<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.3 20210610//EN" "JATS-journalpublishing1-3.dtd">
<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">pulmo</journal-id><journal-title-group><journal-title xml:lang="ru">Пульмонология</journal-title><trans-title-group xml:lang="en"><trans-title>PULMONOLOGIYA</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">0869-0189</issn><issn pub-type="epub">2541-9617</issn><publisher><publisher-name>Scientific and Practical Journal “PULMONOLOGIYA” LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.18093/0869-0189-2012-0-2-90-98</article-id><article-id custom-type="elpub" pub-id-type="custom">pulmo-57</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОБЗОРЫ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>REVIEW</subject></subj-group></article-categories><title-group><article-title>Клиническая фармакология рофлумиласта</article-title><trans-title-group xml:lang="en"><trans-title>Clinical pharmacology of roflumilast</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Архипов</surname><given-names>В. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Arkhipov</surname><given-names>V. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>д. м. н., проф. кафедры клинической фармакологии и пропедевтики внутренних болезней</p><p>109249, Москва, ул. Яузская, 11, корп. 5. Тел.: +7-903-966-54-14.</p></bio><email xlink:type="simple">arkhipov@gmx.us</email><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff xml:lang="ru" id="aff-1"><institution>ГОУ ВПО "Первый МГМУ им. И.М.Сеченова"</institution><country>Russian Federation</country></aff><pub-date pub-type="collection"><year>2012</year></pub-date><pub-date pub-type="epub"><day>28</day><month>04</month><year>2012</year></pub-date><volume>0</volume><issue>2</issue><fpage>90</fpage><lpage>98</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Архипов В.В., 2012</copyright-statement><copyright-year>2012</copyright-year><copyright-holder xml:lang="ru">Архипов В.В.</copyright-holder><copyright-holder xml:lang="en">Arkhipov V.V.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://journal.pulmonology.ru/pulm/article/view/57">https://journal.pulmonology.ru/pulm/article/view/57</self-uri><abstract><p>Клиническая фармакология рофлумиласта.</p></abstract><trans-abstract xml:lang="en"><p>Clinical pharmacology of roflumilast.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>хроническая обструктивная болезнь легких</kwd><kwd>фосфодиэстераза</kwd><kwd>обострения</kwd><kwd>рофлумиласт</kwd></kwd-group><kwd-group xml:lang="en"><kwd>chronic obstructive pulmonary disease</kwd><kwd>phosphodiesterase</kwd><kwd>exacerbation</kwd><kwd>roflumilast</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Jeon Y., Heo Y., Kim C. et al. Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell. Mol. Life Sci. 2005; 62 (11): 1198–1220.</mixed-citation><mixed-citation xml:lang="en">Jeon Y., Heo Y., Kim C. et al. Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell. Mol. Life Sci. 2005; 62 (11): 1198–1220.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Boswell*Smith V., Spina D., Page C.P. Phosphodiesterase inhibitors. Br. J. Pharmacol. 2006; 147: S252–S257.</mixed-citation><mixed-citation xml:lang="en">Boswell*Smith V., Spina D., Page C.P. Phosphodiesterase inhibitors. Br. J. Pharmacol. 2006; 147: S252–S257.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Uckert S., Kuthe A., Stief C.G., Jonas U. Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. Wld J. Urol. 2001; 19: 14–22.</mixed-citation><mixed-citation xml:lang="en">Uckert S., Kuthe A., Stief C.G., Jonas U. Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. Wld J. Urol. 2001; 19: 14–22.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">McIvor R.A. Future options for disease intervention: important advances in phosphodiesterase 4 inhibitors. Eur. Respir. Rev. 2007; 16 (105): 105–112.</mixed-citation><mixed-citation xml:lang="en">McIvor R.A. Future options for disease intervention: important advances in phosphodiesterase 4 inhibitors. Eur. Respir. Rev. 2007; 16 (105): 105–112.