upon complex formation and therefore would not be recognized by virtual screening approaches. The structure analysis further reveals that the inhibitors act by inducing conformational changes that propagate to the active site, resulting in a displacement of the catalytic triad and the inability to bind NADPH. PMID:24015914

  12. Enhancement of β-carotene production by over-expression of HMG-CoA reductase coupled with addition of ergosterol biosynthesis inhibitors in recombinant Saccharomyces cerevisiae.

    PubMed

    Yan, Guo-liang; Wen, Ke-rui; Duan, Chang-qing

    2012-02-01

    In this study, the synergistic effect of overexpressing the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene and adding ergosterol synthesis inhibitor, ketoconazole, on β-carotene production in the recombinant Saccharomyces cerevisiae was investigated. The results showed that the over-expression of HMG-CoA reductase gene and adding 100 mg/l ketoconazole alone can result in 135.1 and 15.6% increment of β-carotene concentration compared with that of the control (2.05 mg/g dry weight of cells), respectively. However, the combination of overexpressing HMG-CoA reductase gene and adding ketoconazole can achieve a 206.8% increment of pigment content (6.29 mg/g dry weight of cells) compared with that of the control. Due to the fact that over-expression of the HMG-CoA reductase gene can simultaneously improve the flux of the sterol and carotenoid biosynthetic pathway, it can be concluded that under the circumstances of blocking sterol biosynthesis, increasing the activity of HMG-CoA reductase can result in more precursors FPP fluxing into carotenoid branch and obtain a high increment of β-carotene production. The results of this study collectively suggest that the combination of overexpressing HMG-CoA reductase gene and supplying ergosterol synthesis inhibitor is an effective strategy to improve the production of desirable isoprenoid compounds such as carotenoids. PMID:22086347

  13. Statin non-adherence: clinical consequences and proposed solutions

    PubMed Central

    Rosenson, Robert S.

    2016-01-01

    Large controlled clinical trials have demonstrated reductions with statin therapy in cardiovascular events in patients presenting with acute coronary syndromes and stable coronary heart disease and individuals at high risk of a cardiovascular event. In trials of acute coronary syndromes and stable coronary heart disease, high-intensity statin therapy is more effective in the prevention of recurrent cardiovascular events than low-intensity statin therapy. Thus, evidence-based guidelines recommend in-hospital initiation of high-intensity statin therapy for all acute coronary syndrome patients. Clinical trials report high adherence to and low discontinuation of high-intensity statin therapy; however, in clinical practice, high-intensity statins are prescribed to far fewer patients, who often discontinue their statin after the first refill. A coordinated effort among the patient, provider, pharmacist, health system, and insurer is necessary to improve utilization and persistence of prescribed medications. The major cause for statin discontinuations reported by patients is perceived adverse events. Evaluation of potential adverse events requires validated tools to distinguish between statin-associated adverse events versus non-specific complaints. Treatment options for statin-intolerant patients include the use of a different statin, often at a lower dose or frequency. In order to lower LDL cholesterol, lower doses of statins may be combined with ezetimibe or bile acid sequestrants. Newer treatment options for patients with statin-associated muscle symptoms may include proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. PMID:27134737

  14. Statin non-adherence: clinical consequences and proposed solutions.

    PubMed

    Rosenson, Robert S

    2016-01-01

    Large controlled clinical trials have demonstrated reductions with statin therapy in cardiovascular events in patients presenting with acute coronary syndromes and stable coronary heart disease and individuals at high risk of a cardiovascular event. In trials of acute coronary syndromes and stable coronary heart disease, high-intensity statin therapy is more effective in the prevention of recurrent cardiovascular events than low-intensity statin therapy. Thus, evidence-based guidelines recommend in-hospital initiation of high-intensity statin therapy for all acute coronary syndrome patients. Clinical trials report high adherence to and low discontinuation of high-intensity statin therapy; however, in clinical practice, high-intensity statins are prescribed to far fewer patients, who often discontinue their statin after the first refill. A coordinated effort among the patient, provider, pharmacist, health system, and insurer is necessary to improve utilization and persistence of prescribed medications. The major cause for statin discontinuations reported by patients is perceived adverse events. Evaluation of potential adverse events requires validated tools to distinguish between statin-associated adverse events versus non-specific complaints. Treatment options for statin-intolerant patients include the use of a different statin, often at a lower dose or frequency. In order to lower LDL cholesterol, lower doses of statins may be combined with ezetimibe or bile acid sequestrants. Newer treatment options for patients with statin-associated muscle symptoms may include proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. PMID:27134737

  15. Molecular modeling toward selective inhibitors of dihydrofolate reductase from the biological warfare agent Bacillus anthracis.

    PubMed

    Giacoppo, Juliana O S; Mancini, Daiana T; Guimarães, Ana P; Gonçalves, Arlan S; da Cunha, Elaine F F; França, Tanos C C; Ramalho, Teodorico C

    2015-02-16

    In the present work, we applied docking and molecular dynamics techniques to study 11 compounds inside the enzymes dihydrofolate reductase (DHFR) from the biological warfare agent Bacillus anthracis (BaDHFR) and Homo sapiens sapiens (HssDHFR). Six of these compounds were selected for a study with the mutant BaF96IDHFR. Our results corroborated with experimental data and allowed the proposition of a new molecule with potential activity and better selectivity for BaDHFR.

  16. 5-alpha reductase inhibitors in patients on active surveillance: do the benefits outweigh the risk?

    PubMed

    Al Edwan, Ghazi; Fleshner, Neil

    2013-06-01

    Prostate cancer (PCa) is a slow, progressive disease. Prostate specific antigen testing, screening, and aggressive case identification has made PCa the most frequently diagnosed cancer. Concerns regarding overdiagnosis and overtreatment flourish on a large scale. In order to avoid overtreatment for those in whom therapeutic intervention is not required, active surveillance for eligible patients with the use of 5-alpha reductase can be considered a safe and a promising approach to delay the progression of the disease with minimal side effects. PMID:23579402

  17. X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP(+) and the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity.

    PubMed

    Ruiz, Francesc Xavier; Cousido-Siah, Alexandra; Mitschler, André; Farrés, Jaume; Parés, Xavier; Podjarny, Alberto

    2013-02-25

    Only one crystal structure is currently available for tumor marker AKR1B10, complexed with NADP(+) and tolrestat, which is an aldose reductase inhibitor (ARI) of the carboxylic acid type. Here, the X-ray structure of the complex of the V301L substituted AKR1B10 holoenzyme with fidarestat, an ARI of the cyclic imide type, was obtained at 1.60Å resolution by replacement soaking of crystals containing tolrestat. Previously, fidarestat was found to be safe in phase III trials for diabetic neuropathy and, consistent with its low in vivo side effects, was highly selective for aldose reductase (AR or AKR1B1) versus aldehyde reductase (AKR1A1). Now, inhibition studies showed that fidarestat was indeed 1300-fold more selective for AR as compared to AKR1B10, while the change of Val to Leu (found in AR) caused a 20-fold decrease in the IC50 value with fidarestat. Structural analysis of the V301L AKR1B10-fidarestat complex displayed enzyme-inhibitor interactions similar to those of the AR-fidarestat complex. However, a close inspection of both the new crystal structure and a computer model of the wild-type AKR1B10 complex with fidarestat revealed subtle changes that could affect fidarestat binding. In the crystal structure, a significant motion of loop A was observed between AR and V301L AKR1B10, linked to a Phe-122/Phe-123 side chain displacement. This was due to the presence of the more voluminous Gln-303 side chain (Ser-302 in AR) and of a water molecule buried in a subpocket located at the base of flexible loop A. In the wild-type AKR1B10 model, a short contact was predicted between the Val-301 side chain and fidarestat, but would not be present in AR or in V301L AKR1B10. Overall, these changes could contribute to the difference in inhibitory potency of fidarestat between AR and AKR1B10.

  18. Statin-induced necrotizing myositis – A discrete autoimmune entity within the “statin-induced myopathy spectrum”

    PubMed Central

    Hamann, Philip; Cooper, Robert; McHugh, Neil; Chinoy, Hector

    2015-01-01

    Statin-induced necrotizing myositis is increasingly being recognised as part of the “statin-induced myopathy spectrum”. As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatine kinase elevations and histological evidence of myonecrosis, and with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the enzyme target of statin therapies), and with HLA-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy. PMID:23851103

  19. A [32P]-NAD+-based method to identify and quantitate long residence time enoyl-ACP reductase inhibitors

    PubMed Central

    Yu, Weixuan; Neckles, Carla; Chang, Andrew; Bommineni, Gopal Reddy; Spagnuolo, Lauren; Zhang, Zhuo; Liu, Nina; Lai, Christina; Truglio, James; Tonge, Peter J.

    2015-01-01

    The classical methods for quantifying drug-target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative strategies. Using the NAD(P)H-dependent FabI enoyl-ACP reductase as a model system, we developed a Penefsky column-based method for direct measurement of tR, where the off-rate of the drug was determined with radiolabeled [adenylate-32P] NAD(P+) cofactor. Twenty-three FabI inhibitors were analyzed and a mathematical model was used to estimate limits to the tR values of each inhibitor based on percent drug-target complex recovery following gel filtration. In general, this method showed good agreement with the classical steady state kinetic methods for compounds with tR values of 10-100 min. In addition, we were able to identify seven long tR inhibitors (100-1500 min) and to accurately determine their tR values. The method was then used to measure tR as a function of temperature, an analysis not previously possible using the standard kinetic approach due to decreased NAD(P)H stability at elevated temperatures. In general, a 4-fold difference in tR was observed when the temperature was increased from 25 °C to 37 °C . PMID:25684450

  20. A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium.

    PubMed

    Mukerjee, Anindita; Iyidogan, Pinar; Castellanos-Gonzalez, Alejandro; Cisneros, José A; Czyzyk, Daniel; Ranjan, Amalendu Prakash; Jorgensen, William L; White, A Clinton; Vishwanatha, Jamboor K; Anderson, Karen S

    2015-01-01

    Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having μM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.

  1. Cloning, recombinant expression and inhibitor profiles of dihydrofolate reductase from the Australian sheep blow fly, Lucilia cuprina.

    PubMed

    Kotze, A C; Bagnall, N H; Ruffell, A P; Pearson, R

    2014-09-01

    While dihydrofolate reductase (DHFR) is an important drug target in mammals, bacteria and protozoa, no inhibitors of this enzyme have been developed as commercial insecticides. We therefore examined the potential of this enzyme as a drug target in an important ectoparasite of livestock, the Australian sheep blow fly, Lucilia cuprina (Diptera: Calliphoridae) (Wiedemann). The non-specific DHFR inhibitors aminopterin and methotrexate significantly inhibited the growth of L. cuprina larvae, with IC50 values at µg levels. Trimethoprim and pyrimethamine were 5-30-fold less active. Relative IC50 values for the inhibition of recombinant L. cuprina DHFR by various inhibitors were in accordance with their relative effects on larval growth. The active-site amino acid residues of L. cuprina DHFR differed by between 34% and 50% when compared with two mammalian species, as well as two bacteria and two protozoa. There were significant charge and size differences in specific residues between the blow fly and human DHFR enzymes, notably the L. cuprina Asn21, Lys31 and Lys63 residues. This study provides bioassay evidence to highlight the potential of blow fly DHFR as an insecticide target, and describes differences in active site residues between blow flies and other organisms which could be exploited in the design of blow fly control chemicals.

  2. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    SciTech Connect

    Sun, Bin; Hoshino, Juma; Jermihov, Katie; Marler, Laura; Pezzuto, John M.; Mesecar, Andrew D.; Cushman, Mark

    2012-07-11

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC{sub 50} 0.59 {mu}M) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC{sub 50} 70 nM) and 84 (IC{sub 50} 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC{sub 50} of 80 {mu}M. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC{sub 50} 1.7 {mu}M and 0.27 {mu}M, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  3. Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase.

    PubMed

    Neckles, Carla; Pschibul, Annica; Lai, Cheng-Tsung; Hirschbeck, Maria; Kuper, Jochen; Davoodi, Shabnam; Zou, Junjie; Liu, Nina; Pan, Pan; Shah, Sonam; Daryaee, Fereidoon; Bommineni, Gopal R; Lai, Cristina; Simmerling, Carlos; Kisker, Caroline; Tonge, Peter J

    2016-05-31

    The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89-100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold → 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156.

  4. Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase.

    PubMed

    Neckles, Carla; Pschibul, Annica; Lai, Cheng-Tsung; Hirschbeck, Maria; Kuper, Jochen; Davoodi, Shabnam; Zou, Junjie; Liu, Nina; Pan, Pan; Shah, Sonam; Daryaee, Fereidoon; Bommineni, Gopal R; Lai, Cristina; Simmerling, Carlos; Kisker, Caroline; Tonge, Peter J

    2016-05-31

    The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89-100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold → 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156. PMID:27136302

  5. Pyrithione-based ruthenium complexes as inhibitors of aldo-keto reductase 1C enzymes and anticancer agents.

    PubMed

    Kljun, Jakob; Anko, Maja; Traven, Katja; Sinreih, Maša; Pavlič, Renata; Peršič, Špela; Ude, Žiga; Codina, Elisa Esteve; Stojan, Jure; Lanišnik Rižner, Tea; Turel, Iztok

    2016-08-01

    Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range. PMID:27357845

  6. GRE2 from Scheffersomyces stipitis as an aldehyde reductase contributes tolerance to aldehyde inhibitors derived from lignocellulosic biomass.

    PubMed

    Wang, Xu; Ma, Menggen; Liu, Z Lewis; Xiang, Quanju; Li, Xi; Liu, Na; Zhang, Xiaoping

    2016-08-01

    Scheffersomyces (Pichia) stipitis is one of the most promising yeasts for industrial bioethanol production from lignocellulosic biomass. S. stipitis is able to in situ detoxify aldehyde inhibitors (such as furfural and 5-hydroxymethylfurfural (HMF)) to less toxic corresponding alcohols. However, the reduction enzymes involved in this reaction remain largely unknown. In this study, we reported that an uncharacterized open reading frame PICST_72153 (putative GRE2) from S. stipitis was highly induced in response to furfural and HMF stresses. Overexpression of this gene in Saccharomyces cerevisiae improved yeast tolerance to furfural and HMF. GRE2 was identified as an aldehyde reductase which can reduce furfural to FM with either NADH or NADPH as the co-factor and reduce HMF to FDM with NADPH as the co-factor. This enzyme can also reduce multiple aldehydes to their corresponding alcohols. Amino acid sequence analysis indicated that it is a member of the subclass "intermediate" of the short-chain dehydrogenase/reductase (SDR) superfamily. Although GRE2 from S. stipitis is similar to GRE2 from S. cerevisiae in a three-dimensional structure, some differences were predicted. GRE2 from S. stipitis forms loops at D133-E137 and T143-N145 locations with two α-helices at E154-K157 and E252-A254 locations, different GRE2 from S. cerevisiae with an α-helix at D133-E137 and a β-sheet at T143-N145 locations, and two loops at E154-K157 and E252-A254 locations. This research provided guidelines for the study of other SDR enzymes from S. stipitis and other yeasts on tolerant mechanisms to aldehyde inhibitors derived from lignocellulosic biomass. PMID:27003269

  7. X-ray structural studies of quinone reductase 2 nanomolar range inhibitors

    PubMed Central

    Pegan, Scott D; Sturdy, Megan; Ferry, Gilles; Delagrange, Philippe; Boutin, Jean A; Mesecar, Andrew D

    2011-01-01

    Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X-ray structures of human QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC50 values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands. PMID:21538647

  8. X-ray structural studies of quinone reductase 2 nanomolar range inhibitors

    SciTech Connect

    Pegan, Scott D.; Sturdy, Megan; Ferry, Gilles; Delagrange, Philippe; Boutin, Jean A.; Mesecar, Andrew D.

    2011-09-06

    Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X-ray structures of human QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC{sub 50} values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands.

  9. Repositioning of a cyclin-dependent kinase inhibitor GW8510 as a ribonucleotide reductase M2 inhibitor to treat human colorectal cancer.

    PubMed

    Hsieh, Y-Y; Chou, C-J; Lo, H-L; Yang, P-M

    2016-01-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death in males and females in the world. It is of immediate importance to develop novel therapeutics. Human ribonucleotide reductase (RRM1/RRM2) has an essential role in converting ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. RRM2 is a prognostic biomarker and predicts poor survival of CRC. In addition, increased RRM2 activity is associated with malignant transformation and tumor cell growth. Bioinformatics analyses show that RRM2 was overexpressed in CRC and might be an attractive target for treating CRC. Therefore, we attempted to search novel RRM2 inhibitors by using a gene expression signature-based approach, connectivity MAP (CMAP). The result predicted GW8510, a cyclin-dependent kinase inhibitor, as a potential RRM2 inhibitor. Western blot analysis indicated that GW8510 inhibited RRM2 expression through promoting its proteasomal degradation. In addition, GW8510 induced autophagic cell death. In addition, the sensitivities of CRC cells to GW8510 were associated with the levels of RRM2 and endogenous autophagic flux. Taken together, our study indicates that GW8510 could be a potential anti-CRC agent through targeting RRM2. PMID:27551518

  10. Repositioning of a cyclin-dependent kinase inhibitor GW8510 as a ribonucleotide reductase M2 inhibitor to treat human colorectal cancer

    PubMed Central

    Hsieh, Y-Y; Chou, C-J; Lo, H-L; Yang, P-M

    2016-01-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death in males and females in the world. It is of immediate importance to develop novel therapeutics. Human ribonucleotide reductase (RRM1/RRM2) has an essential role in converting ribonucleoside diphosphate to 2′-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. RRM2 is a prognostic biomarker and predicts poor survival of CRC. In addition, increased RRM2 activity is associated with malignant transformation and tumor cell growth. Bioinformatics analyses show that RRM2 was overexpressed in CRC and might be an attractive target for treating CRC. Therefore, we attempted to search novel RRM2 inhibitors by using a gene expression signature-based approach, connectivity MAP (CMAP). The result predicted GW8510, a cyclin-dependent kinase inhibitor, as a potential RRM2 inhibitor. Western blot analysis indicated that GW8510 inhibited RRM2 expression through promoting its proteasomal degradation. In addition, GW8510 induced autophagic cell death. In addition, the sensitivities of CRC cells to GW8510 were associated with the levels of RRM2 and endogenous autophagic flux. Taken together, our study indicates that GW8510 could be a potential anti-CRC agent through targeting RRM2. PMID:27551518

  11. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells

    PubMed Central

    Zhou, Tian-yi; Zhuang, Lin-han; Hu, Yan; Zhou, Yu-lu; Lin, Wen-kai; Wang, Dan-dan; Wan, Zi-qian; Chang, Lin-lin; Chen, Ying; Ying, Mei-dan; Chen, Zi-bo; Ye, Song; Lou, Jian-shu; He, Qiao-jun; Zhu, Hong; Yang, Bo

    2016-01-01

    Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients. PMID:27476430

  12. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells.

    PubMed

    Zhou, Tian-Yi; Zhuang, Lin-Han; Hu, Yan; Zhou, Yu-Lu; Lin, Wen-Kai; Wang, Dan-Dan; Wan, Zi-Qian; Chang, Lin-Lin; Chen, Ying; Ying, Mei-Dan; Chen, Zi-Bo; Ye, Song; Lou, Jian-Shu; He, Qiao-Jun; Zhu, Hong; Yang, Bo

    2016-01-01

    Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients. PMID:27476430

  13. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

    PubMed

    Fong, Clifford W

    2014-10-01

    The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the

  14. [Muscle problems due to statins: underestimated].

    PubMed

    Janssen, Stan P; Smulders, Yvo M; Gerdes, Victor E; Visseren, Frank L J

    2010-01-01

    Statin-associated muscle problems are more common than the 1-5% prevalence reported in large clinical trials. Observational studies show a prevalence of about 10%. Muscle problems can occur anytime during statin treatment, but usually occur in the first 6 months. The occurrence of rhabdomyolysis is rare. Depletion of isoprenoids due to HMG-CoA reductase inhibition is probably the main cause of the myopathy. Statin-associated myopathy is treated by prevention and treatment of risk factors. The main risk factors are multiple drug treatment, alcohol abuse, hypothyroidism and a family history of muscle problems due to statin therapy. The first step in the treatment of muscle problems or of elevated creatine kinase levels is lowering or stopping the statin. The chance of another type of statin not having the same muscular effects is about 40%.The benefit of Q10 or other supplements is unproven thus far. In the presence of recurrent creatine kinase elevation or muscle problems, other cholesterol-lowering agents can be considered.

  15. The Anticancer Agent Chaetocin Is a Competitive Substrate and Inhibitor of Thioredoxin Reductase

    PubMed Central

    Tibodeau, Jennifer D.; Benson, Linda M.; Isham, Crescent R.; Owen, Whyte G.

    2009-01-01

    Abstract We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of underlying molecular mechanisms, we now report that chaetocin is a competitive and selective substrate for the oxidative stress mitigation enzyme thioredoxin reductase-1 (TrxR1) with lower Km than the TrxR1 native substrate thioredoxin (Trx; chaetocin Km = 4.6 ± 0.6 μM, Trx Km = 104.7 ± 26 μM), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. Consistent with a role for TrxR1 targeting in the anticancer effects of chaetocin, overexpression of the TrxR1 downstream effector Trx in HeLa cells conferred resistance to chaetocin-induced, but not to doxorubicin-induced, cytotoxicity. As the TrxR/Trx pathway is of central importance in limiting cellular reactive oxygen species (ROS)—and as chaetocin exerts its selective anticancer effects via ROS imposition—the inhibition of TrxR1 by chaetocin has potential to explain its selective anticancer effects. These observations have important implications not just with regard to the mechanism of action and clinical development of chaetocin and related thiodioxopiperazines, but also with regard to the utility of molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents. Antioxid. Redox Signal. 11, 1097–1106. PMID:18999987

  16. Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl-Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

    PubMed Central

    Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A.; Muench, Stephen P.; Zhou, Ying; Lai, Bo-Shiun; Bissati, Kamal El; Hickman, Mark R.; Lee, Patty J.; Leed, Susan E.; Auschwitz, Jennifer M.; Sommervile, Caroline; Woods, Stuart; Roberts, Craig W.; Rice, David; Prigge, Sean T.; McLeod, Rima; Kozikowski, Alan P.

    2013-01-01

    Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was utilized to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogs. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against the recombinant TgENR were 43 and 26 nM, respectively. Additionally, 11 other analogs in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be an excellent starting point for the development of new medicines to effectively treat Toxoplasma gondii infections. PMID:23776166

  17. Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry.

    PubMed

    Upreti, Rita; Naredo, Gregorio; Faqehi, Abdullah M M; Hughes, Katherine A; Stewart, Laurence H; Walker, Brian R; Homer, Natalie Z M; Andrew, Ruth

    2015-01-01

    Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 × 3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 → 97), DHT (m/z 291 → 255), androstenedione (m/z 287 → 97), dutasteride (m/z 529 → 461), finasteride (m/z 373 → 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased. PMID:25281165

  18. The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression.

    PubMed

    Traish, Abdulmaged M; Mulgaonkar, Ashwini; Giordano, Nicholas

    2014-06-01

    With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy. PMID:24955220

  19. Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry.

    PubMed

    Upreti, Rita; Naredo, Gregorio; Faqehi, Abdullah M M; Hughes, Katherine A; Stewart, Laurence H; Walker, Brian R; Homer, Natalie Z M; Andrew, Ruth

    2015-01-01

    Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 × 3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 → 97), DHT (m/z 291 → 255), androstenedione (m/z 287 → 97), dutasteride (m/z 529 → 461), finasteride (m/z 373 → 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.

  20. Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know?

    PubMed

    Traish, Abdulmaged M; Melcangi, Roberto Cosimo; Bortolato, Marco; Garcia-Segura, Luis M; Zitzmann, Michael

    2015-09-01

    Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings. PMID

  1. Effect of coenzyme Q10 supplementation on statin-induced myalgias.

    PubMed

    Bookstaver, David A; Burkhalter, Nancy A; Hatzigeorgiou, Christos

    2012-08-15

    Coenzyme Q10 (CoQ10) deficiency has been proposed to be causal in 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor (statin)-induced myopathies. However, the clinical benefit of supplementation is unproved. The purpose of the present study was to assess the effect of CoQ10 supplementation on myalgias presumed to be caused by statins. Patients currently receiving a statin who developed new-onset myalgias in ≥ 2 extremities within 60 days of initiation or a dosage increase were eligible. Patients continued statin therapy and were randomized using a matched design to either CoQ10 60 mg twice daily or matching placebo. Double-blind treatment continued for 3 months, and patients completed a 10-cm visual analog scale (VAS) and the Short-Form McGill Pain Questionnaire at baseline and at each monthly visit. The primary end point was the comparison of the VAS score at 1 month. A total of 76 patients were enrolled (40 in the CoQ10 arm and 36 in the placebo arm). The mean VAS score was 6 cm at baseline in both groups. At 1 month, no difference was seen in the mean VAS score between the 2 groups (3.9 cm in the CoQ10 group and 4 cm in the placebo group; p = 0.97). However, 5 patients in the CoQ10 group and 3 in the placebo group discontinued therapy during the first month because of myalgias. The baseline median score on the Sensory Pain Rating Index subscale was 10 in the CoQ10 group and 11.5 in the placebo group. At 1 month, these scores had decreased to 6.5 and 7.5, respectively, with no statistically significant difference (p = 0.34). In conclusion, CoQ10 did not produce a greater response than placebo in the treatment of presumed statin-induced myalgias.

  2. The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes.

    PubMed

    Laumen, Helmut; Skurk, Thomas; Hauner, Hans

    2008-02-01

    Human preadipocytes and adipocytes are known to produce the proatherogenic factor PAI-1 and proinflammatory cytokines, and obesity was found to be state of increased adipose production of these factors. In the present study, we investigated the effect of rosuvastatin on the regulation of PAI-1 gene expression in human adipocytes. Human preadipocytes, adipocytes in primary culture and the SGBS cell line were used as cell models. Cells were transfected using various constructs and promoter activity was measured as luciferase activity. PAI-1 expression was measured by quantitative RT-PCR and ELISA. Rosuvastatin inhibited PAI-1 mRNA expression and secretion of the protein in a concentration-dependent manner. This effect was reversed by isoprenoids. Addition of MEK-inhibitors and NFkappaB inhibitors also reduced PAI-1 expression and PAI-1 promoter luciferase activity. Further experiments revealed that rosuvastatin down-regulated the MEKK-1 mediated activation of the PAI-1 promoter. In conclusion our data suggest that rosuvastatin inhibits PAI-1 expression and release from human adipocytes via a MEKK-1-dependent but not a NFkappaB-dependent mechanism.

  3. Design and Synthesis of Aryl Ether Inhibitors of the Bacillus Anthracis Enoyl–ACP Reductase

    PubMed Central

    Tipparaju, Suresh K.; Mulhearn, Debbie C.; Klein, Gary M.; Chen, Yufeng; Tapadar, Subhasish; Bishop, Molly H.; Yang, Shuo; Chen, Juan; Ghassemi, Mahmood; Santarsiero, Bernard D.; Cook, James L.; Johlfs, Mary; Mesecar, Andrew D.; Johnson, Michael E.; Kozikowski, Alan P.

    2009-01-01

    The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. This includes such pathogens as methicillin–resistant Staphylococcus aureus and the potential for developing drug–resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether, antibacterial triclosan exhibits broad–spectrum activity and provides a potential scaffold for the development of new, broad–spectrum antibiotics targeting the fatty acid biosynthetic pathway, via inhibition of enoyl–acyl carrier protein reductase (ENR). We have utilized a structure–based approach to develop novel aryl ether analogs of triclosan that target ENR, the product of the FabI gene, from Bacillus anthracis (BaENR). Structure–based design methods were used for the expansion of the compound series including X-ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2-phenoxyphenyl core. A number of compounds were derived that exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin–resistant strain of S. aureus. X-ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimisation that might be used to improve their potency. PMID:18663709

  4. Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.

    PubMed

    Tipparaju, Suresh K; Mulhearn, Debbie C; Klein, Gary M; Chen, Yufeng; Tapadar, Subhasish; Bishop, Molly H; Yang, Shuo; Chen, Juan; Ghassemi, Mahmood; Santarsiero, Bernard D; Cook, James L; Johlfs, Mary; Mesecar, Andrew D; Johnson, Michael E; Kozikowski, Alan P

    2008-08-01

    The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. Known resistant pathogens such as methicillin-resistant Staphylococcus aureus are becoming more prevalent, while the potential exists for developing drug-resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether antibacterial agent, triclosan, exhibits broad-spectrum activity by targeting the fatty acid biosynthetic pathway through inhibition of enoyl-acyl carrier protein reductase (ENR) and provides a potential scaffold for the development of new, broad-spectrum antibiotics. We used a structure-based approach to develop novel aryl ether analogues of triclosan that target ENR, the product of the fabI gene, from B. anthracis (BaENR). Structure-based design methods were used for the expansion of the compound series including X-ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2-phenoxyphenyl core. A number of compounds exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin-resistant strain of S. aureus. X-ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimization that might be used to improve their potency.

  5. Mechanisms and assessment of statin-related muscular adverse effects.

    PubMed

    Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

    2014-09-01

    Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.

  6. Coenzyme Q10 and statin-related myopathy.

    PubMed

    2015-05-01

    Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is involved in the production of mevalonic acid in the cholesterol biosynthesis pathway. This pathway also results in the production of other bioactive molecules including coenzyme Q10 (also known as ubiquinone or ubidecarenone). Coenzyme Q10 is a naturally-occurring coenzyme with antioxidant effects that is involved in electron transport in mitochondria and is thought to play a role in energy transfer in skeletal muscle. Muscle-related problems are a frequently reported adverse effect of statins, and it has been hypothesised that a reduced endogenous coenzyme Q10 concentration is a cause of statin-induced myopathy. Coenzyme Q10 supplementation has therefore been proposed to reduce the adverse muscular effects sometimes seen with statins. Here, we consider whether coenzyme Q10 has a place in the management of statin-induced myopathy.

  7. Statins enhance cognitive performance in object location test in albino Swiss mice: involvement of beta-adrenoceptors.

