Xanthines and phosphodiesterase inhibitors

Handbook of Experimental Pharmacology

Volumn 237, Issue , 2016, Pages 63-91

  Spina, D ^a   Page, C P ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Adenosine receptor antagonism; Bamifylline; Doxofylline; HDAC; Phosphodiesterases; PI3 kinase; Theophylline

Indexed keywords

4 [2 [3 (CYCLOPENTYLOXY) 4 METHOXYPHENYL] 2 PHENYLETHYL]PYRIDINE; 6 [3 (DIMETHYLCARBAMOYL)PHENYLSULFONYL] 4 (3 METHOXYANILINO) 8 METHYL 3 QUINOLINECARBOXAMIDE; ACICLOVIR; ADENOSINE RECEPTOR; ALLOPURINOL; AMINOPHYLLINE; BAMIFYLLINE; BECLOMETASONE DIPROPIONATE; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CHF 6001; CILOMILAST; CORTICOSTEROID; DOXOFYLLINE; ENPROFYLLINE; ERYTHROMYCIN; FLUCONAZOLE; HISTONE DEACETYLASE; PENTOXIFYLLINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHODIESTERASE; PHOSPHODIESTERASE INHIBITOR; PICLAMILAST; PLACEBO; PROPAFENONE; ROFLUMILAST; RPL 554; THEOPHYLLINE; UK 500501; UNCLASSIFIED DRUG; UNINDEXED DRUG; XANTHINE DERIVATIVE; PHOSPHODIESTERASE IV INHIBITOR;

AIRWAY OBSTRUCTION; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ASTHMA; BRAIN DAMAGE; BRONCHODILATATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIAPHRAGM MOVEMENT; DIARRHEA; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG COMPETITION; DRUG CONTRAINDICATION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG FATALITY; DRUG HALF LIFE; DRUG INDICATION; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG SENSITIVITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; DYSPNEA; ENZYME ACTIVITY; ENZYME INHIBITION; FIRST PASS EFFECT; FOOD; FOOD DRUG INTERACTION; GASTROINTESTINAL SYMPTOM; HEADACHE; HUMAN; IC50; IMMUNOMODULATION; INSOMNIA; IRRITABILITY; LOW DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NONHUMAN; SEIZURE; SIDE EFFECT; SINGLE DRUG DOSE; VOMITING; WEIGHT REDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CONTRAINDICATIONS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

ANIMALS; ASTHMA; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHODIESTERASE 4 INHIBITORS; PHOSPHODIESTERASE INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; THEOPHYLLINE; XANTHINES;

EID: 85013836618     PISSN: 01712004     EISSN: 18650325     Source Type: Book Series    
DOI: 10.1007/164_2016_71     Document Type: Chapter

References (148)

