Skip to main content
SpringerLink
Log in
Book cover

Pharmacology and Therapeutics of Asthma and COPD pp 63–91Cite as

Xanthines and Phosphodiesterase Inhibitors

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 237))

Abstract

Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug–drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.

More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abbott-Banner KH, Page CP (2014) Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol 114:365–376

    Article  CAS  PubMed  Google Scholar 

  • Adenuga D, Rahman I (2010) Protein kinase CK2-mediated phosphorylation of HDAC2 regulates co-repressor formation, deacetylase activity and acetylation of HDAC2 by cigarette smoke and aldehydes. Arch Biochem Biophys 498:62–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adenuga D, Yao H, March TH, Seagrave J, Rahman I (2009) Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol 40:464–473

    Article  CAS  PubMed  Google Scholar 

  • Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007–1011

    Article  CAS  PubMed  Google Scholar 

  • Ashutosh K, Sedat M, Fragale-Jackson J (1997) Effects of theophylline on respiratory drive in patients with chronic obstructive pulmonary disease. J Clin Pharmacol 37:1100–1107

    Article  CAS  PubMed  Google Scholar 

  • Aubier M, Roussos C (1985) Effect of theophylline on respiratory muscle function. Chest 88:91S–97S

    Article  CAS  PubMed  Google Scholar 

  • Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C (1981) Aminophylline improves diaphragmatic contractility. N Engl J Med 305:249–252

    Article  CAS  PubMed  Google Scholar 

  • Aubier M, Neukirch C, Maachi M, Boucara D, Engelstatter R, Steinijans V, Samoyeau R, Dehoux M (1998) Effect of slow-release theophylline on nasal antigen challenge in subjects with allergic rhinitis. Eur Respir J 11:1105–1110

    Article  CAS  PubMed  Google Scholar 

  • Banner KH, Hoult JR, Taylor MN, Landells LJ, Page CP (1999) Possible contribution of Prostaglandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononuclear cells. Biochem Pharmacol 58:1487–1495

    Article  CAS  PubMed  Google Scholar 

  • Barlinski J, Lockhart A, Frossard N (1992) Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi. Eur Respir J 5:1201–1205

    CAS  PubMed  Google Scholar 

  • Barnes PJ (2011) Glucocorticosteroids: current and future directions. Br J Pharmacol 163:29–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes PJ, Jonsson B, Klim JB (1996) The costs of asthma. Eur Respir J 9:636–642

    Article  CAS  PubMed  Google Scholar 

  • Bel EH, Timmers MC, Zwinderman AH, Dijkman JH, Sterk PJ (1991a) The effect of inhaled corticosteroids on the maximal degree of airway narrowing to methacholine in asthmatic subjects. Am Rev Respir Dis 143:109–113

    Article  CAS  PubMed  Google Scholar 

  • Bel EH, Zwinderman AH, Timmers MC, Dijkman JH, Sterk PJ (1991b) The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease. Thorax 46:9–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjorck T, Gustafsson LE, Dahlen SE (1992) Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am Rev Respir Dis 145:1087–1091

    Article  CAS  PubMed  Google Scholar 

  • Boswell-Smith V, Cazzola M, Page CP (2006a) Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 117:1237–1243

    Article  CAS  PubMed  Google Scholar 

  • Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP (2006b) The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]i soquinolin-4-one]. J Pharmacol Exp Ther 318:840–848

    Article  CAS  PubMed  Google Scholar 

  • Brenner M, Berkowitz R, Marshall N, Strunk RC (1988) Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 18:143–150

    Article  CAS  PubMed  Google Scholar 

  • Brown RA, Clarke GW, Ledbetter CL, Hurle MJ, Denyer JC, Simcock DE, Coote JE, Savage TJ, Murdoch RD, Page CP, Spina D, O’Connor BJ (2008) Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects. Eur Respir J 31:311–319

    Article  CAS  PubMed  Google Scholar 

  • Calzetta L, Spina D, Cazzola M, Page CP, Facciolo F, Rendina EA, Matera MG (2011) Pharmacological characterization of adenosine receptors on isolated human bronchi. Am J Respir Cell Mol Biol 45:1222–1231

    Article  CAS  PubMed  Google Scholar 

  • Calzetta L, Page CP, Spina D, Cazzola M, Rogliani P, Facciolo F, Matera MG (2013) Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 346:414–423