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Wang P., Wu P., Ohleth K.M. et al. Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. Mol. Pharmacol. 1999; 56: 170–174.</mixed-citation><mixed-citation xml:lang="en">Wang P., Wu P., Ohleth K.M. et al. Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. Mol. Pharmacol. 1999; 56: 170–174.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Erdogan S., Houslay M.D. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant. Biochem. J. 2003; 321 (Pt 1): 165–175.</mixed-citation><mixed-citation xml:lang="en">Erdogan S., Houslay M.D. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant. Biochem. J. 2003; 321 (Pt 1): 165–175.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Mehats C., Jin S.L., Wahlstrom J. et al. PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB J. 2003; 17: 1831–1841.</mixed-citation><mixed-citation xml:lang="en">Mehats C., Jin S.L., Wahlstrom J. et al. PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB J. 2003; 17: 1831–1841.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Giembycz M.A. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Exp. Opin. Invest. Drugs 2001; 10: 1361–1379.</mixed-citation><mixed-citation xml:lang="en">Giembycz M.A. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Exp. Opin. Invest. Drugs 2001; 10: 1361–1379.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Jin S.L., Conti M. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc. Natl Acad. Sci. USA 2002; 99: 7628–7633.</mixed-citation><mixed-citation xml:lang="en">Jin S.L., Conti M. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc. Natl Acad. Sci. USA 2002; 99: 7628–7633.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Robichaud A., Stamatiou P.B., Jin S.L. et al. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor- mediated anaesthesia, a behavioural correlate of emesis. J. Clin. Invest. 2002; 110: 1045–1052.</mixed-citation><mixed-citation xml:lang="en">Robichaud A., Stamatiou P.B., Jin S.L. et al. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor- mediated anaesthesia, a behavioural correlate of emesis. J. Clin. Invest. 2002; 110: 1045–1052.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Wang D., Cui X. Evaluation of PDE4 inhibition for COPD. Int. J. Chron. Obstruct. Pulm. Dis. 2006; 1 (4): 373–379.</mixed-citation><mixed-citation xml:lang="en">Wang D., Cui X. Evaluation of PDE4 inhibition for COPD. Int. J. Chron. Obstruct. Pulm. Dis. 2006; 1 (4): 373–379.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">LeadDiscovery. 2006. Phosphodiesterase 4 (PDE4) &amp; phosphodiesterase 5 (PDE5) inhibitors [online]. Accessed 16 June 2006. URL: http://www.leaddiscovery.co.uk/reports/Phosphodiesterase*library.html</mixed-citation><mixed-citation xml:lang="en">LeadDiscovery. 2006. Phosphodiesterase 4 (PDE4) &amp; phosphodiesterase 5 (PDE5) inhibitors [online]. Accessed 16 June 2006. URL: http://www.leaddiscovery.co.uk/reports/Phosphodiesterase*library.html</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Hatzelmann A., Morcillo E.J., Lungarella G. et. al. The preclinical pharmacology of roflumilast – a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2010; 23: 235–256.</mixed-citation><mixed-citation xml:lang="en">Hatzelmann A., Morcillo E.J., Lungarella G. et. al. The preclinical pharmacology of roflumilast – a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2010; 23: 235–256.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Bethke T.D., Böhmer G.M., Hermann R. et al. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J. Clin. Pharmacol. 2007; 47: 26–36.</mixed-citation><mixed-citation xml:lang="en">Bethke T.D., Böhmer G.M., Hermann R. et al. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J. Clin. Pharmacol. 2007; 47: 26–36.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Lahu G., Hünnemeyer A., Diletti E. et al. Population pharmacokinetic modelling of roflumilast and roflumilast N-Oxide by total phosphodiesterase 4 inhibitory activity and development of a population pharmacodynamicadverse event model. Clin. Pharmacokinet. 