    PubMed

    Vandresen-Filho, Samuel; França, Lucas Moreira; Alcantara-Junior, José; Nogueira, Lucas Caixeta; de Brito, Thiago Marques; Lopes, Lousã; Junior, Fernando Mesquita; Vanzeler, Maria Luzinete; Bertoldo, Daniela Bohn; Dias, Paula Gomes; Colla, André R S; Hoeller, Alexandre; Duzzioni, Marcelo; Rodrigues, Ana Lúcia S; de Lima, Thereza C M; Tasca, Carla Inês; Viola, Giordano Gubert

    2015-05-01

    Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby inhibiting cell synthesis of cholesterol and isoprenoids. Moreover, several studies have been evaluating pleiotropic effects of statins, mainly because they present neuroprotective effects in various pathological conditions. However, knowledge about behavioral effects of statins per se is relatively scarce. Considering these facts, we aimed to analyze behavioral responses of atorvastatin or simvastatin-treated mice in the open field test, elevated plus maze and object location test. Atorvastatin treatment for 7 consecutive days at 1 mg/kg or 10 mg/kg (v.o.) or simvastatin 10 mg/kg or 20 mg/kg enhanced cognitive performance in object location test when compared to control group (saline-treated mice). Simvastatin effects on mice performance in the object location test was abolished by post-training infusion of the beta-adrenoceptor antagonist propranolol. Atorvastatin and simvastatin did not change the behavioral response in open field and elevated plus-maze (EPM) tests in any of the used doses. These data demonstrate the positive effects of both statins in cognitive processes in mice, without any alteration in locomotor parameters in the open field test or anxiolytic-like behavior in EPM. In conclusion, we demonstrate that atorvastatin and simvastatin per se improve the cognitive performance in a rodent model of spatial memory and this effect is related to beta-adrenergic receptors modulation.

  8. Novel applications of statins for bone regeneration

    PubMed Central

    Shah, Sarita R.; Werlang, Caroline A.; Kasper, F. Kurtis; Mikos, Antonios G.

    2015-01-01

    The use of statins for bone regeneration is a promising and growing area of research. Statins, originally developed to treat high cholesterol, are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl, the rate-limiting enzyme of the mevalonate pathway. Because the mevalonate pathway is responsible for the synthesis of a wide variety of important biochemical molecules, including cholesterol and other isoprenoids, the effects of statins are pleiotropic. In particular, statins can greatly affect the process of bone turnover and regeneration via effects on important cell types, including mesenchymal stem cells, osteoblasts, endothelial cells, and osteoclasts. Statins have also been shown to have anti-inflammatory and antimicrobial properties that may be useful since infection can derail normal bone healing. This review will explore the pleiotropic effects of statins, discuss the current use of statins for bone regeneration, particularly with regard to biomaterials-based controlled delivery, and offer perspectives on the challenges and future directions of this emerging area of bone tissue engineering. PMID:26543666

  9. Novel antitumor adamantane-azole gold(I) complexes as potential inhibitors of thioredoxin reductase.

    PubMed

    Garcia, Adriana; Machado, Rafael Carvalhaes; Grazul, Richard Michael; Lopes, Miriam Teresa Paz; Corrêa, Charlane Cimini; Dos Santos, Hélio F; de Almeida, Mauro Vieira; Silva, Heveline

    2016-04-01

    Gold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane-1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum-mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand-enzyme complex prior the formation of covalent bond with gold center. The structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds. PMID:26841791

  10. Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo

    SciTech Connect

    Wang Xufang; Zhang Jinsong . E-mail: zjszyzzc@mail.hf.ah.cn; Xu Tongwen

    2007-01-01

    Cyclophosphamide (CTX) is in the nitrogen mustard group of alkylating antineoplastic chemotherapeutic agents. It is one of the most frequently used antitumor agents for the treatment of a broad spectrum of human cancers. Thioredoxin reductase (TrxR) catalyze the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This enzyme represents a promising target for the development of cytostatic agents. The purpose of this study is to determine whether CTX could target TrxR in vivo. Lewis lung carcinoma and solid H22 hepatoma treated with 50-250 mg/kg CTX for 3 h lost TrxR activity in a dose-dependent fashion. Over 75% and 95% of TrxR activity was lost at the dose of 250 mg/kg. There was, however, a recovery of TrxR activity such that it attained normal levels by 120 h after a dose of 250 mg/kg. In addition, we found that CTX caused a preferential TrxR inhibition over other antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase. We also used ascites H22 cells to investigate cancer cells response after TrxR was inhibited by CTX in vivo since CTX is needed to be activated by liver cytochrome P450 enzymes. The time course and dose-dependent changes of cellular TrxR activity were similar with those in tumor tissue. CTX caused a dose-dependent cellular proliferation inhibition which was positively correlated with TrxR inhibition at 3 h. Furthermore, when 3 h CTX-treated cells with various TrxR backgrounds, harvested from ascites-bearing mice, were implanted into mice, the proliferations of these cells were again proportionally dependent on TrxR activity. The TrxR inhibition could thereby be considered as a crucial mechanism contributing to anticancer effect seen upon clinical use of CTX.

  11. Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

    PubMed

    Pfefferkorn, Jeffrey A; Litchfield, John; Hutchings, Richard; Cheng, Xue-Min; Larsen, Scott D; Auerbach, Bruce; Bush, Mark R; Lee, Chitase; Erasga, Noe; Bowles, Daniel M; Boyles, David C; Lu, Gina; Sekerke, Catherine; Askew, Valerie; Hanselman, Jeffrey C; Dillon, Lisa; Lin, Zhiwu; Robertson, Andrew; Olsen, Karl; Boustany, Carine; Atkinson, Karen; Goosen, Theunis C; Sahasrabudhe, Vaishali; Chupka, Jonathan; Duignan, David B; Feng, Bo; Scialis, Renato; Kimoto, Emi; Bi, Yi-An; Lai, Yurong; El-Kattan, Ayman; Bakker-Arkema, Rebecca; Barclay, Paul; Kindt, Erick; Le, Vu; Mandema, Jaap W; Milad, Mark; Tait, Bradley D; Kennedy, Robert; Trivedi, Bharat K; Kowala, Mark

    2011-05-01

    The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

  12. Radiolabelling and positron emission tomography of PT70, a time-dependent inhibitor of InhA, the Mycobacterium tuberculosis enoyl-ACP reductase

    DOE PAGES

    Wang, Hui; Liu, Li; Lu, Yang; Pan, Pan; Hooker, Jacob M.; Fowler, Joanna S.; Tonge, Peter J.

    2015-07-14

    PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24 min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography.

  13. Enzyme-linked immunosorbent assays for doping control of 5alpha-reductase inhibitors finasteride and dutasteride.

    PubMed

    Brun, Eva M; Torres, Ana; Ventura, Rosa; Puchades, Rosa; Maquieira, Angel

    2010-06-25

    Finasteride and dutasteride are 5alpha-reductase inhibitors included in the World Anti-Doping Agency's list of banned substances. Two highly sensitive and selective ELISA assays were developed for these compounds. Polyclonal rabbit antibodies were raised using synthesized haptens and other commercial products. The best immunoassay obtained, based on an antibody-coated format, showed a limit of detection of 0.01 microg L(-1) and an IC(50) of 0.75 microg L(-1) for finasteride (cross-reactivity with dutasteride<4%). The second assay allowed finasteride and dutasteride determination, with limits of detection of 0.013 and 0.021 microg L(-1), and IC(50) values 0.18 and 1.18 microg L(-1), respectively. Both assays were highly selective to a set of anabolic steroids, but they showed 37% and 30% cross-reactivity with the major urinary metabolite of finasteride, allowing its determination. The developed ELISA had better sensitivity than HPLC/MS/MS method and was applied as a screening technique to quantify dutasteride, finasteride, and its main metabolite in human urine without sample pre-treatment. Moreover, the analysis of dutasteride's excretion urines by ELISA was used to obtain its human excretion rate, essential to improve the analytical strategies about this type of drugs (permitted as medicines and prohibited in sport) and to establish an effective anti-doping policy. PMID:20541645

  14. 5-Alpha reductase inhibitors in men with an enlarged prostate: an evaluation of outcomes and therapeutic alternatives.

    PubMed

    Naslund, Michael; Regan, Timothy S; Ong, Christine; Hogue, Susan L

    2008-05-01

    This article presents background information and highlights key findings from a managed care perspective related to enlarged prostate (EP) in Medicare-eligible patients. This article does not provide a comprehensive review of EP but instead attempts to increase the current understanding of EP through discussion of its prevalence in men aged > or =65 years, its associated economic burden, and some available treatment options. This supplement includes 3 additional articles, all of which present data from a naturalistic, managed care setting. The article by Fenter et al assesses differences in outcomes between elderly EP patients treated with finasteride and those treated with dutasteride in relation to the risks of acute urinary retention and prostate-related surgery. Issa et al conduct a comparative analysis of the combined use of alpha-blockers and 5-alpha reductase inhibitors to treat EP. The final article compares medical costs incurred within the first year of initiating treatment for EP patients receiving finasteride versus dutasteride. This supplement is intended to assist managed care formulary decision makers in evaluating key clinical and economic data that differentiate dutasteride and finasteride within the Medicare-aged population. Although the information presented is not designed to illustrate the superiority of one product over the other, it answers important questions in relation to treating EP in elderly men and raises substantial issues beyond medication costs. PMID:18611088

  15. The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer

    PubMed Central

    Sheng, Xiugui; Han, Xiaoyun; Schointuch, Monica N.; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae-Jump, Victoria L.

    2016-01-01

    Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials. PMID:26503475

  16. Growth of LAPC4 prostate cancer xenograft tumor is insensitive to 5α-reductase inhibitor dutasteride.

    PubMed

    Garcia, Raquel Ramos; Masoodi, Khalid Z; Pascal, Laura E; Nelson, Joel B; Wang, Zhou

    2014-01-01

    Intermittent androgen deprivation therapy (IADT) allows prostate cancer patients a break from the side-effects of continuous androgen deprivation therapy (ADT). Although clinical studies suggest that IADT can significantly improve patient quality of life over ADT, it has not been demonstrated to improve patient survival. Recently, increased survival has been demonstrated when 5α-reductase inhibitors have been used during the off-cycle of IADT in animal xenograft tumor models LNCaP and LuCaP35. In the current study, the sensitivity of LAPC4 xenograft tumor regrowth to the 5ARI dutasteride was determined. Tumor regrowth and gene expression changes in LAPC4 tumors were compared to the previously determined response of LNCaP and LuCaP35 xenograft tumors to 5ARI treatment during the off-cycle of IADT, LAPC4, LNCaP and LuCaP35 tumors were sensitive to androgen manipulation. However, in contrast to LNCaP and LuCaP35, dutasteride treatment during testosterone-stimulated prostate regrowth did not affect tumor regrowth or the expression of androgen responsive genes. Tumor response to dutasteride during the off-cycle of IADT is variable in xenograft prostate tumor models. Future studies will be required to elucidate the mechanisms contributing to the dutasteride resistance observed in the LAPC4 model during the off-cycle. PMID:25374909

  17. Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors.

    PubMed

    Desai, N C; Trivedi, A R; Khedkar, Vijay M

    2016-08-15

    A series of novel dihydropyrimidine derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via Biginelli multi-component reaction. The newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR and Mass spectroscopy. In vitro antitubercular evaluation of all the newly synthesized compounds 4a-p against Mycobacterium tuberculosis (Mtb) H37Rv showed, 4j (MIC: 0.39μg/mL; SI: >25.64), 4m (MIC: 0.78μg/mL; SI: >12.82) and 4p (MIC: 0.39μg/mL; SI: 24.10) as the most promising lead analogues. Compounds 4j, 4m and 4p displayed effective reduction in residual Mtb growth within the tuberculosis-infected macrophage model. Further, molecular docking study of active molecules 4j, 4m and 4p against Mycobacterium tuberculosis dihydrofolate reductase (Mtb DHFR) proved their potency as Mtb DHFR inhibitors acting as potential leads for further development. Pharmacokinetic properties leading to drug-likeness were also predicted for most active molecules 4j, 4m and 4p. PMID:27397497

  18. A novel zwitterionic inhibitor of aldose reductase interferes with polyol pathway in ex vivo and in vivo models of diabetic complications.

    PubMed

    Karasova, M Juskova; Prnova, M Soltesova; Stefek, M

    2014-10-01

    Recently a zwitterionic principle has been suggested as an alternative to bioisosteric replacement for increasing low bioavailability of aldose reductase inhibitors bearing an acidic function. In the present work we studied the effect of a novel zwitterionic inhibitor of aldose reductase [(2-benzyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole-8-yl)-acetic acid, compound 1] on sorbitol accumulation in ex vivo and in vivo models of diabetic complications. The effect of 1 on sorbitol accumulation in isolated rat eye lenses incubated with high glucose and in selected organs of streptozotocin-induced diabetic rats was evaluated. Significantly increased sorbitol levels were recorded in the lenses incubated with 50 mM glucose in comparison with controls. Sorbitol production was inhibited by 1 at concentrations of 25 and 100 μM. Under in vivo conditions in diabetic rats, significant elevation of sorbitol levels in selected organs was recorded. Compound 1 administered i.g. for five consecutive days (twice a day 25 mg/kg) inhibited sorbitol accumulation in erythrocytes and the sciatic nerve, yet it was without effect in eye lenses. A similar picture of inhibition was observed after i.p. administration of 1. To conclude, the results suggest that the zwitterionic principle may represent a practicable way of improving bioavailability of aldose reductase inhibitors bearing an acidic function.

  19. Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men

    EPA Science Inventory

    Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. During drug development it was shown that statins inhibit production of cholesterol in the testis. We evaluated testosterone production in vitro, using highly purified rat ...

  20. Statins Promote Long-Term Recovery after Ischemic Stroke by Reconnecting Noradrenergic Neuronal Circuitry

    PubMed Central

    Cho, Kyoung Joo; Cheon, So Young; Kim, Gyung Whan

    2015-01-01

    Inhibitors of HMG-CoA reductase (statins), widely used to lower cholesterol in coronary heart and vascular disease, are effective drugs in reducing the risk of stroke and improving its outcome in the long term. After ischemic stroke, cardiac autonomic dysfunction and psychological problems are common complications related to deficits in the noradrenergic (NA) system. This study investigated the effects of statins on the recovery of NA neuron circuitry and its function after transient focal cerebral ischemia (tFCI). Using the wheat germ agglutinin (WGA) transgene technique combined with the recombinant adenoviral vector system, NA-specific neuronal pathways were labeled, and were identified in the locus coeruleus (LC), where NA neurons originate. NA circuitry in the atorvastatin-treated group recovered faster than in the vehicle-treated group. The damaged NA circuitry was partly reorganized with the gradual recovery of autonomic dysfunction and neurobehavioral deficit. Newly proliferated cells might contribute to reorganizing NA neurons and lead anatomic and functional recovery of NA neurons. Statins may be implicated to play facilitating roles in the recovery of the NA neuron and its function. PMID:26448880

  1. Statin-related myotoxicity.

    PubMed

    Fernandes, Vera; Santos, Maria Joana; Pérez, Antonio

    2016-05-01

    Statin therapy has a very important role in decreasing cardiovascular risk, and treatment non-compliance may therefore be a concern in high cardiovascular risk patients. Myotoxicity is a frequent side effect of statin therapy and one of the main causes of statin discontinuation, which limits effective treatment of patients at risk of or with cardiovascular disease. Because of the high proportion of patients on statin treatment and the frequency of statin-related myotoxicity, this is a subject of concern in clinical practice. However, statin-related myotoxicity is probably underestimated because there is not a gold standard definition, and its diagnosis is challenging. Moreover, information about pathophysiology and optimal therapeutic options is scarce. Therefore, this paper reviews the knowledge about the definition, pathophysiology and predisposing conditions, diagnosis and management of statin-related myotoxicity, and provides a practical scheme for its management in clinical practice.

  2. Statin-related myotoxicity.

    PubMed

    Fernandes, Vera; Santos, Maria Joana; Pérez, Antonio

    2016-05-01

    Statin therapy has a very important role in decreasing cardiovascular risk, and treatment non-compliance may therefore be a concern in high cardiovascular risk patients. Myotoxicity is a frequent side effect of statin therapy and one of the main causes of statin discontinuation, which limits effective treatment of patients at risk of or with cardiovascular disease. Because of the high proportion of patients on statin treatment and the frequency of statin-related myotoxicity, this is a subject of concern in clinical practice. However, statin-related myotoxicity is probably underestimated because there is not a gold standard definition, and its diagnosis is challenging. Moreover, information about pathophysiology and optimal therapeutic options is scarce. Therefore, this paper reviews the knowledge about the definition, pathophysiology and predisposing conditions, diagnosis and management of statin-related myotoxicity, and provides a practical scheme for its management in clinical practice. PMID:27005745

  3. Trends in Statin Use in Seniors 1999 to 2013: Time Series Analysis

    PubMed Central

    Corkum, Amber; Sketris, Ingrid; Fisher, Judith; Zhang, Ying; Saleh, Ahmed

    2016-01-01

    Purpose To examine HMG-CoA reductase inhibitor (statin) drug dispensing patterns to Nova Scotia Seniors' Pharmacare program (NSSPP) beneficiaries over a 14-year period in response to: 1) rosuvastatin market entry in 2003, 2) JUPITER trial publication in 2008, and 3) generic atorvastatin availability in 2010. Methods All NSSPP beneficiaries who redeemed at least one prescription for a statin from April 1, 1999 to March 31, 2013 were included. Aggregated, anonymous monthly prescription counts were extracted by the Nova Scotia Department of Health and Wellness (Nova Scotia, Canada) and changes in dispensing patterns of statins were measured. Data were analyzed using descriptive analyses and interrupted time series methods. Results The percentage of NSSPP beneficiaries dispensed any statin increased from 5.3% in April 1999 to 20.7% in March 2013. In 1999, most NSSPP beneficiaries were dispensed either simvastatin (29.5%) or atorvastatin (28.7%). When rosuvastatin was added to the NSSPP Formulary in August 2003, prescriptions dispensed for simvastatin, lovastatin, pravastatin, and fluvastatin declined significantly (slope change, -0.0027; 95% confidence interval (CI), (-0.0046, -0.0009)). This significant decline continued following the publication of JUPITER (level change, -0.1974; 95% CI, (-0.2991, -0.0957)) and the availability of generic atorvastatin (level change, -0.2436; 95% CI, (-0.3314, -0.1558)). Atorvastatin was not significantly affected by any of the three interventions, although it maintained an overall decreasing trend. Only upon the availability of generic atorvastatin did the upward trend in rosuvastatin use decrease significantly (slope change, -0.0010, 95% CI, (-0.0015, -0.0005)). Conclusions The type and rate of statins dispensed to NSSPP beneficiaries changed from 1999 to 2013 in response to the availability of new agents and publication of the JUPITER trial. The overall proportion of NSSPP beneficiaries dispensed a statin increased approximately 4

  4. Pleiotropic effects of statins in the diseases of the liver.

    PubMed

    Janicko, Martin; Drazilova, Sylvia; Pella, Daniel; Fedacko, Jan; Jarcuska, Peter

    2016-07-21

    Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies. PMID:27468210

  5. Optimal management of combined dyslipidemia: what have we behind statins monotherapy?

    PubMed

    Tenenbaum, Alexander; Fisman, Enrique Z; Motro, Michael; Adler, Yehuda

    2008-01-01

    Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin

  6. Risk of Fractures and Falls during and after 5-α Reductase Inhibitor Use: A Nationwide Cohort Study

    PubMed Central

    Robinson, David; Garmo, Hans; Stattin, Pär; Michaëlsson, Karl

    2015-01-01

    Background Lower urinary tract symptoms are common among older men and 5-α reductase inhibitors (5-ARI) are a group of drugs recommended in treating these symptoms. The effect on prostate volume is mediated by a reduction in dihydrotestosterone; however, this reduction is counterbalanced by a 25% rise in serum testosterone levels. Therefore, 5-ARI use might have systemic effects and differentially affect bone mineral density, muscular mass and strength, as well as falls, all of which are major determinants of fractures in older men. Methods We conducted a nationwide cohort study of all Swedish men who used 5-ARI by comparing their risk of hip fracture, any type of fracture and of falls with matched control men randomly selected from the population and unexposed to 5-ARI. Results During 1 417 673 person-years of follow-up, 10 418 men had a hip fracture, 19 570 any type of fracture and 46 755 a fall requiring hospital care. Compared with unexposed men, current users of 5-ARI had an adjusted hazard ratio (HR) of 0.96 (95% CI 0.91–1.02) for hip fracture, an HR of 0.94 (95% CI 0.90–0.98) for all fracture and an HR of 0.99 (95% CI 0.96–1.02) for falls. Former users had an increased risk of hip fractures (HR 1.10, 95% CI 1.01–1.19). Conclusion 5-ARI is safe from a bone health perspective with an unaltered risk of fractures and falls during periods of use. After discontinuation of 5-ARI, there is a modest increase in the rate of fractures and falls. PMID:26469978

  7. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim

    SciTech Connect

    Heaslet, Holly; Harris, Melissa; Fahnoe, Kelly; Sarver, Ronald; Putz, Henry; Chang, Jeanne; Subramanyam, Chakrapani; Barreiro, Gabriela; Miller, J. Richard; Pfizer

    2010-09-02

    Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites. Because of its importance in multiple cellular functions, DHFR has been the subject of much research targeting the enzyme with anticancer, antibacterial, and antimicrobial agents. Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections. DAP inhibitors of DHFR have been used clinically for >30 years and resistance to these agents has become widespread. Methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of many serious nosocomial and community acquired infections, and other gram-positive organisms can show resistance to DAPs through mutation of the chromosomal gene or acquisition of an alternative DHFR termed 'S1 DHFR.' To develop new therapies for health threats such as MRSA, it is important to understand the molecular basis of DAP resistance. Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP. We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP. The structural and thermodynamic data point to important molecular differences between the two enzymes that lead to dramatically reduced affinity of DAPs to S1 DHFR. These differences in enzyme binding affinity translate into reduced antibacterial activity against strains of S. aureus that express S1 DHFR.

  8. Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

    SciTech Connect

    Zeng, Ke-Wu; Li, Jun; Dong, Xin; Wang, Ying-Hong; Ma, Zhi-Zhong; Jiang, Yong; Jin, Hong-Wei; Tu, Peng-Fei

    2013-11-15

    Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators. Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.

  9. Potentiated cytotoxic effects of statins and ajoene in murine melanoma cells.

    PubMed

    Ledezma, Eliades; Wittig, Olga; Alonso, Jose; Cardier, Jose E

    2009-04-01

    Because statins and ajoene inhibit the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, we evaluated the hypothesis that the cytotoxic effect of these compounds may be potentiated when both are used in combination on tumor cells. We showed that cotreatment of the murine melanoma B16F10 cell with statins (atorvastatin and pravastatin) and ajoene, all at nontoxic doses, dramatically increased their cytotoxicity. B16F10 cell death induced by statins, but not by ajoene, was prevented by mevalonate and geranylgeranylpyrophosphate. To our knowledge, this is the first report that the combination of statins and ajoene, which alters the mevalonate pathway, might potentiate their cytotoxic effects on tumor cells.

  10. Statins: An undesirable class of aquatic contaminants?

    PubMed

    Santos, Miguel M; Ruivo, Raquel; Lopes-Marques, Mónica; Torres, Tiago; de los Santos, Carmen B; Castro, L Filipe C; Neuparth, Teresa

    2016-05-01

    Emerging pollutants, such as pharmaceuticals, may pose a considerable environment risk. Hypocholesterolaemic drugs such as statins are among the most prescribed human pharmaceuticals in western European countries. In vertebrates, this therapeutic class disrupts the cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), responsible for the limiting step in the mevalonate pathway. Recently, functional studies have shown that statins competitively inhibit HMGR in vertebrates and arthropods, two taxa that have diverged over 450 million years ago. Importantly, chronic simvastatin exposure disrupts crustacean reproduction and development at environmentally relevant concentrations. Hence, a fundamental question emerges: what is the taxonomic scope of statins-induced HMGR inhibition across metazoans? Here, we address this central question in a large sampling of metazoans using comparative genomics, homology modelling and molecular docking. Sequence alignment of metazoan HMGRs allowed the annotation of highly conserved catalytic, co-factor and substrate binding sites, including residues highjacked for statin binding. Furthermore, molecular docking shows that the catalytic domains of metazoan HMGRs are highly conserved regarding interactions, not only with HMG-CoA, but also with both simvastatin and atorvastatin, the top prescribed statins in Europe and USA. Hence, the data indicates that both statins are expected to competitively inhibit metazoan's HMGRs, and therefore all metazoan taxa might be at risk. The environmental relevance of these findings are discussed and research priorities established. We believe that the conceptual framework used in this study can be applied to other emerging pollutants and assist in the design of toxicity testing and risk assessment. PMID:26896816

  11. HMG-CoA reductase inhibitory activity and phytocomponent investigation of Basella alba leaf extract as a treatment for hypercholesterolemia.

    PubMed

    Baskaran, Gunasekaran; Salvamani, Shamala; Ahmad, Siti Aqlima; Shaharuddin, Noor Azmi; Pattiram, Parveen Devi; Shukor, Mohd Yunus

    2015-01-01

    The enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of the mevalonate pathway that produces cholesterol. Inhibition of HMG-CoA reductase reduces cholesterol biosynthesis in the liver. Synthetic drugs, statins, are commonly used for the treatment of hypercholesterolemia. Due to the side effects of statins, natural HMG-CoA reductase inhibitors of plant origin are needed. In this study, 25 medicinal plant methanol extracts were screened for anti-HMG-CoA reductase activity. Basella alba leaf extract showed the highest inhibitory effect at about 74%. Thus, B. alba was examined in order to investigate its phytochemical components. Gas chromatography with tandem mass spectrometry and reversed phase high-performance liquid chromatography analysis revealed the presence of phenol 2,6-bis(1,1-dimethylethyl), 1-heptatriacotanol, oleic acid, eicosyl ester, naringin, apigenin, luteolin, ascorbic acid, and α-tocopherol, which have been reported to possess antihypercholesterolemic effects. Further investigation of in vivo models should be performed in order to confirm its potential as an alternative treatment for hypercholesterolemia and related cardiovascular diseases. PMID:25609924

  12. HMG-CoA reductase inhibitory activity and phytocomponent investigation of Basella alba leaf extract as a treatment for hypercholesterolemia

    PubMed Central

    Baskaran, Gunasekaran; Salvamani, Shamala; Ahmad, Siti Aqlima; Shaharuddin, Noor Azmi; Pattiram, Parveen Devi; Shukor, Mohd Yunus

    2015-01-01

    The enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of the mevalonate pathway that produces cholesterol. Inhibition of HMG-CoA reductase reduces cholesterol biosynthesis in the liver. Synthetic drugs, statins, are commonly used for the treatment of hypercholesterolemia. Due to the side effects of statins, natural HMG-CoA reductase inhibitors of plant origin are needed. In this study, 25 medicinal plant methanol extracts were screened for anti-HMG-CoA reductase activity. Basella alba leaf extract showed the highest inhibitory effect at about 74%. Thus, B. alba was examined in order to investigate its phytochemical components. Gas chromatography with tandem mass spectrometry and reversed phase high-performance liquid chromatography analysis revealed the presence of phenol 2,6-bis(1,1-dimethylethyl), 1-heptatriacotanol, oleic acid, eicosyl ester, naringin, apigenin, luteolin, ascorbic acid, and α-tocopherol, which have been reported to possess antihypercholesterolemic effects. Further investigation of in vivo models should be performed in order to confirm its potential as an alternative treatment for hypercholesterolemia and related cardiovascular diseases. PMID:25609924

  13. Pleiotropic effects of statins in the diseases of the liver

    PubMed Central

    Janicko, Martin; Drazilova, Sylvia; Pella, Daniel; Fedacko, Jan; Jarcuska, Peter

    2016-01-01

    Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins’ potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies. PMID:27468210

  14. Evaluation of epigallocatechin gallate and related plant polyphenols as inhibitors of the FabG and FabI reductases of bacterial type II fatty-acid synthase.

    PubMed

    Zhang, Yong-Mei; Rock, Charles O

    2004-07-23

    Epigallocatechin gallate (EGCG) is the major component of green tea extracts and possesses antibacterial, antiviral, and antitumor activity. Our study focused on validating the inhibition of the bacterial type II fatty acid synthesis system as a mechanism for the antibacterial effects of EGCG and related plant polyphenols. EGCG and the related tea catechins potently inhibited both the FabG and FabI reductase steps in the fatty acid elongation cycle with IC(50) values between 5 and 15 microm. The presence of the galloyl moiety was essential for activity, and EGCG was a competitive inhibitor of FabI and a mixed type inhibitor of FabG demonstrating that EGCG interfered with cofactor binding in both enzymes. EGCG inhibited acetate incorporation into fatty acids in vivo, although it was much less potent than thiolactomycin, a validated fatty acid synthesis inhibitor, and overexpression of FabG, FabI, or both did not confer resistance. A panel of other plant polyphenols was screened for FabG/FabI inhibition and antibacterial activity. Most of these inhibited both reductase steps, possessed antibacterial activity, and inhibited cellular fatty acid synthesis. The ability of the plant secondary metabolites to interfere with the activity of multiple NAD(P)-dependent cellular processes must be taken into account when assessing the specificity of their effects.

  15. Pleiotropic effects of statins: new therapeutic targets in drug design.

    PubMed

    Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

    2016-07-01

    The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins. PMID:27146293

  16. Drosophila Lung Cancer Models Identify Trametinib Plus Statin as Candidate Therapeutic

    PubMed Central

    Levine, Benjamin D.

