Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases

F1000Prime Reports

Volumn 7, Issue , 2015, Pages

  Giembycz, Mark A ^a   Newton, Robert ^b  

^a UNIVERSITY OF CALGARY   (Canada)

^b UNIVERSITY OF CALGARY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CYCLIC AMP; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; LONG ACTING BETA 2 ADRENOCEPTOR AGONIST; PHOSPHODIESTERASE IV INHIBITOR; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL EFFECTIVENESS; CLINICAL TRIAL (TOPIC); CONCEPTUAL FRAMEWORK; CYTOKINE PRODUCTION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; INTRACELLULAR SIGNALING; LUNG FUNCTION; MONOTHERAPY; OUTCOME ASSESSMENT; PHARMACODYNAMICS; PHASE 4 CLINICAL TRIAL (TOPIC); PNEUMONIA; TREATMENT RESPONSE; UPREGULATION;

EID: 84922377451     PISSN: None     EISSN: 20517599     Source Type: Journal    
DOI: 10.12703/P7-16     Document Type: Article

References (103)

1. Bateman ED, Hurd SS, Barnes P.J., Bousquet J., Drazen JM, FitzGerald M, Gibson P, Ohta K., O'Byrne P, Pedersen SE, Pizzichini E, Sullivan S.D., Wenzel SE, Zar HJ: Global strategy for asthma management and prevention: GINA executive summary. The European respiratory journal 2008, 31:143-78.
2. 2-agonists and corticosteroids. The European respiratory journal 2002, 19:182-91.
3. Greening AP, Ind PW, Northfield M, Shaw G: Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994, 344:219-24.
4. Woolcock A, Lundback B, Ringdal N., Jacques LA: Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. American journal of respiratory and critical care medicine 1996, 153:1481-8.
5. Pauwels RA, Löfdahl CG, Postma D.S., Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A: Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. The New England journal of medicine 1997, 337:1405-1 1.
6. Arrowsmith J: A decade of change. Nature reviews. Drug discovery 2012, 11:17-8.
7. 2-adrenoceptor agonists: current and future direction. British journal of pharmacology 2011, 163:4-17.
8. 2-agonists for chronic obstructive pulmonary disease. The Cochrane database of systematic reviews 2012, 9:CD006829.
9. Kew KM, Dias S, Cates CJ: Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. The Cochrane database of systematic reviews 2014, 3:CD010844.
10. Barnes NC, Qiu Y, Pavord I.D., Parker D., Davis PA, Zhu J, Johnson M, Thomson N.C., Jeffery PK: Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. American journal of respiratory and critical care medicine 2006, 173:736-43.
11. Celli BR, Thomas NE, Anderson J.A., Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K., Yates JC, Calverley, Peter MA: Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. American journal of respiratory and critical care medicine 2008, 178:332-8.
12. Calverley P, Pauwels R, Vestbo J., Jones P, Pride N, Gulsvik A., Anderson J, Maden C: Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003, 361:449-56.
13. Rennard SI, Calverley, Peter MA, Goehring UM, Bredenbröker D, Martinez FJ: Reduction of exacerbations by the PDE4 inhibitor roflumilast-the importance of defining different subsets of patients with COPD. Respiratory research 2011, 12:18.
14. 2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. British journal of pharmacology 2008, 153:1090-104.
15. Chung KF, Caramori G, Adcock IM: Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. European journal of clinical pharmacology 2009, 65:853-71.
16. Newton R, Leigh R, Giembycz MA: Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases. Pharmacology & therapeutics 2010, 125:286-327.
17. Giembycz MA, Newton R: How phosphodiesterase 4 inhibitors work in patients with chronic obstructive pulmonary disease of the severe, bronchitic, frequent exacerbator phenotype. Clinics in chest medicine 2014, 35:203-17.
18. De Bosscher K, Vanden Berghe W, Haegeman G: The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocrine reviews 2003, 24:488-522.
19. Clark AR, Belvisi MG: Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor. Pharmacology & therapeutics 2012, 134:54-67.
20. Newton R, Holden NS: Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Molecular pharmacology 2007, 72:799-809.
21. Clark AR: Anti-inflammatory functions of glucocorticoid-induced genes. Molecular and cellular endocrinology 2007, 275:79-97.
22. King EM, Chivers JE, Rider C.F., Minnich A., Giembycz MA, Newton R: Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivation- and transrepression-dependent mechanisms. PloS one 2013, 8:e53936.
