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Review

Could simvastatin be considered as a potential therapy for chronic lung diseases? A debate on the pros and cons

, , , & ORCID Icon
Pages 1407-1420 | Received 03 Feb 2016, Accepted 18 May 2016, Published online: 06 Jun 2016

References

  • Athanazio R. Airway disease: similarities and differences between asthma, COPD and bronchiectasis. Clinics. 2012;67(11):1335–1343.
  • Barnes PJ. Future treatments for chronic obstructive pulmonary disease and its comorbidities. Proc Am Thoracic Soc. 2008;5(8):857–864.
  • Murray TS, Egan M, Kazmierczak BI. Pseudomonas aeruginosa chronic colonization in cystic fibrosis patients. Curr Opin Pediatr. 2007;19(1):83–88.
  • Barker AF. Bronchiectasis. N Engl J Med. 2002;346(18):1383–1393.
  • James A, Wenzel S. Clinical relevance of airway remodelling in airway diseases. Eur Respir J. 2007;30(1):134–155.
  • Szilasi M, Dolinay T, Nemes Z, et al. Pathology of chronic obstructive pulmonary disease. Pathol Oncol Res. 2006;12(1):52–60.
  • Guerra S, Sherrill DL, Venker C, et al. Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax. 2009;64(10):894–900.
  • Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol. 2007;35(1):116–129.
  • Yang Y, Tsifansky MD, Shin S, et al. Mannitol‐Guided delivery of ciprofloxacin in artificial cystic fibrosis mucus model. Biotechnol Bioeng. 2011;108(6):1441–1449.
  • Marin L, Colombo P, Bebawy M, et al. Chronic obstructive pulmonary disease: patho-physiology, current methods of treatment and the potential for simvastatin in disease management. Expert Opin Drug Delivery. 2011;8(9):1205–1220.
  • Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. The Lancet. 2004;363(9410):731–733.
  • Rao S, Prasad T, Mohanta G, et al. An overview of statins as hypolipidemic drugs. Int J Pharm Sci Drug Res. 2011;3:178–183.
  • Jun SW, Kim M-S, Kim J-S, et al. Preparation and characterization of simvastatin/hydroxypropyl-β-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process. Eur J Pharm Biopharm. 2007;66(3):413–421.
  • Hoffman WF, Alberts AW, Anderson PS, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side chain ester derivatives of mevinolin. J Med Chem. 1986;29(5):849–852.
  • Tobert JA. Case history: Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discovery. 2003;2(7):517–526.
  • Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogensis produced by Penicillium citrinum. J Antibiot. 1976;29(12):1346–1348.
  • Endo A. The origin of the statins. Atheroscler Suppl. 2004;5(3):125–130.
  • Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010;140(6):935–950.
  • Armitage J. The safety of statins in clinical practice. The Lancet. 2007;370(9601):1781–1790.
  • Merx MW, Weber C. Statins in the intensive care unit. Curr Opin Criti Care. 2006;12(4):309–314.
  • Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103(15):1933–1935.
  • ALKharfy KM, Kellum JA, Matzke GR. Unintended immunomodulation: part II. Effects of pharmacological agents on cytokine activity. Shock. 2000;13(5):346–360.
  • Gullestad L, Aukrust P, Ueland T, et al. Effect of high-versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol. 1999;34(7):2061–2067.
  • Endo A, Tsujita Y, Kuroda M, et al. Inhibition of cholesterol synthesis in vitro and in vivo by ML‐236A and ML‐236B, competitive inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase. Eur J Biochem. 1977;77(1):31–36.
  • Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. The Lancet. 1996;348(9034):1079–1082.
  • McAuley DF, O’Kane CM, Craig TR, et al. Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury. BMC Pulmonary Med. 2013;13(1):47.
  • Grommes J, Vijayan S, Drechsler M, et al. Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation. PLoS One. 2012;7(6):e38917.
  • Rezaie-Majd A, Maca T, Bucek RA, et al. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002;22(7):1194–1199.
  • Walsh GM. Statins as emerging treatments for asthma and chronic obstructive pulmonary disease. Expert Rev Respir Med. 2008;2(3):329–335.