    2016-01-01

    Summary We have developed a Drosophila lung cancer model by targeting Ras1G12V—alone or in combination with PTEN knockdown—to the Drosophila tracheal system. This led to overproliferation of tracheal tissue, formation of tumor-like growths, and animal lethality. Screening a library of FDA approved drugs identified several that improved overall animal survival. We explored two hits: the MEK inhibitor trametinib and the HMG-CoA reductase inhibitor fluvastatin. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively; in addition, fluvastatin inhibited protein prenylation downstream of HMG-CoA reductase to promote survival. Combining drugs led to synergistic suppression of tumor formation and rescue lethality; similar synergy was observed in human A549 lung adenocarcinoma cells. Notably, fluvastatin acted both within transformed cells and also to reduce whole body trametinib toxicity in flies. Our work supports and provides further context for exploring the potential of combining statins with MAPK inhibitors such as trametinib to improve overall therapeutic index. PMID:26832408

  17. HMG-CoA Reductase Inhibitor Improves Endothelial Dysfunction in Spontaneous Hypertensive Rats Via Down-regulation of Caveolin-1 and Activation of Endothelial Nitric Oxide Synthase

    PubMed Central

    Suh, Jung-Won; Chang, Hyuk-Jae; Cho, Young-Seok; Youn, Tae-Jin; Chae, In-Ho; Kim, Kwang-Il; Kim, Cheol-Ho; Kim, Hyo-soo; Oh, Buyng-Hee; Park, Young-Bae

    2010-01-01

    Hypertension is associated with endothelial dysfunction and increased cardiovascular risk. Caveolin-1 regulates nitric oxide (NO) signaling by modulating endothelial nitric oxide synthase (eNOS). The purpose of this study was to examine whether HMG-CoA reductase inhibitor improves impaired endothelial function of the aorta in spontaneous hypertensive rat (SHR) and to determine the underlying mechanisms involved. Eight-week-old male SHR were assigned to either a control group (CON, n=11) or a rosuvastatin group (ROS, n=12), rosuvastatin (10 mg/kg/day) administered for eight weeks. Abdominal aortic rings were prepared and responses to acetylcholine (10-9-10-4 M) were determined in vitro. To evaluate the potential role of NO and caveolin-1, we examined the plasma activity of NOx, eNOS, phosphorylated-eNOS and expression of caveolin-1. The relaxation in response to acetylcholine was significantly enhanced in ROS compared to CON. Expression of eNOS RNA was unchanged, whereas NOx level and phosphorylated-eNOS at serine-1177 was increased accompanied with depressed level of caveolin-1 in ROS. We conclude that 3-Hydroxy-3-methylglutaryl Coenzyme-A (HMG-CoA) reductase inhibitor can improve impaired endothelial dysfunction in SHR, and its underlying mechanisms are associated with increased NO production. Furthermore, HMG-CoA reductase inhibitor can activate the eNOS by phosphorylation related to decreased caveolin-1 abundance. These results imply the therapeutic strategies for the high blood pressure-associated endothelial dysfunction through modifying caveolin status. PMID:20052342

  18. Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase.

    PubMed

    Talawanich, Yuwadee; Kamchonwongpaisan, Sumalee; Sirawaraporn, Worachart; Yuthavong, Yongyuth

    2015-09-01

    Interaction between antimalarial drugs is important in determining the outcome of chemotherapy using drug combinations. Inhibitors of dihydrofolate reductase (DHFR) such as pyrimethamine and of dihydropteroate synthase (DHPS) such as sulfa drugs are known to have synergistic interactions. However, studies of the synergism are complicated by the fact that the malaria parasite can also salvage exogenous folates, and the salvage may also be affected by the drugs. It is desirable to have a convenient system to study interaction of DHFR and DHPS inhibitors without such complications. Here, we describe the use of Escherichia coli transformed with malarial DHFR and DHPS, while its own corresponding genes have been inactivated by optimal concentration of trimethoprim and genetic knockout, respectively, to study the interaction of the inhibitors. Marked synergistic effects are observed for all combinations of pyrimethamine and sulfa inhibitors in the presence of trimethoprim. At 0.05μM trimethoprim, sum of fractional inhibitory concentrations, ΣFIC of pyrimethamine with sulfadoxine, pyrimethamine with sulfathiazole, pyrimethamine with sulfamethoxazole, and pyrimethamine with dapsone are in the range of 0.24-0.41. These results show synergism between inhibitors of the two enzymes even in the absence of folate transport and uptake. This bacterial surrogate system should be useful as a tool for assessing the interactions of drug combinations between the DHFR and DHPS inhibitors.

  19. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB

    PubMed Central

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved. PMID:26069888

  20. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB.

    PubMed

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved. PMID:26069888

  1. 1H and 13C NMR Chemical Shift Assignments and Conformational Analysis for the Two Diastereomers of the Vitamin K Epoxide Reductase Inhibitor Brodifacoum

    SciTech Connect

    Cort, John R.; Cho, Herman M.

    2009-10-01

    Proton and 13C NMR chemical shift assignments and 1H-1H scalar couplings for the two diastereomers of the vitamin K epoxide reductase (VKOR) inhibitor brodifacoum have been determined from acetone solutions containing both diastereomers. Data were obtained from homo- and heteronuclear correlation spectra acquired at 1H frequencies of 750 and 900 MHz over a 268-303 K temperature range. Conformations inferred from scalar coupling and 1-D NOE measurements exhibit large differences between the diastereomers. Pacific Northwest National Laboratory is operated by Battelle for the US Department of Energy.

  2. Design of an Amide N-glycoside Derivative of β-Glucogallin: A Stable, Potent, and Specific Inhibitor of Aldose Reductase

    PubMed Central

    Li, Linfeng; Chang, Kun-Che; Zhou, Yaming; Shieh, Biehuoy; Ponder, Jessica; Abraham, Adedoyin D.; Ali, Hadi; Snow, Anson; Petrash, J. Mark; LaBarbera, Daniel V.

    2014-01-01

    β-glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose-reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original 2-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent and selective lead therapeutic toward the treatment of diabetic eye disease. PMID:24341381

  3. [Problems with statins and the marketing of these medications].

    PubMed

    Whayne, Thomas F

    2010-04-01

    All statins inhibit hydroxymethylglutaryl Coenzyme A Reductase but each has a different chemical structure that may have individual advantages. Some pharmaceutical companies have minimized side effects and stated that dose has no relation to incidence. To the contrary, dose is related to side effects with all statins. Myopathy occurs in up to 10.5% of patients taking a high dose. There is an attempt to sell statins that have lost patent protection over-the-counter. However, evidence supports medical supervision as offering greatest patient safety. Concerns were raised about ezetimibe after the initial ENHANCE (efficacy) and SEAS (cancer risk) study but these concerns appear to have been answered. Fenofibrate can be used with a statin but gemfibrozil is contraindicated. Coenzyme Q-10 possibly helps to mitigate the risk of myopathy with a statin but evidence is not universally accepted. JUPITER represented a valid outcomes study but made a claim that rosuvastatin has special value in risk management because of decreased high sensitivity C-Reactive Protein. This actually occurs with any statin, a decrease also enhanced by ezetimibe. Statins have benefited the lives of our patients but, as with any treatment, the physician needs to look critically at all the problems and claims made.

  4. Statin Use and Risk of Primary Liver Cancer in the Clinical Practice Research Datalink

    PubMed Central

    Hagberg, Katrina; Chen, Jie; Graubard, Barry I.; London, W. Thomas; Jick, Susan; Sahasrabuddhe, Vikrant V.

    2015-01-01

    Background: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed to reduce cholesterol levels. Studies have suggested that statins are associated with reduced risk of liver cancer, but much of the evidence is from regions of the world with high liver cancer incidence rates. The current study examined the statins–liver cancer relationship in a low-rate region and examined the effects of preexisting liver disease and diabetes on that association. Methods: A nested case-control study was conducted within the United Kingdom’s Clinical Practice Research Datalink (CPRD). Persons diagnosed with primary liver cancer between 1988 and 2011 were matched to controls at a four-to-one ratio. Matches stratified on liver disease and on diabetes were also completed. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations of statins with liver cancer were estimated using conditional logistic regression. Results: In total, 1195 persons with primary liver cancer were matched to 4640 control patients. Statin use was associated with a statistically significantly reduced risk of liver cancer (ORadj = 0.55, 95% CI = 0.45 to 0.69), especially among current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). The reduced risk was statistically significant in the presence (ORadj = 0.32, 95% CI = 0.17 to 0.57) and absence of liver disease (ORadj = 0.65, 95% CI = 0.52 to 0.81) and in the presence (ORadj = 0.30, 95% CI = 0.21 to 0.42) and absence of diabetes (ORadj = 0.66, 95% CI = 0.51 to 0.85). Conclusions: In the current study in a low-rate area, statin use was associated with a statistically significantly reduced risk of liver cancer overall. Risk was particularly reduced among persons with liver disease and persons with diabetes, suggesting that statin use may be especially beneficial in persons at elevated risk of liver cancer. PMID:25722350

  5. Statin therapy: rationale for a new agent, rosuvastatin.

    PubMed

    Korlipara, K

    2002-06-01

    Cardiovascular disease (CVD) remains a major cause of death in industrialised societies, and elevated serum lipids are a significant, highly prevalent and undertreated risk factor for this condition. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have revolutionised the treatment of hyperlipidaemia, and results from large-scale, long-term clinical trials have shown that the substantial reductions in low-density lipoprotein cholesterol (LDL-C) achieved with these drugs are associated with dramatic decreases in cardiovascular risk. Results from recent comparative clinical trials that have included a new drug in this class, rosuvastatin (Crestor), have demonstrated that it is significantly superior to atorvastatin, pravastatin and simvastatin in reducing total cholesterol, LDL-C and apolipoprotein B (Apo B). It is also significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I). Rosuvastatin was also superior to all these agents in helping patients meet European Atherosclerosis Society (EAS) and National Cholesterol Education Programme (NCEP) goals for LDL-C. The results of an increasing number of studies indicate that statins have a wide range of pleiotropic properties that almost certainly contribute to their ability to decrease cardiovascular risk and may also make them valuable for treatment of other diseases. These actions include plaque stabilisation, improvement of endothelial function, inhibition of smooth muscle cell proliferation and migration, reduction of expression of adhesion molecules, prevention of cholesterol esterification and accumulation, reduction of secretion of matrix metalloproteinases by macrophages, reduction of platelet activity, reduction of formation of thrombogenic factors, chemoprotection and induction of bone morphogenic protein-2 (BMP-2). Further exploration of these actions will provide key information about class effects

  6. Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study.

    PubMed

    Kamsri, Pharit; Punkvang, Auradee; Saparpakorn, Patchareenart; Hannongbua, Supa; Irle, Stephan; Pungpo, Pornpan

    2014-07-01

    Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R1 substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R3 and R4 positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R2 substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD(+) and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA. PMID:24935113

  7. Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study.

    PubMed

    Kamsri, Pharit; Punkvang, Auradee; Saparpakorn, Patchareenart; Hannongbua, Supa; Irle, Stephan; Pungpo, Pornpan

    2014-07-01

    Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R1 substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R3 and R4 positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R2 substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD(+) and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA.

  8. The role of 5-alpha reductase inhibitors in prostate pathophysiology: Is there an additional advantage to inhibition of type 1 isoenzyme?

    PubMed

    Goldenberg, Larry; So, Alan; Fleshner, Neil; Rendon, Ricardo; Drachenberg, Darrel; Elhilali, Mostafa

    2009-06-01

    Normal growth and function of the prostate are contingent on the reduction of testosterone to dihydrotestosterone (DHT) by 5-alpha reductase (5-AR) enzymes types 1 and 2. It has been theorized that an overabundance of DHT may be implicated in the pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. Inhibitors of 5-AR such as dutasteride and finasteride may therefore have an important role in the prevention and treatment of BPH and prostate cancer. Dutasteride provides greater suppression of DHT than finasteride, thereby underlying the hypothesis that inhibition of both type 1 and type 2 would provide correspondingly greater protection than inhibition of type 2 alone. We review the potential significance of the 5-AR inhibitors in reducing the risk of prostate cancer according to the basic biology of prostate disease. PMID:19543428

  9. Structural and Biological Evaluation of a Novel Series of Benzimidazole Inhibitors of Francisella tularensis Enoyl-ACP Reductase (FabI)

    PubMed Central

    Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E; Su, Pin-Chih; Boci, Teuta; Brubaker, Libby; Truong, Lena; Mistry, Tina; Deng, Jiangping; Cook, James L; Santarsiero, Bernard D; Ghosh, Arun K; Johnson, Michael E

    2015-01-01

    Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and S. aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity. PMID:25677657

  10. Statin Intolerance: the Clinician's Perspective.

    PubMed

    Stulc, Tomáš; Ceška, Richard; Gotto, Antonio M

    2015-12-01

    Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.

  11. New Drugs for Treating Dyslipidemia: Beyond Statins

    PubMed Central

    Ahn, Chang Ho

    2015-01-01

    Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment. PMID:25922802

  12. Selective induction of apoptosis in the hamster flank sebaceous gland organ by a topical liposome 5-alpha-reductase inhibitor: a treatment strategy for acne.

    PubMed

    Li, Lingna; Tang, Li; Baranov, Eugene; Yang, Meng; Amoh, Yasuyuki; Katsuoka, Kensei; Hoffman, Robert M

    2010-02-01

    Acne is a very widespread cosmesis problem. Isotretinoin, a synthetic oral retinoid is used to treat acne, which is androgen dependent. Numerous side-effects occur from this treatment. 5-alpha-Reductase plays a critical role in normal and pathological androgen-dependent processes. We have taken the approach to develop a selective, effective, topically-applied 5-alpha-reductase inhibitor to modify unwanted or pathological processes in the pilosebaceous unit such as acne. Toward this goal, we have previously developed a selective liposome hair follicle targeting system. We demonstrate in this report that the 5-alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide (4-MA) incorporated into liposomes induces apoptosis and inhibits growth of the dihydrotestosterone (DHT)-dependent hamster flank organ sebaceous gland. We have compared topical application of liposome 4-MA and solvent-formulated 4-MA and observed selective efficacy of topical application of liposome 4-MA by the reduction of size and induction of apoptosis only in the treated hamster flank organ. Apoptosis induced by liposome 4-MA in the treated flank organ sebaceous gland cells was observed both by assays for DNA fragments (transferase deoxytidyl uridine end labeling) and by observation of condensed and fragmented nuclei. When 4-MA was topically applied formulated in ethanol and glycerol without liposomes, the selective efficacy was lost. Liposome 4-MA did not significantly affect prostate weight, testosterone/DHT ratios or bodyweight gain compared to controls indicating safety as well as efficacy of topical application of liposome 4-MA for pathological processes such as acne. PMID:20175850

  13. Managing the underestimated risk of statin-associated myopathy.

    PubMed

    Rallidis, Loukianos S; Fountoulaki, Katerina; Anastasiou-Nana, Maria

    2012-09-01

    In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.

  14. Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.

    PubMed

    Leite, Franco Henrique A; Santiago, Priscila Brandão Gomes da Silva; Froes, Thamires Quadros; da Silva Filho, João; da Silva, Suellen Gonçalves; Ximenes, Rafael M; de Faria, Antônio Rodolfo; Brondani, Dalci José; de Albuquerque, Julianna F C; Castilho, Marcelo Santos

    2016-11-10

    Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 μM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors. PMID:27517809

  15. Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents.

    PubMed

    Maccari, Rosanna; Vitale, Rosa Maria; Ottanà, Rosaria; Rocchiccioli, Marco; Marrazzo, Agostino; Cardile, Venera; Graziano, Adriana Carol Eleonora; Amodeo, Pietro; Mura, Umberto; Del Corso, Antonella

    2014-06-23

    A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammatory processes associated both to diabetes mellitus and to other pathologies. In vitro inhibitory activity indicated that compounds 6-9a-d were generally good AR inhibitors. Acetic acid derivatives 8a-d and 9a-d were shown to be the best enzyme inhibitors among the tested compounds endowed with significant inhibitory ability levels reaching submicromolar IC50 values. Moreover, some representative AR inhibitors (7a, 7c, 9a, 9c, 9d) were assayed in cultures of human keratinocytes in order to evaluate their capability to reduce NF-kB activation and iNOS expression. Compound 9c proved to be the best derivative endowed with both interesting AR inhibitory effectiveness and ability to reduce NF-kB activation and iNOS expression. Molecular docking and molecular dynamics simulations were undertaken to investigate the binding modes of selected compounds into the active site of AR in order to rationalize the inhibitory effectiveness of these derivatives.

  16. Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase, a Potent Drug Target for Diabetes and Its Complications

    PubMed Central

    Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh

    2013-01-01

    Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects. PMID:23613832

  17. Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.

    PubMed

    Leite, Franco Henrique A; Santiago, Priscila Brandão Gomes da Silva; Froes, Thamires Quadros; da Silva Filho, João; da Silva, Suellen Gonçalves; Ximenes, Rafael M; de Faria, Antônio Rodolfo; Brondani, Dalci José; de Albuquerque, Julianna F C; Castilho, Marcelo Santos

    2016-11-10

    Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 μM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.

  18. MedlinePlus: Statins

    MedlinePlus

    ... Clinical Trials. Article: Perioperative Rosuvastatin in Cardiac Surgery. Article: In primary prevention, the ACC/AHA risk-based approach predicted ASCVD better... Statins -- see more articles Find an Expert American Heart Association Food and ...

  19. Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function

    SciTech Connect

    Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D.

    2009-07-10

    We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.

  20. An Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase Enzymes

    PubMed Central

    Arooj, Mahreen; Sakkiah, Sugunadevi; Cao, Guang ping; Lee, Keun Woo

    2013-01-01

    Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. We have developed a novel computational approach by integrating the affinity predictions from structure-based virtual screening with dual ligand-based pharmacophore to discover potential dual inhibitors of human Thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR). These are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA, DNA, and protein. Their inhibition has found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. A druglike database was utilized to perform dual-target docking studies. Hits identified through docking experiments were mapped over a dual pharmacophore which was developed from experimentally known dual inhibitors of hTS and hDHFR. Pharmacophore mapping procedure helped us in eliminating the compounds which do not possess basic chemical features necessary for dual inhibition. Finally, three structurally diverse hit compounds that showed key interactions at both active sites, mapped well upon the dual pharmacophore, and exhibited lowest binding energies were regarded as possible dual inhibitors of hTS and hDHFR. Furthermore, optimization studies were performed for final dual hit compound and eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of hTS and hDHFR. In general, the strategy used in the current study could be a promising computational approach and may be generally applicable to other dual target drug designs. PMID:23577115

  1. Statin-induced Myopathy.

    PubMed

    Fitzgerald, Kara; Redmond, Elizabeth; Harbor, Cathryn

    2012-05-01

    Heart disease (HD) is the number one killer in the United States.(1) In 2006, the direct and indirect costs associated with cardiovascular disease in the United States were estimated at 400 billion dollars.(2) Statin therapy for cholesterol reduction is a mainstay intervention for cardiovascular disease (CVD) as reflected in atorvastatin's status as the number one prescribed medication in the United States.(3) Statin therapy, however, is also associated with side effects that signal mitochondrial distress. A commonly reported statin-induced symptom is myalgia, which is defined as muscle pain without an associated elevation of serum creatine kinase (CK). In clinical trials, the reports of myalgia vary from less than 1% to 25% of patients.(4) Myopathy is a general term defined as an abnormal condition or disease of muscle tissue. Myopathy includes myalgia, myositis (inflammation of muscle tissue associated with elevated CK) and the very serious condition rhabdomyolysis (extreme myositis). Histological findings in statin-induced myopathy demonstrate electron chain dysfunction making "mitochondrial myopathy" the more precise term.(5) Mitochondrial myopathy has been associated with statin-induced CoQ10 depletion.(5) Given the density of mitochondria in cardiomyocytes, and CoQ10's role in mitochondrial energy production, depletion has long been associated with increased risk for heart disease.(6-7) In the case below, mitochondrial-specific organic acids, serum CoQ10, vitamin D and clinical history all suggest statin-induced mitochondrial myopathy, despite normal serum CK.

  2. Inhibition of Human Steroid 5-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex

    SciTech Connect

    Drury, J.; Di Costanzo, L; Penning, T; Christianson, D

    2009-01-01

    The {Delta}{sup 4}-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5{alpha}- or 5{beta}-reductase. Finasteride is a mechanism-based inactivator of 5{alpha}-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5{beta}-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1 {center_dot} NADP{sup +} {center_dot} finasteride complex determined at 1.7 {angstrom} resolution shows that it is not possible for NADPH to reduce the {Delta}{sup 1-2}-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.

  3. DNA cleavage, antimicrobial studies and a DFT-based QSAR study of new antimony(III) complexes as glutathione reductase inhibitor.

    PubMed

    Tunç, Turgay; Koç, Yasemin; Açık, Leyla; Karacan, Mehmet Sayım; Karacan, Nurcan

    2015-02-01

    New antimony(III) complexes, [Sb(2-aminopyridine)2Cl3] (1a), [Sb(2-aminopyridine)2Br3] (1b), [Sb(5-methyl-2-aminopyridine)2Cl3] (2a), [Sb(5-methyl-2-aminopyridine)2Br3] (2b), [Sb(2-aminopyrimidine)2Cl3] (3a), [Sb(2-aminopyrimidine)2Br3] (3b), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Cl3] (4a), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Br3] (4b), [Sb(2-amino-1,3,5-triazine)2Cl3] (5a), [Sb(2-amino-1,3,5-triazine)2Br3] (5b), [Sb(2-guanidinobenzimidazole) Cl3] (6a), [Sb(2-guanidinobenzimidazole)Br3] (6b) [Sb(2- benzyl-2-thiopseudeourea)2Cl3] (7a) and [Sb(2- benzyl-2-thiopseudeourea)2Br3] (7b) were synthesized. Their structures were characterized by elemental analysis, molecular conductivity, FT-IR, (1)H NMR, LC-MS techniques. Glutathione reductase inhibitor activity, antimicrobial activity and DNA cleavage studies of the complexes were determined. The geometrical structures of the complexes were optimized by DFT/B3LYP method with LANL2DZ as basis set. Calculation results indicated that the equilibrium geometries of all complexes have square pyramidal shape. About 350 molecular descriptors (constitutional, topological, geometrical, electrostatic and quantum chemical parameters) of the complexes were calculated by DFT/B3LYP/LANL2DZ method with CODESSA software. Calculated molecular parameters were correlated to glutathione reductase inhibitory activity values (pIC50) of all complexes by Best Multi-Linear Regression (BMLR) method. Obtained two-parameter QSAR equation shows that increase in "maximum partial charge for a H atom" and decrease in HOMO-LUMO gap would be favorable for the glutathione reductase inhibitory activity. PMID:25459701

  4. Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1.

    PubMed

    Silva-Ortiz, Aylin Viviana; Bratoeff, Eugene; Ramírez-Apan, Teresa; Heuze, Yvonne; Sánchez, Araceli; Soriano, Juan; Cabeza, Marisa

    2015-12-15

    Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3β-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.

  5. DNA cleavage, antimicrobial studies and a DFT-based QSAR study of new antimony(III) complexes as glutathione reductase inhibitor

    NASA Astrophysics Data System (ADS)

    Tunç, Turgay; Koç, Yasemin; Açık, Leyla; Karacan, Mehmet Sayım; Karacan, Nurcan

    2015-02-01

    New antimony(III) complexes, [Sb(2-aminopyridine)2Cl3] (1a), [Sb(2-aminopyridine)2Br3] (1b), [Sb(5-methyl-2-aminopyridine)2Cl3] (2a), [Sb(5-methyl-2-aminopyridine)2Br3] (2b), [Sb(2-aminopyrimidine)2Cl3] (3a), [Sb(2-aminopyrimidine)2Br3] (3b), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Cl3] (4a), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Br3] (4b), [Sb(2-amino-1,3,5-triazine)2Cl3] (5a), [Sb(2-amino-1,3,5-triazine)2Br3] (5b), [Sb(2-guanidinobenzimidazole) Cl3] (6a), [Sb(2-guanidinobenzimidazole)Br3] (6b) [Sb(2- benzyl-2-thiopseudeourea)2Cl3] (7a) and [Sb(2- benzyl-2-thiopseudeourea)2Br3] (7b) were synthesized. Their structures were characterized by elemental analysis, molecular conductivity, FT-IR, 1H NMR, LC-MS techniques. Glutathione reductase inhibitor activity, antimicrobial activity and DNA cleavage studies of the complexes were determined. The geometrical structures of the complexes were optimized by DFT/B3LYP method with LANL2DZ as basis set. Calculation results indicated that the equilibrium geometries of all complexes have square pyramidal shape. About 350 molecular descriptors (constitutional, topological, geometrical, electrostatic and quantum chemical parameters) of the complexes were calculated by DFT/B3LYP/LANL2DZ method with CODESSA software. Calculated molecular parameters were correlated to glutathione reductase inhibitory activity values (pIC50) of all complexes by Best Multi-Linear Regression (BMLR) method. Obtained two-parameter QSAR equation shows that increase in "maximum partial charge for a H atom" and decrease in HOMO-LUMO gap would be favorable for the glutathione reductase inhibitory activity.

  6. Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1.

    PubMed

    Silva-Ortiz, Aylin Viviana; Bratoeff, Eugene; Ramírez-Apan, Teresa; Heuze, Yvonne; Sánchez, Araceli; Soriano, Juan; Cabeza, Marisa

    2015-12-15

    Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3β-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity. PMID:26631442

  7. Construction of an Indonesian herbal constituents database and its use in Random Forest modelling in a search for inhibitors of aldose reductase.

    PubMed

    Naeem, Sadaf; Hylands, Peter; Barlow, David

    2012-02-01

    Data on phytochemical constituents of plants commonly used in traditional Indonesian medicine have been compiled as a computer database. This database (the Indonesian Herbal constituents database, IHD) currently contains details on ∼1,000 compounds found in 33 different plants. For each entry, the IHD gives details of chemical structure, trivial and systematic name, CAS registry number, pharmacology (where known), toxicology (LD(50)), botanical species, the part(s) of the plant(s) where the compounds are found, typical dosage(s) and reference(s). A second database has been also been compiled for plant-derived compounds with known activity against the enzyme, aldose reductase (AR). This database (the aldose reductase inhibitors database, ARID) contains the same details as the IHD, and currently comprises information on 120 different AR inhibitors. Virtual screening of all compounds in the IHD has been performed using Random Forest (RF) modelling, in a search for novel leads active against AR-to provide for new forms of symptomatic relief in diabetic patients. For the RF modelling, a set of simple 2D chemical descriptors were employed to classify all compounds in the combined ARID and IHD databases as either active or inactive as AR inhibitors. The resulting RF models (which gave misclassification rates of 21%) were used to identify putative new AR inhibitors in the IHD, with such compounds being identified as those giving RF scores >0.5 (in each of the three different RF models developed). In vitro assays were subsequently performed for four of the compounds obtained as hits in this in silico screening, to determine their inhibitory activity against human recombinant AR. The two compounds having the highest RF scores (prunetin and ononin) were shown to have the highest activities experimentally (giving ∼58% and ∼52% inhibition at a concentration of 15μM, respectively), while the compounds with lowest RF scores (vanillic acid and cinnamic acid) showed the

  8. National Drug Formulary review of statin therapeutic group using the multiattribute scoring tool

    PubMed Central

    Ramli, Azuana; Aljunid, Syed Mohamed; Sulong, Saperi; Md Yusof, Faridah Aryani

    2013-01-01

    Purpose HMG-CoA reductase inhibitors (statins) are extensively used in treating hypercholesterolemia. The statins available in Malaysia include atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and fluvastatin. Over the years, they have accumulated in the National Drug Formulary; hence, the need for review. Effective selection of the best drugs to remain in the formulary can become complex due to the multiple drug attributes involved, and is made worse by the limited time and resources available. The multiattribute scoring tool (MAST) systematizes the evaluation of the drug attributes to facilitate the drug selection process. In this study, a MAST framework was developed to rank the statins based on their utilities or benefits. Methods Published literature on multicriteria decision analysis (MCDA) were studied and five sessions of expert group discussions were conducted to build the MAST framework and to review the evidence. The attributes identified and selected for analysis were efficacy (clinical efficacy, clinical endpoints), safety (drug interactions, serious side effects and documentation), drug applicability (drug strength/formulation, indications, dose frequency, side effects, food–drug interactions, and dose adjustments), and cost. The average weights assigned by the members for efficacy, safety, drug applicability and cost were 32.6%, 26.2%, 24.1%, and 17.1%, respectively. The utility values of the attributes were scored based on the published evidence or/and agreements during the group discussions. The attribute scores were added up to provide the total utility score. Results Using the MAST, the six statins under review were successfully scored and ranked. Atorvastatin scored the highest total utility score (TUS) of 84.48, followed by simvastatin (83.11). Atorvastatin and simvastatin scored consistently high, even before drug costs were included. The low scores on the side effects for atorvastatin were compensated for by the higher

  9. Steroidal 5α-reductase and 17α-hydroxylase/17,20-lyase (CYP17) inhibitors useful in the treatment of prostatic diseases.

    PubMed

    Salvador, Jorge A R; Pinto, Rui M A; Silvestre, Samuel M

    2013-09-01

    The role of steroidal inhibitors of androgen biosynthesis as potential weapons in the treatment of prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer will be reviewed. Two enzymes have been targeted in the development of inhibitors that potentially could be useful in the management of such conditions. 5α-Reductase is primarily of interest in benign prostatic disease, though some role in the chemoprevention of prostatic carcinoma have been considered, whereas the 17α-hydroxylase/17,20-lyase (CYP17) enzyme is of interest in the treatment of malignant disease. An overview of the main achievements obtained during the past years will be presented, however special focus will be made on steroidal molecules that reached clinical trials or have been commercially launched. Relevant examples of such drugs are finasteride, dutasteride, abiraterone acetate and galeterone (TOK-001, formerly known as VN/124-1). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID:23688836

  10. Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.

    PubMed

    Adeniji, Adegoke; Uddin, Md Jashim; Zang, Tianzhu; Tamae, Daniel; Wangtrakuldee, Phumvadee; Marnett, Lawrence J; Penning, Trevor M

    2016-08-25

    Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.

  11. Structure Guided Chemical Modifications of Propylthiouracil Reveal Novel Small Molecule Inhibitors of Cytochrome b5 Reductase 3 That Increase Nitric Oxide Bioavailability*

    PubMed Central

    Rahaman, Md. Mizanur; Reinders, Fabio G.; Koes, David; Nguyen, Anh T.; Mutchler, Stephanie M.; Sparacino-Watkins, Courtney; Alvarez, Roger A.; Miller, Megan P.; Cheng, Dongmei; Chen, Bill B.; Jackson, Edwin K.; Camacho, Carlos J.; Straub, Adam C.