    Article  CAS  PubMed  Google Scholar 

  • Calzetta L, Cazzola M, Page CP, Rogliani P, Facciolo F, Matera MG (2015) Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways. Pulm Pharmacol Ther 32:15–23

    Article  CAS  PubMed  Google Scholar 

  • Cazzola M, Calzetta L, Rogliani P, Matera MG (2016) The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Discov 11:733–744

    Article  CAS  PubMed  Google Scholar 

  • Chappe V, Mettey Y, Vierfond JM, Hanrahan JW, Gola M, Verrier B, Becq F (1998) Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel. Br J Pharmacol 123:683–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clarke H, Cushley MJ, Persson CG, Holgate ST (1989) The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 5′-monophosphate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma. Pulm Pharmacol 2:147–154

    Article  CAS  PubMed  Google Scholar 

  • Cockcroft DW, Murdock KY, Gore BP, O’Byrne PM, Manning P (1989) Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine. J Allergy Clin Immunol 83:913–920

    Article  CAS  PubMed  Google Scholar 

  • Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, Ayres JG, Creemers JP, Schultze-Werninghaus G, Brambilla C, Barnes NC (2001) Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 358:265–270

    Article  CAS  PubMed  Google Scholar 

  • Cortijo J, Bou J, Beleta J, Cardelus I, Llenas J, Morcillo E, Gristwood RW (1993) Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus. Br J Pharmacol 108:562–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crescioli S, Spinazzi A, Plebani M, Pozzani M, Mapp CE, Boschetto P, Fabbri LM (1991) Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. Ann Allergy 66:245–251

    CAS  PubMed  Google Scholar 

  • Crescioli S, de Marzo N, Boschetto P, Spinazzi A, Plebani M, Mapp CE, Fabbri LM, Ciaccia A (1992) Theophylline inhibits late asthmatic reactions induced by toluene diisocyanate in sensitised subjects. Eur J Pharmacol 228:45–50

    CAS  PubMed  Google Scholar 

  • Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ (2002) Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 165:1371–1376

    Article  PubMed  Google Scholar 

  • D’Alonzo GE, Smolensky MH, Feldman S, Gianotti LA, Emerson MB, Staudinger H, Steinijans VW (1990) Twenty-four hour lung function in adult patients with asthma. Chronoptimized theophylline therapy once-daily dosing in the evening versus conventional twice-daily dosing. Am Rev Respir Dis 142:84–90

    Article  PubMed  Google Scholar 

  • De Backer W, Vos W, Van Holsbeke C, Vinchurkar S, Claes R, Hufkens A, Parizel PM, Bedert L, De Backer J (2014) The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients. Eur Respir J 44:527–529

    Article  PubMed  CAS  Google Scholar 

  • De Monchy JG, Kauffman HF, Venge P, Koeter GH, Jansen HM, Sluiter HJ, de Vries K (1985) Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 131:373–376

    PubMed  Google Scholar 

  • DeGarmo C, Cerny F, Conboy K, Ellis EF (1988) In vivo effects of theophylline on diaphragm, bicep, and quadricep strength and fatigability. J Allergy Clin Immunol 82:1041–1046

    Article  CAS  PubMed  Google Scholar 

  • Dennis RJ, Solarte I (2011) Asthma in adults. Clin Evid (Online) 2011:1512–1572

    Google Scholar 

  • Dowling RB, Johnson M, Cole PJ, Wilson R (1997) The effect of rolipram, a type IV phosphodiesterase inhibitor, on Pseudomonas aeruginosa infection of respiratory mucosa. J Pharmacol Exp Ther 282:1565–1571

    CAS  PubMed  Google Scholar 

  • Dubuis E, Wortley MA, Grace MS, Maher SA, Adcock JJ, Birrell MA, Belvisi MG (2014) Theophylline inhibits the cough reflex through a novel mechanism of action. J Allergy Clin Immunol 133:1588–1598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Hashim A, D’Agostino B, Matera MG, Page C (1996) Characterization of adenosine receptors involved in adenosine-induced bronchoconstriction in allergic rabbits. Br J Pharmacol 119:1262–1268

    Article  PubMed  PubMed Central  Google Scholar 

  • Eldridge FL, Millhorn DE, Kiley JP (1985) Antagonism by theophylline of respiratory inhibition induced by adenosine. J Appl Physiol 59:1428–1433

