Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

REFERENCES

• Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163:1256–1276.
   PubMedGoogle Scholar
• American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168:818–900.
   PubMed Web of Science ®Google Scholar
• Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, Calverley PMA, Chavannes N, Dillard T, Fahy B, Fein A, Heffner J, Lareau S, Meek P, Martinez F, McNicholas W, Muris J, Austegard E, Pauwels R, Rennard S, Rossi A, Siafakas N, Tiep B, Vestbo J, Wouters E, ZuWallack R. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper 10.1183/09031936.04.00014304. Eur Respir J 2004; 23:932–946.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775–789.
   PubMed Web of Science ®Google Scholar
• Tashkin DP. Long-acting anticholinergic use in chronic obstructive pulmonary disease: efficacy and safety. Curr Opin Pulm Med 2010; 16:97–105.
   PubMed Web of Science ®Google Scholar
• Rennard SI. Treatment of stable chronic obstructive pulmonary disease. Lancet 2004; 364:791–802.
   PubMed Web of Science ®Google Scholar
• Connors AF, Jr., Dawson NV, Thomas C, Harrell FE, Jr., Desbiens N, Fulkerson WJ, Kussin P, Bellamy P, Goldman L, Knaus WA. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med 1996; 154:959–967.
   PubMed Web of Science ®Google Scholar
• Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57:847–852.
   PubMed Web of Science ®Google Scholar
• Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1418–1422.
   PubMed Web of Science ®Google Scholar
• Snow V, Lascher S, Mottur-Pilson C. The evidence base for management of acute exacerbations of COPD: clinical practice guideline, part 1. Chest 2001; 119:1185–1189.
   PubMed Web of Science ®Google Scholar
• Ramirez-Venegas A, Ward J, Lentine T, Mahler DA. Salmeterol reduces dyspnea and improves lung function in patients with COPD. Chest 1997; 112:336–340.
   PubMed Web of Science ®Google Scholar
• Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, Wisniewski M, Rickard K. Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:1087–1092.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Rennard SI. What have we learned from large drug treatment trials in COPD? Lancet 2007; 370:774–785.
   PubMed Web of Science ®Google Scholar
• Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000; 343:1902–1909.
   PubMed Web of Science ®Google Scholar
• Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial 10.1136/bmj.320.7245.1297. BMJ 2000; 320:1297–1303.
   PubMed Web of Science ®Google Scholar
• Vestbo J. The TORCH (towards a revolution in COPD health) survival study protocol. Eur Respir J 2004; 24:206–210.
   PubMed Web of Science ®Google Scholar
• Kojima S, Sakakibara H, Motani S, Hirose K, Mizuno F, Ochiai M, Hashimoto S. Incidence of chronic obstructive pulmonary disease, and the relationship between age and smoking in a Japanese population. J Epidemiol 2007; 17:54–60.
   PubMed Web of Science ®Google Scholar
• Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006; 27:397–412.
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Stockley RA. COPD: current therapeutic interventions and future approaches. Eur Respir J 2005; 25:1084–1106.
   PubMed Web of Science ®Google Scholar
• Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:1635– 1639.
   PubMed Web of Science ®Google Scholar
• Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155:542–548.
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117:10S–14S.
   PubMed Web of Science ®Google Scholar
• Fabbri LM, Romagnoli M, Corbetta L, Casoni G, Busljetic K, Turato G, Ligabue G, Ciaccia A, Saetta M, Papi A. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167:418–424.
   PubMed Web of Science ®Google Scholar
• O’Byrne P M, Postma DS. The many faces of airway inflammation. Asthma and chronic obstructive pulmonary disease. Asthma Research Group. Am J Respir Crit Care Med 1999; 159:S41–S63.
   Web of Science ®Google Scholar
• Yawn BP. Differential assessment and management of asthma vs chronic obstructive pulmonary disease. Medscape J Med 2009; 11:20.
   PubMedGoogle Scholar
• Torphy TJ. Action of mediators on airway smooth muscle: functional antagonism as a mechanism for bronchodilator drugs. Agents Actions Suppl 1988; 23:37–53.
   PubMedGoogle Scholar
• Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157:351–370.
   PubMed Web of Science ®Google Scholar
• Torphy TJ, Cieslinski LB. Characterization and selective inhibition of cyclic nucleotide phosphodiesterase isozymes in canine tracheal smooth muscle. Mol Pharmacol 1990; 37:206–214.
   PubMed Web of Science ®Google Scholar
• Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991; 46:512–523.
   PubMed Web of Science ®Google Scholar
• Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58:488–520.