    2015-01-01

    NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism, and methemoglobin reduction. Although the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors. Because of this restriction, we modeled the binding mode of propylthiouracil, a weak inhibitor of CYB5R3 (IC50 = ∼275 μm), and used it as a guide to predict thiouracil-biased inhibitors from the set of commercially available compounds in the ZINC database. Using this approach, we validated two new potent derivatives of propylthiouracil, ZINC05626394 (IC50 = 10.81 μm) and ZINC39395747 (IC50 = 9.14 μm), both of which inhibit CYB5R3 activity in cultured cells. Moreover, we found that ZINC39395747 significantly increased NO bioavailability in renal vascular cells, augmented renal blood flow, and decreased systemic blood pressure in response to vasoconstrictors in spontaneously hypertensive rats. These compounds will serve as a new tool to examine the biological functions of CYB5R3 in physiology and disease and also as a platform for new drug development. PMID:26001785

  12. Structure Guided Chemical Modifications of Propylthiouracil Reveal Novel Small Molecule Inhibitors of Cytochrome b5 Reductase 3 That Increase Nitric Oxide Bioavailability.

    PubMed

    Rahaman, Md Mizanur; Reinders, Fabio G; Koes, David; Nguyen, Anh T; Mutchler, Stephanie M; Sparacino-Watkins, Courtney; Alvarez, Roger A; Miller, Megan P; Cheng, Dongmei; Chen, Bill B; Jackson, Edwin K; Camacho, Carlos J; Straub, Adam C

    2015-07-01

    NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism, and methemoglobin reduction. Although the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors. Because of this restriction, we modeled the binding mode of propylthiouracil, a weak inhibitor of CYB5R3 (IC50 = ∼275 μM), and used it as a guide to predict thiouracil-biased inhibitors from the set of commercially available compounds in the ZINC database. Using this approach, we validated two new potent derivatives of propylthiouracil, ZINC05626394 (IC50 = 10.81 μM) and ZINC39395747 (IC50 = 9.14 μM), both of which inhibit CYB5R3 activity in cultured cells. Moreover, we found that ZINC39395747 significantly increased NO bioavailability in renal vascular cells, augmented renal blood flow, and decreased systemic blood pressure in response to vasoconstrictors in spontaneously hypertensive rats. These compounds will serve as a new tool to examine the biological functions of CYB5R3 in physiology and disease and also as a platform for new drug development. PMID:26001785

  13. Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: pursuing new antimalarial agents.

    PubMed

    Suwito, Hery; Jumina; Mustofa; Pudjiastuti, Pratiwi; Fanani, Much Zaenal; Kimata-Ariga, Yoko; Katahira, Ritsuko; Kawakami, Toru; Fujiwara, Toshimichi; Hase, Toshiharu; Sirat, Hasnah Mohd; Puspaningsih, Ni Nyoman Tri

    2014-01-01

    Some chalcones have been designed and synthesized using Claisen-Schmidt reactions as inhibitors of the ferredoxin and ferredoxin-NADP+ reductase interaction to pursue a new selective antimalaria agent. The synthesized compounds exhibited inhibition interactions between PfFd-PfFNR in the range of 10.94%-50%. The three strongest inhibition activities were shown by (E)-1-(4-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (50%), (E)-1-(4-aminophenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one (38.16%), and (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one (31.58%). From the docking experiments we established that the amino group of the methoxyamino chlacone derivatives plays an important role in the inhibition activity by electrostatic interaction through salt bridges and that it forms more stable and better affinity complexes with FNR than with Fd.

  14. Structure-Based Design, Synthesis, and Evaluation of 2'-(2-Hydroxyethyl)-2'-deoxyadenosine and the 5'-Diphosphate Derivative as Ribonucleotide Reductase Inhibitors

    SciTech Connect

    Sun, D.; Xu, H.; Wijerathna, S.R.; Dealwis, C.; Lee, R.E.

    2010-08-27

    Analysis of the recently solved X-ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2'-hydroxy group of the nucleoside ribose. In this study 2'-(2-hydroxyethyl)-2'-deoxyadenosine 1 and the 5'-diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2, and the co-crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized.

  15. The 5α-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson's disease.

    PubMed

    Litim, Nadhir; Bourque, Mélanie; Al Sweidi, Sara; Morissette, Marc; Di Paolo, Thérèse

    2015-10-01

    Finasteride and Dutasteride are 5α-reductase inhibitors used in the clinic to treat endocrine conditions and were recently found to modulate brain dopamine (DA) neurotransmission and motor behavior. We investigated if Finasteride and Dutasteride have a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice as a model of Parkinson's disease (PD). Experimental groups included saline treated controls and mice treated with saline, Finasteride (5 and 12.5 mg/kg) or Dutasteride (5 and 12.5 mg/kg) for 5 days before and 5 days after MPTP administration (4 MPTP injections, 6.5 mg/kg on day 5 inducing a moderate DA depletion) and then they were euthanized. MPTP administration decreased striatal DA contents measured by HPLC while serotonin contents remained unchanged. MPTP mice treated with Dutasteride 5 and 12.5 mg/kg had higher striatal DA and metabolites (DOPAC and HVA) contents with a decrease of metabolites/DA ratios compared to saline-treated MPTP mice. Finasteride had no protective effect on striatal DA contents. Tyrosine hydroxylase (TH) mRNA levels measured by in situ hybridization in the substantia nigra pars compacta were unchanged. Dutasteride at 12.5 mg/kg reduced the effect of MPTP on specific binding to striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) measured by autoradiography. MPTP reduced compared to controls plasma testosterone (T) and dihydrotestosterone (DHT) concentrations measured by liquid chromatography-tandem mass spectrometry; Dutasteride and Finasteride increased plasma T levels while DHT levels remained low. In summary, our results showed that a 5α-reductase inhibitor, Dutasteride has neuroprotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers. PMID:26006269

  16. Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth.

    PubMed

    Bessoff, Kovi; Sateriale, Adam; Lee, K Kyungae; Huston, Christopher D

    2013-04-01

    Cryptosporidiosis, a diarrheal disease usually caused by Cryptosporidium parvum or Cryptosporidium hominis in humans, can result in fulminant diarrhea and death in AIDS patients and chronic infection and stunting in children. Nitazoxanide, the current standard of care, has limited efficacy in children and is no more effective than placebo in patients with advanced AIDS. Unfortunately, the lack of financial incentives and the technical difficulties associated with working with Cryptosporidium parasites have crippled efforts to develop effective treatments. In order to address these obstacles, we developed and validated (Z' score = 0.21 to 0.47) a cell-based high-throughput assay and screened a library of drug repurposing candidates (the NIH Clinical Collections), with the hopes of identifying safe, FDA-approved drugs to treat cryptosporidiosis. Our screen yielded 21 compounds with confirmed activity against C. parvum growth at concentrations of <10 μM, many of which had well-defined mechanisms of action, making them useful tools to study basic biology in addition to being potential therapeutics. Additional work, including structure-activity relationship studies, identified the human 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor itavastatin as a potent inhibitor of C. parvum growth (50% inhibitory concentration [IC(50)] = 0.62 μM). Bioinformatic analysis of the Cryptosporidium genomes indicated that the parasites lack all known enzymes required for the synthesis of isoprenoid precursors. Additionally, itavastatin-induced growth inhibition of C. parvum was partially reversed by the addition of exogenous isopentenyl pyrophosphate, suggesting that itavastatin reduces Cryptosporidium growth via on-target inhibition of host HMG-CoA reductase and that the parasite is dependent on the host cell for synthesis of isoprenoid precursors.

  17. Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM.

    PubMed

    Bhatnagar, D; Durrington, P N; Kumar, S; Mackness, M I; Dean, J; Boulton, A J

    1995-04-01

    Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL. PMID:7698516

  18. Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.

    PubMed

    Guarna, A; Machetti, F; Occhiato, E G; Scarpi, D; Comerci, A; Danza, G; Mancina, R; Serio, M; Hardy, K

    2000-10-01

    The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5alpha-reductase (5alphaR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5alphaR-1 and 5alphaR-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC(50)) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39-40 and 45-47), associated with a substituent at position 8, determined the highest inhibition potency (IC(50) from 7.6 to 20 nM). Compounds 39 and 40, having K(i) values of 5.8+/-1.8 and 2.7+/-0.6 nM, respectively, toward 5alphaR-1 expressed in CHO cells, were also tested toward native 5alphaR-1 in human scalp and 5alphaR-2 in human prostate homogenates, in comparison with finasteride and the known 5alphaR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5alphaR-1 with IC(50) values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women. PMID:11020287

  19. A novel therapeutic effect of statins on nephrogenic diabetes insipidus.

    PubMed

    Bonfrate, Leonilde; Procino, Giuseppe; Wang, David Q-H; Svelto, Maria; Portincasa, Piero

    2015-02-01

    Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional 'pleiotropic' effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed.

  20. Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors.

    PubMed

    Aggarwal, Saurabh; Mahapatra, Manoj Kumar; Kumar, Rajnish; Bhardwaj, Tilak R; Hartmann, Rolf W; Haupenthal, Jörg; Kumar, Manoj

    2016-02-15

    In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM). PMID:26780831

  1. Anti-HMG-CoA Reductase, Antioxidant, and Anti-Inflammatory Activities of Amaranthus viridis Leaf Extract as a Potential Treatment for Hypercholesterolemia

    PubMed Central

    Salvamani, Shamala; Gunasekaran, Baskaran; Shukor, Mohd Yunus; Shaharuddin, Noor Azmi; Sabullah, Mohd Khalizan

    2016-01-01

    Inflammation and oxidative stress are believed to contribute to the pathology of several chronic diseases including hypercholesterolemia (elevated levels of cholesterol in blood) and atherosclerosis. HMG-CoA reductase inhibitors of plant origin are needed as synthetic drugs, such as statins, which are known to cause adverse effects on the liver and muscles. Amaranthus viridis (A. viridis) has been used from ancient times for its supposedly medically beneficial properties. In the current study, different parts of A. viridis (leaf, stem, and seed) were evaluated for potential anti-HMG-CoA reductase, antioxidant, and anti-inflammatory activities. The putative HMG-CoA reductase inhibitory activity of A. viridis extracts at different concentrations was determined spectrophotometrically by NADPH oxidation, using HMG-CoA as substrate. A. viridis leaf extract revealed the highest HMG-CoA reductase inhibitory effect at about 71%, with noncompetitive inhibition in Lineweaver-Burk plot analysis. The leaf extract showed good inhibition of hydroperoxides, 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), and ferric ion radicals in various concentrations. A. viridis leaf extract was proven to be an effective inhibitor of hyaluronidase, lipoxygenase, and xanthine oxidase enzymes. The experimental data suggest that A. viridis leaf extract is a source of potent antioxidant and anti-inflammatory agent and may modulate cholesterol metabolism by inhibition of HMG-CoA reductase. PMID:27051453

  2. Anti-HMG-CoA Reductase, Antioxidant, and Anti-Inflammatory Activities of Amaranthus viridis Leaf Extract as a Potential Treatment for Hypercholesterolemia.

    PubMed

    Salvamani, Shamala; Gunasekaran, Baskaran; Shukor, Mohd Yunus; Shaharuddin, Noor Azmi; Sabullah, Mohd Khalizan; Ahmad, Siti Aqlima

    2016-01-01

    Inflammation and oxidative stress are believed to contribute to the pathology of several chronic diseases including hypercholesterolemia (elevated levels of cholesterol in blood) and atherosclerosis. HMG-CoA reductase inhibitors of plant origin are needed as synthetic drugs, such as statins, which are known to cause adverse effects on the liver and muscles. Amaranthus viridis (A. viridis) has been used from ancient times for its supposedly medically beneficial properties. In the current study, different parts of A. viridis (leaf, stem, and seed) were evaluated for potential anti-HMG-CoA reductase, antioxidant, and anti-inflammatory activities. The putative HMG-CoA reductase inhibitory activity of A. viridis extracts at different concentrations was determined spectrophotometrically by NADPH oxidation, using HMG-CoA as substrate. A. viridis leaf extract revealed the highest HMG-CoA reductase inhibitory effect at about 71%, with noncompetitive inhibition in Lineweaver-Burk plot analysis. The leaf extract showed good inhibition of hydroperoxides, 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), and ferric ion radicals in various concentrations. A. viridis leaf extract was proven to be an effective inhibitor of hyaluronidase, lipoxygenase, and xanthine oxidase enzymes. The experimental data suggest that A. viridis leaf extract is a source of potent antioxidant and anti-inflammatory agent and may modulate cholesterol metabolism by inhibition of HMG-CoA reductase. PMID:27051453

  3. Early Statin Use and the Progression of Alzheimer Disease

    PubMed Central

    Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

    2015-01-01

    Abstract The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population. This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression. There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76–0.95, P = 0.0066) to have AD progression than those without. Early statin use was significantly associated

  4. Modulation of atherosclerosis, blood pressure and arterial elasticity by statins.

    PubMed

    Sinha, Anjan K; Mehta, Jawahar L

    2007-01-01

    It is well known that dyslipidemia and hypertension frequently coexist. There is increasing recognition of a mutually facilitative interaction between dyslipidemia and renin- angiotensin system (RAS) activation in the development of atherosclerosis. Both of these systems share many of the same properties in terms of activation of pro-inflammatory, pro-oxidant and pro-atherosclerosis pathways. Statins in particular have been shown to influence the biology of endothelial cells, vascular smooth muscle cells and constituents of the interstitial matrix, particularly fibroblasts. It is no wonder that concurrent therapy of dyslipidemia with statins enhances the effects of RAS inhibitors. Although the effects of statins on the regulation of determinants of vascular stiffness are not well defined, it is quite likely that these regulatory pathways will be influenced by dyslipidemia therapy, especially statins.

  5. Statins and ATP regulate nuclear pAkt via the P2X7 purinergic receptor in epithelial cells

    SciTech Connect

    Mistafa, Oras; Hoegberg, Johan; Stenius, Ulla

    2008-01-04

    Many studies have documented P2X7 receptor functions in cells of mesenchymal origin. P2X7 is also expressed in epithelial cells and its role in these cells remains largely unknown. Our data indicate that P2X7 regulate nuclear pAkt in epithelial cells. We show that low concentration of atorvastatin, a drug inhibiting HMG-CoA reductase and cholesterol metabolism, or the natural agonist extracellular ATP rapidly decreased the level of insulin-induced phosphorylated Akt in the nucleus. This effect was seen within minutes and was inhibited by P2X7 inhibitors. Experiments employing P2X7 siRNA and HEK293 cells heterologously expressing P2X7 and in vivo experiments further supported an involvement of P2X7. These data indicate that extracellular ATP and statins via the P2X7 receptor modulate insulin-induced Akt signaling in epithelial cells.

  6. QSAR and Molecular Docking Studies of Oxadiazole-Ligated Pyrrole Derivatives as Enoyl-ACP (CoA) Reductase Inhibitors

    PubMed Central

    Asgaonkar, Kalyani D.; Mote, Ganesh D.; Chitre, Trupti S.

    2014-01-01

    A quantitative structure-activity relationship model was developed on a series of compounds containing oxadiazole-ligated pyrrole pharmacophore to identify key structural fragments required for anti-tubercular activity. Two-dimensional (2D) and three-dimensional (3D) QSAR studies were performed using multiple linear regression (MLR) analysis and k-nearest neighbour molecular field analysis (kNN-MFA), respectively. The developed QSAR models were found to be statistically significant with respect to training, cross-validation, and external validation. New chemical entities (NCEs) were designed based on the results of the 2D- and 3D-QSAR. NCEs were subjected to Lipinski’s screen to ensure the drug-like pharmacokinetic profile of the designed compounds in order to improve their bioavailability. Also, the binding ability of the NCEs with enoyl-ACP (CoA) reductase was assessed by docking. PMID:24634843

  7. Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors

    PubMed Central

    da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Kaiser, Carlos Roland; de Souza, Marcus Vinícius Nora; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

    2015-01-01

    Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20–40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ) and electrostatic (EC) interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi = 7.772 − 0.1885 × Gly96 + 0.0517 × Tyr158 (R2 = 0.80; n = 10), where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs. PMID:26457706

  8. Tumor responsiveness to statins requires overexpression of the ARF6 pathway.

    PubMed

    Sabe, Hisataka; Hashimoto, Ari; Hashimoto, Shigeru; Oikawa, Tsukasa

    2016-07-01

    The mevalonate pathway results in the prenylation of small GTPases, which are pivotal for oncogenesis and cancer malignancies. However, inhibitors of this pathway, such as statins, have not necessarily produced favorable results in clinical trials. We recently identified properties of statin responders, together with the underlying molecular mechanisms and simple biomarkers to predict these responders. PMID:27652329

  9. Mechanisms and assessment of statin-related muscular adverse effects

    PubMed Central

    Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

    2014-01-01

    Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers. PMID:25069381

  10. GRE2 from Scheffersomyces stipitis as an aldehyde reductase contributes tolerance to aldehyde inhibitors derived from lignocellulosic biomass

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scheffersomyces (Pichia) stipitis is one of the most promising yeasts for industrial bioethanol production from lignocellulosic biomass. S. stipitis is able to in situ detoxify aldehyde inhibitors [such as furfural and 5-hydroxymethylfurfural (HMF)] to less toxic corresponding alcohols. However, the...

  11. In silico screening, structure-activity relationship, and biologic evaluation of selective pteridine reductase inhibitors targeting visceral leishmaniasis.

    PubMed

    Kaur, Jaspreet; Kumar, Pranav; Tyagi, Sargam; Pathak, Richa; Batra, Sanjay; Singh, Prashant; Singh, Neeloo

    2011-02-01

    In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active on L. donovani amastigotes (50% inhibitory concentration [IC(50)] = 3 μM) than on promastigotes (IC(50) = 29 μM). Compound 7 exhibited a K(i) value of 0.72 μM in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis. PMID:21115787

  12. Structure-based de novo design, molecular docking and molecular dynamics of primaquine analogues acting as quinone reductase II inhibitors.

    PubMed

    Murce, Erika; Cuya-Guizado, Teobaldo Ricardo; Padilla-Chavarria, Helmut Isaac; França, Tanos Celmar Costa; Pimentel, Andre Silva

    2015-11-01

    Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C-6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecular dynamics simulations. Our results suggest that all analogues bind better to NQO2 than primaquine and may become better antimalarials. However, the analogues 3 and 4 are predicted to have a better activity/toxicity balance.

  13. Synthesis and biological evaluation of novel inhibitors against 1,3,8-trihydroxynaphthalene reductase from Magnaporthe grisea.

    PubMed

    Chen, Haifeng; Han, Xinya; Qin, Nian; Wei, Lin; Yang, Yue; Rao, Li; Chi, Bo; Feng, Lingling; Ren, Yanliang; Wan, Jian

    2016-03-15

    1,3,8-Trihydroxynaphthalene reductase (3HNR) is an essential enzymes that is involved in fungal melanin biosynthesis. Based on the structural informations of active site of 3HNR, a series of β-nitrostyrene compounds were rationally designed and synthesized. The enzymatic activities of these compounds showed that most of them exhibited high inhibitory activities (<5.0 μM) against 3HNR; compound 3-2 exhibit the highest inhibitory activity (IC50=0.29 μM). In particular, some of these compounds had moderate fungicidal activity against Magnaporthe grisea. Compound 3-4 showed high in vivo activities against M. grisea (EC50=9.5 ppm). Furthermore, compound 3-2 was selected as a representative molecule, and the probable binding mode of this compound and the surrounding residues in the active site of 3HNR was elucidated by using molecular dock. The positive results suggest that β-nitrostyrene derivatives are most likely to be promising leads toward the discovery of novel agent of rice blast. PMID:26860927

  14. Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as promising 5alpha-reductase inhibitors.

    PubMed

    Amr, Abd El-Galil El-Sayed; Abdel-Latif, Nehad Ahmed; Abdalla, Mohamed Mostafa

    2006-06-01

    Condensation of 3beta-hydroxy-16-[(4-chlorophenyl)methylene]androst-5-en-17-one (1) with hydrazine hydrate in acetic acid afforded N-acetyl pyrazoline derivative 2, while condensation of 1 with semicarbazide afforded compound 3. Also, compound 1 was treated with hydrazine hydrate in absolute methanol or ethanol to afford the corresponding alpha-methoxy (4) and alpha-ethoxy (5) derivatives, which were cyclized with etherated boron trifluoride to the pyrazoline derivative 6. The latter could be prepared directly by refluxing 1 with hydrazine hydrate in dioxane. Oxidation of compound 6 with Oppenour or Moffat oxidizing agents yielded 3-oxo-derivatives 7 and 8, respectively. On the other hand, condensation of compound 1 with substituted hydrazines, gave the corresponding 3beta-hydroxyandrostenopyrazolines 9a,b, which were oxidized using the Moffat method to give 3-oxo-androstenopyrazolines 10a,b, which were condensed with ethylene triphenyl-phosphorane in DMSO to yield 3-ethylene androstenopyrazolines 11a,b. Dehydrogenation of 9a,b with Wettestein oxidation afforded Delta4,6-diene-3-one analogues 12a,b, which were treated with chloranil to yield Delta(4,6,8(14))-tri-ene-3-one analogues 13a,b. Oppenour oxidation of 9a,b afforded Delta4-ene-3-one analogues 14a,b, which were treated with dichlorodicyanoquinone (DDQ) in dioxane to give Delta1,4,6-triene-3-one analogues 15a,b. Pharmacological screening showed that many of these compounds inhibit 5alpha-reductase activity. PMID:16613726

  15. Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells.

    PubMed

    Kim, Hye-Young H; Korade, Zeljka; Tallman, Keri A; Liu, Wei; Weaver, C David; Mirnics, Karoly; Porter, Ned A

    2016-05-16

    A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS. PMID:27097157

  16. AFN-1252 is a potent inhibitor of enoyl-ACP reductase from Burkholderia pseudomallei—Crystal structure, mode of action, and biological activity

    PubMed Central

    Narasimha Rao, Krishnamurthy; Lakshminarasimhan, Anirudha; Joseph, Sarah; Lekshmi, Swathi U; Lau, Ming-Seong; Takhi, Mohammed; Sreenivas, Kandepu; Nathan, Sheila; Yusof, Rohana; Abd Rahman, Noorsaadah; Ramachandra, Murali; Antony, Thomas; Subramanya, Hosahalli

    2015-01-01

    Melioidosis is a tropical bacterial infection caused by Burkholderia pseudomallei (B. pseudomallei; Bpm), a Gram-negative bacterium. Current therapeutic options are largely limited to trimethoprim-sulfamethoxazole and β-lactam drugs, and the treatment duration is about 4 months. Moreover, resistance has been reported to these drugs. Hence, there is a pressing need to develop new antibiotics for Melioidosis. Inhibition of enoyl-ACP reducatase (FabI), a key enzyme in the fatty acid biosynthesis pathway has shown significant promise for antibacterial drug development. FabI has been identified as the major enoyl-ACP reductase present in B. pseudomallei. In this study, we evaluated AFN-1252, a Staphylococcus aureus FabI inhibitor currently in clinical development, for its potential to bind to BpmFabI enzyme and inhibit B. pseudomallei bacterial growth. AFN-1252 stabilized BpmFabI and inhibited the enzyme activity with an IC50 of 9.6 nM. It showed good antibacterial activity against B. pseudomallei R15 strain, isolated from a melioidosis patient (MIC of 2.35 mg/L). X-ray structure of BpmFabI with AFN-1252 was determined at a resolution of 2.3 Å. Complex of BpmFabI with AFN-1252 formed a symmetrical tetrameric structure with one molecule of AFN-1252 bound to each monomeric subunit. The kinetic and thermal melting studies supported the finding that AFN-1252 can bind to BpmFabI independent of cofactor. The structural and mechanistic insights from these studies might help the rational design and development of new FabI inhibitors. PMID:25644789

  17. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles.

    PubMed

    Kouassi, Affiba Florance; Kone, Mawa; Keita, Melalie; Esmel, Akori; Megnassan, Eugene; N'Guessan, Yao Thomas; Frecer, Vladimir; Miertus, Stanislav

    2015-01-01

    We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50(exp)). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50(exp). Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50(exp) (pIC50(exp) = -0.1552·ΔΔGcom + 5.0448, R² = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50(pre) reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles. PMID:26703572

  18. Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching

    PubMed Central

    Hevener, Kirk E.; Mehboob, Shahila; Su, Pin-Chih; Truong, Kent; Boci, Teuta; Deng, Jiangping; Ghassemi, Mahmood; Cook, James L.; Johnson, Michael E.

    2011-01-01

    Enoyl-acyl carrier protein (ACP) reductase, FabI, is a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is an NADH-dependent oxidoreductase that acts to reduce enoyl-ACP substrates in a final step of the pathway. The absence of this enzyme in humans makes it an attractive target for the development of new antibacterial agents. FabI is known to be unresponsive to structure-based design efforts due to a high degree of induced fit and a mobile flexible loop encompassing the active site. Here we discuss the development, validation, and careful application of a ligand-based virtual screen used for the identification of novel inhibitors of the Francisella tularensis FabI target. In this study, four known classes of FabI inhibitors were used as templates for virtual screens that involved molecular shape and electrostatic matching. The program ROCS was used to search a high-throughput screening library for compounds that matched any of the four molecular shape queries. Matching compounds were further refined using the program EON, which compares and scores compounds by matching electrostatic properties. Using these techniques, 50 compounds were selected, ordered, and tested. The tested compounds possessed novel chemical scaffolds when compared to the input query compounds. Several hits with low micromolar activity were identified and follow-up scaffold-based searches resulted in the identification of a lead series with sub-micromolar enzyme inhibition, high ligand efficiency, and a novel scaffold. Additionally, one of the most active compounds showed promising whole-cell antibacterial activity against several Gram-positive and Gram-negative species, including the target pathogen. The results of a preliminary structure-activity relationship analysis are presented. PMID:22098466

  19. Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure

    PubMed Central

    Di Filippo, C.; Ferraro, B.; Maisto, R.; Trotta, M. C.; Di Carluccio, N.; Sartini, S.; La Motta, C.; Ferraraccio, F.; Rossi, F.; D'Amico, M.

    2016-01-01

    This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP. PMID:26839893

  20. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles

    PubMed Central

    Kouassi, Affiba Florance; Kone, Mawa; Keita, Melalie; Esmel, Akori; Megnassan, Eugene; N’Guessan, Yao Thomas; Frecer, Vladimir; Miertus, Stanislav

    2015-01-01

    We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles. PMID:26703572

  1. Mechanism of Drug-Drug Interactions Between Warfarin and Statins.

    PubMed

    Shaik, Abdul Naveed; Bohnert, Tonika; Williams, David A; Gan, Lawrence L; LeDuc, Barbara W

    2016-06-01

    was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition. PMID:27103011

  2. Statins Reduce Melanoma Development and Metastasis through MICA Overexpression.

    PubMed

    Pich, Christine; Teiti, Iotefa; Rochaix, Philippe; Mariamé, Bernard; Couderc, Bettina; Favre, Gilles; Tilkin-Mariamé, Anne-Françoise

    2013-01-01

    Survival of melanoma patients after metastases detection remains short. Several clinical trials have shown moderate efficiency in improving patient survival, and the search for pharmacological agents to enhance the immune response and reduce melanoma metastases is still necessary. Statins block the mevalonate pathway, which leads to decreases in GTPase isoprenylation and activity, particularly those of the Ras superfamily. They are widely used as hypocholesterolemic agents in cardiovascular diseases and several studies have shown that they also have protective effects against cancers. Furthermore, we have previously demonstrated that treatment of melanoma cells with inhibitors of the mevalonate pathway, such as statins, favor the development of specific adaptive immune responses against these tumors. In the present study, we tested statin impact on the innate immune response against human metastatic melanoma cells. Our data shows that treatment of two human melanoma cell lines with statins induced a weak but significant increase of MHC class I Chain-related protein A (MICA) membrane expression. Peroxisome Proliferator-Activated Receptor gamma is involved in this statin-induced MICA overexpression, which is independent of Ras and Rho GTPase signaling pathways. Interestingly, this MICA overexpression makes melanoma cells more sensitive to in vitro lysis by NK cells. The impact of statin treatment on in vivo development of melanoma tumors and metastases was investigated in nude mice, because murine NK cells, which express NKG2D receptors, are able to recognize and kill human tumor cells expressing MICA. The results demonstrated that both local tumor growth and pulmonary metastases were strongly inhibited in nude mice injected with statin-treated melanoma cells. These results suggest that statins could be effective in melanoma immunotherapy treatments. PMID:23493799

  3. A systematic review of the effects and mechanisms of preoperative 5α-reductase inhibitors on intraoperative haemorrhage during surgery for benign prostatic hyperplasia.

    PubMed

    Zong, Huan-Tao; Peng, Xiao-Xia; Yang, Chen-Chen; Zhang, Yong

    2011-11-01

    5α-reductase inhibitors (5α-RIs), including finasteride and dutasteride, are commonly used medical therapies for benign prostatic hyperplasia (BPH). Many studies reported that preoperative 5α-RI had impact on intraoperative haemorrhage during surgery for BPH, but it was still in controversial. So, we conducted a systematic review of the effects and mechanisms of 5α-RIs on intraoperative bleeding for BPH. MEDLINE, EMBASE, the Cochrane Controlled Trail Register of Controlled Trials and the reference lists of retrieved studies were searched in the analysis. Sixteen publications involving 15 different randomized controlled trials (RCTs) and a total of 1156 patients were used in the analysis, including 10 RCTs for finasteride and five RCTs for dutasteride. We found that preoperative finasteride treatment decreases microvessel density (MVD) in resected prostate specimens. Total blood loss, blood loss per gram of resected prostate tissue and decreases in haemoglobin were all greatly reduced in the finasteride group as compared to controls. Dutasteride appeared to have no effect on bleeding. This meta-analysis shows that preoperative finasteride treatment could decrease intraoperative haemorrhage during surgery for BPH. Preoperative dutasteride had no effect on intraoperative haemorrhage, but further high-quality prospective studies are still needed to confirm this observation. PMID:21892196

  4. Pressure-induced inhibition of fast axonal transport of proteins in the rabbit vagus nerve in galactose neuropathy: prevention by an aldose reductase inhibitor.