  • Zeki AA, Oldham J, Wilson M, et al. Statin use and asthma control in patients with severe asthma. BMJ Open. 2013;3(8):e003314.
  • Tse SM, Charland SL, Stanek E, et al. Statin use in asthmatics on inhaled corticosteroids is associated with decreased risk of emergency department visits. Cur Med Res Opin. 2013;30(4):685–693.
  • Braganza G, Chaudhuri R, McSharry C, et al. Effects of short-term treatment with atorvastatin in smokers with asthma-a randomized controlled trial. BMC Pulmonary Med. 2011;11(1):16.
  • Ostroukhova M, Kouides RW, Friedman E. The effect of statin therapy on allergic patients with asthma. Ann Allergy, Asthma Immunol. 2009;103(6):463–468.
  • Menzies D, Nair A, Meldrum KT, et al. Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma. J Allergy Clin Immunol. 2007;119(2):328–335.
  • Fahimi F, Salamzadeh J, Jamaati H, et al. Do statins improve lung function in asthmatic patients? A randomized and double-blind trial. Iranian J Pharm Sci. 2009;5(1):13–20.
  • Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, et al. Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase. J Allergy Clin Immunol. 2010;126(4):754–62. e1.
  • Hothersall EJ, Chaudhuri R, McSharry C, et al. Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax. 2008;63(12):1070–1075.
  • Huang CC, Chan WL, Chen YC, et al. Statin use in patients with asthma–a nationwide population‐based study. Eur J Clin Invest. 2011;41(5):507–512.
  • Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014;370(23):2201–2210.
  • Lee T, Chen C, Shen H, et al. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (London, England: 1979). 2009;116(6):497–505.
  • Blamoun A, Batty G, DeBari V, et al. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract. 2008;62(9):1373–1378.
  • Mancini GJ, Etminan M, Zhang B, et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;47(12):2554–2560.
  • Frost FJ, Petersen H, Tollestrup K, et al. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. CHEST J. 2007;131(4):1006–1012.
  • Lahousse L, Loth DW, Joos GF, et al. Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulmonary Pharmacol Ther. 2013;26(2):212–217.
  • Keddissi JI, Younis WG, Chbeir EA, et al. The use of statins and lung function in current and former smokers. CHEST J. 2007;132(6):1764–1771.
  • McAuley DF, Laffey JG, O’Kane CM, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371(18):1695–1703.
  • Cowan DC, Cowan JO, Palmay R, et al. Simvastatin in the treatment of asthma: lack of steroid-sparing effect. Thorax. 2010;65(10):891–896.
  • Gazzerro P, Proto MC, Gangemi G, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64(1):102–146.
  • Porter KE, Naik J, Turner NA, et al. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vasc Surg. 2002;36(1):150–157.
  • Shyamsundar M, McKeown ST, O’Kane CM, et al. Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179(12):1107–1114.
  • Group HPSC. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. The Lancet. 2003;361(9374):2005–2016.
  • Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):. 7–22.
  • Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998;19(1):26–37.
  • Romaine S, Bailey K, Hall A, et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharm J. 2010;10(1):1–11.
  • Prueksaritanont T, Gorham LM, Ma B, et al. In vitro metabolism of simvastatin in humans [SBT] identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos. 1997;25(10):1191–1199.
  • Vickers S, Duncan C, Chen I-W, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metabol Dispos. 1990;18(2):138–145.
  • Serajuddin A, Ranadive SA, Mahoney EM. Relative lipophilicities, solubilities, and structure‐pharmacological considerations of 3‐hydroxy‐3‐methylglutaryl‐coenzyme a (HMG‐COA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. J Pharm Sci. 1991;80(9):830–834.
  • Kommanaboyina B, Rhodes C. Trends in stability testing, with emphasis on stability during distribution and storage. Drug Devel Ind Pharm. 1999;25(7):857–868.
  • Guideline IHT. Stability testing of new drug substances and products. Q1A (R2), Current Step. 2003;4:1–22. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073369.pdf
  • Malenović A, Jančić-Stojanović B, Ivanović D, et al. Forced degradation studies of simvastatin using microemulsion liquid chromatography. J Liq Chromatogr Relat Technol. 2010;33(4):536–547.