2010; 49: 589–606.</mixed-citation><mixed-citation xml:lang="en">Lahu G., Hünnemeyer A., Diletti E. et al. Population pharmacokinetic modelling of roflumilast and roflumilast N-Oxide by total phosphodiesterase 4 inhibitory activity and development of a population pharmacodynamicadverse event model. Clin. Pharmacokinet. 2010; 49: 589–606.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Nassr N., Lahu G., Hunnemeyer A. et al. 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.</mixed-citation><mixed-citation xml:lang="en">Nassr N., Lahu G., Hunnemeyer A. et al. 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.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Lahu G., Hunnemeyer A., Herzog R. et al. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int. J. Clin. Pharmacol. Ther. 2009; 47: 236–245.</mixed-citation><mixed-citation xml:lang="en">Lahu G., Hunnemeyer A., Herzog R. et al. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int. J. Clin. Pharmacol. Ther. 2009; 47: 236–245.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Lahu G., Hünnemeyer A., von Richter O. et al. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J. Clin. Pharmacol. 2008; 48: 1339–1349.</mixed-citation><mixed-citation xml:lang="en">Lahu G., Hünnemeyer A., von Richter O. et al. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J. Clin. Pharmacol. 2008; 48: 1339–1349.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Nassr N., Huennemeyer A., Herzog R. et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br. J. Clin. Pharmacol. 2009; 68: 580–587.</mixed-citation><mixed-citation xml:lang="en">Nassr N., Huennemeyer A., Herzog R. et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br. J. Clin. Pharmacol. 2009; 68: 580–587.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">von Richter O., Lahu G., Hunnemeyer A. et al. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin. Pharmacokinet. 2007; 46: 613–622.</mixed-citation><mixed-citation xml:lang="en">von Richter O., Lahu G., Hunnemeyer A. et al. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin. Pharmacokinet. 2007; 46: 613–622.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Ram F.S. Use of theophylline in chronic obstructive pulmonary disease: examining the evidence. Curr. Opin. Pulm. Med. 2006;12 (2): 132–139.</mixed-citation><mixed-citation xml:lang="en">Ram F.S. Use of theophylline in chronic obstructive pulmonary disease: examining the evidence. Curr. Opin. Pulm. Med. 2006;12 (2): 132–139.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Bennett J.A., Thompson Coon I., Pavord P. et al. The airway effects of stopping regular oral theophylline in patients with asthma. Br. J. Clin. Pharmacol. 1998; 45: 402–404.</mixed-citation><mixed-citation xml:lang="en">Bennett J.A., Thompson Coon I., Pavord P. et al. The airway effects of stopping regular oral theophylline in patients with asthma. Br. J. Clin. Pharmacol. 1998; 45: 402–404.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Boswell*Smith V., Cazzola M., Page C.P. Are phosphodiesterase 4 inhibitors just more theophylline? J. Allergy Clin. Immunol. 2006; 117 (6):1237–1243.</mixed-citation><mixed-citation xml:lang="en">Boswell*Smith V., Cazzola M., Page C.P. Are phosphodiesterase 4 inhibitors just more theophylline? J. Allergy Clin. Immunol. 2006; 117 (6):1237–1243.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Profita M., Sala A., Bonanno A. et al. Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products. Am. J. Physiol. Lung Cell. Mol. Physiol. 2010; 298 (2): L261–L269.</mixed-citation><mixed-citation xml:lang="en">Profita M., Sala A., Bonanno A. et al. Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products. Am. J. Physiol. Lung Cell. Mol. Physiol. 2010; 298 (2): L261–L269.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Brightling C.E., Monteiro W., Ward R. et al. Sputum eosinophilia and short–term response to prednisolone in chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2000; 356: 1480–1485.