    PubMed

    McLean, W G

    1988-07-01

    Fast and slow anterograde axonal transport and retrograde axonal transport of proteins were studied in the mainly non-myelinated sensory fibres of the vagus nerve of rabbits fed a diet of 50% galactose over a period of 29 days. Galactose feeding had no effect on the rate or protein composition of slow transport nor on the amount of retrogradely transported proteins. There was a slight retardation of fast transported proteins although their composition was unchanged. The galactose feeding led to a significant increase (p less than 0.005) in nerve water content and nerve galactitol but no significant change in myo-inositol. When 20 mm Hg pressure was applied locally to the cervical vagus nerve, fast transported proteins accumulated proximal to the compression zone in the galactose-fed but not in control rabbits. Administration of the aldose reductase inhibitor Statil (ICI 128436) throughout the experiment prevented the increased susceptibility to pressure and the increase in nerve galactitol and water content. The effects of pressure are similar to those found in the streptozotocin-diabetic rat although the underlying mechanisms may differ.

  5. Effects of Long-Term Treatment with Ranirestat, a Potent Aldose Reductase Inhibitor, on Diabetic Cataract and Neuropathy in Spontaneously Diabetic Torii Rats

    PubMed Central

    Ota, Ayumi; Kakehashi, Akihiro; Toyoda, Fumihiko; Kinoshita, Nozomi; Shinmura, Machiko; Takano, Hiroko; Obata, Hiroto; Matsumoto, Takafumi; Tsuji, Junichi; Dobashi, Yoh; Fujimoto, Wilfred Y.; Kawakami, Masanobu; Kanazawa, Yasunori

    2013-01-01

    We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0–6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P < 0.01). Ranirestat significantly (P < 0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 ± 0.6 m/s) in SDT rats dose-dependently (P < 0.01). Epalrestat also reversed the prevented MNCV decrease (P < 0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 ± 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P < 0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only. PMID:23671855

  6. In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin.

    PubMed

    Atil, Bihter; Berger-Sieczkowski, Evelyn; Bardy, Johanna; Werner, Martin; Hohenegger, Martin

    2016-01-01

    Extrusion of chemotherapeutics by ATP-binding cassette (ABC) transporters like ABCB1 (P-glycoprotein) represents a crucial mechanism of multidrug resistance in cancer therapy. We have previously shown that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin directly inhibits ABCB1, alters the glycosylation of the transporter, and enhances the intracellular accumulation of doxorubicin with subsequent anti-cancer action. Here, we show that simvastatin reduces endogenous dolichol levels and ABCB1 in human neuroblastoma SH-SY5Y cells. Coapplication with dolichol prevents the downregulation of the ABCB1 transporter. Importantly, dolichol also attenuated simvastatin-induced apoptosis, unmasking involvement of unfolded protein response. Direct monitoring of the fluorescent fusion protein YFP-ABCB1 further confirms concentration-dependent reduction of ABCB1 in HEK293 cells by simvastatin. In simvastatin-treated murine xenografts, ABCB1 was also reduced in the liver and rhabdomyosarcoma but did not reach significance in neuroblastoma. Nevertheless, the in vivo anti-cancer effects of simvastatin are corroborated by increased apoptosis in tumor tissues. These findings provide experimental evidence for usage of simvastatin in novel chemotherapeutic regimens and link dolichol depletion to simvastatin-induced anti-cancer activity.

  7. Relation of Na+, K(+)-ATPase to delayed motor nerve conduction velocity: effect of aldose reductase inhibitor, ADN-138, on Na+, K(+)-ATPase activity.

    PubMed

    Hirata, Y; Okada, K

    1990-06-01

    The role of sorbitol, myo-inositol, and Na+, K(+)-adenosine triphosphatase (ATPase) activity on motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-diabetic rats was studied. Reduction of MNCV and Na+, K(+)-ATPase in caudal nerves appeared after 3 weeks of diabetes, and at this time treatment with aldose reductase inhibitor (ARI), ADN-138 and 1% myo-inositol supplement was begun. One percent myo-inositol supplement for 3 weeks resulted in a significant increase in myo-inositol levels in diabetic nerves, but left MNCV and sorbitol levels unchanged. In contrast, treatment with ADN-138 for 3 weeks reduced sorbitol levels in diabetic nerves and resulted in significant increases in MNCV and Na+, K(+)-ATPase in the nerves. Since ADN-138 did not restore myo-inositol levels, the increase in Na+, K(+)-ATPase levels by ADN-138 treatment was independent of myo-inositol levels. Also, nerve Na+ levels in ADN-138-treated rats were reduced and the ratio of K+ to Na+ was raised, while 1% myo-inositol supplement did not affect them. These results suggest that treatment with ADN-138 elevates MNCV through a series of processes: ARI----reduction of sorbitol level----increase in Na+, K(+)-ATPase activity----correction of K+, Na+ imbalance----increase in MNCV.

  8. Statins Often Interact with Other Heart Drugs

    MedlinePlus

    ... a couple of other potential consequences of statin interactions, the AHA says. Statins may, for example, raise ... the risk of internal bleeding. Many of the interactions between statins and other heart drugs are "minor," ...

  9. Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer.

    PubMed

    Wei, Tzu-Tang; Lin, Yi-Ting; Chen, Wen-Shu; Luo, Ping; Lin, Yu-Chin; Shun, Chia-Tung; Lin, Yi-Hsin; Chen, Jhih-Bin; Chen, Nai-Wei; Fang, Jim-Min; Wu, Ming-Shiang; Yang, Kai-Chien; Chang, Li-Chun; Tai, Kang-Yu; Liang, Jin-Tung; Chen, Ching-Chow

    2016-08-01

    Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc(Min/+) CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC. PMID:27448759

  10. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

    PubMed Central

    Trapani, Laura; Segatto, Marco; Pallottini, Valentina

    2013-01-01

    Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of

  11. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase modulator: toward age- and sex-personalized medicine.

    PubMed

    Pallottini, Valentina

    2015-01-01

    Cholesterol homeostasis maintenance is regulated by a cellular feedback system that senses cholesterol amount in cellular membranes. 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR) plays a pivotal role in cholesterol metabolism as it is the key rate-limiting enzyme of its biosynthetic pathway; its inhibition provokes a feedback response capable of reducing plasma cholesterol content. HMGR inhibition is a keystone in the treatment and prevention of cardiovascular disease and, therefore, statins (HMGR inhibitors) are widely prescribed even though they may sometimes induce side effects. These drugs are prescribed indifferently to both man and women even if there are several well-known differences in cholesterol metabolism depending on the gender and the age. Thus, gender-related differences in cholesterol metabolism should be taken into account to identify new targets for customized pharmacological treatments for hypercholesterolemia. PMID:26135220

  12. CoQ10 and L-carnitine for statin myalgia?

    PubMed

    DiNicolantonio, James J

    2012-10-01

    Statins are a standard of care in many clinical settings such as acute myocardial infarction and for patients having or at risk of cardiovascular (CV) disease. This is based on a plethora of data showing reductions in CV events and mortality. The CV benefit of statins can be partly explained by their ability to inhibit of HMG-CoA reductase, which subsequently lowers cholesterol and decreases the formation of mevalonate. However, the inhibition of the mevalonate pathway decreases the formation of coenzyme Q10 (CoQ10) within the body. It has been a long-standing theory that statin-associated muscle pain (myalgia) is caused, or at least partly contributed by, a reduction in CoQ10 levels in muscle mitochondria. One of the main side effects of statins is myalgia, which causes the patient to either stop their statin or significantly reduce the dose of their statin. The question of whether CoQ10 can help treat statin myopathy is a common one encountered by clinicians in current day practice.

  13. Do statins really cause diabetes?

    PubMed Central

    Rahal, Alaa J.; ElMallah, Ahmed I.; Poushuju, Rita J.; Itani, Rana

    2016-01-01

    Objectives: To investigate and establish the relationship between the use of statin therapy and the risk of development of diabetes. Methods: PubMed and the Cochrane Central Register of Controlled Trials was searched for randomized controlled end-point trials of statins, with more than 1000 subjects and a minimum of one-year follow-up period, published until August 2015. The odds ratio (OR) of diabetes incidence with overall statin therapy as well as with different statins in question was calculated through random effect meta-analysis model. Results: Fourteen studies were included in the analysis with a total of 94,943 participants. Of these, 2392 subjects developed incident diabetes in the statin and 2167 in the placebo groups during a 4-year follow-up. The OR of diabetes incidence with statin therapy was significantly higher as compared with the placebo group (OR=1.11; 95% confidence interval = 1.0 to 1.2; p=0.007). There was an insignificant level of heterogeneity between the included trials (Cochran Q= 19.463, p=0.109, I2=33.20). Subgroup analysis showed that only 2 statins namely, atorvastatin (OR= 1.29; p=0.042) and rosuvastatin (OR = 1.17; px=0.01) were significantly associated. Conclusion: Statin therapy can slightly increase risk of incident diabetes in subjects with hypercholesterolemia. PMID:27652354

  14. Perturbation of Staphylococcus aureus Gene Expression by the Enoyl-Acyl Carrier Protein Reductase Inhibitor AFN-1252

    PubMed Central

    Parsons, Joshua B.; Kukula, Maciej; Jackson, Pamela; Pulse, Mark; Simecka, Jerry W.; Valtierra, David; Weiss, William J.; Kaplan, Nachum

    2013-01-01

    This study examines the alteration in Staphylococcus aureus gene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN-1252 did not alter virulence mRNA levels in a saeR deletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabH mRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivo was determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC0–48]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabH mRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabH and virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria. PMID:23459481

  15. Immune-mediated statin myopathy.

    PubMed

    Loganathan, Priyadarshini; Oddis, Chester V; Aggarwal, Rohit

    2016-01-01

    Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood.

  16. X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

    SciTech Connect

    Bennett, Brad C.; Wan, Qun; Ahmad, Md Faiz; Langan, Paul; Dealwis, Chris G.

    2009-11-18

    For reasons of bioterrorism and drug resistance, it is imperative to identify and develop new molecular points of intervention against anthrax. Dihydrofolate reductase (DHFR) is a highly conserved enzyme and an established target in a number of species for a variety of chemotherapeutic programs. Recently, the crystal structure of B. anthracis DHFR (baDHFR) in complex with methotrexate (MTX) was determined and, based on the structure, proposals were made for drug design strategies directed against the substrate binding site. However, little is gleaned about the binding site for NADPH, the cofactor responsible for hydride transfer in the catalytic mechanism. In the present study, X-ray crystallography at 100 K was used to determine the structure of baDHFR in complex with MTX and NADPH. Although the NADPH binding mode is nearly identical to that seen in other DHFR ternary complex structures, the adenine moiety adopts an off-plane tilt of nearly 90 deg. and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues. A comparison of the binding site, focusing on this region, between baDHFR and the human enzyme is discussed, with an aim at designing species-selective therapeutics. Indeed, the ternary model, refined to 2.3{angstrom} resolution, provides an accurate template for testing the feasibility of identifying dual-site inhibitors, compounds that target both the substrate and cofactor binding site. With the ternary model in hand, using in silico methods, several compounds were identified which could potentially form key bonding contacts in the substrate and cofactor binding sites. Ultimately, two structurally distinct compounds were verified that inhibit baDHFR at low {mu}M concentrations. The apparent K{sub d} for one of these, (2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone oxime), was measured by fluorescence spectroscopy to be 5.3 {mu}M.

  17. B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy.

    PubMed

    Shao, Fang-Yuan; Du, Zhi-Yun; Ma, Dong-Lei; Chen, Wen-Bo; Fu, Wu-Yu; Ruan, Bi-Bo; Rui, Wen; Zhang, Jia-Xuan; Wang, Sheng; Wong, Nai Sum; Xiao, Hao; Li, Man-Mei; Liu, Xiao; Liu, Qiu-Ying; Zhou, Xiao-Dong; Yan, Hai-Zhao; Wang, Yi-Fei; Chen, Chang-Yan; Liu, Zhong; Chen, Hong-Yuan

    2015-10-13

    The synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy. PMID:26439985

  18. Potent increased risk of the initiation of DNA replication in human prostate cancer with the use of 5α-reductase inhibitors.

    PubMed

    Kosaka, Takeo; Yasumizu, Yota; Miyazaki, Yasumasa; Miyajima, Akira; Kikuchi, Eiji; Oya, Mototsugu

    2014-01-01

    Recent clinical studies have raised the clinically important question of the relationship between dihydrotestosterone (DHT) and prostate cancer (PCa) progression. The significance of DHT or 5α-reductase inhibitors (5ARI) in PCa development and progression has not yet been fully characterized. The aim of this study was to determine whether the initiation of DNA replication was influenced by DHT in PCa. Three cell lines were used. LNCaP: a human PCa cell line that exhibits androgen-dependent proliferation, C4-2: a human PCa cell line that exhibits androgen-independent proliferation, and C4-2AT6: a castration resistant prostate cancer cell line. Two 5ARIs, finasteride and dutasteride, were used. We examined the mRNA expression of the components of pre-replication complex (Pre-RC), CDC6, CDT1, and MCM2-7. DHT induced cell proliferation of LNCaP accompanied by significantly increased CDC6, CDT1, and MCM2-7 expression. In contrast to LNCaP, DHT inhibited cell proliferation in C4-2AT6 cells accompanied by decreased expression of CDC6, CDT1, and MCM2-7. These reverse effects resemble the effects of 5ARIs in Pre-RC. Treatment with finasteride or dutasteride inhibited CDC6 expression in LNCaP, but both 5ARIs induced CDC6 expression in C4-2 and C4-2AT6 cells.These results indicate that DHT showed reversal effects on PCa cell proliferation among prostate cancer cells based on androgen-dependence, accompanied by regulation of the initiation of DNA replication. 5ARIs may modulate the DNA replication system in someaggressive PCa through up-regulation of CDC6 expression. PMID:25374915

  19. B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy.

    PubMed

    Shao, Fang-Yuan; Du, Zhi-Yun; Ma, Dong-Lei; Chen, Wen-Bo; Fu, Wu-Yu; Ruan, Bi-Bo; Rui, Wen; Zhang, Jia-Xuan; Wang, Sheng; Wong, Nai Sum; Xiao, Hao; Li, Man-Mei; Liu, Xiao; Liu, Qiu-Ying; Zhou, Xiao-Dong; Yan, Hai-Zhao; Wang, Yi-Fei; Chen, Chang-Yan; Liu, Zhong; Chen, Hong-Yuan

    2015-10-13

    The synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.

  20. In Vitro Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors in Sandwich-Cultured Rat Hepatocytes: Comparison to In Vivo Biliary Clearance

    PubMed Central

    Abe, Koji; Bridges, Arlene S.; Yue, Wei; Brouwer, Kim L. R.

    2008-01-01

    Previous reports have indicated that in vitro biliary clearance (Clbiliary) determined in sandwich-cultured hepatocytes correlates well with in vivo Clbiliary for limited sets of compounds. This study was designed to estimate the in vitro Clbiliary in sandwich-cultured rat hepatocytes (SCRH) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Clbiliary values with published in vivo Clbiliary data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. Average biliary excretion index (BEI) and in vitro Clbiliary of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15%, 19%, 43%, 45%, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Clbiliary predicted from SCRH, accounting for plasma unbound fraction, correlated with reported in vivo Clbiliary for these drugs. The rank order of Clbiliary values predicted from SCRH was consistent with in vivo Clbiliary values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Clbiliary values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp)2 substrates, were reduced in SCRH from Mrp2-deficient (TR−) compared to wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Clbiliary were reduced in TR− compared to WT SCRH; Bcrp expression in SCRH from TR− rats was decreased. In conclusion, in vitro Clbiliary determined in SCRH can be used to estimate and compare in vivo Clbiliary of compounds in rats, and to characterize transport proteins responsible for their hepatic uptake and excretion. PMID:18574002

  1. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke

    PubMed Central

    Chmielewski, Henryk; Kaczorowska, Beata; Przybyła, Monika; Baj, Zbigniew

    2015-01-01

    Introduction Low-density lipoprotein cholesterol (LDL-C) has been reported to increase platelet activation. Reducing the level of LDL-C with statins induces important pleiotropic effects such as platelet inhibition. This association between platelet activity and statin therapy may be clinically important in reducing the risk of ischemic stroke. We investigated the effect of simvastatin therapy on platelet activation markers (platelet CD62P, sP-selectin, and platelet-derived microparticles (PDMPs)) in hyperlipidemic patients after ischemic stroke. Material and methods The study group consisted of 21 hyperlipidemic patients after ischemic stroke confirmed by CT, and 20 healthy subjects served as controls. We assessed the CD62P expression on resting and thrombin-activated blood platelets. CD62P and PDMPs were analyzed by the use of monoclonal antibodies anti-CD61 and anti-CD62 on a flow cytometer. The level of sP-selectin in serum was measured by the ELISA (enzyme-linked immunosorbent assay) method. All markers were re-analyzed after 6 months of treatment with simvastatin (20 mg/day). Results Hyperlipidemic patients presented a significantly higher percentage of CD62+ platelets and higher reactivity to thrombin compared to control subjects. After simvastatin therapy hyperlipidemic patients showed a reduction of the percentage of resting CD62P(+) platelets (p = 0.005) and a reduction of expression and percentage of CD62P(+) platelets after activation by thrombin (median p < 0.05; percentage: p = 0.001). A decrease of sP-selectin levels (p = 0.001) and percentage of PDMPs (p < 0.05) in this group was also observed. Conclusions HMG-CoA reductase inhibitor therapy in stroke patients with hyperlipidemia may be useful not only due to the lipid-lowering effect but also because of a significant role in reduction of platelet activation and reactivity. PMID:25861297

  2. Effect of Statin Use on Outcomes of Adults with Candidemia

    PubMed Central

    Cuervo, Guillermo; Garcia-Vidal, Carolina; Nucci, Marcio; Puchades, Francesc; Fernández-Ruiz, Mario; Mykietiuk, Analía; Manzur, Adriana; Gudiol, Carlota; Pemán, Javier; Viasus, Diego; Ayats, Josefina; Carratalà, Jordi

    2013-01-01

    Background Statins have immunomodulatory properties and hinder Candida growth. However, it is unknown whether they may improve prognosis in patients with candidemia. We sought to determine the effect of prior statin use on the clinical outcomes of patients suffering candidemia. Methods and Findings Multicenter cohort study of hospitalized adults with candidemia between 2005 and 2011 in six hospitals in Spain, Brazil and Argentina. Of 326 candidemias, 44 (13.5%) occurred in statin users and 282 (86.5%) in statin non-users. The median value of APACHE II at candidemia diagnosis was similar between groups (18 vs. 16; p=.36). Candida albicans was the most commonly isolated species, followed by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei. There were no differences regarding appropriate empirical antifungal treatment. Statin users had a lower early (5 d) case-fatality rate than non-users (4.5 vs. 17%; p=.031). This effect was not observed with other cardiovascular drugs (aspirin, beta blockers and ACE inhibitors). Independent factor related to early case-fatality rate was APACHE II score (AOR, 1.08; 95% CI, 1.03–1.14; p=.002). An appropriate empirical antifungal therapy (AOR, 0.11; 95% CI, 0.04–0.26; p=<.001) and prior statin use were independently associated with lower early case-fatality (AOR, 0.17; 95% CI, 0.03–0.93; p=.041). Fourteen days (14d) and overall (30d) case-fatality rates were similar between groups (27% vs. 29%; p=0.77 and 40% vs. 44%; p=.66). Conclusions The use of statins might have a beneficial effect on outcomes of patients with candidemia. This hypothesis deserves further evaluation in randomized trials. PMID:24155941

  3. Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.

    PubMed

    Schirris, Tom J J; Renkema, G Herma; Ritschel, Tina; Voermans, Nicol C; Bilos, Albert; van Engelen, Baziel G M; Brandt, Ulrich; Koopman, Werner J H; Beyrath, Julien D; Rodenburg, Richard J; Willems, Peter H G M; Smeitink, Jan A M; Russel, Frans G M

    2015-09-01

    Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.

  4. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

    PubMed Central

    Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations

  5. Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed by the 5α-reductase inhibitor, finasteride.

    PubMed

    Wiebe, John P; Rivas, Martin A; Mercogliano, Maria F; Elizalde, Patricia V; Schillaci, Roxana

    2015-05-01

    Progesterone has long been linked to breast cancer but its actual role as a cancer promoter has remained in dispute. Previous in vitro studies have shown that progesterone is converted to 5α-dihydroprogesterone (5αP) in breast tissue and human breast cell lines by the action of 5α-reductase, and that 5αP acts as a cancer-promoter hormone. Also studies with human breast cell lines in which the conversion of progesterone to 5αP is blocked by a 5α-reductase inhibitor, have shown that the in vitro stimulation in cell proliferation with progesterone treatments are not due to progesterone itself but to the metabolite 5αP. No similar in vivo study has been previously reported. The objective of the current studies was to determine in an in vivo mouse model if the presumptive progesterone-induced mammary tumorigenesis is due to the progesterone metabolite, 5αP. BALB/c mice were challenged with C4HD murine mammary cells, which have been shown to form tumors when treated with progesterone or the progestin, medroxyprogesterone acetate. Cells and mice were treated with various doses and combinations of progesterone, 5αP and/or the 5α-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. Proliferation of C4HD cells and induction and growth of tumors was stimulated by treatment with either progesterone or 5αP. The progesterone-induced stimulation was blocked by finasteride and reinstated by concomitant treatment with 5αP. The 5αP-induced tumors expressed high levels of ER, PR and ErbB-2. Hormone measurements showed significantly higher levels of 5αP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5αP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. The results indicate that

  6. MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.

    PubMed

    Schwartz, J I; Tanaka, W K; Wang, D Z; Ebel, D L; Geissler, L A; Dallob, A; Hafkin, B; Gertz, B J

    1997-05-01

    Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment. The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (- 14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in

  7. Antitumor and apoptosis promoting properties of atorvastatin, an inhibitor of HMG-CoA reductase, against Dalton's Lymphoma Ascites tumor in mice.

    PubMed

    Ajith, Thekkoottuparambil Ananthanarayanan; Anu, Vijayan; Riji, Thomas

    2008-01-01

    Epidemiological and experimental data indicate that high body fat or high dietary fat can be ascribed to the induction of human cancers. Increased level of products of lipid peroxidation and cholesterol-enriched lipid domains in the plasma membrane can favorthe malignant transformation of cells. An effective chemopreventive agent with hypolipaedemic effect will be worthwhile to intervene early in the process of carcinogenesis to eliminate the pre-malignant cells. Apoptotic promoting and antitumor activities of a HMG-Co A reductase inhibitor, atorvatstain were investigated. The antitumor activity was evaluated using Daltons' Lymphoma Ascites (DLA) cell line transplanted ascites tumor model in mice. Proapoptotic activity was evaluated in DLA cell line induced ascites animals after the treatment of atorvastatin (4 and 16 mg/kg, i.p). Apoptosis was analyzed morphologically by staining with giemsa and biochemically by observing the laddering of DNA in agarose gel electrophoresis. In vitro short term cytotoxic activity of atorvatstain was studied by trypan blue dye exclusion method. Doxorubicin was used as the reference standard. Atorvastatin significantly (P < 0.01) inhibited the ascites tumor growth at 16 mg/kg body wt (i.p). The percent increase in life span (%ILS) in the 16 mg/kg treated group was 41.1%. Single dose of atorvastatin (16 mg/kg body wt) was also effective to promote the apoptosis of DLA cells in the ascites tumor bearing mice that was evident from the multiple fragmentation of DNA in agarose gel electrophoresis. Further the morphological analysis of DLA cells aspirated from the atorvastatin treated ascites tumor bearing animals showed 36.34 +/- 6.78% apoptotic cells compared to the control animals (10.50 +/- 3.53%). Concentration of atorvastatin required for the 50% of the cytotoxicity was 30 +/- 2 microg/ml. Results of the study concluded that the antitumor activity of atorvastatin may be due to its proapoptotic and cytotoxic activities. These

  8. A meta-analysis of trials on aldose reductase inhibitors in diabetic peripheral neuropathy. The Italian Study Group. The St. Vincent Declaration.

    PubMed

    Nicolucci, A; Carinci, F; Cavaliere, D; Scorpiglione, N; Belfiglio, M; Labbrozzi, D; Mari, E; Benedetti, M M; Tognoni, G; Liberati, A

    1996-12-01

    Peripheral neuropathy is one of the most common and disabling long-term sequelae of diabetes mellitus. Aldose reductase inhibitors (ARIs) have been proposed and are increasingly used in many countries for the prevention and treatment of diabetic neuropathy. The aim of this study was to review existing evidence on the effectiveness of ARIs in the treatment of peripheral diabetic neuropathy, with particular reference to the type and clinical relevance of the end point used and to the consistency of results across studies. Thirteen randomized clinical trials (RTCs) comparing ARIs with placebo, published between 1981 and 1993 were included in the meta-analysis. Nerve conduction velocity (NCV) was the only end point reported in all trials. Treatment effect was thus evaluated in terms of NCV mean difference in four different nerves: median motor, median sensory, peroneal motor, and sural sensory. A statistically significant reduction in decline of median motor NCV was present in the treated group as compared to the control group (mean 0.91 ms-1; 95% CI 0.41-1.42 ms-1). For peroneal motor, median sensory, and sural sensory nerves results did not show any clear benefit for patients treated with ARIs. When the analysis was limited to trials with at least 1-year treatment duration, a significant effect was present for peroneal motor NCV (mean 1.24 ms-1; 95% CI 0.32-2.15 ms-1) and a benefit of borderline statistical significance was also present for median motor NCV (mean 0.69 ms-1; 95% CI-0.07-1.45 ms-1). A heterogeneous picture emerged when looking at the results of different studies and serious inconsistencies were also present in the direction of treatment effects among nerves in the same studies. Although the results of 1-year treatment on motor NCV seem encouraging, the uncertainty about the reliability of the end-point employed and the short treatment duration do not allow any clear conclusion about the efficacy of ARIs in the treatment of peripheral diabetic

  9. Statins and neuroprotection: basic pharmacology needed.

    PubMed

    Wood, W Gibson; Mΰller, Walter E; Eckert, Gunter P

    2014-08-01

    Statins are attracting great interest albeit with some controversy in treating certain neurodegenerative diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, ischemic stroke, and traumatic brain injury. Support for the use of statins has come from human studies and animal and cell models. Despite the intense level of interest, there is a deficiency in information on the basic pharmacokinetics and pharmacodynamics of statins in the brain. The purpose of this focused review is to examine what is known and the gaps in our knowledge on detectability of statin lactones and acids in the brain, membrane partitioning and active transport of statins across the blood-brain barrier, and statin effects on brain isoprenoid levels. Statins may be efficacious in treating certain neurodegenerative diseases. Having basic information on statin pharmacokinetics and pharmacodynamics in the brain would provide insight into specific drug targets and also provide the rationale for optimizing statins in terms of enhancing brain influx and inhibiting efflux.

  10. Molecular mechanisms of statin intolerance

    PubMed Central

    Franczyk, Beata; Toth, Peter P.; Rysz, Jacek; Banach, Maciej

    2016-01-01

    Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose. PMID:27279860

  11. The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

    PubMed

    Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, José Antonio; Tamariz, Joaquín; Hernández-Rodríguez, César; Villa-Tanaca, Lourdes

    2014-01-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012). PMID:24270073

  12. The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

    PubMed

    Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, José Antonio; Tamariz, Joaquín; Hernández-Rodríguez, César; Villa-Tanaca, Lourdes

    2014-01-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).

  13. 5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis.

    PubMed

    Traish, Abdulmaged M; Guay, Andre T; Zitzmann, Michael

    2014-12-01

    5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease. PMID:25460297

  14. Co-Medication of Statins with Contraindicated Drugs

    PubMed Central

    Yang, Bo Ram; Seong, Jong-Mi; Choi, Nam-Kyong; Shin, Ju-Young; Lee, Joongyub; Kim, Ye-Jee; Kim, Mi-Sook; Park, Soyoung; Song, Hong Ji; Park, Byung-Joo

    2015-01-01

    Background The concomitant use of cytochrome P450 3A4 (CYP3A4) metabolized statins (simvastatin, lovastatin, and atorvastatin) with CYP3A4 inhibitors has been shown to increase the rate of adverse events. Objective This study was performed to describe the co-medication prevalence of CYP3A4-metabolized statins with contraindicated drugs. Methods The patients aged 40 or older receiving CYP3A4-metabolized statin prescriptions in 2009 were identified using the national patient sample from a Korea Health Insurance Review and Assessment Service database. Contraindicated co-medication was defined as prescription periods of statins and contraindicated drugs overlapping by at least one day. Co-medication patterns were classified into 3 categories as follows: co-medication in the same prescription, co-medication by the same medical institution, and co-medication by different medical institutions. The proportion of co-medication was analyzed by age, gender, co-morbidities, and the statin’s generic name. Results A total of 2,119,401 patients received CYP3A4-metabolized statins and 60,254 (2.84%) patients were co-medicated with contraindicated drugs. The proportion of co-medication was 4.6%, 2.2%, and 1.8% in simvastatin, lovastatin, and atorvastatin users, respectively. The most frequent combination was atorvastatin-itraconazole, followed by simvastatin-clarithromycin and simvastatin-itraconazole. Among the co-medicated patients, 85.3% were prescribed two drugs by different medical institutions. Conclusion The proportion of co-medication of statins with contraindicated drugs was relatively lower than that of previous studies; however, the co-medication occurring by different medical institutions was not managed appropriately. There is a need to develop an effective system and to conduct outcomes research confirming the association between co-medication and the risk of unfavorable clinical outcomes. PMID:25932626

  15. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on progression of diabetic neuropathy and other microvascular complications: multivariate epidemiological analysis based on patient background factors and severity of diabetic neuropathy

    PubMed Central

    Hotta, N; Kawamori, R; Fukuda, M; Shigeta, Y

    2012-01-01

    Abstract Aims The goal of the study was to evaluate the efficacy of epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor–Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and epalrestat therapy (epalrestat group) in Japanese patients with mild diabetic neuropathy. Methods The subjects of the study were patients enrolled in the Aldose Reductase Inhibitor–Diabetes Complications Trial for whom data for major patient characteristics, severity of diabetic neuropathy at the end of the study and time-courses of diabetic retinopathy and diabetic nephropathy were available (57 and 52 patients from the control and epalrestat groups, respectively). Progression of diabetic retinopathy/nephropathy (a primary endpoint) in relation to major patient characteristics, severity of diabetic neuropathy at the end of the study (assessed from the mean of z-scores in four neurological function tests) and epalrestat treatment were analysed using univariate analysis and multiple logistic regression analysis. Results Progression of diabetic retinopathy/nephropathy was significantly inhibited in the epalrestat group compared with the control group (odds ratio = 0.323, P = 0.014) and was dependent on the severity of diabetic neuropathy at the end of the study (odds ratio = 2.131, P = 0.025). Conclusions Epalrestat prevented progression of diabetic neuropathy and retinopathy/nephropathy. The effect on diabetic retinopathy/nephropathy may have occurred indirectly because of the prevention of progression of diabetic neuropathy, in addition to the inhibitory action of epalrestat on aldose reductase. PMID:22507139

  16. Statin Hepatotoxicity: Is it a Real Concern?

    PubMed Central

    Sikka, Pranav; Saxena, K. K.; Kapoor, Seema

    2011-01-01

    Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests. PMID:22567196

  17. ATP-dependent transport of statins by human and rat MRP2/Mrp2

    SciTech Connect

    Ellis, Lucy C.J.; Hawksworth, Gabrielle M.; Weaver, Richard J.