    CAS  PubMed  Google Scholar 

  • Etlik O, Sakarya ME, Uzun K, Harman M, Temizoz O, Durmus A (2004) Demonstrating the effect of theophylline treatment on diaphragmatic movement in chronic obstructive pulmonary disease patients by MR-fluoroscopy. Eur J Radiol 51:150–154

    Article  PubMed  Google Scholar 

  • Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ (1997) A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 337:1412–1418

    Article  CAS  PubMed  Google Scholar 

  • Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 374:695–703

    Article  CAS  PubMed  Google Scholar 

  • Feoktistov I, Biaggioni I (1995) Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 96:1979–1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feske S, Skolnik EY, Prakriya M (2012) Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12:532–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST (1996) Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 9:1672–1677

    Article  CAS  PubMed  Google Scholar 

  • Finney MJ, Karlsson JA, Persson CG (1985) Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol 85:29–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ (2010) Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137:1338–1344

    Article  CAS  PubMed  Google Scholar 

  • Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR (2002) Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem 277:37124–37130

    Article  CAS  PubMed  Google Scholar 

  • Foxworth JW, Reisz GR, Knudson SM, Cuddy PG, Pyszczynski DR, Emory CE (1988) Theophylline and diaphragmatic contractility. Investigation of a dose-response relationship. Am Rev Respir Dis 138:1532–1534

    Article  CAS  PubMed  Google Scholar 

  • Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker MJ, Page CP (2013) Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med 1:714–727

    Article  CAS  PubMed  Google Scholar 

  • Gamble E, Pavord ID, Vignola AM, Kroegel C, Morell F, Hansel TT, Compton C, Troy S, Edelson JE, Amit O, Tat T, Rabe KF, Barnes NC, Jeffery PK (2001) Cilomilast reduces CD8+ T-lymphocytes and macrophages in patients with chronic obstructive pulmonary disease (COPD): a double-blind placebo-controlled, parallel-group quantitative study of bronchial biopsies. Eur Respir J 17:P2238

    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 (2003) Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168:976–982

    Article  PubMed  Google Scholar 

  • Gauthier AP, Yan S, Sliwinski P, Macklem PT (1995) Effects of fatigue, fiber length, and aminophylline on human diaphragm contractility. Am J Respir Crit Care Med 152:204–210

    Article  CAS  PubMed  Google Scholar 

  • Gauvreau GM, Boulet LP, Schmid-Wirlitsch C, Cote J, Duong M, Killian KJ, Milot J, Deschesnes F, Strinich T, Watson RM, Bredenbroker D, O’Byrne PM (2011) Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects. Respir Res 12:140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gigliotti F, Spinelli A, Lo Conte C, Duranti R, Gorini M, Scano G (1987) Effects of aminophylline on respiratory drive and neuromuscular coupling in normal man and in patients with chronic airflow obstruction. Eur J Clin Pharmacol 33:231–236

    Article  CAS  PubMed  Google Scholar 

  • Goldie RG, Spina D, Henry PJ, Lulich KM, Paterson JW (1986) In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline. Br J Clin Pharmacol 22:669–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorini M, Duranti R, Misuri G, Valenza T, Spinelli A, Goti P, Gigliotti F, Scano G (1994) Aminophylline and respiratory muscle interaction in normal humans. Am J Respir Crit Care Med 149:1227–1234

    Article  CAS  PubMed  Google Scholar 

  • Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62:1081–1087

    Article  PubMed  PubMed Central  Google Scholar 

  • Harbinson PL, MacLeod D, Hawksworth R, O’Toole S, Sullivan PJ, Heath P, Kilfeather S, Page CP, Costello J, Holgate ST, Lee TH (1997) The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 10:1008–1014

    Article  CAS  PubMed  Google Scholar 

  • Hendeles L, Massanari M, Weinberger M (1985) Update on the pharmacodynamics and pharmacokinetics of theophylline. Chest 88:103S–111S

    Article  CAS  PubMed  Google Scholar 

  • Hendeles L, Harman E, Huang D, O’Brien R, Blake K, Delafuente J (1995) Theophylline attenuation of airway responses to allergen: comparison with cromolyn metered-dose inhaler. J Allergy Clin Immunol 95:505–514