  • Luo Y, Xu L, Tao X, et al. Preparation, characterization, stability and in vitro-in vivo evaluation of pellet-layered Simvastatin nanosuspensions. Drug Dev Ind Pharm. 2013;39(7):936–946.
  • Álvarez-Lueje A, Valenzuela C, Squella JA, et al. Stability study of simvastatin under hydrolytic conditions assessed by liquid chromatography. J AOAC Int. 2005;88(6):1631–1636.
  • Krishna SR, Deshpande GR, Rao BM, et al. A stability-indicating rp-lc method for the determination of related substances in simvastatin. J Chem Pharm Res. 2010;2(1):91–99.
  • Piecha M, Sarakha M, Trebše P, et al. Stability studies of cholesterol lowering statin drugs in aqueous samples using HPLC and LC–MS. Environ Chem Lett. 2010;8(2):185–191.
  • Bews HJ, Carlson JC, Jha A, et al. Simultaneous quantification of simvastatin and simvastatin hydroxy acid in blood serum at physiological pH by ultrahigh performance liquid chromatography–tandem mass spectrometry (UHPLC/MS/MS). J Chromatogr B. 2014;947:145–150.
  • Sawant S, Ghante M. A validated stability indicating RP-HPLC method for Simvastatin, identification and characterization of forced degradation products of Simvastatin using LC-ESI-MS/MS. Adv Anal Chem. 2015;5(1):8–16.
  • Tong P, Zografi G. Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin. AAPS Pharmscitech. 2004;5(2):9–16.
  • Graeser KA, Strachan CJ, Patterson JE, et al. Physicochemical properties and stability of two differently prepared amorphous forms of simvastatin. Cryst Growth Des. 2008;8(1):128–135.
  • Laitinen R, Löbmann K, Grohganz H, et al. Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability. Mol Pharm. 2014;11(7):2381–2389.
  • Simões RG, Diogo HP, Dias A, et al. Thermal stability of simvastatin under different atmospheres. J Pharm Sci. 2014;103(1):241–248.
  • Murtaza G. Solubility enhancement of simvastatin: a review. Acta Pol Pharm. 2012;69(4):581–590.
  • Prueksaritanont T, Ma B, Yu N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharm. 2003;56(1):120–124.
  • Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30(5):505–512.
  • Igel M, Sudhop T, Bergmann K. Pharmacology of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol. 2002;42(8):835–845.
  • Tillyer RD, Reider PJ, Grabowski EJJ, et al. DihydroxyOpen-Acid and salts of HMG-Coa reductase inhibitors. Patent Number US 6,569,461 B1. Rahawy (NJ): Merck & Co., Inc; 2003.
  • Marin L, Traini D, Bebawy M, et al. Multiple dosing of simvastatin inhibits airway mucus production of epithelial cells: implications in the treatment of chronic obstructive airway pathologies. Eur J Pharm Biopharm. 2013;84(3):566–572.
  • Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006;61(8):729–734.
  • Yeganeh B, Wiechec E, Ande SR, et al. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharm Ther. 2014;143(1):87–110.
  • Zeki AA, Franzi L, Last J, et al. Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond. Am Journal Respir Crit Care Med. 2009;180(8):731–740.
  • Takeda N, Kondo M, Ito S, et al. Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. Am J Respiratory Cell Mole Biol. 2006;35(6):722–729.
  • Pryor WA, Prier DG, Church DF. Electron-spin resonance study of mainstream and sidestream cigarette smoke: nature of the free radicals in gas-phase smoke and in cigarette tar. Environ Health Perspect. 1983;47:345–355.
  • MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol. 2001;429(1–3):195–207.
  • Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16(3):534–554.
  • Brennan F, Maini R, Feldmann M. Cytokine expression in chronic inflammatory disease. Br Med Bull. 1995;51(2):368–384.
  • Drost E, Selby C, Lannan S, et al. Changes in neutrophil deformability following in vitro smoke exposure: mechanism and protection. Am J Resp Cell Mol. 1992;6(3):287–295.
  • Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax. 1998;53(7):601–612.