    2013-06-01

    Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD{sub 7.0}) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC{sub 50} values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. - Highlights: • We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins. • We show statins were transported by human and rat MRP2/Mrp2. • Statins competed with a known substrate for transport by MRP2/Mrp2. • Competition involved more than one binding site on the MRP2/Mrp2 protein.

  18. Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

    PubMed Central

    Lange, Philip T.; Darrah, Eric J.; Vonderhaar, Emily P.; Mboko, Wadzanai P.; Rekow, Michaela M.; Patel, Shailendra B.; Sidjanin, Duska J.

    2016-01-01

    ABSTRACT The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCE Statins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. population. Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. PMID:26739055

  19. Chemical and Genetic Validation of the Statin Drug Target to Treat the Helminth Disease, Schistosomiasis

    PubMed Central

    Rojo-Arreola, Liliana; Long, Thavy; Asarnow, Dan; Suzuki, Brian M.; Singh, Rahul; Caffrey, Conor R.

    2014-01-01

    The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, S. mansoni, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration- and time-dependent killing of immature (somule) and adult S. mansoni in vitro at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules in vitro and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules in vitro subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that S. mansoni HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug. PMID:24489942

  20. A novel therapeutic effect of statins on nephrogenic diabetes insipidus

    PubMed Central

    Bonfrate, Leonilde; Procino, Giuseppe; Wang, David Q-H; Svelto, Maria; Portincasa, Piero

    2015-01-01

    Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional ‘pleiotropic’ effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed. PMID:25594563

  1. Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies.

    PubMed

    Lin, Chun-Jung; Liao, Wei-Chih; Lin, Hwai-Jeng; Hsu, Yuan-Man; Lin, Cheng-Li; Chen, Yu-An; Feng, Chun-Lung; Chen, Chih-Jung; Kao, Min-Chuan; Lai, Chih-Ho; Kao, Chia-Hung

    2016-01-01

    Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70-0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12-0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer.

  2. Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies

    PubMed Central

    Hsu, Yuan-Man; Lin, Cheng-Li; Chen, Yu-An; Feng, Chun-Lung; Chen, Chih-Jung; Kao, Min-Chuan; Lai, Chih-Ho; Kao, Chia-Hung

    2016-01-01

    Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70–0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12–0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer. PMID:26730715

  3. The relationship between HMGCR genetic variation, alternative splicing, and statin efficacy.

    PubMed

    Medina, Marisa Wong

    2010-06-01

    Statins are a class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme which catalyzes the rate limiting step of cholesterol biosynthesis. Although numerous trials have demonstrated statin efficacy in the reduction of cardiovascular disease risk, there is substantial variation between individuals in the magnitude of plasma LDL-cholesterol reduction. Pharmacogenetic studies have identified HMGCR genetic variation associated with this inter-individual variation. Here we describe how these studies lead to the discovery that HMGCR alternative splicing of exon 13 is not only a marker, but also a determinant of statin efficacy; not only for the treatment of hypercholesterolemia, but also as a chemopreventive agent for colorectal cancer.

  4. Many with Diabetes Missing Out on Statins

    MedlinePlus

    ... on statins." But analysis of data from 204 cardiology practices across the United States revealed that 38 ... not been prescribed statins. The American College of Cardiology, the American Heart Association and the American Diabetes ...

  5. Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

    SciTech Connect

    Miyata, Ryohei; Hiraiwa, Kunihiko; Cheng, Jui Chih; Bai, Ni; Vincent, Renaud; Francis, Gordon A.; Sin, Don D.; Van Eeden, Stephan F.

    2013-10-01

    Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{sub 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased intimal

  6. Statin intolerance: more questions than answers.

    PubMed

    Guyton, John R; Campbell, Kristen B; Lakey, Wanda C

    2014-01-01

    The dramatic effectiveness of statins in improving the course of atherosclerotic cardiovascular disease tends to overshadow questions of statin intolerance. Thus after more than 25 years of clinical statin use, intolerance remains a poorly understood, frustrating issue for patients and providers. It has been extraordinarily difficult to define statin intolerance and its implications for clinical practice. Here, we briefly summarize current knowledge and raise questions that need to be addressed.

  7. N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity.

    PubMed

    Guardia, Ana; Gulten, Gulcin; Fernandez, Raquel; Gómez, Jesus; Wang, Feng; Convery, Maire; Blanco, Delia; Martínez, María; Pérez-Herrán, Esther; Alonso, Marta; Ortega, Fátima; Rullás, Joaquín; Calvo, David; Mata, Lydia; Young, Robert; Sacchettini, James C; Mendoza-Losana, Alfonso; Remuiñán, Modesto; Ballell Pages, Lluís; Castro-Pichel, Julia

    2016-04-01

    Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis. PMID:26934341

  8. Statins and stem cell modulation.

    PubMed

    Xu, Hui; Yang, Yue-Jin; Yang, Tao; Qian, Hai-Yan

    2013-01-01

    Stem cell-based therapy is a promising option for the treatment of ischemic heart diseases. As to a successful stem cell-based therapy, one of the most important issues is that the stable engraftment and survival of implanted stem cells in cardiac microenvironment. There are evidences suggest that pharmacological treatment devoted to regulate stem cell function might represent a potential new therapeutic strategy and are drawing nearer to becoming a part of treatment in clinical settings. Statins could exert cholesterol-independent or pleiotropic effects to cardiovascular system. Recent studies have shown that statins could modulate the biological characteristics and function of various stem cells, thus could be an effective method to facilitate stem cell therapy. This review will focus on statins and their modulation effects on various stem cells.

  9. Cholesterol confusion and statin controversy

    PubMed Central

    DuBroff, Robert; de Lorgeril, Michel

    2015-01-01

    The role of blood cholesterol levels in coronary heart disease (CHD) and the true effect of cholesterol-lowering statin drugs are debatable. In particular, whether statins actually decrease cardiac mortality and increase life expectancy is controversial. Concurrently, the Mediterranean diet model has been shown to prolong life and reduce the risk of diabetes, cancer, and CHD. We herein review current data related to both statins and the Mediterranean diet. We conclude that the expectation that CHD could be prevented or eliminated by simply reducing cholesterol appears unfounded. On the contrary, we should acknowledge the inconsistencies of the cholesterol theory and recognize the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD. PMID:26225201

  10. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.

    PubMed

    Das, Undurti N

    2008-01-01

    Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites: gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and other products such as prostaglandins E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins (LXs), resolvins, protectins including neuroprotectin D1 (NPD1) prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-gamma ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of omega-3 and omega-6 fatty acids and the

  11. Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling.

    PubMed

    Atochina-Vasserman, Elena N; Goncharov, Dmitry A; Volgina, Alla V; Milavec, Megan; James, Melane L; Krymskaya, Vera P

    2013-11-01

    Mutations of the tumor suppressor genes tuberous sclerosis complex (TSC)1 and TSC2 cause pulmonary lymphangioleiomyomatosis (LAM) and tuberous sclerosis (TS). Current rapamycin-based therapies for TS and LAM have a predominantly cytostatic effect, and disease progression resumes with therapy cessation. Evidence of RhoA GTPase activation in LAM-derived and human TSC2-null cells suggests that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor statins can be used as potential adjuvant agents. The goal of this study was to determine which statin (simvastatin or atorvastatin) is more effective in suppressing TSC2-null cell growth and signaling. Simvastatin, but not atorvastatin, showed a concentration-dependent (0.5-10 μM) inhibitory effect on mouse TSC2-null and human LAM-derived cell growth. Treatment with 10 μM simvastatin induced dramatic disruption of TSC2-null cell monolayer and cell rounding; in contrast, few changes were observed in cells treated with the same concentration of atorvastatin. Combined treatment of rapamycin with simvastatin but not with atorvastatin showed a synergistic growth-inhibitory effect on TSC2-null cells. Simvastatin, but not atorvastatin, inhibited the activity of prosurvival serine-threonine kinase Akt and induced marked up-regulation of cleaved caspase-3, a marker of cell apoptosis. Simvastatin, but not atorvastatin, also induced concentration-dependent inhibition of p42/p44 Erk and mTORC1. Thus, our data show growth-inhibitory and proapoptotic effects of simvastatin on TSC2-null cells compared with atorvastatin. These findings have translational significance for combinatorial therapeutic strategies of simvastatin to inhibit TSC2-null cell survival in TS and LAM.

  12. Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole.

    PubMed

    Dybro, Anne Mette; Damkier, Per; Rasmussen, Torsten Bloch; Hellfritzsch, Maja

    2016-01-01

    A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment. PMID:27605198

  13. Statin Use Is Associated With Incident Diabetes Mellitus Among Patients in the HIV Outpatient Study

    PubMed Central

    Lichtenstein, Kenneth A.; Hart, Rachel L. D.; Wood, Kathleen C.; Bozzette, Samuel; Buchacz, Kate; Brooks, John T.

    2015-01-01

    Introduction Statin therapy is effective in the prevention of cardiovascular disease in the general population but has been shown to modestly increase the risk for incident diabetes mellitus (DM). Methods We analyzed incident DM in HIV Outpatient Study (HOPS) participants followed at 8 HIV clinic sites during 2002–2011, comparing rates among those who initiated statin therapy during that period with those who did not. Using Cox proportional hazards models, we examined the association between cumulative years of statin exposure and the risk of developing DM, after controlling for age, sex, race/ethnicity, antiretroviral history, prevalent hepatitis C, body mass index, and cumulative exposure to protease inhibitor therapy. We also adjusted for propensity scores to account for residual confounding by indication. Results Of 4692 patients analyzed, 590 (12.6%) initiated statin therapy and 355 (7.2%) developed DM. Incident DM was independently associated with statin therapy (adjusted hazard ratio, 1.14 per year of statin use), as well as older age, Hispanic/Latino ethnicity, non-Hispanic/Latino black race, antiretroviral-naive status, prevalent hepatitis C, and body mass index ≥30 kg/m2 (P < 0.05 for all). The association of statin use with incident DM was similar in the model adjusted for propensity score. Conclusions Statin use was associated with a modestly increased risk of incident DM in an HIV-infected population, similar to existing data for the general population. HIV-infected patients should be monitored for glucose intolerance, but statins should not be withheld if clinically indicated for cardiovascular disease risk reduction. PMID:26181706

  14. STATINS MORE THAN CHOLESTEROL LOWERING AGENTS IN ALZHEIMER DISEASE: THEIR PLEIOTROPIC FUNCTIONS AS POTENTIAL THERAPEUTIC TARGETS

    PubMed Central

    Barone, Eugenio; Domenico, Fabio Di; Butterfield, D. Allan

    2013-01-01

    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative ad nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. PMID:24231510

  15. [PCSK9 inhibitors. A new approach for treatment of hypercholesterolemia].

    PubMed

    Saußele, Tanja

    2015-07-01

    To date HMG-CoA-reductase inhibitors are the most effective drugs for reduction of LDL-cholesterol levels and for prevention of cardiovascular events. Inhibition of the enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9), which is involved in depletion of the LDL-receptor, is a new pharmacologic approach. Inhibition of PCSK9 by monoclonal antibodies provokes an additional reduction of LDL-cholesterol levels by 50-60 % in addition to statins. Previous phase III studies indicate good compatibility. Ongoing long-term studies will answer questions of safety and influence on cardiovascular events. Although those results are not available yet, alirocumab and evolocumab have already been recommendd for approval. PMID:26364362

  16. Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2, 4-diamino-6-(2′-hydroxydibenz[b, f]azepin-5-yl)methylpteridine

    SciTech Connect

    Cody, Vivian; Pace, Jim; Rosowsky, Andre

    2008-09-01

    The structures of mouse DHFR holo enzyme and a ternary complex with NADPH and a potent inhibitor are described. It has been shown that 2, 4-diamino-6-arylmethylpteridines and 2, 4-diamino-5-arylmethylpyrimidines containing an O-carboxylalkyloxy group in the aryl moiety are potent and selective inhibitors of the dihydrofolate reductase (DHFR) from opportunistic pathogens such as Pneumocystis carinii, the causative agent of Pneumocystis pneumonia in HIV/AIDS patients. In order to understand the structure–activity profile observed for a series of substituted dibenz[b, f]azepine antifolates, the crystal structures of mouse DHFR (mDHFR; a mammalian homologue) holo and ternary complexes with NADPH and the inhibitor 2, 4-diamino-6-(2′-hydroxydibenz[b, f]azepin-5-yl)methylpteridine were determined to 1.9 and 1.4 Å resolution, respectively. Structural data for the ternary complex with the potent O-(3-carboxypropyl) inhibitor PT684 revealed no electron density for the O-carboxylalkyloxy side chain. The side chain was either cleaved or completely disordered. The electron density fitted the less potent hydroxyl compound PT684a. Additionally, cocrystallization of mDHFR with NADPH and the less potent 2′-(4-carboxybenzyl) inhibitor PT682 showed no electron density for the inhibitor and resulted in the first report of a holoenzyme complex despite several attempts at crystallization of a ternary complex. Modeling data of PT682 in the active site of mDHFR and P. carinii DHFR (pcDHFR) indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit into the active site or that the inhibitor side chain would have to adopt an alternative binding mode to that observed for other carboxyalkyloxy inhibitors. These data also show that the mDHFR complexes have a decreased active-site volume as reflected in the relative shift of helix C (residues 59–64) by 0.6 Å compared with pcDHFR ternary complexes. These data are consistent with the

  17. Statins Increase Rifampin Mycobactericidal Effect

    PubMed Central

    Lobato, Lívia Silva; Rosa, Patrícia Sammarco; Ferreira, Jessica da Silva; Neumann, Arthur da Silva; da Silva, Marlei Gomes; do Nascimento, Dejair Caitano; Soares, Cleverson Teixeira; Pedrini, Silvia Cristina Barbosa; de Oliveira, Diego Sá Leal; Monteiro, Cláudia Peres; Pereira, Geraldo Moura Batista; Ribeiro-Alves, Marcelo; Hacker, Mariana Andrea; Moraes, Milton Ozório; Pessolani, Maria Cristina Vidal; Duarte, Rafael Silva

    2014-01-01

    Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation. PMID:25049257

  18. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  19. Association of flavonoid-rich foods and statins in the management of hypercholesterolemia: a dangerous or helpful combination?

    PubMed

    Peluso, Ilaria; Palmery, Maura; Serafini, Mauro

    2015-01-01

    Statins and dietary modifications are the cornerstone of hypercholesterolemia management. Although it is well known that possible adverse effect of statins can occur due to drug-drug interactions, food-drug interactions are a commonly overlooked aspect. In particular, flavonoids could interfere with statins' bioavailability through different mechanisms, such as competition with cytochrome P450 (CYP) enzymes, esterases, uridine diphosphate glucuronosyltransferases and transporters (P-glycoprotein, multi-drug resistance-associated proteins, organic anion transporting polypeptides, breast cancer-resistance protein and monocarboxylate transporters). Transporters are characterized by low substrate specificity and flavonoid- rich foods could interfere with the bioavailability of all statins at this level. On the other hand, in addition to being substrates of drug metabolism/ transport systems, flavonoids are also able to modulate gene expression of enzymes and transporters. Therefore, long-term transcriptional induction may increase the clearance of statins, despite flavonoids act as competitive inhibitors after bolus consumption. In humans, major interactions were observed between grapefruit juice and statins that are substrates of P-glycoprotein/CYP3A, but other fruit juices also affect the bioavailability of statins that are not metabolised by CYP. Even if flavonoids could play a role in the prevention of hypercholesterolemia, the question whether there's a helpful or dangerous association between flavonoid-rich foods and statins, due to the interactions between flavonoid-rich foods and statins and the potential associated adverse effects of statins, remain unanswered. Therefore, the anamnesis of patients must include detailed information about their eating habits and the present review suggests monitoring and reporting any possible case of interaction between a prescribed statin and food. PMID:26467069

  20. Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3.

    PubMed

    Heinrich, Daniel M; Flanagan, Jack U; Jamieson, Stephen M F; Silva, Shevan; Rigoreau, Laurent J M; Trivier, Elisabeth; Raynham, Tony; Turnbull, Andrew P; Denny, William A

    2013-04-01

    High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells.

  1. Statins and biomineralization: data from the past and stratagies for the future

    NASA Astrophysics Data System (ADS)

    Kearney, S.

    The background to this paper is based on research conducted by Dr. Gregory Mundy, at the University of Texas Health Science Center, and published in Science, 3rd December 1999. In it, he identified two types of statins (a highly prescribed class of pharmacological compounds, otherwise known as HMG Coa Reductase Inhibitors, that are currently used to lower high cholesterol and treat heart disease) that may have the potential to treat osteoporosis. This research is significant, given that his research found that the two types of statins in question (lovostatin and simvastatin) both decreased osteoclast (i.e. bone decomposing cells) activity while also, and importantly, increasing osteoblast (i.e. bone forming cells) activity. The advantages of such a drug, if found to be truly effective, are many when compared to the current pharmacological treatments of osteoporosis. This is for two primary reasons, namely greater effectiveness and lesser side effects. For example, the widely prescribed class of drugs known as bisphosphonates only block resorption (i.e. stop osteoclast activity) while another drug, calcitonin, causes nausea, vomiting and diarrhea. Hence, this research may have important implications for human spaceflight, in particular as a countermeasure against the bone wastage suffered by astronauts during long duration spaceflight. However, since Mundy's paper was first published, a number of epidemiological (i.e. observational) studies on the relationship between statin use and increased bone mass have been published. While some of these papers supported Mundy's results, a number have thrown doubt on the supposed benefits of statin use to treat osteoporosis. Hence the need to further investigate the actual effectiveness of this drug. It is proposed to utilize the facilities available onboard the international space station (ISS) to supplement ground-based research into this drug. This may encompass utilization of ESA's Biolab and NASA's Human Research Facility

  2. Unmet Needs in LDL-C Lowering: When Statins Won't Do!

    PubMed

    Krähenbühl, Stephan; Pavik-Mezzour, Ivana; von Eckardstein, Arnold

    2016-08-01

    The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments. PMID:27456066

  3. Structural Analysis of a Holoenzyme Complex of Mouse Dihydrofolate Reductase With NADPH And a Ternary Complex With the Potent And Selective Inhibitor 2,4-Diamino-6-(2'-Hydroxydibenz[b,F]azepin-5-YI)

    SciTech Connect

    Cody, V.; Pace, J.; Rosowsky, A.

    2009-05-12

    It has been shown that 2,4-diamino-6-arylmethylpteridines and 2,4-diamino-5-arylmethylpyrimidines containing an O-carboxylalkyloxy group in the aryl moiety are potent and selective inhibitors of the dihydrofolate reductase (DHFR) from opportunistic pathogens such as Pneumocystis carinii, the causative agent of Pneumocystis pneumonia in HIV/AIDS patients. In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structures of mouse DHFR (mDHFR; a mammalian homologue) holo and ternary complexes with NADPH and the inhibitor 2,4-diamino-6-(2{prime}-hydroxydibenz[b,f]azepin-5-yl)methylpteridine were determined to 1.9 and 1.4 A resolution, respectively. Structural data for the ternary complex with the potent O-(3-carboxypropyl) inhibitor PT684 revealed no electron density for the O-carboxylalkyloxy side chain. The side chain was either cleaved or completely disordered. The electron density fitted the less potent hydroxyl compound PT684a. Additionally, cocrystallization of mDHFR with NADPH and the less potent 2{prime}-(4-carboxybenzyl) inhibitor PT682 showed no electron density for the inhibitor and resulted in the first report of a holoenzyme complex despite several attempts at crystallization of a ternary complex. Modeling data of PT682 in the active site of mDHFR and P. carinii DHFR (pcDHFR) indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit into the active site or that the inhibitor side chain would have to adopt an alternative binding mode to that observed for other carboxyalkyloxy inhibitors. These data also show that the mDHFR complexes have a decreased active-site volume as reflected in the relative shift of helix C (residues 59-64) by 0.6 A compared with pcDHFR ternary complexes. These data are consistent with the greater inhibitory potency against pcDHFR.

  4. Design and synthesis of pyridazinone-substituted benzenesulphonylurea derivatives as anti-hyperglycaemic agents and inhibitors of aldose reductase - an enzyme embroiled in diabetic complications.

    PubMed

    Yaseen, Raed; Pushpalatha, H; Reddy, G Bhanuprakash; Ismael, Ameer; Ahmed, Ayad; Dheyaa, Alhamza; Ovais, Syed; Rathore, Pooja; Samim, Mohammed; Akthar, Mymoona; Sharma, Kalicharan; Shafi, Syed; Singh, Surender; Javed, Kalim

    2016-12-01

    Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III-VI, XII, XVI-XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242 μM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs. PMID:26879420

  5. Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells.

    PubMed

    Statt, Sarah; Ruan, Jhen-Wei; Hung, Li-Yin; Chang, Ching-Yun; Huang, Chih-Ting; Lim, Jae Hyang; Li, Jian-Dong; Wu, Reen; Kao, Cheng-Yuan

    2015-11-01

    Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, α-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.

  6. Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

    PubMed

    Sieg, Adam; Weeks, Phillip; Krustchinsky, Lori; Rajapreyar, Indranee

    2016-07-01

    Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication. PMID:27079752

  7. A Novel NADPH-Dependent Aldehyde Reductase Gene from Saccharomyces cerevisiae NRRL Y-12632 Involved in the Detoxification of Aldehyde Inhibitors Derived from Lignocellulosic Biomass Conversion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aldehyde inhibitors such as furfural, 5-hydroxymethylfurfural (HMF), anisaldehyde, benzaldehyde, cinnamaldehyde, and phenylaldehyde are commonly generated during lignocellulosic biomass conversion process for low-cost cellulosic ethanol production that interferes with subsequent microbial growth and...

  8. Statins and cognitive function: an updated review.

    PubMed

    Chatterjee, Saurav; Krishnamoorthy, Parasuram; Ranjan, Pragya; Roy, Ahana; Chakraborty, Anasua; Sabharwal, Manpreet Singh; Ro, Richard; Agarwal, Vikram; Sardar, Partha; Danik, Jacqueline; Giri, Jay S; DeGoma, Emil M; Kumbhani, Dharam J

    2015-02-01

    Ischemic heart disease remains the leading cause of death in the USA. Statins have substantially contributed to the decline in mortality due to heart disease. Historically, statins are hypothesized to be neuroprotective and beneficial in dementia, but recent reports have suggested an association with transient cognitive decline. We have critically appraised the relationship between statins and cognitive function in this review. Most of the data are observational and reported a protective effect of statins on dementia and Alzheimer's disease in patients with normal cognition at baseline. Few studies, including two randomized control trials, were unable to find a statistically significant decrease in the risk or improvement in patients with established dementia or decline in cognitive function with statin use. As more randomized control trials are required to definitively settle this, cardiovascular benefits of statins must be weighed against the risks of cognitive decline on an individual basis. PMID:25618304

  9. Cardiovascular Disease, Statins, and HIV.

    PubMed

    Eckard, Allison Ross; Meissner, Eric G; Singh, Inderjit; McComsey, Grace A

    2016-10-01

    Human immunodeficiency virus (HIV)-infected patients are at an increased risk of serious, non-AIDS-defining comorbidities, even in the setting of viral suppression with combination antiretroviral therapy. This increased risk is due in part to immune dysfunction and heightened inflammation and immune activation associated with chronic HIV infection. Statins have wide-reaching immunomodulatory effects, and their use in the HIV-infected population may be of particular benefit. In this article, we review the pathogenesis of increased inflammation during HIV infection and how it contributes to the risk of cardiovascular disease among HIV-infected individuals. We then we review the immunomodulatory effects of statins and how they may attenuate the risk of cardiovascular disease and other comorbidities in this unique patient population. PMID:27625435

  10. [Help me--I do not tolerate my statin].

    PubMed

    Nater, Harald; Perger, Ludwig; Suter, Paolo M

    2015-05-01

    Statins represent the most widely prescribed drugs. Accordingly, in daily practice statin-related muscle pain and other myopathic sensations are frequently seen. In this practice review the clinical approach to statin myopathy is discussed.

  11. Statin-associated necrotizing autoimmune myopathy.

    PubMed

    Fernandes, Geórgea Hermogenes; Zanoteli, Edmar; Shinjo, Samuel Katsuyuki

    2014-09-01

    Necrotizing autoimmune myopathy (NAM) is a severe adverse effect of statins. We report a 66-year-old Caucasian female who had progressive proximal muscle weakness after treatment with statins. Results of a muscle biopsy showed necrotizing myopathy with minimal inflammatory cell infiltrate and increased major histocompatibility class I antigen expression in muscle fibers. The clinical and laboratory parameters improved significantly with immunosuppressive treatment. Although it is a rare event, statin-induced NAM should be included as a differential diagnosis of myopathies.

  12. [Statins in primary prophylaxis of cardiovascular diseases].

    PubMed

    Kobalava, Zh D; Villeval'de, S V

    2011-01-01

    The review summarises data on statins efficacy in primary prophylaxis of cardiovascular complications. Main results of the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial are analysed in detail. Its role in possible changes in current recommendations on prophylaxis and treatment of atherosclerosis is shown. Statins are considered as drugs essential in the strategy of improvement of life quality.

  13. In vivo and in vitro effect of novel 4,16-pregnadiene-6,20-dione derivatives, as 5alpha-reductase inhibitors.

    PubMed

    Bratoeff, Eugene; Cabeza, Marisa; Pérez-Ornelas, Victor; Recillas, Sergio; Heuze, Ivonne

    2008-09-01

    In this study, we report the synthesis and biological evaluation of several new 3-substituted pregna-4,16-diene-6,20-dione derivatives (11a-11d). These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological effect of these steroids was demonstrated in in vivo and in vitro experiments. In the in vivo experiments, we measured the activity of the 11a-11d on the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with the new steroids. For the studies in vitro, we determined the IC50 values by measuring the steroid concentration that inhibits 50% of the activity of 5alpha-reductase present in human prostate. In order to study the mechanism of action of 11a-11d, we also determined the capacity of these steroids to bind to the androgen receptor (AR) present in the rat prostate cytosol using labeled mibolerone as a tracer. The results from this work indicated that compounds 11a-11d significantly decreased the weight of the prostate as compared to testosterone treated animals and this reduction of the weight of the prostate was comparable to that produced by the finasteride. On the other hand 11a-11d exhibited a high inhibitory activity for the human 5alpha-reductase enzyme with IC50 values of 1.4 x 10(-8), 1.8 x 10(-9), 1.0 x 10(-8) and 4 x 10(-5) respectively. However the IC50 value of 11a (1.8 x 10(-9)) was the only one lower than that of finasteride (8.5 x 10(-9)). Nevertheless this compound did not show a higher potency in vivo as compared to that of compounds 11b-11d. The competition analysis for the androgen receptor indicated that the IC50 value of non-labeled mibolerone used in this experiment was 1nM, whereas steroids 10, 11a-11d did not inhibit the labeled mibolerone binding to the androgen receptor. On the other hand, steroid 10 did not show any activities in vitro or in vivo, and for this reason these steroidal derivatives (11a-11d) cannot be considered as

  14. Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors.

    PubMed

    Mendieta, Aarón; Jiménez, Fabiola; Garduño-Siciliano, Leticia; Mojica-Villegas, Angélica; Rosales-Acosta, Blanca; Villa-Tanaca, Lourdes; Chamorro-Cevallos, Germán; Medina-Franco, José L; Meurice, Nathalie; Gutiérrez, Rsuini U; Montiel, Luisa E; Cruz, María Del Carmen; Tamariz, Joaquín

    2014-11-01

    In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.

  15. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia.