    Article  CAS  PubMed  Google Scholar 

  • Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049–1053

    Article  CAS  PubMed  Google Scholar 

  • Huang WC, Chen CC (2005) Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. Mol Cell Biol 25:6592–6602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 99:8921–8926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaffar ZH, Sullivan P, Page CP, Costello J (1996) Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 9:456–462

    Article  CAS  PubMed  Google Scholar 

  • Jonker GJ, Tijhuis GJ, de Monchey JGR (1996) RP 73401 (a phosphodiesterase IV inhibitor) single does not prevent allergen induced bronchoconstriction during the early phase reaction in asthmatics. Eur Respir J 9:82s

    Google Scholar 

  • Kasetty G, Papareddy P, Bhongir RK, Egesten A (2016) Roflumilast increases bacterial load and dissemination in a model of Pseudomononas aeruginosa airway infection. J Pharmacol Exp Ther 357:66–72

    Article  CAS  PubMed  Google Scholar 

  • Kelloway JS, Wyatt RA, Adlis SA (1994) Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 154:1349–1352

    Article  CAS  PubMed  Google Scholar 

  • Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ (1995) Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 151:1907–1914

    Article  CAS  PubMed  Google Scholar 

  • Kongragunta VR, Druz WS, Sharp JT (1988) Dyspnea and diaphragmatic fatigue in patients with chronic obstructive pulmonary disease. Responses to theophylline. Am Rev Respir Dis 137:662–667

    Article  CAS  PubMed  Google Scholar 

  • Kosmas EN, Michaelides SA, Polychronaki A, Roussou T, Toukmatzi S, Polychronopoulos V, Baxevanis CN (1999) Theophylline induces a reduction in circulating interleukin-4 and interleukin-5 in atopic asthmatics. Eur Respir J 13:53–58

    CAS  PubMed  Google Scholar 

  • Kraft M, Pak J, Borish L, Martin RJ (1996a) Theophylline’s effect on neutrophil function and the late asthmatic response. J Allergy Clin Immunol 98:251–257

    Article  CAS  PubMed  Google Scholar 

  • Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ (1996b) Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 97:1242–1246

    Article  CAS  PubMed  Google Scholar 

  • Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD (2006) Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J 20:455–465

    Article  CAS  PubMed  Google Scholar 

  • Levy RD, Nava S, Gibbons L, Bellemare F (1990) Aminophylline and human diaphragm strength in vivo. J Appl Physiol (1985) 68:2591–2596

    CAS  Google Scholar 

  • Lim S, Tomita K, Caramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Chung KF, Barnes PJ (2001) Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 164:273–276

    Article  CAS  PubMed  Google Scholar 

  • Lloyd CM, Hessel EM (2010) Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol 10:838–848

    Article  CAS  PubMed  Google Scholar 

  • Magnussen H, Reuss G, Jorres R (1987) Theophylline has a dose-related effect on the airway response to inhaled histamine and methacholine in asthmatics. Am Rev Respir Dis 136:1163–1167

    Article  CAS  PubMed  Google Scholar 

  • Magnussen H, Reuss G, Jorres R (1988) Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentration and in a dose-dependent fashion. J Allergy Clin Immunol 81:531–537

    Article  CAS  PubMed  Google Scholar 

  • Mahler DA (1987) The role of theophylline in the treatment of dyspnea in COPD. Chest 92:2S–6S

    Article  CAS  PubMed  Google Scholar 

  • Mapp C, Boschetto P, dal Vecchio L, Crescioli S, de Marzo N, Paleari D, Fabbri LM (1987) Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. Am Rev Respir Dis 136:1403–1407

    Google Scholar 

  • Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF (2015) Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 385:857–866

    Article  CAS  PubMed  Google Scholar 

  • Marwick JA, Caramori G, Stevenson CS, Casolari P, Jazrawi E, Barnes PJ, Ito K, Adcock IM, Kirkham PA, Papi A (2009) Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 179:542–548

    Article  CAS  PubMed  Google Scholar 

  • Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13:290–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McIvor RA, Tunks M, Todd DC (2011) Copd. Clin Evid (Online) 2011:1502–1602

    Google Scholar 

  • Moonen HJ, Geraets L, Vaarhorst A, Bast A, Wouters EF, Hageman GJ (2005) Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells. Biochem Biophys Res Commun 338:1805–1810