   PubMed Web of Science ®Google Scholar
• Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 2005; 10:1503–1519.
   PubMed Web of Science ®Google Scholar
• Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? Br J Pharmacol 2008; 155:288–290.
   PubMed Web of Science ®Google Scholar
• Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001; 297:267–279.
   PubMed Web of Science ®Google Scholar
• Giembycz MA. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2001; 10:1361–1379.
   PubMed Web of Science ®Google Scholar
• Giembycz MA. Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol 1992; 43:2041–2051.
   PubMed Web of Science ®Google Scholar
• Press NJ, Banner KH. PDE4 inhibitors—a review of the current field. Prog Med Chem 2009; 47:37–74.
   PubMedGoogle Scholar
• Giembycz MA. Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here? Drugs 2000; 59:193–212.
   PubMed Web of Science ®Google Scholar
• Currie GP, Butler CA, Anderson WJ, Skinner C. Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment. Br J Clin Pharmacol 2008; 65:803–810.
   PubMed Web of Science ®Google Scholar
• Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs 2007; 8:364–372.
   PubMed Web of Science ®Google Scholar
• Field SK. Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma. Expert Opin Investig Drugs 2008; 17:811–818.
   PubMed Web of Science ®Google Scholar
• Jeffrey AM, Luo FQ, Amin S, Krzeminski J, Zech K, Williams GM. Lack of DNA binding in the rat nasal mucosa and other tissues of the nasal toxicants roflumilast, a phosphodiesterase 4 inhibitor, and a metabolite, 4-amino-3,5-dichloropyridine, in contrast to the nasal carcinogen 2,6-dimethylaniline. Drug Chem Toxicol 2002; 25:93–107.
   PubMed Web of Science ®Google Scholar
• Reid P. Roflumilast Altana Pharma. Curr Opin Investig Drugs 2002; 3:1165–1170.
   PubMedGoogle Scholar
• Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 2001; 297:280–290.
   PubMed Web of Science ®Google Scholar
• Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005; 172:848–853.
   PubMed Web of Science ®Google Scholar
• Martorana PA, Lunghi B, Lucattelli M, De Cunto G, Beume R, Lungarella G. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med 2008; 8:17.
   PubMedGoogle Scholar
• Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol 2007; 152:481–492.
   PubMed Web of Science ®Google Scholar
• Wollin L, Bundschuh DS, Wohlsen A, Marx D, Beume R. Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. Pulm Pharmacol Ther 2006; 19:343–352.
   PubMed Web of Science ®Google Scholar
• Wollin L, Marx D, Wohlsen A, Beume R. Roflumilast inhibition of pulmonary leukotriene production and bronchoconstriction in ovalbumin-sensitized and -challenged Guinea pigs. J Asthma 2005; 42:873–878.
   PubMed Web of Science ®Google Scholar
• Grootendorst DC, Gauw SA, Baan R, Kelly J, Murdoch RD, Sterk PJ, Rabe KF. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Pulm Pharmacol Ther 2003; 16:115–120.
   PubMed Web of Science ®Google Scholar
• Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62:1081–1087.
   PubMed Web of Science ®Google Scholar
• Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, Schaumann F, Mueller M, Bredenbroeker D, Krug N, Hermann R. Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial. Pulm Pharmacol Ther 2008; 21:616–623.
   PubMed Web of Science ®Google Scholar
• Timmer W, Leclerc V, Birraux G, Neuhauser M, Hatzelmann A, Bethke T, Wurst W. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol 2002; 42:297–303.
   PubMed Web of Science ®Google Scholar
• Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, Kroegel C, Morell F, Hansel TT, Rennard SI, Compton C, Amit O, Tat T, Edelson J, Pavord ID, Rabe KF, Barnes NC, Jeffery PK. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168:976–982.
   PubMed Web of Science ®Google Scholar
• Bethke TD, Bohmer GM, Hermann R, Hauns B, Fux R, Morike K, David M, Knoerzer D, Wurst W, Gleiter CH. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J Clin Pharmacol 2007; 47:26–36.
   PubMed Web of Science ®Google Scholar
• Hauns B, Hermann R, Hunnemeyer A, Herzog R, Hauschke D, Zech K, Bethke TD. Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects. J Clin Pharmacol 2006; 46:1146–1153.
   PubMed Web of Science ®Google Scholar
• Neville KA, Szefler SJ, Abdel-Rahman SM, Lahu G, Zech K, Herzog R, Bethke TD, Gleason MC, Kearns GL. Single-dose pharmacokinetics of roflumilast in children and adolescents. J Clin Pharmacol 2008; 48:978–985.