    PubMed Central

    Eckernäs, S A; Roos, B E; Kvidal, P; Eriksson, L O; Block, G A; Neafus, R P; Haigh, J R

    1993-01-01

    1. It has been suggested that HMG CoA reductase inhibitors which are administered as inactive, lipophilic lactones (e.g. simvastatin) have a greater propensity to evoke nocturnal sleep disturbances than pravastatin, an inhibitor given in the active, hydrophilic, open-acid form. 2. The effects of 4 weeks treatment with equipotent doses of simvastatin (20 mg day-1) and pravastatin (40 mg day-1) have been compared using polysomnography and subjective sleep assessments in a double-blind, placebo-controlled, two-period, incomplete block design study involving 24 male patients with primary moderate hypercholesterolaemia (mean LDL cholesterol 5.11 mmol l-1). 3. Analysis of sleep EEG measures relevant to insomnia provided no evidence of significant differences between pravastatin, simvastatin and placebo, except in terms of entries and latency to stage I sleep. The number of entries to stage I sleep was significantly greater after simvastatin treatment than after either pravastatin or placebo (P < 0.05), but by contrast the latency to stage I sleep was significantly prolonged only in the pravastatin group (P < 0.05 vs placebo). 4. Subjective ratings of sleep initiation, maintenance and quality made during and after therapy were not significantly different between the three treatment groups. 5. It appears that the inherent hydrophobicity of simvastatin does not increase the occurrence of sleep disturbances in this patient population at a dose shown to elicit a characteristic hypolipidaemic response. PMID:8471404

  16. Development of Potent and Selective Inhibitors of Aldo-Keto Reductase 1C3 (type 5 17β-Hydroxysteroid Dehydrogenase) Based on N-Phenyl-Aminobenzoates and Their Structure Activity Relationships

    PubMed Central

    Adeniji, Adegoke O.; Twenter, Barry M.; Byrns, Michael C.; Jin, Yi; Chen, Mo; Winkler, Jeffrey D.; Penning, Trevor M.

    2012-01-01

    Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castrate resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required since compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular are potent but non-selective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid as lead compound, five classes of structural analogs were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads towards new therapeutics for CRPC. PMID:22263837

  17. Statins and transcriptional regulation: The FXR connection

    SciTech Connect

    Habeos, Ioannis; Ziros, Panos G.; Psyrogiannis, Agathoklis; Vagenakis, Apostolos G.; Papavassiliou, Athanasios G. . E-mail: papavas@med.upatras.gr

    2005-08-26

    Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism.

  18. Statins and vascular dementia: a review.

    PubMed

    Giannopoulos, Sotirios; Katsanos, Aristeidis H; Kosmidou, Maria; Tsivgoulis, Georgios

    2014-01-01

    The impact of statin therapy on dementia has been a hot topic of debate over the last decade and still remains highly controversial. Among all causes of dementia, vascular dementia (VaD) is the one type that is more likely to benefit from statins. To date no randomized clinical trials have been published and no systematic review has investigated a possible preventive effect of statins on the VaD subtype. In the present literature review, we tried to identify all available data on the effect of statins specifically in patients with VaD, and to further discuss this possible association. Our literature search highlighted two cross-sectional studies, two prospective cohort studies, and one retrospective cohort study. Two of the studies found a significant positive effect of statin treatment on VaD, depicted by the lower incidence of VaD in statin users, while the others reported non-significant associations. The relatively small numbers of VaD patients and statin users, as well as the presence of confounders and biases, make the interpretation of results extremely difficult. Statins may exert a benefit in the prevention of all-type dementia and VaD, through several mechanisms except for hyperlipidemia reduction. A well-designed randomized clinical trial is the ideal study design to address the effect of statin therapy in VaD and to draw final conclusions.

  19. Augmentation of CFTR maturation by S-nitrosoglutathione reductase.

    PubMed

    Zaman, Khalequz; Sawczak, Victoria; Zaidi, Atiya; Butler, Maya; Bennett, Deric; Getsy, Paulina; Zeinomar, Maryam; Greenberg, Zivi; Forbes, Michael; Rehman, Shagufta; Jyothikumar, Vinod; DeRonde, Kim; Sattar, Abdus; Smith, Laura; Corey, Deborah; Straub, Adam; Sun, Fei; Palmer, Lisa; Periasamy, Ammasi; Randell, Scott; Kelley, Thomas J; Lewis, Stephen J; Gaston, Benjamin

    2016-02-01

    S-nitrosoglutathione (GSNO) reductase regulates novel endogenous S-nitrosothiol signaling pathways, and mice deficient in GSNO reductase are protected from airways hyperreactivity. S-nitrosothiols are present in the airway, and patients with cystic fibrosis (CF) tend to have low S-nitrosothiol levels that may be attributed to upregulation of GSNO reductase activity. The present study demonstrates that 1) GSNO reductase activity is increased in the cystic fibrosis bronchial epithelial (CFBE41o(-)) cells expressing mutant F508del-cystic fibrosis transmembrane regulator (CFTR) compared with the wild-type CFBE41o(-) cells, 2) GSNO reductase expression level is increased in the primary human bronchial epithelial cells expressing mutant F508del-CFTR compared with the wild-type cells, 3) GSNO reductase colocalizes with cochaperone Hsp70/Hsp90 organizing protein (Hop; Stip1) in human airway epithelial cells, 4) GSNO reductase knockdown with siRNA increases the expression and maturation of CFTR and decreases Stip1 expression in human airway epithelial cells, 5) increased levels of GSNO reductase cause a decrease in maturation of CFTR, and 6) a GSNO reductase inhibitor effectively reverses the effects of GSNO reductase on CFTR maturation. These studies provide a novel approach to define the subcellular location of the interactions between Stip1 and GSNO reductase and the role of S-nitrosothiols in these interactions.

  20. Nitrate reductase from Rhodopseudomonas sphaeroides.

    PubMed Central

    Kerber, N L; Cardenas, J

    1982-01-01

    The facultative phototroph Rhodopseudomonas sphaeroides DSM158 was incapable of either assimilating or dissimilating nitrate, although the organism could reduce it enzymatically to nitrite either anaerobically in the light or aerobically in the dark. Reduction of nitrate was mediated by a nitrate reductase bound to chromatophores that could be easily solubilized and functioned with chemically reduced viologens or photochemically reduced flavins as electron donors. The enzyme was solubilized, and some of its kinetic and molecular parameters were determined. It seemed to be nonadaptive, ammonia did not repress its synthesis, and its activity underwent a rapid decline when the cells entered the stationary growth phase. Studies with inhibitors and with metal antagonists indicated that molybdenum and possibly iron participate in the enzymatic reduction of nitrate. The conjectural significance of this nitrate reductase in phototrophic bacteria is discussed. PMID:6978883

  1. Azasterol inhibitors in yeast. Inhibition of the 24-methylene sterol delta24(28)-reductase and delta24-sterol methyltransferase of Saccharomyces cerevisiae by 23-azacholesterol.

    PubMed

    Pierce, H D; Pierce, A M; Srinivasan, R; Unrau, A M; Oehlschlager, A C

    1978-06-23

    The effects of 23-azacholesterol on sterol biosynthesis and growth of Saccharomyces cervisiae were examined. In the presence of 0.2, 0.5, and 1 micron 23-azacholesterol, aerobically-growing yeast produced a nearly constant amount of ergosta-5,7,22,24(28)-tetraenol (approx. 36% of total sterol) and slowly accumulated zymosterol with a concommitant decline in ergosterol synthesis. Growth and total sterol content of yeast cultures treated with 0.2-1 micron 23-azacholesterol were similar to that of the control culture. Yeast cultures treated with 5 and 10 micron 23-azacholesterol produced mostly zymosterol (58-61% of total sterol), while ergosta-5,7,22,24(28)-tetraenol production declined to less than 10% of total sterol. The observed changes in the distribution of sterols in treated cultures are consistent with inhibition of 24-methylene sterol 24(28)-sterol reductase (total inhibition at 1 micron 23-azacholesterol) and of 24-sterol methyltransferase (71% inhibition at 10 micron 23-azacholesterol). Yeast cultures treated with 10 micron 23-azacholesterol were found to contain 4,4-dimethylcholesta-8,14,24-trienol and 4alpha-methylcholesta-8,14,24-trienol, which were isolated and characterized for the first time. PMID:352402

  2. Statins and Nonadherence: Should We RELATE Better?

    PubMed

    Turin, Alexander; Pandit, Jay; Stone, Neil J

    2015-09-01

    Statin nonadherence is a major challenge to optimal management. Patients nonadherent to statin therapy do not receive the expected benefit relative to the degree of low-density lipoprotein cholesterol (LDL-C) lowering obtained. This is important because new evidence guidelines recommend statins as the first-line therapy for those in high-risk groups (secondary prevention, patients with diabetes 40-75 years of age, and LDL-C ≥ 190 mg/dL) and in selected primary prevention patients. Statin assignment in the latter group occurs only in those with an estimated ≥7.5% 10-year atherosclerotic cardiovascular disease risk after shared decision making in a clinician-patient risk discussion. However, in numerous studies, statin nonadherence shows little or no benefit in reducing cardiovascular events or mortality compared to placebo, effectively negating the risk reduction expected from statin use and concomitantly increasing the total cost of health care. The causes and solutions for nonadherence are multifactorial and include patient, clinician, and health system factors. We believe that a clinician-patient partnership that facilitates patients' understanding of the potential for optimal benefit with the least adverse effects is an important first step toward improving adherence. A transtheoretical model of stages of behavior change helps clinicians address many of the common factors limiting adherence to statins. We conclude with a teaching tool emphasizing a structured approach to statin therapy with patient-centered risk discussions. PMID:25827856

  3. Structural and Enzymatic Analyses Reveal the Binding Mode of a Novel Series of Francisella tularensis Enoyl Reductase (FabI) Inhibitors

    SciTech Connect

    Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent; Boci, Teuta; Santarsiero, Bernard D.; Johnson, Michael E.

    2012-10-10

    Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.

  4. Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors

    PubMed Central

    Mehboob, Shahila; Hevener, Kirk E; Truong, Kent; Boci, Teuta; Santarsiero, Bernard D; Johnson, Michael E

    2012-01-01

    Due to structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds. PMID:22642319

  5. Early Statin Use and the Progression of Alzheimer Disease: A Total Population-Based Case-Control Study.

    PubMed

    Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

    2015-11-01

    The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population.This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression.There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76-0.95, P = 0.0066) to have AD progression than those without.Early statin use was significantly associated with a reduction in AD

  6. Mode of action of human pharmaceuticals in fish: the effects of the 5-alpha-reductase inhibitor, dutasteride, on reproduction as a case study.

    PubMed

    Margiotta-Casaluci, Luigi; Hannah, Robert E; Sumpter, John P

    2013-03-15

    In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L-low μg/L). In most cases, these compounds are characterised by highly specific modes of action, and the evolutionary conservation of drug targets in wildlife species suggests the possibility that pharmaceuticals present in the environment may cause toxicological effects by acting through the same targets as they do in humans. Our research addressed the question of whether or not dutasteride, a pharmaceutical used to treat benign prostatic hyperplasia, may cause adverse effects in a teleost fish, the fathead minnow (Pimephales promelas), by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme that converts testosterone into dihydrotestosterone (DHT). Mammalian pharmacological and toxicological information were used to guide the experimental design and the selection of relevant endpoints, according to the so-called "read-across approach", suggesting that dutasteride may affect male fertility and steroid hormone dynamics. Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100 μg/L) on fish reproduction. Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females. However, none of the observed adverse effects occurred at concentrations of exposure lower than 32 μg/L; this, together with the low volume of drug prescribed every year (10.34 kg in the UK in 2011), and the extremely low predicted environmental concentration (0.03 ng/L), suggest that, at present, the potential presence of dutasteride in the environment does not represent a threat to wild fish populations. PMID:23280489

  7. The inhibitory activity of aldose reductase in vitro by constituents of Garcinia mangostana Linn.

    PubMed

    Fatmawati, Sri; Ersam, Taslim; Shimizu, Kuniyoshi

    2015-01-15

    We investigated aldose reductase inhibition of Garcinia mangostana Linn. from Indonesia. Dichloromethane extract of the root bark of this tree was found to demonstrate an IC50 value of 11.98 µg/ml for human aldose reductase in vitro. From the dichloromethane fraction, prenylated xanthones were isolated as potent human aldose reductase inhibitors. We discovered 3-isomangostin to be most potent against aldose reductase, with an IC50 of 3.48 µM.

  8. Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors

    PubMed Central

    Zhang, Xin; Zhou, Xilin; L.Kisliuk, Roy; Piraino, Jennifer; Cody, Vivian

    2011-01-01

    Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH3 substituents inhibited human (h) TS (IC50 = 0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH3 with a 2-NH2 increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC50 = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate. PMID:21550809

  9. Thioredoxin reductase inhibitor ethaselen increases the drug sensitivity of the colon cancer cell line LoVo towards cisplatin via regulation of G1 phase and reversal of G2/M phase arrest.

    PubMed

    Fu, Jia-Ning; Li, Jing; Tan, Qiang; Yin, Han-Wei; Xiong, Kun; Wang, Tian-Yu; Ren, Xiao-Yuan; Zeng, Hui-Hui

    2011-08-01

    We evaluated the combination treatment of ethaselen (BBSKE) as a thioredoxin reductase (TrxR) inhibitor plus cisplatin (CDDP) on the human colon adenocarcinoma cell line LoVo. Therapeutic effects ranging from nearly additive to clearly synergistic demonstrated an effective combination, i.e., the cytostatic dose of CDDP could be reduced without a loss in efficacy. To further investigate the cellular response mechanisms of these favorable outcomes, we analyzed the cell-cycle profiles, mRNA expression patterns, and protein levels of several key genes after incubation with BBSKE or CDDP separately and in combination. In appropriate conditions, CDDP induced arrest at the G2/M phase accompanied by the enhanced inhibitory phosphorylation of Cdk1 and the elevated protein expression of cyclin B1. BBSKE downregulated expression of cyclin D1 by increasing mRNA and protein levels of p21, and thus induced G1 phase arrest. BBSKE returned Cdk1 to an activated state, and reduced the protein level of cyclin B1 after incubation in combination with CDDP, which was consistent with the reduction in the percentage of cells in G2/M identified by flow cytometry. By regulating the G1 phase and reversing CDDP-induced G2/M phase arrest, BBSKE increases drug sensitivity of LoVo cells toward CDDP, and probably provides a meaningful anticancer strategy for further clinical studies.

  10. Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis.

    PubMed

    Stec, Jozef; Vilchèze, Catherine; Lun, Shichun; Perryman, Alexander L; Wang, Xin; Freundlich, Joel S; Bishai, William; Jacobs, William R; Kozikowski, Alan P

    2014-11-01

    New triclosan (TRC) analogues were evaluated for their activity against the enoyl-acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well-known inhibitor of InhA, and specific modifications to its positions 5 and 4' afforded 27 derivatives; of these compounds, seven derivatives showed improved potency over that of TRC. These analogues were active against both drug-susceptible and drug-resistant Mtb strains. The most active compound in this series, 4-(n-butyl)-1,2,3-triazolyl TRC derivative 3, had an MIC value of 0.6 μg mL(-1) (1.5 μM) against wild-type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC50 value of 90 nM. Compound 3 and the 5-methylisoxazole-modified TRC 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc(2) 4914, an Mtb strain overexpressing inhA, was found to be less susceptible to compounds 3 and 14, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.

  11. An assessment by the Statin Intolerance Panel: 2014 update.

    PubMed

    Guyton, John R; Bays, Harold E; Grundy, Scott M; Jacobson, Terry A; The National Lipid Association Statin Intolerance Panel

    2014-01-01

    This article from the National Lipid Association Statin Intolerance Panel provides a framework for understanding statin intolerance and makes general recommendations for health professionals. For specific guidance on adverse events related to muscle, liver, cognition, and glucose metabolism, one should refer to the other reports of the Statin Safety Task Force for those topics. Although statin adverse effects rarely lead to permanent sequelae, symptomatic intolerance frequently hinders cardiovascular risk reduction by statins. We emphasize here the advisory role of the clinician helping each patient to make personal decisions on statin tolerability. We identify a pressing need for further research on statin intolerance and make suggestions for research design.

  12. Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib.

    PubMed

    Miyares, Marta A; Davis, Kyle

    2012-01-01

    Cardiovascular disease (CVD) is responsible for significant morbidity and mortality within the United States and worldwide. Although targeting low-density lipoprotein cholesterol (LDL-C) in the prevention of CVD has been shown to be effective, evidence exists to indicate that significant cardiovascular (CV) risk remains in patients receiving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) - a risk that may be correlated with low levels of high-density lipoprotein cholesterol (HDL-C). Among the various tactics under investigation to increase HDL-C, inhibition of cholesteryl ester transfer protein (CETP) appears the most adept to raise these levels. Although torcetrapib, a CETP inhibitor, demonstrated significant beneficial changes in HDL-C and LDL-C after 12 months of therapy when coadministered with atorvastatin, patients in the torcetrapib arm experienced a rise in mortality, including increased risk of death from CV and non-CV causes as well as a significant rise in major CV events. Later studies established that the adverse effects of torcetrapib were produced from molecule-specific off-target effects and not to the mechanism of CETP inhibition. These untoward outcomes have not been detected with anacetrapib, the third of the CETP inhibitors to enter Phase III trials. Furthermore, treatment with anacetrapib revealed both a statistically significant decrease in LDL-C and increase in HDL-C over placebo. While the place in therapy of niacin and fibrates to reduce CV events is currently in question secondary to the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes and the Action to Control CV Risk in Diabetes trials, the ongoing large-scale, randomized-placebo, controlled-outcomes study with anacetrapib coadministered with statin treatment will not only test the hypothesis if CETP inhibition lowers residual CV risk but will also provide insight as to which patient

  13. Clinical perspectives of statin-induced rhabdomyolysis.

    PubMed

    Antons, Kenneth A; Williams, Craig D; Baker, Steven K; Phillips, Paul S

    2006-05-01

    Fear of muscle toxicity remains a major reason that patients with hyperlipidemia are undertreated. Recent evaluations of statin-induced rhabdomyolysis offer new insights on the clinical management of both muscle symptoms and hyperlipidemia after rhabdomyolysis. The incidence of statin-induced rhabdomyolysis is higher in practice than in controlled trials in which high-risk subjects are excluded. Accepted risks include age; renal, hepatic, and thyroid dysfunction; and hypertriglyceridemia. New findings suggest that exercise, Asian race, and perioperative status also may increase the risk of statin muscle toxicity. The proposed causes and the relationship of drug levels to statin rhabdomyolysis are briefly reviewed along with the problems with the pharmacokinetic theory. Data suggesting that patients with certain metabolic abnormalities are predisposed to statin rhabdomyolysis are presented. The evaluation and treatment of patients' muscle symptoms and hyperlipidemia after statin rhabdomyolysis are presented. Patients whose symptoms are related to other disorders need to be identified. Lipid management of those whose symptoms are statin-related is reviewed including treatment suggestions.

  14. Statins.

    PubMed

    Skinner, Anita

    2014-08-26

    While I was aware of the link between high serum cholesterol and cardiovascular disease, I was unaware of the mechanism of atheroma development. The CPD article discussed the role of low-density lipoprotein in the development of atherosclerosis, which I found very interesting.

  15. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.

    PubMed

    Mangravite, Lara M; Engelhardt, Barbara E; Medina, Marisa W; Smith, Joshua D; Brown, Christopher D; Chasman, Daniel I; Mecham, Brigham H; Howie, Bryan; Shim, Heejung; Naidoo, Devesh; Feng, QiPing; Rieder, Mark J; Chen, Yii-Der I; Rotter, Jerome I; Ridker, Paul M; Hopewell, Jemma C; Parish, Sarah; Armitage, Jane; Collins, Rory; Wilke, Russell A; Nickerson, Deborah A; Stephens, Matthew; Krauss, Ronald M

    2013-10-17

    Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.

  16. FDA Expands Advice on Statin Risks

    MedlinePlus

    ... of liver damage. back to top Reports of Memory Loss FDA has been investigating reports of cognitive ... included assessments of cognitive function. The reports about memory loss, forgetfulness and confusion span all statin products ...

  17. Phenotype Standardization for Statin-Induced Myotoxicity

    PubMed Central

    Alfirevic, A; Neely, D; Armitage, J; Chinoy, H; Cooper, R G; Laaksonen, R; Carr, D F; Bloch, K M; Fahy, J; Hanson, A; Yue, Q-Y; Wadelius, M; Maitland-van Der Zee, A H; Voora, D; Psaty, B M; Palmer, C N A; Pirmohamed, M

    2014-01-01

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy. PMID:24897241

  18. Statin tolerability: In defence of placebo-controlled trials

    PubMed Central

    Newman, Connie B

    2015-01-01

    Background Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant. Methods Examination of differences between statin and placebo in withdrawal rates due to adverse events – a good measure of tolerability – in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined. Results Rates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice. Conclusions Given the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute. PMID:26318980

  19. [Are statins a therapeutic alternative in sepsis?].

    PubMed

    Carrillo-Esper, Raúl; Rivera-Buendía, Santos; Carrillo-Córdova, Jorge Raúl; Carrillo-Córdova, Luis Daniel

    2007-01-01

    Sepsis continues to be a major cause of morbidity and mortality. Evidence is emerging from observational studies and basic science research that statins might be associated with reduced mortality in sepsis. Statins have diverse immunomodulatory and antiinflammatory properties independent of their lipid-lowering ability. The protective association between statins and sepsis persisted in high-risk subgroups including patients with diabetes mellitus, those with malignancy, and those receiving steroids. This review discusses the basis of these observations and the current place of statin therapy in patients with sepsis. This is a rapidly growing field of fascinating experimental biology. It suggests an urgent need to investigate the pharmacology of these drugs and reappraise their therapeutic indications in critically ill patients. If this finding is supported by prospective controlled trials, statins may play an important role in sepsis related mortality. By the other hand statins are significantly cheaper than other therapies that have been shown to improve outcome in sepsis, and the demonstration of mortality benefit would have enormous cost-benefit implication.

  20. Identification of a determinant for strict NADP(H)-specificity and high sensitivity to mixed-type steroid inhibitor of rabbit aldo-keto reductase 1C33 by site-directed mutagenesis.

    PubMed

    Endo, Satoshi; Matsunaga, Toshiyuki; Ikari, Akira; El-Kabbani, Ossama; Hara, Akira; Kitade, Yukio

    2015-03-01

    In rabbit tissues, hydroxysteroid dehydrogenase belonging to the aldo-keto reductase (AKR) superfamily exists in six isoforms (AKRs: 1C5 and 1C29-1C33), sharing >73% amino acid sequence identity. AKR1C33 is strictly NADPH-specific, in contrast to dual NADPH/NADH specificity of the other isoforms. All coenzyme-binding residues of the structurally elucidated AKR1C5 are conserved in other isoforms, except that S217 (interacting with the pyrophosphate moiety) and T273 (interacting with the 2'-phosphate moiety) are replaced with F217 and N272, respectively, in AKR1C33. To explore the determinants for the NADPH specificity of AKR1C33, we prepared its F217S and N272T mutant enzymes. The mutation of F217S, but not N272T, converted AKR1C33 into a dually coenzyme-specific form that showed similar kcat values for NAD(P)H to those of AKR1C32. The reverse mutation (S217F) in dually coenzyme-specific AKR1C32 produced a strictly NADPH-specific form. The F217S mutation also abolished the activity towards 3-keto-5β-cholestanes that are substrates specific to AKR1C33, and markedly decreased the sensitivity to 4-pregnenes (such as deoxycorticosterone and medroxyprogesterone acetate) that were found to be potent mixed-type inhibitors of the wild-type enzyme. The results indicate the important role of F217 in the strict NADPH-dependency, as well as its involvement in the unique catalytic properties of AKR1C33.

  1. Statins do not alter the incidence of mesothelioma in asbestos exposed mice or humans.

    PubMed

    Robinson, Cleo; Alfonso, Helman; Woo, Samantha; Walsh, Amy; Olsen, Nola; Musk, Arthur W; Robinson, Bruce W S; Nowak, Anna K; Lake, Richard A

    2014-01-01

    Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44-2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61-1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos.

  2. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy

    PubMed Central

    Mangravite, Lara M.; Engelhardt, Barbara E.; Medina, Marisa W.; Smith, Joshua D.; Brown, Christopher D.; Chasman, Daniel I.; Mecham, Brigham H.; Howie, Bryan; Shim, Heejung; Naidoo, Devesh; Feng, QiPing; Rieder, Mark J.; Chen, Y-D I.; Rotter, Jerome I.; Ridker, Paul M.; Hopewell, Jemma C.; Parish, Sarah; Armitage, Jane; Collins, Rory; Wilke, Russell A.; Nickerson, Deborah A.; Stephens, Matthew; Krauss, Ronald M.

    2013-01-01

    Statins are widely prescribed for lowering plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk1, but there is considerable interindividual variation in treatment response2,3 and increasing concern regarding the potential for adverse effects, including myopathy4 and type 2 diabetes5. Despite evidence for substantial genetic influence on LDL concentrations6, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy7-9 or toxicity10, and have yielded little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment7. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure including rs9806699, a cis-eQTL for the gene GATM that encodes glycine amidinotransferase, a rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60, 95% confidence interval = 0.45-0.81, P=6.0×10-4). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated cholesterol lowering and susceptibility to statin-induced myopathy. PMID:23995691

  3. Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins.

    PubMed

    Mohammadi-Bardbori, Afshin; Najibi, Asma; Amirzadegan, Najmeh; Gharibi, Raziyeh; Dashti, Ayat; Omidi, Mahmoud; Saeedi, Arastoo; Ghafarian-Bahreman, Ali; Niknahad, Hossein

    2015-09-01

    CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10. PMID:26007644

  4. Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins.

    PubMed

    Mohammadi-Bardbori, Afshin; Najibi, Asma; Amirzadegan, Najmeh; Gharibi, Raziyeh; Dashti, Ayat; Omidi, Mahmoud; Saeedi, Arastoo; Ghafarian-Bahreman, Ali; Niknahad, Hossein

    2015-09-01

    CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10.

  5. The risks of statin use in pregnancy: A systematic review.

    PubMed

    Karalis, Dean G; Hill, Alethea N; Clifton, Shari; Wild, Robert A

    2016-01-01

    Statins are contraindicated in pregnancy; however, as women delay pregnancy and statin use increases the risk of statin exposure in pregnancy is likely to rise. In contrast to some early reports that statins are teratogenic, more recent observational studies have called into question the teratogenic risk of statins. Therefore, whether statins are associated with congenital anomalies or other pregnancy complications remains an important clinical question. This article provides an up-to-date systematic review on the risks of statins in pregnancy. We conducted a literature search to identify relevant English language studies related to statin exposure and pregnancy. Single case reports, animal studies, studies only published in abstract form, and non-English language studies were excluded. A total of 16 clinical studies were included in this systematic review. Although early uncontrolled case series reported congenital anomalies associated with statin use, more recent observational studies did not report an increased risk of congenital anomalies with statin exposure in pregnancy when compared to control groups or the prevalence of congenital anomalies in the general population. Our findings show no clear relationship of congenital anomalies with statin use in pregnancy, and our study supports the findings that statins are probably not teratogenic. However, until more information is available, statins should still be avoided in pregnancy. PMID:27678424

  6. Research Finds Link Between Statin Use and Progressive Muscle Disease

    MedlinePlus

    ... Research Finds Link Between Statin Use and Progressive Muscle Disease Each year, millions of Americans take statins, ... people these benefits come at a cost: widespread muscle pain that persists as long as the drugs ...

  7. Potential anticancer effects of statins: fact or fiction?

    PubMed

    Kaushal, Varsha; Kohli, Manish; Mehta, Paulette; Mehta, Jawahar L

    2003-01-01

    Deregulation of any of the steps in cell growth, proliferation and apoptosis may result in its malignant transformation. Statins, along with their lipid-lowering potential, modify several processes in the cell cycle. These agents inhibit cell proliferation and arrest cell cycle progression by interrupting growth-promoting signals. Statins selectively induce proapoptotic protential in tumor cells and synergistically enhance proapoptotic potential of several cytotoxic agents. Statins alter angiogenic potential of cells by modulating apoptosis inhibitory effects of VEGF and decrease secretion of metalloproteases. Statins also alter adhesion and migration of tumor cells, thereby inhibiting tumor invasion and metastasis. Statins suppress rate of activation of multiple coagulation factors and thus prevent coagulation-mediated angiogenesis. Statins have been shown to have anti-tumor activity in experimental models. Various anti-neoplastic properties of statins are probably a result of inhibition of posttranslational modifications of growth regulatory proteins. Molecular mechanisms of antiproliferative, proapoptotic and antiangiogenic effects of statins are reviewed in this chapter.

  8. Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.

    PubMed

    Musset, Lucile; Allenbach, Yves; Benveniste, Olivier; Boyer, Olivier; Bossuyt, Xavier; Bentow, Chelsea; Phillips, Joe; Mammen, Andrew; Van Damme, Philip; Westhovens, René; Ghirardello, Anna; Doria, Andrea; Choi, May Y; Fritzler, Marvin J; Schmeling, Heinrike; Muro, Yoshinao; García-De La Torre, Ignacio; Ortiz-Villalvazo, Miguel A; Bizzaro, Nicola; Infantino, Maria; Imbastaro, Tiziana; Peng, Qinglin; Wang, Guochun; Vencovský, Jiří; Klein, Martin; Krystufkova, Olga; Franceschini, Franco; Fredi, Micaela; Hue, Sophie; Belmondo, Thibaut; Danko, Katalin; Mahler, Michael

    2016-10-01

    In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria. PMID:27491568

  9. Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.

    PubMed

    Musset, Lucile; Allenbach, Yves; Benveniste, Olivier; Boyer, Olivier; Bossuyt, Xavier; Bentow, Chelsea; Phillips, Joe; Mammen, Andrew; Van Damme, Philip; Westhovens, René; Ghirardello, Anna; Doria, Andrea; Choi, May Y; Fritzler, Marvin J; Schmeling, Heinrike; Muro, Yoshinao; García-De La Torre, Ignacio; Ortiz-Villalvazo, Miguel A; Bizzaro, Nicola; Infantino, Maria; Imbastaro, Tiziana; Peng, Qinglin; Wang, Guochun; Vencovský, Jiří; Klein, Martin; Krystufkova, Olga; Franceschini, Franco; Fredi, Micaela; Hue, Sophie; Belmondo, Thibaut; Danko, Katalin; Mahler, Michael

    2016-10-01

    In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.

  10. Does reduced creatine synthesis protect against statin myopathy?

    PubMed

    Ballard, Kevin D; Thompson, Paul D

    2013-12-01

    Statins, widely used to lower cholesterol levels, cause myopathy in some patients. Mangravite et al. (2013) show that a single nucleotide polymorphism decreasing expression of glycine amidinotransferase (GATM), the enzyme regulating creatine biosynthesis, is associated with reduced statin myopathy. Whether reduced creatine production protects against statin myopathy remains to be determined.