</mixed-citation><mixed-citation xml:lang="en">Brightling C.E., Monteiro W., Ward R. et al. Sputum eosinophilia and short–term response to prednisolone in chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2000; 356: 1480–1485.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Tenor H., Hatzelmann A., Church M.K. et al. Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. Br. J. Pharmacol. 1996; 118: 1727–1235.</mixed-citation><mixed-citation xml:lang="en">Tenor H., Hatzelmann A., Church M.K. et al. Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. Br. J. Pharmacol. 1996; 118: 1727–1235.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Grootendorst D.C., Gauw S.A., Verhoosel R.M. et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62 (12): 1081–1087.</mixed-citation><mixed-citation xml:lang="en">Grootendorst D.C., Gauw S.A., Verhoosel R.M. et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62 (12): 1081–1087.</mixed-citation></citation-alternatives></ref><ref id="cit28"><label>28</label><citation-alternatives><mixed-citation xml:lang="ru">Jones N.A., Boswell*Smith V., Lever R., Page C.P. The eff ect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm. Pharmacol. Ther. 2005; 18: 93–101.</mixed-citation><mixed-citation xml:lang="en">Jones N.A., Boswell*Smith V., Lever R., Page C.P. The eff ect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm. Pharmacol. Ther. 2005; 18: 93–101.</mixed-citation></citation-alternatives></ref><ref id="cit29"><label>29</label><citation-alternatives><mixed-citation xml:lang="ru">Hidi R., Timmermans S., Liu E. et al. Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of T-lymphocyte chemotaxis. Eur. Respir. J. 2000; 15: 342–349.</mixed-citation><mixed-citation xml:lang="en">Hidi R., Timmermans S., Liu E. et al. Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of T-lymphocyte chemotaxis. Eur. Respir. J. 2000; 15: 342–349.</mixed-citation></citation-alternatives></ref><ref id="cit30"><label>30</label><citation-alternatives><mixed-citation xml:lang="ru">Au B.T., Teixeira M.M., Collins P.D., Williams T.J. Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol. Br. J. Pharmacol. 1998; 123: 1260–1266.</mixed-citation><mixed-citation xml:lang="en">Au B.T., Teixeira M.M., Collins P.D., Williams T.J. Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol. Br. J. Pharmacol. 1998; 123: 1260–1266.</mixed-citation></citation-alternatives></ref><ref id="cit31"><label>31</label><citation-alternatives><mixed-citation xml:lang="ru">Cortijo J., Villagrasa V., Navarrete C. et al. Effects of SCA40 on human isolated bronchus and human polymorphonuclear leukocytes: comparison with rolipram, SKF94120 and levcromakalim. Br. J. Pharmacol. 1996; 119: 99–106.</mixed-citation><mixed-citation xml:lang="en">Cortijo J., Villagrasa V., Navarrete C. et al. Effects of SCA40 on human isolated bronchus and human polymorphonuclear leukocytes: comparison with rolipram, SKF94120 and levcromakalim. Br. J. Pharmacol. 1996; 119: 99–106.</mixed-citation></citation-alternatives></ref><ref id="cit32"><label>32</label><citation-alternatives><mixed-citation xml:lang="ru">Nadel J.A. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies. Chest 2000; 117 (5, Suppl. 2): S386–S389.</mixed-citation><mixed-citation xml:lang="en">Nadel J.A. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies. Chest 2000; 117 (5, Suppl. 2): S386–S389.</mixed-citation></citation-alternatives></ref><ref id="cit33"><label>33</label><citation-alternatives><mixed-citation xml:lang="ru">Fitzgerald M.F., Spicer D., McAulay A.E. et al. Roflumilast butnot methylprednisolone inhibited cigarette smokeinduced pulmonary inflammation in guinea pigs. Eur. Respir. J. Suppl. 2006; 663s: P3850.</mixed-citation><mixed-citation xml:lang="en">Fitzgerald M.F., Spicer D., McAulay A.E. et al. Roflumilast butnot methylprednisolone inhibited cigarette smokeinduced pulmonary inflammation in guinea pigs. Eur. Respir. J. Suppl. 2006; 663s: P3850.</mixed-citation></citation-alternatives></ref><ref id="cit34"><label>34</label><citation-alternatives><mixed-citation xml:lang="ru">Barnes N.C., Qiu Y.S., Pavord I.D. et al. Antiinflammatory effects of salmeterol / fluticasone propionate in chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 2006; 173 (7): 736–743.