    Article  CAS  PubMed  Google Scholar 

  • Moxham J, Miller J, Wiles CM, Morris AJ, Green M (1985) Effect of aminophylline on the human diaphragm. Thorax 40:288–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulloy E, McNicholas WT (1993) Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 148:1030–1036

    Article  CAS  PubMed  Google Scholar 

  • Murciano D, Aubier M, Lecocguic Y, Pariente R (1984) Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 311:349–353

    Article  CAS  PubMed  Google Scholar 

  • Murciano D, Aubier M, Viires N, Mal H, Pariente R (1987) Effects of theophylline and enprofylline on diaphragmatic contractility. J Appl Physiol (1985) 63:51–57

    CAS  Google Scholar 

  • Murciano D, Auclair MH, Pariente R, Aubier M (1989) A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 320:1521–1525

    Article  CAS  PubMed  Google Scholar 

  • Nicholson CD, Shahid M (1994) Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes-- their potential utility in the therapy of asthma. Pulm Pharmacol 7:1–17

    Article  CAS  PubMed  Google Scholar 

  • Nicholson CD, Challiss RA, Shahid M (1991) Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci 12:19–27

    Article  CAS  PubMed  Google Scholar 

  • Nielson CP, Crowley JJ, Cusack BJ, Vestal RE (1986) Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation. J Allergy Clin Immunol 78:660–667

    Article  CAS  PubMed  Google Scholar 

  • Nielson CP, Crowley JJ, Morgan ME, Vestal RE (1988) Polymorphonuclear leukocyte inhibition by therapeutic concentrations of theophylline is mediated by cyclic-3′,5′-adenosine monophosphate. Am Rev Respir Dis 137:25–30

    Article  CAS  PubMed  Google Scholar 

  • Nyce JW, Metzger WJ (1997) DNA antisense therapy for asthma in an animal model. Nature 385:721–725

    Article  CAS  PubMed  Google Scholar 

  • Ohta K, Yamashita N (1999) Apoptosis of eosinophils and lymphocytes in allergic inflammation. J Allergy Clin Immunol 104:14–21

    Article  CAS  PubMed  Google Scholar 

  • Page CP (2014) Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 165:152–164

    Article  CAS  PubMed  Google Scholar 

  • Page C, Cazzola M (2014) Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease. Eur Respir J 44:475–482

    Article  CAS  PubMed  Google Scholar 

  • Page CP, Spina D (2011) Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol: 391–414

    Google Scholar 

  • Page CP, Spina D (2012) Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol 12:275–286

    Article  CAS  PubMed  Google Scholar 

  • Page CP, Cotter T, Kilfeather S, Sullivan P, Spina D, Costello JF (1998) Effect of chronic theophylline treatment on the methacholine dose-response curve in allergic asthmatic subjects. Eur Respir J 12:24–29

    Article  CAS  PubMed  Google Scholar 

  • Pauwels R, van Renterghem D, van der Straeten M, Johannesson N, Persson CG (1985) The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol 76:583–590

    Article  CAS  PubMed  Google Scholar 

  • Persson CGA, Pauwels R (1991) Pharmacology of anti-asthma xanthines. In: Page CP, Barnes PJ (eds) Pharmacology of asthma. Springer-Verlag, Berlin, pp 207–225

    Chapter  Google Scholar 

  • Peterson TC, Slysz G, Isbrucker R (1998) The inhibitory effect of ursodeoxycholic acid and pentoxifylline on platelet derived growth factor-stimulated proliferation is distinct from an effect by cyclic AMP. Immunopharmacology 39:181–191

    Article  CAS  PubMed  Google Scholar 

  • Phillips P, Bennetts M, Banner K, Ward J, Wessels D, Fuhr R (2007) The PDE4 inhibitor UK-500,001 does not significantly inhibit airway responses to allergen and histamine. Eur Resp J: 490s

    Google Scholar 

  • Puri KD, Doggett TA, Douangpanya J, Hou Y, Tino WT, Wilson T, Graf T, Clayton E, Turner M, Hayflick JS, Diacovo TG (2004) Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. Blood 103:3448–3456

    Article  CAS  PubMed  Google Scholar 

  • Rabe KF, Tenor H, Dent G, Schudt C, Liebig S, Magnussen H (1993) Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Physiol 264:L458–L464