  11. Quinone Reductase 2 Is a Catechol Quinone Reductase

    SciTech Connect

    Fu, Yue; Buryanovskyy, Leonid; Zhang, Zhongtao

    2008-09-05

    The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference between quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.

  12. Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain.

    PubMed

    Chan, David C M; Fu, Hongning; Forsch, Ronald A; Queener, Sherry F; Rosowsky, Andre

    2005-06-30

    As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2',5'-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(omega-carboxyalkyl) or omega-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2'-(omega-carboxy-1-alkynyl)dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2'-(5-carboxy-1-butynyl)-5'-methoxy]benzyl]pyrimidine (13), with an IC(50) value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC(50) = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC(50) data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2'-(5-carboxy-1-butynyl)dibenz[b,f]azepinyl derivative 20 (IC(50) = 2.9 nM), whereas the most selective was the 2'-(5-carboxy-1-pentynyl) analogue 21, with SI values of >100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3'-(4-carboxy-1-butynyl)-4'-bromo-5'-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC(50) = 0.47 nM, SI

  13. Structural analysis of human dihydrofolate reductase as a binary complex with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpteridine reveals an unusual binding mode.

    PubMed

    Cody, Vivian; Pace, Jim; Nowak, Jessica

    2011-10-01

    In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structure of the binary complex of human dihydrofolate reductase (hDHFR) with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpteridine (PT684) was determined to 1.8 Å resolution. These data revealed that the carboxylate side chain of PT684 occupies two alternate positions, neither of which interacts with the conserved Arg70 in the active-site pocket, which in turn hydrogen bonds to water. These observations are in contrast to those reported for the ternary complex of mouse DHFR (mDHFR) with NADPH [Cody et al. (2008), Acta Cryst. D64, 977-984], in which the 3-carboxypropyl side chain of PT684 was hydrolyzed to its hydroxyl derivative, PT684a. The crystallization conditions differed for the human and mouse DHFR crystals (100 mM K2HPO4 pH 6.9, 30% ammonium sulfate for hDHFR; 15 mM Tris pH 8.3, 75 mM sodium cacodylate, PEG 4K for mDHFR). Additionally, the side chains of Phe31 and Gln35 in the hDHFR complex have a single conformation, whereas in the mDHFR complex they occupied two alternative conformations. These data show that the hDHFR complex has a decreased active-site volume compared with the mDHFR complex, as reflected in a relative shift of helix C (residues 59-64) of 1.2 Å, and a shift of 1.5 Å compared with the ternary complex of Pneumocystis carinii DHFR (pcDHFR) with the parent dibenz[b,f]azepine PT653. These data suggest that the greater inhibitory potency of PT684 against pcDHFR is consistent with the larger active-site volume of pcDHFR and the predicted interactions of the carboxylate side chain with Arg75.

  14. Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial

    PubMed Central

    Golomb, Beatrice A.; Dimsdale, Joel E.; Koslik, Hayley J.; Evans, Marcella A.; Lu, Xun; Rossi, Steven; Mills, Paul J.; Criqui, Michael H.

    2015-01-01

    Background Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized. Methods 1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified–Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age. Results The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change ≥40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age≤40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: β=0.64(SE=0.30)P=0.034, particularly on simvastatin: β=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: β=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): β=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) β=0.70(SE=0.34)P=0.039. The increase was

  15. SKI-1/S1P inhibition: a promising surrogate to statins to block hepatitis C virus replication.

    PubMed

    Blanchet, Matthieu; Seidah, Nabil G; Labonté, Patrick

    2012-08-01

    Hepatitis C virus (HCV) is often associated with steatosis, cirrhosis and hepatocellular carcinoma (HCC). Statins (HMG-CoAR inhibitors) have been shown to exert an antiviral effect in vitro, principally on replicon harboring cells, but the effect of their use alone in vivo remains controversial. In clinical trials, when used in combination with the standards of care (SOC), they led to an increased proportion of sustained virological responder (SVR). Here we investigated the implication of SKI-1/S1P, a master lipogenic pathways regulator upstream of HMG-CoAR, on different steps of HCV life cycle. We compared the HCV antiviral effect of the most potent SKI-1/S1P small molecule inhibitor (PF-429242) with a set of two statins on different steps of the viral life cycle, and showed that SKI-1/S1P inhibitor blocked HCVcc (strain JFH-1) RNA replication (EC(50)= 5.8 μM) more efficiently than statins. Moreover, we showed that PF-429242 could reduce lipid droplets accumulation in Huh7 cells. Interestingly, PF-429242 dramatically reduced infectious particles production (EC(90)= 4.8 μM). Such inhibition could not be achieved with statins. SKI-1/S1P activity is thus essential for viral production and its inhibition should be considered for antiviral drug development. PMID:22626636

  16. Are statins beneficial for chronic heart failure?

    PubMed

    Rain, Carmen; Rada, Gabriel

    2015-05-27

    There is controversy about the role of statins in chronic heart failure. Even though it is clear they decrease inflammatory markers and probably improve some echocardiographic parameters, it is not clear if they impact clinically important outcomes. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 21 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded statins in chronic heart failure do not decrease mortality, and might lead to little or no decrease in hospitalizations for heart failure or other clinical outcomes.

  17. [Response of N transformation related soil enzyme activities to inhibitor applications].

    PubMed

    Chen, Lijun; Wu, Zhijie; Jiang, Yong; Zhou, Likai

    2002-09-01

    With an aerobic incubation test, this paper studied the response of soil urease, nitrate reductase, nitrite reductase, and hydroxylamine reductase to urease inhibitor hydroquinone (HQ) applied in combination with nitrification inhibitor encapsulated calcium carbide (HQ + ECC) or dicyandiamide (HQ + DCD). The results showed that HQ + DCD could inhibit urease activity and increase activities of nitrate reductase, nitrite reductase, and hydroxylamine reductase significantly in comparison with CK, HQ and HQ + ECC. Under the condition of our test, there existed a significant relationship between soil urease, nitrate reductase, nitrite reductase, and hydroxylamine reductase activities and soil NH4+ and NO3- contents, NH3 volatilization and N2O emission rate, and regression analysis indicated that there were significantly positive relationships between soil urease, nitrite reductase and hydroxylamine reductase activities.

  18. Statin-induced myopathy in a patient with previous poliomyelitis.

    PubMed

    Martikainen, Mika H; Gardberg, Maria; Kohonen, Ia; Lähdesmäki, Janne

    2013-11-01

    This report describes a patient with a history of poliomyelitis who developed new, progressive symptoms of muscle fatigue and weakness, suggestive of postpoliomyelitis syndrome. However, comprehensive investigations led to the diagnosis of statin-induced myopathy as the cause of the patient's symptoms. This case highlights the possibility of statin-induced myopathy in patients with a history of poliomyelitis and the differential diagnosis between postpoliomyelitis syndrome and statin-induced myopathy in these patients. The possibility of statin-induced myopathy should be considered when patients with previous poliomyelitis who take statin medication develop symptoms suggestive of postpoliomyelitis syndrome.

  19. Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation.

    PubMed

    Vosper, Jonathan; Masuccio, Alessia; Kullmann, Michael; Ploner, Christian; Geley, Stephan; Hengst, Ludger

    2015-02-20

    Statins, such as lovastatin, can induce a cell cycle arrest in the G1 phase. This robust antiproliferative activity remains intact in many cancer cells that are deficient in cell cycle checkpoints and leads to an increased expression of CDK inhibitor proteins p27Kip1 and p21Cip1. The molecular details of this statin-induced growth arrest remains unclear. Here we present evidence that lovastatin can induce the degradation of Skp2, a subunit of the SCFSkp2 ubiquitin ligase that targets p27Kip1 and p21Cip1 for proteasomal destruction. The statin-induced degradation of Skp2 is cell cycle phase independent and does not require its well characterised degradation pathway mediated by APC/CCdh1- or Skp2 autoubiquitination. An N-terminal domain preceding the F-box of Skp2 is both necessary and sufficient for its statin mediated degradation. The degradation of Skp2 results from statin induced depletion of geranylgeranyl isoprenoid intermediates of cholesterol biosynthesis. Inhibition of geranylgeranyl-transferase-I also promotes APC/CCdh1- independent degradation of Skp2, indicating that de-modification of a geranylgeranylated protein triggers this novel pathway of Skp2 degradation.

  20. Statins and diabetes: the good, the bad, and the unknown.

    PubMed

    Axsom, Kelly; Berger, Jeffrey S; Schwartzbard, Arthur Z

    2013-02-01

    The ability for statins to reduce major cardiovascular events and mortality has lead to this drug class being the most commonly prescribed in the world. In particular, the benefit of these drugs in type 2 diabetes (T2D) is well established. In February 2012, the Food and Drug Administration released changes to statin safety label to include that statins have been associated with increases in hemoglobin A1C and fasting serum glucose levels. This has stirred much debate in the medical community. Estimate for new onset diabetes from statin treatment is approximately one in 255 patients over four years. The number needed to treat for statin benefit is estimated at one in 40 depending on the population. The mechanism of this link remains unknown. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin resistance and cellular metabolism of carbohydrates. It remains clear that the benefit of statin therapy outweighs the risk of developing diabetes. PMID:23299640

  1. Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes.

    PubMed

    Abdoli, Narges; Heidari, Reza; Azarmi, Yadollah; Eghbal, Mohammad Ali

    2013-06-01

    Statins are potent drugs, used as lipid-lowering agents in cardiovascular diseases. Hepatotoxicity is one of the serious adverse effects of statins, and the exact mechanism of hepatotoxicity is not yet clear. In this study, the cytotoxic effects of the most commonly used statins, that is, atorvastatin, lovastatin, and simvastatin toward isolated rat hepatocytes, were evaluated. Markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, and the amount of reduced and oxidized glutathione in the statin-treated hepatocytes, were investigated. It was found that the statins caused cytotoxicity toward rat hepatocytes dose dependently. An elevation in ROS formation, accompanied by a significant amount of lipid peroxidation and mitochondrial depolarization, was observed. Cellular glutathione reservoirs were decreased, and a significant amount of oxidized glutathione was formed. This study suggests that the adverse effect of statins toward hepatocytes is mediated through oxidative stress and the hepatocytes mitochondria play an important role in the statin-induced toxicity.

  2. Synthesis of Nitrate Reductase in Chlorella

    PubMed Central

    Funkhouser, Edward A.; Shen, Teh-Chien; Ackermann, Renate

    1980-01-01

    Synthesis of nitrate reductase (EC 1.6.6.1) in Chlorella vulgaris was studied under inducing conditions, i.e. with cells grown on ammonia and then transferred to nitrate medium. Cycloheximide (but not chloramphenicol) completely inhibited synthesis of the enzyme, but only if it was added at the start (i.e. at the time of nitrate addition) of the induction period. Cycloheximide inhibition became less effective as induction by nitrate proceeded. Enzyme from small quantities of culture (1 to 3 milliliters of packed cells) was purified to homogeneity with the aid of blue dextran-Sepharose chromatography. Incorporation of radioactivity from labeled arginine into nitrate reductase was measured in the presence and absence of cycloheximide. Conditions were found under which the inhibitor completely blocked the incorporation of labeled amino acid, but only slightly decreased the increase in nitrate reductase activity. The results indicate that synthesis of nitrate reductase from amino acids proceeds by way of a protein precursor which is inactive enzymically. PMID:16661310

  3. Evidence, Guidelines, and Gut Checks: Musings on Entering the Post-Statin Era of Lipid Management.

    PubMed

    Mancini, G B John

    2016-03-01

    This viewpoint describes the results of a survey administered to 55 physicians who are key opinion leader experts in dyslipidemia management and thoroughly knowledgeable about current guidelines and emerging therapies. The purpose was to determine the level of low density lipoprotein-cholesterol (LDL-C) achieved with maximally tolerated statin monotherapy that would trigger a preference by most for use of the soon to be available proprotein convertase subtilisin/kexin type 9 inhibitor as the next add-on agent. Because current guidelines suggest a uniform LDL-C goal when treating patients meeting guideline indications for therapy, it was expected that the size of the gap between LDL-C goal and LDL-C attained with maximally tolerated statins would uniformly dictate when proprotein convertase subtilisin/kexin type 9 inhibitors would be desired. This expectation, however, was not met. In particular, the results suggest that primary prevention patients and patients with chronic kidney disease do not appear to represent high priority circumstances for achieving even the current LDL-C goal despite existing guidelines. Implications for future guidelines in the post-statin era are discussed.

  4. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency

    PubMed Central

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4. PMID:27604655

  5. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.

    PubMed

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.

  6. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.

    PubMed

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4. PMID:27604655

  7. [Effects of the statins in kidney transplantation].

    PubMed

    Trimarchi, H M; Brennan, S; González, J M; Suki, W N

    2000-01-01

    A retrospective analysis was performed to assess the immunosuppressive activity of statins in kidney transplantation, determining their effects on serum cholesterol and triglyceride levels post-transplantation, on the incidence of acute rejection episodes and on renal function. A total of 97 patients who underwent a kidney transplant in a three-year period, had more than one-month graft survival, and a minimum of one year of follow-up, were included. Group A consisted of 38 patients who received statins; this group was subsequently divided into four subgroups, according to the time post-transplant when statins were prescribed. Group B consisted of 59 patients (control Group). Initial and final serum total cholesterol levels in Group A were not different (218 +/- 7.8 mg/dl vs 222 +/- 7.5 mg/dl); however, final levels were higher than initial values in Group B (216 +/- 6.0 mg/dl vs 189 +/- 6.4 mg/dl, P = 0.0021). Initial serum triglyceride levels were higher than final levels in Group A (305 +/- 25.5 mg/dl vs 188 +/- 10.6 mg/dl, P < 0.0001). Group A showed a better allograft survival (P = 0.0350), a reduction in the incidence of acute rejection episodes (1 vs 38 events, P < 0.0001) and a lower serum creatinine level (1.96 +/- 0.21 mg/dl vs 2.77 +/- 0.27 mg/dl, P = 0.0374). In Group A subgroups, kidney function was significantly better in patients who received statins early after transplantation. These data suggest that in kidney transplantation statins exert additional immunosuppressive effects, reduce the number of acute rejection episodes, improve allograft survival and kidney function and are effective in preventing serum cholesterol from rising; these effects correlate with a significant decrease in serum triglyceride but are independent of a hypocholesterolemic action. PMID:11188951

  8. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy.

    PubMed

    Kohli, Payal; Desai, Nihar R; Giugliano, Robert P; Kim, Jae B; Somaratne, Ransi; Huang, Fannie; Knusel, Beat; McDonald, Shannon; Abrahamsen, Timothy; Wasserman, Scott M; Scott, Robert; Sabatine, Marc S

    2012-01-01

    Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.

  9. Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics

    PubMed Central

    Gismondi, Ronaldo Altenburg; Bedirian, Ricardo; Pozzobon, Cesar Romaro; Ladeira, Márcia Cristina; Oigman, Wille; Neves, Mário Fritsch

    2015-01-01

    Background Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes. PMID:26465872

  10. Transcription of the three HMG-CoA reductase genes of Mucor circinelloides

    PubMed Central

    2014-01-01

    Background Precursors of sterols, carotenoids, the prenyl groups of several proteins and other terpenoid compounds are synthesised via the acetate-mevalonate pathway. One of the key enzyme of this pathway is the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which catalyses the conversion of HMG-CoA to mevalonate. HMG-CoA reductase therefore affects many biological processes, such as morphogenesis, synthesis of different metabolites or adaptation to environmental changes. In this study, transcription of the three HMG-CoA reductase genes (designated as hmgR1, hmgR2 and hmgR3) of the β-carotene producing Mucor circinelloides has been analysed under various culturing conditions; effect of the elevation of their copy number on the carotenoid and ergosterol content as well as on the sensitivity to statins has also been examined. Results Transcripts of each gene were detected and their relative levels varied under the tested conditions. Transcripts of hmgR1 were detected only in the mycelium and its relative transcript level seems to be strongly controlled by the temperature and the oxygen level of the environment. Transcripts of hmgR2 and hmgR3 are already present in the germinating spores and the latter is also strongly regulated by oxygen. Overexpression of hmgR2 and hmgR3 by elevating their copy numbers increased the carotenoid content of the fungus and decreased their sensitivity to statins. Conclusions The three HMG-CoA reductase genes of M. circinelloides displayed different relative transcript levels under the tested conditions suggesting differences in their regulation. They seem to be especially involved in the adaptation to the changing oxygen tension and osmotic conditions of the environment as well as to statin treatment. Overexpression of hmgR2 and hmgR3 may be used to improve the carotenoid content. PMID:24731286

  11. Statin-Associated Diabetes Mellitus: Review and Clinical Guide.

    PubMed

    Backes, James M; Kostoff, Matthew D; Gibson, Cheryl A; Ruisinger, Janelle F

    2016-03-01

    A small but significant link between new-onset diabetes mellitus (NOD) and statin therapy was noted with rosuvastatin users in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin study. Since then multiple analyses have further confirmed this association, with most studies demonstrating a modest increase in NOD with statin therapy, especially among individuals with risk factors for developing diabetes mellitus. More recent observational analyses suggest a stronger correlation between statin use and NOD, however. A definitive mechanism confirming causation between statins and glucose impairment remains elusive, but many have been proposed. Although considered a class effect by the US Food and Drug Administration, most data indicate NOD is dependent upon the dose and potency of the statin, with certain agents appearing to be less diabetogenic. The consensus is that the benefits of statin therapy far outweigh the risk of NOD, especially among patients with high cardiovascular risk. Nonetheless, more studies are needed to better understand this association and long-term clinical implications. In the meantime, we provide clinicians with a practical guide to assist with clinical decision making when prescribing statin therapy. Overall, this article serves to provide the primary care physician with a timely review of the most clinically relevant data regarding statins and NOD, with hopes to ultimately optimize statin prescribing and limit any potential drug-induced glucose impairment.

  12. Statin-induced diabetes: incidence, mechanisms, and implications

    PubMed Central

    Ganda, Om P.

    2016-01-01

    Persuasive data from many randomized controlled trials and large, long-term observational studies indicate a modestly increased risk for the emergence of new diabetes after statin initiation. Several meta-analyses of many statin trials as well as longitudinal population-based studies suggest that the risk factors for diabetes in statin-treated persons include underlying risk for diabetes at baseline (specifically features of metabolic syndrome), the intensity of statin therapy, certain genetic traits independent of diabetes risk, and adherence to lifestyle factors. Limited data suggest statins modestly worsen hyperglycemia and A1c levels in those with pre-existing diabetes or glucose intolerance. The precise mechanism(s) of diabetogenesis with statin therapy are unclear, but impaired insulin sensitivity and compromised β cell function via enhanced intracellular cholesterol uptake due to inhibition of intracellular cholesterol synthesis by statins, as well as other mechanisms, may be involved. Furthermore, while statins are known to have anti-inflammatory effects, it is hypothesized that, under dysmetabolic conditions, they might have pro-inflammatory effects via induction of certain inflammasomes. This concept requires further elucidation in the human. Finally, it is clear that the risk–benefit ratio for cardiovascular disease events is strongly in favor of statin therapy in those at risk, despite the emergence of new diabetes. Adherence to lifestyle regimen is critical in the prevention of new diabetes on statins. PMID:27408693

  13. Pharmacogenomics of statins: understanding susceptibility to adverse effects

    PubMed Central

    Kitzmiller, Joseph P; Mikulik, Eduard B; Dauki, Anees M; Murkherjee, Chandrama; Luzum, Jasmine A

    2016-01-01

    Statins are a cornerstone of the pharmacologic treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerotic disease is a predominant cause of mortality and morbidity worldwide. Statins are among the most commonly prescribed classes of medications, and their prescribing indications and target patient populations have been significantly expanded in the official guidelines recently published by the American and European expert panels. Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy. Statin-associated muscle symptoms occur in ~10% of patients on statins and constitute the most commonly reported adverse effect associated with statin pharmacotherapy. Substantial clinical and nonclinical research effort has been dedicated to determining whether genetics can provide meaningful insight regarding an individual patient’s risk of statin adverse effects. This contemporary review of the relevant clinical research on polymorphisms in several key genes that affect statin pharmacokinetics (eg, transporters and metabolizing enzymes), statin efficacy (eg, drug targets and pathways), and end-organ toxicity (eg, myopathy pathways) highlights several promising pharmacogenomic candidates. However, SLCO1B1 521C is currently the only clinically relevant pharmacogenetic test regarding statin toxicity, and its relevance is limited to simvastatin myopathy. PMID:27757045

  14. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions.

    PubMed

    Scheen, André J

    2010-09-01

    Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally

  15. A peri-operative statin update for non-cardiac surgery. Part II: Statin therapy for vascular surgery and peri-operative statin trial design.

    PubMed

    Biccard, B M

    2008-02-01

    This is the second of two review articles evaluating peri-operative statin therapy. In surgical patients, the utility of peri-operative statin therapy is strongly suggested by retrospective studies, although it is probably overestimated, as important confounding factors have not been controlled for and hence the literature is considered to be currently inconclusive. This review examines the potential mechanisms and indications for peri-operative statin protection, the efficacy of acute peri-operative beta-blockade in addition to statin therapy, the effect of peri-operative statin therapy withdrawal and the implications of comorbidities associated with peri-operative cardiovascular risk on statin therapy. Recommendations concerning appropriate dosing, duration, therapeutic targets and necessary investigations when prescribing peri-operative statins are made. Peri-operative study design recommendations are suggested, so that future meta-analyses may be more informative. Recommendations are made regarding retrospective reporting of statin studies to minimise the bias inherent in a number of the current retrospective studies on this subject. PMID:18211448

  16. Green analytical method development for statin analysis.

    PubMed

    Assassi, Amira Louiza; Roy, Claude-Eric; Perovitch, Philippe; Auzerie, Jack; Hamon, Tiphaine; Gaudin, Karen

    2015-02-01

    Green analytical chemistry method was developed for pravastatin, fluvastatin and atorvastatin analysis. HPLC/DAD method using ethanol-based mobile phase with octadecyl-grafted silica with various grafting and related-column parameters such as particle sizes, core-shell and monolith was studied. Retention, efficiency and detector linearity were optimized. Even for column with particle size under 2 μm, the benefit of keeping efficiency within a large range of flow rate was not obtained with ethanol based mobile phase compared to acetonitrile one. Therefore the strategy to shorten analysis by increasing the flow rate induced decrease of efficiency with ethanol based mobile phase. An ODS-AQ YMC column, 50 mm × 4.6 mm, 3 μm was selected which showed the best compromise between analysis time, statin separation, and efficiency. HPLC conditions were at 1 mL/min, ethanol/formic acid (pH 2.5, 25 mM) (50:50, v/v) and thermostated at 40°C. To reduce solvent consumption for sample preparation, 0.5mg/mL concentration of each statin was found the highest which respected detector linearity. These conditions were validated for each statin for content determination in high concentrated hydro-alcoholic solutions. Solubility higher than 100mg/mL was found for pravastatin and fluvastatin, whereas for atorvastatin calcium salt the maximum concentration was 2mg/mL for hydro-alcoholic binary mixtures between 35% and 55% of ethanol in water. Using atorvastatin instead of its calcium salt, solubility was improved. Highly concentrated solution of statins offered potential fluid for per Buccal Per-Mucous(®) administration with the advantages of rapid and easy passage of drugs. PMID:25582487

  17. Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

    PubMed Central

    Kessinger, Chase W.; Kim, Jin Won; Henke, Peter K.; Thompson, Brian; McCarthy, Jason R.; Hara, Tetsuya; Sillesen, Martin; Margey, Ronan J. P.; Libby, Peter; Weissleder, Ralph; Lin, Charles P.; Jaffer, Farouc A.

    2015-01-01

    Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. PMID:25680183

  18. [PROSPECTS FOR CLINICAL APPLICATION OF STATINS IN GASTROENTEROLOGY].

    PubMed

    Svistunov, A A; Osadchuk, M A; Kireeva, N V

    2016-01-01

    We present the analytical review of non-cardial effects of statins used in gastroenterology with the data illustrating their high antibacterial activity as exemplified by combined therapy of conditions associated with Helicobacter pylori infection. Special emphasis is laid on anti-inflammatory and oncoprotective mechanisms of statin action that are successfully made use of for the treatment of liver, pancreas, gallbladder, and biliary system diseases. Prophylactic aspects of statin application to overcome an addiction to fast food are discussed. PMID:27522720

  19. Effect of Statin Use on Influenza Vaccine Effectiveness

    PubMed Central

    McLean, Huong Q.; Chow, Brian D. W.; VanWormer, Jeffrey J.; King, Jennifer P.; Belongia, Edward A.

    2016-01-01

    Background. Recent studies suggest that statin use may reduce influenza vaccine effectiveness (VE), but laboratory-confirmed influenza was not assessed. Methods. Patients ≥45 years old presenting with acute respiratory illness were prospectively enrolled during the 2004–2005 through 2014–2015 influenza seasons. Vaccination and statin use were extracted from electronic records. Respiratory samples were tested for influenza virus. Results. The analysis included 3285 adults: 1217 statin nonusers (37%), 903 unvaccinated statin nonusers (27%), 847 vaccinated statin users (26%), and 318 unvaccinated statin users (10%). Statin use modified VE and the risk of influenza A(H3N2) virus infection (P = .002) but not 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) or influenza B virus infection (P = .2 and .4, respectively). VE against influenza A(H3N2) was 45% (95% confidence interval [CI], 27%–59%) among statin nonusers and −21% (95% CI, −84% to 20%) among statin users. Vaccinated statin users had significant protection against influenza A(H1N1)pdm09 (VE, 68%; 95% CI, 19%–87%) and influenza B (VE, 48%; 95% CI, 1%–73%). Statin use did not significantly modify VE when stratified by prior season vaccination. In validation analyses, the use of other cardiovascular medications did not modify influenza VE. Conclusions. Statin use was associated with reduced VE against influenza A(H3N2) but not influenza A(H1N1)pdm09 or influenza B. Further research is needed to assess biologic plausibility and confirm these results. PMID:27471318

  20. Is immunity a mechanism contributing to statin-induced diabetes?

    PubMed Central

    Henriksbo, Brandyn D; Schertzer, Jonathan D

    2015-01-01

    Statins lower cholesterol and are commonly prescribed for prevention and treatment of cardiovascular disease risk. Statins have pleotropic actions beyond cholesterol lowering, including decreased protein prenylation, which can alter immune function. The general anti-inflammatory effect of statins may be a key pleiotropic effect that improves cardiovascular disease risk. However, a series of findings have shown that statins increase the pro-inflammatory cytokine, IL-1β, via decreased protein prenylation in immune cells. IL-1β can be regulated by the NLRP3 inflammasome containing caspase-1. Statins have been associated with an increased risk of new onset diabetes. Inflammation can promote ineffective insulin action (insulin resistance), which often precedes diabetes. This review highlights the links between statins, insulin resistance and immunity via the NLRP3 inflammasome. We propose that statin-induced changes in immunity should be investigated as a mechanism underlying increased risk of diabetes. It is possible that statin-related insulin resistance occurs through a separate pathway from various mechanisms that confer cardiovascular benefits. Therefore, understanding the potential mechanisms that segregate statin-induced cardiovascular effects from those that cause dysglycemia may lead to improvements in this drugs class. PMID:26451278

  1. Statins and Ezetimibe Modulate Plasma Proprotein Convertase Subtilisin Kexin-9 (PCSK9) Levels

    PubMed Central

    Davignon, Jean; Dubuc, Geneviève

    2009-01-01

    PCSK9 is a natural inhibitor of the LDL receptor. Gain-of-function mutations may cause the familial hypercholesterolemia phenotype, whereas loss-of-function variants associate with reduced LDL-C levels and lower coronary risk. Statins up-regulate PCSK9 in hepatocytes. We developed an assay to measure total PCSK9 in human plasma and evaluated the effect of statins and ezetimibe on PCSK9 in vivo and in vitro. In 254 normal subjects, the mean plasma PCSK9 was 89 ± 32 ng/ml. PCSK9 levels correlated with plasma cholesterol, LDL-C, triglycerides, fasting glucose, age and body mass index. Sequencing PCSK9 from subjects at the extremes of plasma distribution revealed new variants. In 200 hypercholesterolemic patients, circulating PCSK9 was higher than in controls, increased with increasing statin dose, and further increased when ezetimibe was added. However, ezetimibe treatment of HepG2 (hepatocytes) and Caco-2 (enterocytes) cells caused a slight increase in PCSK9 and NPC1L1 mRNA, but no significant rise in PCSK9 protein secretion, suggesting that these transformed cells are not ideal model cell lines. PMID:19768174

  2. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration

    SciTech Connect

    Nadanaciva, Sashi; Dykens, James A.; Bernal, Autumn; Capaldi, Roderick A.; Will, Yvonne

    2007-09-15

    Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II + III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II + III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.

  3. PCSK9 inhibitors--past, present and future.

    PubMed

    Reiner, Željko

    2015-01-01

    Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality. Statins are the treatment of choice for lowering LDL-C but a considerable number of patients treated with statins are unable to achieve LDL-C target values and many are statin-intolerant. New LDL-C-lowering drugs--antibodies to PCSK9 (alirocumab, evolocumab and bococizumab)--have been developed and are being tested in large clinical trials. They further reduce LDL-C above maximally tolerated statin therapy by up to > 70%; they also reduce Lp(a), non-HDL-C, apolipoprotein-B, and modestly increase HDL-C. These drugs are well tolerated and even patients who achieved very low LDL-C ≤ 0.65 mmol/l (∼ 25 mg/dl) did not have any significant adverse effects. Treatment with PCSK9 inhibitors resulted in LDL-C target values in 70-90% of patients according to the guidelines. However, although PCSK9 inhibitors seem to be the most promising emerging therapeutic option for LDL-C lowering today, outcome data with endpoints on their effects are still lacking. Another important open question is their long-term safety. Their use in statin-intolerant patients also raises questions, as the criteria for statin-intolerance are neither clear nor generally accepted. The presumed high cost of PCSK9 inhibitors might be an obstacle for their broader use.

  4. PCSK9 inhibitors--past, present and future.

    PubMed

    Reiner, Željko

    2