</mixed-citation><mixed-citation xml:lang="en">Barnes N.C., Qiu Y.S., Pavord I.D. et al. Antiinflammatory effects of salmeterol / fluticasone propionate in chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 2006; 173 (7): 736–743.</mixed-citation></citation-alternatives></ref><ref id="cit35"><label>35</label><citation-alternatives><mixed-citation xml:lang="ru">Confalonieri M., Mainardi E., Della Porta R. et al. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998; 53: 583–585.</mixed-citation><mixed-citation xml:lang="en">Confalonieri M., Mainardi E., Della Porta R. et al. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998; 53: 583–585.</mixed-citation></citation-alternatives></ref><ref id="cit36"><label>36</label><citation-alternatives><mixed-citation xml:lang="ru">Keatings V., Jatakanon A., Worsdell Y. et al. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155: 548.</mixed-citation><mixed-citation xml:lang="en">Keatings V., Jatakanon A., Worsdell Y. et al. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155: 548.</mixed-citation></citation-alternatives></ref><ref id="cit37"><label>37</label><citation-alternatives><mixed-citation xml:lang="ru">Leigh R., Pizzichini M.M., Morris M.M. et al. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur. Respir. J. 2006; 27 (5): 964–971.</mixed-citation><mixed-citation xml:lang="en">Leigh R., Pizzichini M.M., Morris M.M. et al. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur. Respir. J. 2006; 27 (5): 964–971.</mixed-citation></citation-alternatives></ref><ref id="cit38"><label>38</label><citation-alternatives><mixed-citation xml:lang="ru">Barnes P.J., Adcock I.M. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373: 1905–1917.</mixed-citation><mixed-citation xml:lang="en">Barnes P.J., Adcock I.M. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373: 1905–1917.</mixed-citation></citation-alternatives></ref><ref id="cit39"><label>39</label><citation-alternatives><mixed-citation xml:lang="ru">Lipworth B.J. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365: 167–175.</mixed-citation><mixed-citation xml:lang="en">Lipworth B.J. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365: 167–175.</mixed-citation></citation-alternatives></ref><ref id="cit40"><label>40</label><citation-alternatives><mixed-citation xml:lang="ru">Boszormenyi*Nagy G., Pieters W.R., Steffen H. et al. The effect of roflumilast treatment and subsequent withdrawal in patients with COPD [abstract]. Proc. Am. Thor. Soc. 2005; 2: A544.</mixed-citation><mixed-citation xml:lang="en">Boszormenyi*Nagy G., Pieters W.R., Steffen H. et al. The effect of roflumilast treatment and subsequent withdrawal in patients with COPD [abstract]. Proc. Am. Thor. Soc. 2005; 2: A544.</mixed-citation></citation-alternatives></ref><ref id="cit41"><label>41</label><citation-alternatives><mixed-citation xml:lang="ru">Grootendorst D.C., Gauw S.A., Baan R. et al. Does a single dose of the phosphodieasterase 4 inhibitor, cilomilast (15 mg), induce bronchodilatation in patients with chronic obstructive pulmonary disease? Pulm. Pharmacol. Ther. 2003; 16: 115–120.</mixed-citation><mixed-citation xml:lang="en">Grootendorst D.C., Gauw S.A., Baan R. et al. Does a single dose of the phosphodieasterase 4 inhibitor, cilomilast (15 mg), induce bronchodilatation in patients with chronic obstructive pulmonary disease? Pulm. Pharmacol. Ther. 2003; 16: 115–120.</mixed-citation></citation-alternatives></ref><ref id="cit42"><label>42</label><citation-alternatives><mixed-citation xml:lang="ru">Calverley P., Pauwels R., Vestbo J. et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361 (9356): 449–456.</mixed-citation><mixed-citation xml:lang="en">Calverley P., Pauwels R., Vestbo J. et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361 (9356): 449–456.</mixed-citation></citation-alternatives></ref><ref id="cit43"><label>43</label><citation-alternatives><mixed-citation xml:lang="ru">Rabe K.F., Bateman E.D., O'Donnell D. et al. Roflumilast – an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005; 366: 563–571.