    CAS  PubMed  Google Scholar 

  • Rabe KF, Magnussen H, Dent G (1995) Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 8:637–642

    CAS  PubMed  Google Scholar 

  • Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbroker D, Bethke TD (2005) Roflumilast--an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366:563–571

    Article  CAS  PubMed  Google Scholar 

  • Rennard S, Knobil K, Rabe KF, Morris A, Schachter N, Locantore N, Canonica WG, Zhu Y, Barnhart F (2008) The efficacy and safety of cilomilast in COPD. Drugs 68(Suppl 2):3–57

    Article  CAS  PubMed  Google Scholar 

  • Reynolds SM, Docherty R, Robbins J, Spina D, Page CP (2008) Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A1 receptor-dependent mechanism. J Appl Physiol 105:187–196

    Article  CAS  PubMed  Google Scholar 

  • Rousseau E, LaDine J, Liu Q-Y, Meissner G (1988) Activation of the Ca+2 release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch Biochem Biophys 267:75–86

    Article  CAS  PubMed  Google Scholar 

  • Schmidt DT, Watson N, Dent G, Ruhlmann E, Branscheid D, Magnussen H, Rabe KF (2000) The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. Br J Pharmacol 131:1607–1618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seddon P, Bara A, Ducharme FM, Lasserson TJ (2006) Oral xanthines as maintenance treatment for asthma in children. Cochrane Database Syst Rev: CD002885

    Google Scholar 

  • Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ (2011) Histone deacetylases as regulators of inflammation and immunity. Trends Immunol 32:335–343

    Article  CAS  PubMed  Google Scholar 

  • Sin DD, McAlister FA, Man SF, Anthonisen NR (2003) Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 290:2301–2312

    Article  CAS  PubMed  Google Scholar 

  • Singh D, Petavy F, Macdonald AJ, Lazaar AL, O’Connor BJ (2010) The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 11:26–35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Singh D, Leaker B, Boyce M, Nandeuil MA, Collarini S, Mariotti F, Santoro D, Barnes PJ (2016) A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients. Pulm Pharmacol Ther

    Google Scholar 

  • Soares AC, Souza DG, Pinho V, Vieira AT, Barsante MM, Nicoli JR, Teixeira M (2003) Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram. Br J Pharmacol 140:855–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spina D, Landells LJ, Page CP (1998) The role of phosphodiesterase enzymes in allergy and asthma. Adv Pharmacol 44:33–89

    Article  CAS  PubMed  Google Scholar 

  • Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma [published erratum appears in Lancet 1994 Jun 11; 343(8911):1512]. Lancet 343:1006–1008

    Article  CAS  PubMed  Google Scholar 

  • Supinski GS, Deal EC Jr, Kelsen SG (1984) The effects of caffeine and theophylline on diaphragm contractility. Am Rev Respir Dis 130:429–433

    CAS  PubMed  Google Scholar 

  • Takeuchi M, Tatsumi Y, Kitaichi K, Baba K, Suzuki R, Shibata E, Takagi K, Miyamoto K, Hasegawa T (2002) Selective phosphodiesterase type 4 inhibitors reduce the prolonged survival of eosinophils stimulated by granulocyte-macrophage colony-stimulating factor. Biol Pharm Bull 25:184–187

    Article  CAS  PubMed  Google Scholar 

  • Tavares LP, Garcia CC, Vago JP, Queiroz-Junior CM, Galvao I, David BA, Rachid MA, Silva PM, Russo RC, Teixeira MM, Sousa LP (2016) Inhibition of phosphodiesterase-4 during pneumococcal pneumonia reduces inflammation and lung injury in mice. Am J Respir Cell Mol Biol 55:24–34

    Article  CAS  PubMed  Google Scholar 

  • Tee AK, Koh MS, Gibson PG, Lasserson TJ, Wilson AJ, Irving LB (2007) Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev: CD001281

    Google Scholar 

  • Tenor H, Hatzelmann A, Beume R, Lahu G, Zech K, Bethke TD (2011) Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics. Handb Exp Pharmacol: 85–119

    Google Scholar 

  • Tinkelman DG, Reed CE, Nelson HS, Offord KP (1993) Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 92:64–77