  • Stockley RA. Neutrophils and the pathogenesis of COPD. CHEST J. 2002;121(5):151S–5S.
  • Chung K, Adcock I. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J. 2008;31(6):1334–1356.
  • Milara J, Cortijo J. Tobacco, inflammation, and respiratory tract cancer. Curr Pharm Des. 2012;18(26):3901–3938.
  • McKay A, Leung BP, McInnes IB, et al. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 2004;172(5):2903–2908.
  • Zeki AA, Thai P, Kenyon NJ, et al. Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells. Respir Res. 2012;13(1):38.
  • Linderholm AL, Bratt JM, Schuster GU, et al. Novel therapeutic strategies for adult obese asthmatics. Immunol All Clin North Am. 2014;34(4):809–823.
  • Hellwig K, Rosseau S, Tschernig T, et al. Simvastatin attenuates ventilator-induced lung injury in mice. Crit Care. 2010;14(4):R143.
  • Jacobson JR, Barnard JW, Grigoryev DN, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am Journal Physiol-Lung Cell Mole Physiol. 2005;288(6):L1026–L1032.
  • Belli S, Basaran O, Ozdemir BH, et al. Protective role of simvastatin on lung damage caused by burn and cotton smoke inhalation in rats. J Surg Res. 2011;167(2):e283–e290.
  • Davis BB, Zeki AA, Bratt JM, et al. Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy. Eur Respir J. 2013;42(2):350–361.
  • Davis B, Zeki A, Wang L, et al. Simvastatin reduces tobacco smoke-induced lung inflammation, airway remodeling and abnormal pulmonary function characteristic of COPD. ; American Thoracic Society 2012 International Conference; 2007 May 18–23; San Francisco, CA. doi:10.1164/ajrccm-conference.2012.185.1_MeetingAbstracts.A1280
  • Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am Journal of Respir Crit Care Med. 2002;166(10):1403–1408.
  • Ghavami S, Mutawe MM, Sharma P, et al. Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53. Plos One. 2011;6(1):e16523.
  • Grisham MB, Jourd’Heuil D, Wink DA. I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. Am J Physiol-Gastrointestinal Liver Physiol. 1999;276(2):G315–G21.
  • Liu B, Gao HM, Wang JY, et al. Role of nitric oxide in inflammation‐mediated neurodegeneration. Ann New York Acad Sci. 2002;962(1):318–331.
  • Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001;108(10):1429.
  • Xavier A, Serafim K, Higashi D, et al. Simvastatin improves morphological and functional recovery of sciatic nerve injury in Wistar rats. Injury. 2012;43(3):284–289.
  • Chen W, Pendyala S, Natarajan V, et al. Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J Physiol-Lung Cell Mole Physiol. 2008;295(4):L575–L83.
  • Sun X, Wang L, Wang J, et al. Effects of simvastatin on lung injury induced by ischaemia–reperfusion of the hind limbs in rats. J Int Med Res. 2007;35(4):523–533.
  • Lee J-H, Lee D-S, Kim E-K, et al. Simvastatin inhibits cigarette smoking–induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med. 2005;172(8):987–993.
  • Ahmad T, Mabalirajan U, Sharma A, et al. Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma. Am J Respir Cell Mole Biol. 2011;44(4):531–539.
  • Altintas ND, Atilla P, Iskit AB, et al. Long-term simvastatin attenuates lung injury and oxidative stress in murine acute lung injury models induced by oleic Acid and endotoxin. Respir Care. 2011;56(8):1156–1163.
  • Nishimoto-Hazuku A, Hirase T, Ide N, et al. Simvastatin stimulates vascular endothelial growth factor production by hypoxia-inducible factor-1α upregulation in endothelial cells. J Cardiovasc Pharmacol. 2008;51(3):267–273.
  • Rose MC, Nickola TJ, Voynow JA. Airway mucus obstruction: mucin glycoproteins, MUC gene regulation and goblet cell hyperplasia. Am J Respir Cell Mole Biol. 2001;25(5):533–537.
  • Lora JM, Zhang DM, Liao SM, et al. Tumor necrosis factor-α triggers mucus production in airway epithelium through an IκB kinase β-dependent mechanism. J Biol Chem. 2005;280(43):36510–36517.