23. Kelly MM, King EM, Rider C.F., Gwozd C., Holden NS, Eddleston J, Zuraw B, Leigh R., O'Byrne PM, Newton R: Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide. British journal ofpharmacology 2012, 165:1737-47.
24. Abraham SM, Clark AR: Dual-specificity phosphatase 1: a critical regulator of innate immune responses. Biochemical Society transactions 2006, 34:1018-23.
25. 2-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells. Molecular pharmacology 2008, 73:203-14.
26. 2-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms. British journal ofpharmacology 2012, 166:2049-59.
27. 2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America 2011, 108:19713-8.
28. 2-adrenoceptor agonists and glucocorticoids in human airway epithelial cells. The Journal of pharmacology and experimental therapeutics 2014, 348:12-24.
29. Chivers JE, Gong W, King E.M., Seybold J., Mak JC, Donnelly LE, Holden NS, Newton R: Analysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoids. Molecular pharmacology 2006, 70:2084-95.
30. Wang JC, Derynck MK, Nonaka D.F., Khodabakhsh DB, Haqq C, Yamamoto KR: Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes. Proceedings of the National Academy of Sciences of the United States of America 2004, 101:15603-8.
31. Heximer SP, Watson N, Linder M.E., Blumer KJ, Hepler JR: RGS2/G0S8 is a selective inhibitor of Gqa function. Proceedings of the National Academy of Sciences of the United States of America 1997, 94:14389-93.
32. Heximer SP: RGS2-mediated regulation of Gqa. Methods in enzymology 2004, 390:65-82.
33. Xie Y, Jiang H, Nguyen H., Jia S, Berro A, Panettieri R.A., Wolff DW, Abel PW, Casale TB, Tu Y: Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness. The Journal of allergy and clinical immunology 2012, 130:968-76.e3.
34. Liu C, Li Q, Zhou X., Kolosov VP, Perelman JM: Regulator of G-protein signaling 2 inhibits acid-induced mucin5AC hypersecretion in human airway epithelial cells. Respiratory physiology & neurobiology 2013, 185:265-71.
35. Vásárhelyi V, Trexler M, Patthy L: Both LCCL-domains of human CRISPLD2 have high affinity for lipid A. Biochimie 2014, 97:66-71.
36. Wang Z, Xing W, Fan H., Wang K, Zhang H, Wang Q., Qi J, Yang H, Yang J., Ren Y, Cui S, Zhang X, Liu F, Lin D, Wang W, Hoffmann MK, Han Z: The novel lipopolysaccharide-binding protein CRISPLD2 is a critical serum protein to regulate endotoxin function. Journal of immunology (Baltimore, Md.: 1950) 2009, 183:6646-56.
37. Snelgrove RJ, Goulding J, Didierlaurent A.M., Lyonga D., Vekaria S, Edwards L, Gwyer E., Sedgwick JD, Barclay AN, Hussell T: A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nature immunology 2008, 9:1074-83.
38. Himes BE, Jiang X, Wagner P., Hu R, Wang Q, Klanderman B., Whitaker RM, Duan Q, Lasky-Su J, Nikolos C, Jester W., Johnson M, Panettieri RA, Tantisira KG, Weiss ST, Lu Q: RNA-Seq transcriptome profiling identifies CRISPLD2 as a glucocorticoid responsive gene that modulates cytokine function in airway smooth muscle cells. PloS one 2014, 9:e99625.
39. Moodley T, Wilson SM, Joshi T, Rider C.F., Sharma P., Yan D, Newton R, Giembycz MA: Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease. Molecular pharmacology 2013, 83:894-906.
40. Yeagley D, Quinn PG: 3',5'-cyclic adenosine monophosphate response element-binding protein and CCAAT enhancer-binding protein are dispensable for insulin inhibition of phosphoenolpyruvate carboxykinase transcription and for its synergistic induction by protein kinase A and glucocorticoids. Molecular endocrinology (Baltimore, Md.) 2005, 19:913-24.
41. Samuelsson MK, Pazirandeh A, Davani B., Okret S: p57Kip2, a glucocorticoid-induced inhibitor of cell cycle progression in HeLa cells. Molecular endocrinology (Baltimore, Md.) 1999, 13:1811-22.
42. 2-terminal kinase/stress-activated protein Kinase. The Journal of biological chemistry 2003, 278:48092-8.
43. 2-adrenoceptor agonists. The Journal of pharmacology and experimental therapeutics 2011, 338:860-9.