    CAS  PubMed  Google Scholar 

  • To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliott WM, Hogg JC, Adcock IM, Barnes PJ (2010) Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 182:897–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai SC, Seto E (2002) Regulation of histone deacetylase 2 by protein kinase CK2. J Biol Chem 277:31826–31833

    Article  CAS  PubMed  Google Scholar 

  • Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW (1997) Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 10:2754–2760

    Article  CAS  PubMed  Google Scholar 

  • Upton RA (1991a) Pharmacokinetic interactions between theophylline and other medication (Part I). Clin Pharmacokinet 20:66–80

    Article  CAS  PubMed  Google Scholar 

  • Upton RA (1991b) Pharmacokinetic interactions between theophylline and other medication (Part II). Clin Pharmacokinet 20:135–150

    Article  CAS  PubMed  Google Scholar 

  • van Mastbergen J, Jolas T, Allegra L, Page CP (2012) The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism. Pulm Pharmacol Ther 25:55–61

    Article  PubMed  CAS  Google Scholar 

  • Vestbo J, Tan L, Atkinson G (2007) A 6 week study of the efficacy and safety of UK-500,001 dry powder for inhalation (DPI) in adults with chronic obstructive pulmonary disease (COPD). Eur Respir J: 612s

    Google Scholar 

  • Vos W, Hajian B, De Backer J, Van Holsbeke C, Vinchurkar S, Claes R, Hufkens A, Parizel PM, Bedert L, De Backer W (2016) Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA. Int J Chron Obstruct Pulmon Dis 11:263–271

    PubMed  PubMed Central  Google Scholar 

  • Wanke T, Merkle M, Zifko U, Formanek D, Lahrmann H, Grisold W, Zwick H (1994) The effect of aminophylline on the force-length characteristics of the diaphragm. Am J Respir Crit Care Med 149:1545–1549

    Article  CAS  PubMed  Google Scholar 

  • Ward AJ, McKenniff M, Evans JM, Page CP, Costello JF (1993) Theophylline--an immunomodulatory role in asthma? Am Rev Respir Dis 147:518–523

    Article  CAS  PubMed  Google Scholar 

  • Waterhouse JC, Pritchard SM, Howard P (1993) Hyperinflation, trapped gas and theophylline in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 48:126–129

    CAS  PubMed  Google Scholar 

  • Watz H, Mistry SJ, Lazaar AL, investigators IPC (2013) Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm Pharmacol Ther 26:588–595

    Google Scholar 

  • Wedzicha JA, Calverley PM, Rabe KF (2016) Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 11:81–90

    Article  PubMed  PubMed Central  Google Scholar 

  • Weinberger M, Hendeles L (1996) Theophylline in asthma. N Engl J Med 334:1380–1388

    Article  CAS  PubMed  Google Scholar 

  • Weinberger M, Hendeles L, Wong L (1981) Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma. J Pediatr 99:145–152

    Article  CAS  PubMed  Google Scholar 

  • White WB, Cooke GE, Kowey PR, Calverley PM, Bredenbroker D, Goehring UM, Zhu H, Lakkis H, Mosberg H, Rowe P, Rabe KF (2013) Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest 144:758–765

    Article  CAS  PubMed  Google Scholar 

  • Wouters EFM, Teichmann P, Brose M, Rabe KF, Fabbri LM (2010) Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 181:A4473

    Google Scholar 

  • Wymann MP, Zvelebil M, Laffargue M (2003) Phosphoinositide 3-kinase signalling--which way to target? Trends Pharmacol Sci 24:366–376

    Article  CAS  PubMed  Google Scholar 

  • Yasui K, Hu B, Nakazawa T, Agematsu K, Komiyama A (1997) Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J Clin Invest 100:1677–1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, Franklin Wilkins Building, London, SE1 9NH, UK

    D. Spina & C. P. Page

Authors
  1. D. Spina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. P. Page
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. P. Page .

Editor information

Editors and Affiliations

  1. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, United Kingdom

    Clive P. Page

  2. Airway Disease Section, Imperial College, National Heart and Lung Institute, London, United Kingdom

    Peter J. Barnes

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Spina, D., Page, C.P. (2016). Xanthines and Phosphodiesterase Inhibitors. In: Page, C., Barnes, P. (eds) Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, vol 237. Springer, Cham. https://doi.org/10.1007/164_2016_71

Download citation

Publish with us

Policies and ethics

Search

Navigation