  • Reid CJ, Gould S, Harris A. Developmental expression of mucin genes in the human respiratory tract. Am J Respir Cell Mole Biol. 1997;17(5):592–598.
  • Hovenberg H, Davies J, Carlstedt I. Different mucins are produced by the surface epithelium and the submucosa in human trachea: identification of MUC5AC as a major mucin from the goblet cells. Biochem J. 1996;318:319–324.
  • Kirkham S, Sheehan J, Knight D, et al. Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. Biochem J. 2002;361:537–546.
  • Williams OW, Sharafkhaneh A, Kim V, et al. Airway mucus: from production to secretion. Am J Respir Cell Mole Biol. 2006;34(5):527–536.
  • Kim WD. Lung mucus: a clinician’s view. Eur Respir J. 1997;10(8):1914–1917.
  • Lundgren JD, Shelhamer JH. Pathogenesis of airway mucus hypersecretion. J Allergy Clin Immunol. 1990;85(2):399–417.
  • Chen Y-J, Chen P, Wang H-X, et al. Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. Int Immunopharmacol. 2010;10(6):685–693.
  • Yanagihara K, Seki M, Cheng P-W. Lipopolysaccharide induces mucus cell metaplasia in mouse lung. Am J Respir Cell Mole Biol. 2001;24(1):66–73.
  • Li D, Gallup M, Fan N, et al. Cloning of the amino-terminal and 5-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J Biol Chem. 1998;273(12):6812–6820.
  • Liu J-N, Suh D-H, Yang E-M, et al. Attenuation of airway inflammation by simvastatin and the implications for asthma treatment: is the jury still out? Exp Mole Med. 2014;46(9):e113.
  • Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164(supplement_2):S28–S38.
  • Zeki AA, Bratt JM, Rabowsky M, et al. Simvastatin inhibits goblet cell hyperplasia and lung arginase in a mouse model of allergic asthma: a novel treatment for airway remodeling? Transl Res. 2010;156(6):335–349.
  • Kim DY, Ryu SY, Lim JE, et al. Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. Eur J Pharmacol. 2007;557(1):76–86.
  • Ou X-M, Wang B-D, Wen F-Q, et al. Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats. Chin Med J. 2008;121(17):1680–1687.
  • Curran DR, Cohn L. Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Respir Cell Mole Biol. 2010;42(3):268–275.
  • Hwang K-E, Na K-S, Park D-S, et al. Apoptotic induction by simvastatin in human lung cancer A549 cells via Akt signaling dependent down-regulation of survivin. Invest New Drugs. 2011;29(5):945–952.
  • Weis M, Heeschen C, Glassford AJ, et al. Statins have biphasic effects on angiogenesis. Circulation. 2002;105(6):739–745.
  • Shang L, Jia -S-S, Jiang H-M, et al. Simvastatin downregulates expression of TGF-βRII and inhibits proliferation of A549 cells via ERK. Tumor Biology. 2015;36(6):4819–4824.
  • Yu X, Pan Y, Ma H, et al. Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells. Oncol Res Featuring Preclin Clin Cancer Ther. 2013;20(8):351–357.
  • Gallelli L, Falcone D, Scaramuzzino M, et al. Effects of simvastatin on cell viability and proinflammatory pathways in lung adenocarcinoma cells exposed to hydrogen peroxide. BMC Pharmacol Toxicol. 2014;15(1):67.
  • Atochina-Vasserman EN, Goncharov DA, Volgina AV, et al. Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2–null cell growth and signaling. Am J Respir Cell Mole Biol. 2013;49(5):704–709.
  • Goncharova EA, Goncharov DA, Li H, et al. mTORC2 is required for proliferation and survival of TSC2-null cells. Mole Cell Biol. 2011;31(12):2484–2498.
  • Goncharova EA, Goncharov DA, Fehrenbach M, et al. Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Sci Transl Med. 2012;4(154):154ra34.
  • Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation. 2003;108(13):1640–1645.
  • Si X-B, Zhang S, Huo L-Y, et al. Statin therapy does not improve lung function in asthma: a meta-analysis of randomized controlled trials. J Int Med Res. 2013;41(2):276–283.