44. Rangarajan PN, Umesono K, Evans RM: Modulation of glucocorticoid receptor function by protein kinase A. Molecular endocrinology (Baltimore, Md.) 1992, 6:1451-7.
45. Gruol DJ, Altschmied J: Synergistic induction of apoptosis with glucocorticoids and 3',5'-cyclic adenosine monophosphate reveals agonist activity by RU 486. Molecular endocrinology (Baltimore, Md.) 1993, 7:104-13.
46. Moyer ML, Borror KC, Bona B.J., DeFranco DB, Nordeen SK: Modulation of cell signaling pathways can enhance or impair glucocorticoid-induced gene expression without altering the state of receptor phosphorylation. The Journal of biological chemistry 1993, 268:22933-40.
47. Zhang H, Li YC, Young AP: Protein kinase A activation of glucocorticoid-mediated signaling in the developing retina. Proceedings of the National Academy of Sciences of the United States of America 1993, 90:3880-4.
48. 2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. The Journal of biological chemistry 1999, 274:1005-10.
49. Usmani OS, Ito K, Maneechotesuwan K., Ito M, Johnson M, Barnes P.J., Adcock IM: Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. American journal of respiratory and critical care medicine 2005, 172:704-12.
50. 2-agonists in primary lung epithelial cells is independent of glucocorticoid receptor. The European respiratory journal 2007, 30:848-56.
51. Essilfie-Quaye S, Ito K, Ito M., Kharitonov SA, Barnes PJ: Comparison of Symbicort® versus Pulmicort® on steroid pharmacodynamic markers in asthma patients. Respiratory medicine 2011, 105:1784-9.
52. 2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD. The Journal of allergy and clinical immunology 2013, 132:1166-73.
53. 2-adrenoceptor agonists do not enhance glucocorticoid activity by increasing glucocorticoid receptor expression or translocation in BEAS-2B cells. Am J Respir Crit Care Med 2014, 189: A4890.
54. So AY, Cooper SB, Feldman B.J., Manuchehri M., Yamamoto KR: Conservation analysis predicts in vivo occupancy of glucocorticoid receptor-binding sequences at glucocorticoid-induced genes. Proceedings of the National Academy of Sciences of the United States of America 2008, 105:5745-9.
55. Xie Z, Liu D, Liu S., Calderon L, Zhao G, Turk J., Guo Z: Identification of a cAMP-response element in the regulator of G-protein signaling-2 (RGS2) promoter as a key cis-regulatory element for RGS2 transcriptional regulation by angiotensin II in cultured vascular smooth muscles. The Journal of biological chemistry 2011, 286:44646-58.
56. Rowan BG, Garrison N, Weigel N.L., O'Malley BW: 8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein. Molecular and cellular biology 2000, 20:8720-30.
57. Constantinescu A, Wu M, Asher O., Diamond I: cAMP-dependent protein kinase type I regulates ethanol-induced cAMP response element-mediated gene expression via activation of CREB-binding protein and inhibition of MAPK. The Journal of biological chemistry 2004, 279:43321-9.
58. Hoang T, Fenne IS, Cook C, Børud B, Bakke M, Lien EA, Mellgren G: cAMP-dependent protein kinase regulates ubiquitin-protea-some-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1. The Journal of biological chemistry 2004, 279:49120-30.
59. Fenne IS, Hoang T, Hauglid M., Sagen JV, Lien EA, Mellgren G: Recruitment of coactivator glucocorticoid receptor interacting protein 1 to an estrogen receptor transcription complex is regulated by the 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase. Endocrinology 2008, 149:4336-45.
60. Wagner BL, Norris JD, Knotts T.A., Weigel NL, McDonnell DP: The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Molecular and cellular biology 1998, 18:1369-78.
61. Chen L, Lei K, Malawana J., Yulia A, Sooranna SR, Bennett P.R., Liang Z., Grammatopoulos D, Johnson MR: Cyclic AMP enhances progesterone action in human myometrial cells. Molecular and cellular endocrinology 2014, 382:334-43.
62. Pujols L, Mullol J, Torrego A., Picado C: Glucocorticoid receptors in human airways. Allergy 2004, 59:1042-52.
63. Su AI, Wiltshire T, Batalov S., Lapp H, Ching KA, Block D, Zhang J., Soden R, Hayakawa M, Kreiman G., Cooke MP, Walker JR, Hogenesch JB: A gene atlas of the mouse and human protein-encoding transcriptomes. Proceedings of the National Academy of Sciences of the United States of America 2004, 101:6062-7.