</mixed-citation><mixed-citation xml:lang="en">Rabe K.F., Bateman E.D., O'Donnell D. et al. Roflumilast – an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005; 366: 563–571.</mixed-citation></citation-alternatives></ref><ref id="cit44"><label>44</label><citation-alternatives><mixed-citation xml:lang="ru">Nycomed data on file.</mixed-citation><mixed-citation xml:lang="en">Nycomed data on file.</mixed-citation></citation-alternatives></ref><ref id="cit45"><label>45</label><citation-alternatives><mixed-citation xml:lang="ru">Calverley P.M., Sanchez*Toril F., McIvor A. et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2007; 176: 154–161.</mixed-citation><mixed-citation xml:lang="en">Calverley P.M., Sanchez*Toril F., McIvor A. et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2007; 176: 154–161.</mixed-citation></citation-alternatives></ref><ref id="cit46"><label>46</label><citation-alternatives><mixed-citation xml:lang="ru">Calverley P.M., Rabe K.F., Goehring U.M. et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374: 685–694.</mixed-citation><mixed-citation xml:lang="en">Calverley P.M., Rabe K.F., Goehring U.M. et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374: 685–694.</mixed-citation></citation-alternatives></ref><ref id="cit47"><label>47</label><citation-alternatives><mixed-citation xml:lang="ru">Fabbri L.M., Calverley P.M.A., Izquierdo*Alonso J.L. et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374 (9691): 695–703.</mixed-citation><mixed-citation xml:lang="en">Fabbri L.M., Calverley P.M.A., Izquierdo*Alonso J.L. et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374 (9691): 695–703.</mixed-citation></citation-alternatives></ref><ref id="cit48"><label>48</label><citation-alternatives><mixed-citation xml:lang="ru">Aaron S.D., Vandemheen K.L., Fergusson D. et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann. Intern. Med. 2007; 146 (8): 545–555.</mixed-citation><mixed-citation xml:lang="en">Aaron S.D., Vandemheen K.L., Fergusson D. et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann. Intern. Med. 2007; 146 (8): 545–555.</mixed-citation></citation-alternatives></ref><ref id="cit49"><label>49</label><citation-alternatives><mixed-citation xml:lang="ru">Casaburi R., Mahler D.A., Jones P.W. et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. 2002; 19: 217–224.</mixed-citation><mixed-citation xml:lang="en">Casaburi R., Mahler D.A., Jones P.W. et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. 2002; 19: 217–224.</mixed-citation></citation-alternatives></ref><ref id="cit50"><label>50</label><citation-alternatives><mixed-citation xml:lang="ru">Burge P.S., Calverley P.M., Jones P.W. et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Bг. Med. J. (Clin. Res. Ed.) 2000; 320 (7245): 1297–1303.</mixed-citation><mixed-citation xml:lang="en">Burge P.S., Calverley P.M., Jones P.W. et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Bг. Med. J. (Clin. Res. Ed.) 2000; 320 (7245): 1297–1303.</mixed-citation></citation-alternatives></ref><ref id="cit51"><label>51</label><citation-alternatives><mixed-citation xml:lang="ru">Vogelmeier C., Hederer B., Glaab T. et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N. Engl. J. Med. 2011; 364 (12): 1093–1103.</mixed-citation><mixed-citation xml:lang="en">Vogelmeier C., Hederer B., Glaab T. et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N. Engl. J. Med. 2011; 364 (12): 1093–1103.</mixed-citation></citation-alternatives></ref><ref id="cit52"><label>52</label><citation-alternatives><mixed-citation xml:lang="ru">Chapman K.R., Rabe K.F. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease (COPD) concomitantly treated with tiotropium or salmeterol. Prim. Care Respir. J. 2010; 19: A12.</mixed-citation><mixed-citation xml:lang="en">Chapman K.R., Rabe K.F. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease (COPD) concomitantly treated with tiotropium or salmeterol. Prim. Care Respir. J. 2010; 19: A12.