  • Rubin BK. Statins for the treatment of asthma: a discovery well, dry hole or just snake oil. Thorax. 2009;64(1):4–5.
  • Yuan C, Zhou L, Cheng J, et al. Statins as potential therapeutic drug for asthma. Respir Res. 2012;13(108):1465–1499.
  • Irngartinger M, Camuglia V, Damm M, et al. Pulmonary delivery of therapeutic peptides via dry powder inhalation: effects of micronisation and manufacturing. Eur J Pharm Biopharm. 2004;58(1):7–14.
  • Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392(1–2):1–19.
  • Tulbah AS, Ong HX, Colombo P, et al. Novel simvastatin inhalation formulation and characterisation. AAPS PharmSciTech. 2014;15(4):956–962.
  • Nezasa K-I, Higaki K, Matsumura T, et al. Liver-specific distribution of rosuvastatin in rats: comparison with pravastatin and simvastatin. Drug Metab Dispos. 2002;30(11):1158–1163.
  • Xu L, Dong X-W, Shen L-L, et al. Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma. Int Immunopharmacol. 2012;12(4):556–564.
  • Tulbah AS, Ong HX, Morgan L, et al. Dry powder formulation of simvastatin. Expert Opin Drug Delivery. 2014;12(6):857–868.
  • Sarr FS, Guillaume YC, André C. Magnesium cation effect on passive diffusion of statin molecules: molecular chromatography approach. J Pharm Biomed Anal. 2008;47(3):651–657.
  • Munger J, Shi G-P, Mark EA, et al. A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. J Biol Chem. 1991;266(28):18832–18838.
  • Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules. 2008;13(2):412–431.
  • Hori T, Hosokawa M. DNA methylation and its involvement in carboxylesterase 1A1 (CES1A1) gene expression. Xenobiotica. 2010;40(2):119–128.
  • Anttila S, Hukkanen J, Hakkola J, et al. Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mole Biol. 1997;16(3):242–249.
  • Piipari R, Savela K, Nurminen T, et al. Expression of CYP1A1, CYP1B1 and CYP3A, and polycyclic aromatic hydrocarbon‐DNA adduct formation in bronchoalveolar macrophages of smokers and non‐smokers. Int J Cancer. 2000;86(5):610–616.
  • Takahashi S, Nakamura H, Seki M, et al. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol-Lung Cell Mole Physiol. 2008;294(5):L882–L890.
  • Tschernig T, Bäumer W, Pabst R. Controversial data on simvastatin in asthma: What about the rat model? J Asthma Allergy. 2010;3(16):57–63.
  • Basu S, Ryu M, Ojo O, et al. Intranasal delivery of simvastatin: improved effects over systemic delivery to suppress allergic airway inflammation and hyperreactivity. Am J Respir Crit Care Med. 2013;187:A4011.
  • Basu S, Ryu M, Ojo O, et al. Inhibition of airway inflammation and hyperreactivity by inhaled simvastatin. Am J Respir Crit Care Med. 2014;189:A2690.
  • Tulbah AS, Ong HX, Lee W-H, et al. Biological effects of simvastatin formulated as pMDI on pulmonary epithelial cells. Pharm Res. 2015. doi:10.1007/s11095-015-1766–3
  • JM.M.M.A. In Koda-Kimble, L.Y. Young, et al. Applied therapeutics: the clinical use of drugs. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.
  • Dirisamer A, Hachemian N, Bucek RA, et al. The effect of low-dose simvastatin in children with familial hypercholesterolaemia: a 1-year observation. Eur J Pediatr. 2003;162(6):421–425.
  • Eiland LS, Luttrell PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr Pharmacol Ther. 2010;15(3):160–172.
  • Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789.
  • Group TS. The TORCH (towards a revolution in COPD health) survival study protocol. Eur Respir J. 2004;24(2):206–210.
  • Sin DD, Man SP, Marciniuk DD, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177(11):1207–1214.
  • Mancini GJ, Road J. Are STATINS out in the COLD?: the STATCOPE Trial. Canadian J Cardiol. 2015;31(8):970–973.

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