64. Pujols L, Mullol J, Roca-Ferrer J, Torrego A., Xaubet A, Cidlowski JA, Picado C: Expression of glucocorticoid receptor alpha- and beta-isoforms in human cells and tissues. American journal of physiology. Cell physiology 2002, 283:C1324-31.
65. Zhang S, Jonklaas J, Danielsen M: The glucocorticoid agonist activities of mifepristone (RU486) and progesterone are dependent on glucocorticoid receptor levels but not on EC50 values. Steroids 2007, 72:600-8.
66. Zhao Q, Pang J, Favata M.F., Trzaskos JM: Receptor density dictates the behavior of a subset of steroid ligands in glucocorticoid receptor-mediated transrepression. International immunopharma-cology 2003, 3:1803-17.
67. Joshi T, Johnson M, Newton R., Giembycz MA: An analysis of glucocorticoid receptor-mediated gene expression in BEAS-2B human airway epithelial cells identifies distinct, ligand-directed, transcription profiles with implications for asthma therapeutics. British journal of pharmacology 2015.
68. Johnson M: Effects of beta2-agonists on resident and infiltrating inflammatory cells. The Journal of allergy and clinical immunology 2002, 110:S282-90.
69. Galant SP, Underwood S, Duriseti L., Insel PA: Characterization of high-affinity beta2-adrenergic receptor binding of (-)-[H]-dihydroalprenolol to human polymorphonuclear cell particulates. The Journal of laboratory and clinical medicine 1978, 92:613-8.
70. Martinsson A, Larsson K, Hjemdahl P: Studies in vivo and in vitro of terbutaline-induced beta-adrenoceptor desensitization in healthy subjects. Clinicalscience (London, England: 1979) 1987,72:47-54.
71. Yukawa T, Ukena D, Kroegel C., Chanez P, Dent G, Chung K.F., Barnes PJ: Beta2-adrenergic receptors on eosinophils. Binding and functional studies. The American review of respiratory disease 1990, 141:1446-52.
72. Rabe KF, Giembycz MA, Dent G, Perkins R.S., Evans P., Barnes PJ: Salmeterol is a competitive antagonist at beta-adrenoceptors mediating inhibition of respiratory burst in guinea-pig eosinophils. European journal of pharmacology 1993, 231:305-8.
73. Muñoz NM, Rabe KF, Vita A.J., McAllister K., Mayer D, Weiss M, Leff AR: Paradoxical blockade of beta adrenergically mediated inhibition of stimulated eosinophil secretion by salmeterol. The Journal of pharmacology and experimental therapeutics 1995, 273:850-4.
74. Rennard SI, Vestbo J: The many "small COPDs": COPD should be an orphan disease. Chest 2008, 134:623-7.
75. Vestbo J: COPD: definition and phenotypes. Clinics in chest medicine 2014, 35:1-6.
76. Miravitlles M, Soler-Cataluña JJ, Calle M, Molina J, Almagro P, Quintano JA, Trigueros JA, Piñera P, Simón A, Riesco JA, Ancochea J, Soriano JB: A new approach to grading and treating COPD based on clinical phenotypes: summary of the Spanish COPD guidelines (GesEPOC). Primary care respiratory journal: journal of the General Practice Airways Group 2013, 22:117-21.
77. Miravitlles M, Soler-Cataluña JJ, Calle M, Soriano JB: Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice. The European respiratory journal 2013, 41:1252-6.
78. Perera WR, Hurst JR, Wilkinson, TMA, Sapsford RJ, Müllerova H, Donaldson GC, Wedzicha JA: Inflammatory changes, recovery and recurrence at COPD exacerbation. The European respiratory journal 2007, 29:527-34.
79. Wedzicha JA, Brill SE, Allinson J.P., Donaldson GC: Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC medicine 2013, 11:181.
80. Calverley, Peter MA, Martinez FJ, Fabbri LM, Goehring U, Rabe KF: Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. International journal of chronic obstructive pulmonary disease 2012, 7:375-82.
81. Abbott-Banner KH, Page CP: Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic & clinical pharmacology & toxicology 2014, 114:365-76.
82. Boswell-Smith V, Spina D, Oxford A.W., Comer MB, Seeds EA, Page CP: 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]isoquinolin-4-one]. The Journal of pharmacology and experimental therapeutics 2006, 318:840-8.