1. 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
2. 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
3. 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
4. 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
5. 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
6. Aubier M, Roussos C (1985) Effect of theophylline on respiratory muscle function. Chest 88:91S- 97S
7. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C (1981) Aminophylline improves diaphragmatic contractility. N Engl J Med 305:249-252
8. 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
9. Banner KH, Hoult JR, Taylor MN, Landells LJ, Page CP (1999) Possible contribution of Prosta- glandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononu- clear cells. Biochem Pharmacol 58:1487-1495
10. 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
11. Barnes PJ (2011) Glucocorticosteroids: current and future directions. Br J Pharmacol 163:29-43
12. Barnes PJ, Jonsson B, Klim JB (1996) The costs of asthma. Eur Respir J 9:636-642
13. 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
14. 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
15. 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
16. Boswell-Smith V, Cazzola M, Page CP (2006a) Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 117:1237-1243
17. Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP (2006b) The pharma- cology 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
18. Brenner M, Berkowitz R, Marshall N, Strunk RC (1988) Need for theophylline in severe steroid- requiring asthmatics. Clin Allergy 18:143-150
19. 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
20. Calzetta L, Spina D, Cazzola M, Page CP, Facciolo F, Rendina EA, Matera MG (2011) Pharma- cological characterization of adenosine receptors on isolated human bronchi. Am J Respir Cell Mol Biol 45:1222-1231
21. 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
22. 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
23. 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
24. 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
25. 0-monophosphate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma. Pulm Pharmacol 2:147-154
26. 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
27. 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
28. 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
29. 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
30. 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
31. 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
32. 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
33. 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
34. 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
35. 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
36. Dennis RJ, Solarte I (2011) Asthma in adults. Clin Evid (Online) 2011:1512-1572
37. Dowling RB, Johnson M, Cole PJ, Wilson R (1997) The effect of rolipram, a type IV phosphodi- esterase inhibitor, on Pseudomonas aeruginosa infection of respiratory mucosa. J Pharmacol Exp Ther 282:1565-1571
38. 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
39. 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
40. Eldridge FL, Millhorn DE, Kiley JP (1985) Antagonism by theophylline of respiratory inhibition induced by adenosine. J Appl Physiol 59:1428-1433
41. 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
42. 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
43. 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
44. 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
45. Feske S, Skolnik EY, Prakriya M (2012) Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12:532-547
46. 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
47. 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
48. 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
49. 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
50. Foxworth JW, Reisz GR, Knudson SM, Cuddy PG, Pyszczynski DR, Emory CE (1988) Theoph- ylline and diaphragmatic contractility. Investigation of a dose-response relationship. Am Rev Respir Dis 138:1532-1534
51. 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
52. 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
53. 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
54. 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
55. 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
56. 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
57. 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
58. 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
59. 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
60. 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
61. Hendeles L, Massanari M, Weinberger M (1985) Update on the pharmacodynamics and pharma- cokinetics of theophylline. Chest 88:103S-111S
62. 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
63. 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
64. 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
65. 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
66. 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
67. 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
68. 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
69. Kelloway JS, Wyatt RA, Adlis SA (1994) Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 154:1349-1352
70. 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
71. 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
72. 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
73. 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
74. 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
75. 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
76. Levy RD, Nava S, Gibbons L, Bellemare F (1990) Aminophylline and human diaphragm strength in vivo. J Appl Physiol (1985) 68:2591-2596
77. 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
78. Lloyd CM, Hessel EM (2010) Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol 10:838-848
79. 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
80. 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
81. Mahler DA (1987) The role of theophylline in the treatment of dyspnea in COPD. Chest 92:2S-6S
82. 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
83. 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
84. 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
85. 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
86. McIvor RA, Tunks M, Todd DC (2011) Copd. Clin Evid (Online) 2011:1502-1602
87. 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
88. Moxham J, Miller J, Wiles CM, Morris AJ, Green M (1985) Effect of aminophylline on the human diaphragm. Thorax 40:288-292
89. 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
90. 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
91. 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
92. 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
93. Nicholson CD, Shahid M (1994) Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes-- their potential utility in the therapy of asthma. Pulm Pharmacol 7:1-17
94. 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
95. 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
96. 0-adenosine monophosphate. Am Rev Respir Dis 137:25-30
97. Nyce JW, Metzger WJ (1997) DNA antisense therapy for asthma in an animal model. Nature 385:721-725
98. Ohta K, Yamashita N (1999) Apoptosis of eosinophils and lymphocytes in allergic inflammation. J Allergy Clin Immunol 104:14-21
99. Page CP (2014) Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 165:152-164
100. Page C, Cazzola M (2014) Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease. Eur Respir J 44:475-482
101. Page CP, Spina D (2011) Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol: 391-414
102. Page CP, Spina D (2012) Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol 12:275-286
103. 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
104. 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
105. 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
106. 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
107. 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
108. 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
109. 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
110. Rabe KF, Magnussen H, Dent G (1995) Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 8:637-642
111. 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
112. 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
113. 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
114. +2 release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch Biochem Biophys 267:75-86
115. 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
116. Seddon P, Bara A, Ducharme FM, Lasserson TJ (2006) Oral xanthines as maintenance treatment for asthma in children. Cochrane Database Syst Rev: CD002885
117. Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ (2011) Histone deacetylases as regulators of inflammation and immunity. Trends Immunol 32:335-343
118. Sin DD, McAlister FA, Man SF, Anthonisen NR (2003) Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 290:2301-2312
119. Singh D, Petavy F, Macdonald AJ, Lazaar AL, O’Connor BJ (2010) The inhaled phosphodiester- ase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 11:26-35
120. 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
121. 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
122. Spina D, Landells LJ, Page CP (1998) The role of phosphodiesterase enzymes in allergy and asthma. Adv Pharmacol 44:33-89
123. 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
124. Supinski GS, Deal EC Jr, Kelsen SG (1984) The effects of caffeine and theophylline on diaphragm contractility. Am Rev Respir Dis 130:429-433
125. 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
126. 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 pneumo- coccal pneumonia reduces inflammation and lung injury in mice. Am J Respir Cell Mol Biol 55:24-34
127. 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
128. 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 pharmacokinet- ics. Handb Exp Pharmacol: 85-119
129. 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
130. 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
131. Tsai SC, Seto E (2002) Regulation of histone deacetylase 2 by protein kinase CK2. J Biol Chem 277:31826-31833
132. 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
133. Upton RA (1991a) Pharmacokinetic interactions between theophylline and other medication (Part I). Clin Pharmacokinet 20:66-80
134. Upton RA (1991b) Pharmacokinetic interactions between theophylline and other medication (Part II). Clin Pharmacokinet 20:135-150
135. 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
136. 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
137. 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
138. 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
139. Ward AJ, McKenniff M, Evans JM, Page CP, Costello JF (1993) Theophylline--an immunomod- ulatory role in asthma? Am Rev Respir Dis 147:518-523
140. Waterhouse JC, Pritchard SM, Howard P (1993) Hyperinflation, trapped gas and theophylline in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 48:126-129
141. 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
142. 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
143. Weinberger M, Hendeles L (1996) Theophylline in asthma. N Engl J Med 334:1380-1388
144. 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
145. 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
146. 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
147. Wymann MP, Zvelebil M, Laffargue M (2003) Phosphoinositide 3-kinase signalling--which way to target? Trends Pharmacol Sci 24:366-376
148. 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