</mixed-citation></citation-alternatives></ref><ref id="cit53"><label>53</label><citation-alternatives><mixed-citation xml:lang="ru">Rennard S.I., Calverley P.M., Goehring U.M. et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast the importance of defining different subsets of patients with COPD. Respir. Res. 2011; 12: 18.</mixed-citation><mixed-citation xml:lang="en">Rennard S.I., Calverley P.M., Goehring U.M. et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast the importance of defining different subsets of patients with COPD. Respir. Res. 2011; 12: 18.</mixed-citation></citation-alternatives></ref><ref id="cit54"><label>54</label><citation-alternatives><mixed-citation xml:lang="ru">Bateman E.D., Rabe K.F., Calverley P.M. et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur. Respir. J. 2011; 38 (3): 553–560.</mixed-citation><mixed-citation xml:lang="en">Bateman E.D., Rabe K.F., Calverley P.M. et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur. Respir. J. 2011; 38 (3): 553–560.</mixed-citation></citation-alternatives></ref><ref id="cit55"><label>55</label><citation-alternatives><mixed-citation xml:lang="ru">Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (updated 2011). http://www.goldcopd.org</mixed-citation><mixed-citation xml:lang="en">Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (updated 2011). http://www.goldcopd.org</mixed-citation></citation-alternatives></ref><ref id="cit56"><label>56</label><citation-alternatives><mixed-citation xml:lang="ru">Mahler D., Wells C. Evaluation of clinical methods for rating dyspnea. Chest 1988; 93: 580–586.</mixed-citation><mixed-citation xml:lang="en">Mahler D., Wells C. Evaluation of clinical methods for rating dyspnea. Chest 1988; 93: 580–586.</mixed-citation></citation-alternatives></ref><ref id="cit57"><label>57</label><citation-alternatives><mixed-citation xml:lang="ru">Jones P.W., Harding G., Berry P. et al. Development and first validation of the COPD Assessment Test. Eur. Respir. J. 2009; 34 (3): 648–654.</mixed-citation><mixed-citation xml:lang="en">Jones P.W., Harding G., Berry P. et al. Development and first validation of the COPD Assessment Test. Eur. Respir. J. 2009; 34 (3): 648–654.</mixed-citation></citation-alternatives></ref><ref id="cit58"><label>58</label><citation-alternatives><mixed-citation xml:lang="ru">Calverley P.M.A., Fabbri L.M., Rabe K.F., Mosberg H. Roflumilast in the treatment of COPD: a pooled safety analysis. In: Presented at the European Respiratory Society annual congress, Barcelona, Spain 18–22 Sept., 2010: Barcelona; 2010. Poster 4732.</mixed-citation><mixed-citation xml:lang="en">Calverley P.M.A., Fabbri L.M., Rabe K.F., Mosberg H. Roflumilast in the treatment of COPD: a pooled safety analysis. In: Presented at the European Respiratory Society annual congress, Barcelona, Spain 18–22 Sept., 2010: Barcelona; 2010. Poster 4732.</mixed-citation></citation-alternatives></ref><ref id="cit59"><label>59</label><citation-alternatives><mixed-citation xml:lang="ru">Boswell*Smith V., Spina D. PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast. Int. J. Chron. Obstruct. Pulm. Dis. 2007; 2: 121–129.</mixed-citation><mixed-citation xml:lang="en">Boswell*Smith V., Spina D. PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast. Int. J. Chron. Obstruct. Pulm. Dis. 2007; 2: 121–129.</mixed-citation></citation-alternatives></ref><ref id="cit60"><label>60</label><citation-alternatives><mixed-citation xml:lang="ru">Rabe K.F. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br. J. Pharmacol. 2011; 163 (1): 53–67.</mixed-citation><mixed-citation xml:lang="en">Rabe K.F. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br. J. Pharmacol. 2011; 163 (1): 53–67.</mixed-citation></citation-alternatives></ref><ref id="cit61"><label>61</label><citation-alternatives><mixed-citation xml:lang="ru">Wouters E.F.M., Teichmann P., Brose M. et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2010; 181: A4473.</mixed-citation><mixed-citation xml:lang="en">Wouters E.F.M., Teichmann P., Brose M. et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2010; 181: A4473.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