83. Franciosi LG, Diamant Z, Banner K.H., Zuiker R., Morelli N, Kamerling, Ingrid MC, de Kam, Marieke L, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker, Michael JA, Page CP: 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. The Lancet Respiratory medicine 2013, 1:714-27.
84. 2-adrenoceptor agonist-iduced gene expression in human airway epithelial cells. Molecular pharmacology 2015, 87:64-76.
85. Nordeen SK, Moyer ML, Bona BJ: The coupling of multiple signal transduction pathways with steroid response mechanisms. Endocrinology 1994, 134:1723-32.
86. Ballard PL, Lee JW, Fang X, Chapin C., Allen L, Segal MR, Fischer H, Illek B., Gonzales LW, Kolla V, Matthay MA: Regulated gene expression in cultured type II cells of adult human lung. American journal of physiology. Lung cellular and molecular physiology 2010, 299:L36-50.
87. Gonzales LW, Guttentag SH, Wade K.C., Postle AD, Ballard PL: Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP. American journal of physiology. Lung cellular and molecular physiology 2002, 283:L940-51.
88. 2B and glucocorticoid receptors in human airway epithelial cells cooperatively induces genes with anti-inflammatory potential: a novel approach to treat chronic obstructive pulmonary disease. The Journal ofpharmacology and experimental therapeutics 2013, 346:473-85.
89. Wilson SM, Shen P, Rider C.F., Traves SL, Proud D, Newton R, Giembycz MA: Selective prostacyclin receptor agonism augments glucocorticoid-induced gene expression in human bronchial epithelial cells. Journal of immunology (Baltimore, Md.: 1950) 2009, 183:6788-99.
90. 2-agonist-induced Expression of Antiinflammatory MKP- in Airway Smooth Muscle Cells. American journal of respiratory cell and molecular biology 2014.
91. Theophilus A, Moore A, Prime D., Rossomanno S, Whitcher B, Chrystyn H: Co-deposition of salmeterol and fluticasone propionate by a combination inhaler. International journal of pharmaceutics 2006, 313:14-22.
92. Nelson HS, Chapman KR, Pyke S.D., Johnson M., Pritchard JN: Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. The Journal of allergy and clinical immunology 2003, 112:29-36.
93. Huchon G, Magnussen H, Chuchalin A., Dymek L, Gonod FB, Bousquet J: Lung function and asthma control with beclo-methasone and formoterol in a single inhaler. Respiratory medicine 2009, 103:41-9.
94. Testa B, Mayer JM: Design of intramolecularly activated prodrugs. Drug metabolism reviews 1998, 30:787-807.
95. Baker WR, Kim M, Phillips G., Rudolph A, Stasiak M: Corticosteroid beta-agonist-linked compounds for use in therapy. Gilead Sciences, Inc 2010, Patent number: WO/2010/126953.
96. Baker WR, Girton BC, Stasiak M: Substituted phenylphosphates as mutual pro-drugs of steroids and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction. Corus Pharma Inc., 2006, Patent number: WO/2006/138212.
97. Giembycz MA, Maurice DH: Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease. Current opinion in pharmacology 2014, 16:89-107.
98. Phillips G, Salmon M: From Bifunctional compounds for the treatment of COPD. In Annual reports in medicinal chemistry. Edited by Desai MC. Oxford: Elsevier; 2012:209-21.
99. Shonberg J, Scammells PJ, Capuano B: Design strategies for bivalent ligands targeting GPCRs. ChemMedChem 2011, 6:963-74.
100. Baker WR, Cai S, Kaplan J.A., Kim M., Loyer-Drew JA, Perrault S, Phillips G., Purvis LJ, Stasiak M, Steven KL, van Veldhuizen J: Bifunctional quinoline derivatives. Gilead Sciences, Inc., Patient number: WO/2011/143105.
101. Tralau-Stewart CJ, Williamson RA, Nials A.T., Gascoigne M., Dawson J, Hart GJ, Angell, Anthony DR, Solanke YE, Lucas FS, Wiseman J, Ward P, Ranshaw LE, Knowles RG: GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. The Journal of pharmacology and experimental therapeutics 2011, 337:145-54.
102. 2-adrenoceptor agonist. The Journal ofpharmacology and experimental therapeutics 2014, 349: 85-93.
103. 2-adrenoceptor agonist in preclinical animal species. Pharmacol Res Perspect 2014, 2.