   PubMed Web of Science ®Google Scholar
• Nassr N, Huennemeyer A, Herzog R, von Richter O, Hermann R, Koch M, Duffy K, Zech K, Lahu G. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol 2009; 68:580–587.
   PubMed Web of Science ®Google Scholar
• David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability. J Allergy Clin Immunol 2004; 113:S220–S221.
   Google Scholar
• Lahu G, Huennemeyer A, von Richter O, Hermann R, Herzog R, McCracken N, Zech K. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol 2008; 48:1339–1349.
   PubMed Web of Science ®Google Scholar
• Nassr N, Lahu G, Hunnemeyer A, von Richter O, Knoerzer D, Reutter F, Zech K, Hermann R. Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast. J Clin Pharmacol 2007; 47:660–666.
   PubMed Web of Science ®Google Scholar
• Nassr N, Lahu G, von Richter O, Reutter F, Knoerzer D, Zech K, Erb KA, Schug B, Blume H, Hermann R. Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects. Br J Clin Pharmacol 2007; 63:365–370.
   PubMed Web of Science ®Google Scholar
• Hermann R, Nassr N, Lahu G, Peterfai E, Knoerzer D, Herzog R, Zech K, de Mey C. Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet 2007; 46:403–416.
   PubMed Web of Science ®Google Scholar
• Bethke TD, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Hauschke D, David M, Lahu G, Zech K, Hermann R, Siegmund W. Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Int J Clin Pharmacol Ther 2006; 44:572–579.
   PubMed Web of Science ®Google Scholar
• Bohmer GM, Nassr N, Wenger M, Hunnemeyer A, Lahu G, Templin S, Gleiter CH, Hermann R. The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions. J Clin Pharmacol 2009; 49:389–397.
   PubMed Web of Science ®Google Scholar
• Hermann R, Siegmund W, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Reutter F, Lahu G, Zech K, Bethke TD. The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. J Clin Pharmacol 2007; 47:1005–1013.
   PubMed Web of Science ®Google Scholar
• Lahu G, Huennemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech K. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int J Clin Pharmacol Ther 2009; 47:236–245.
   PubMed Web of Science ®Google Scholar
• von Richter O, Lahu G, Huennemeyer A, Herzog R, Zech K, Hermann R. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin Pharmacokinet 2007; 46:613–622.
   PubMed Web of Science ®Google Scholar
• Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther 1976; 19:546–551.
   PubMed Web of Science ®Google Scholar
• Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 1979; 9:221–236.
   PubMed Web of Science ®Google Scholar
• Powell JR, Vozeh S, Hopewell P, Costello J, Sheiner LB, Riegelman S. Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airway obstruction, and pneumonia. Am Rev Respir Dis 1978; 118:229–238.
   PubMed Web of Science ®Google Scholar
• Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005; 366:563–571.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 176:154–161.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374:685–694.
   PubMed Web of Science ®Google Scholar
• Donohue JF. Minimal clinically important differences in COPD lung function. COPD 2005; 2:111–124.
   PubMedGoogle Scholar
• Hanania NA. The impact of inhaled corticosteroid and long-acting beta-agonist combination therapy on outcomes in COPD. Pulm Pharmacol Ther 2008; 21:540–550.
   PubMed Web of Science ®Google Scholar
• Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374:695–703.
   PubMed Web of Science ®Google Scholar
• Giembycz MA. 4D or not 4D—the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci 2002; 23:548.
   PubMedGoogle Scholar
• Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDonald D, Laliberte F, Liu S, Huang Z, Conti M, Chan CC. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 2002; 110:1045–1052.
   PubMed Web of Science ®Google Scholar
• Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, Nieman RB, Compton CH. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther 1999; 12:131–135.
   PubMed Web of Science ®Google Scholar
• Boswell-Smith V, Page CP. Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of respiratory disease. Expert Opin Investig Drugs 2006; 15:1105–1113.
   PubMed Web of Science ®Google Scholar
• Cyr MC, Beauchesne MF, Lemiere C, Blais L. Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol 2008; 65:40–50.
   PubMed Web of Science ®Google Scholar
• Gross NJ. The COPD Pipeline. COPD 2009; 6:488–489.
   PubMedGoogle Scholar
• Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 2009; 28: 63–70.
   PubMed Web of Science ®Google Scholar
• Gupta P, O’Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging 2008; 25:415– 443.
   PubMed Web of Science ®Google Scholar