Pharmacogenomics of long-acting β2-agonists

Expert Opinion on Drug Metabolism and Toxicology

Volumn 11, Issue 11, 2015, Pages 1733-1751

  Blake, Kathryn ^a   Lima, John ^a  

^a NEMOURS CHILDREN S CLINIC   (United States)

Author keywords

asthma; children; long acting 2 agonists; pharmacogenomic; rare variants; serious adverse events

Indexed keywords

BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; FORMOTEROL; INDACATEROL; OLODATEROL; SALMETEROL; VILANTEROL; ADRB2 PROTEIN, HUMAN; ANTIASTHMATIC AGENT; BETA 2 ADRENERGIC RECEPTOR; DELAYED RELEASE FORMULATION;

ADRB2 GENE; ASTHMA; CHRONIC OBSTRUCTIVE LUNG DISEASE; CINAHL; CLINICAL TRIAL (TOPIC); COCHRANE LIBRARY; DATA BASE; DESENSITIZATION; DISEASE CONTROL; DISEASE EXACERBATION; DNA POLYMORPHISM; DRUG MECHANISM; GENE; GENE INTERACTION; GENETIC VARIABILITY; GENOTYPE; HIGH RISK POPULATION; HOSPITALIZATION; HUMAN; MEDLINE; PHARMACOGENETICS; PHARMACOGENOMICS; PHARMACOKINETICS; REVIEW; RISK ASSESSMENT; SEARCH ENGINE; ADULT; CHILD; DELAYED RELEASE FORMULATION; GENETICS;

ADRENERGIC BETA-2 RECEPTOR AGONISTS; ADULT; ANTI-ASTHMATIC AGENTS; ASTHMA; CHILD; DELAYED-ACTION PREPARATIONS; GENOTYPE; HUMANS; PHARMACOGENETICS; RECEPTORS, ADRENERGIC, BETA-2;

EID: 84947031464     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2015.1071793     Document Type: Review

References (147)

1. The Global Asthma Report 2014. Global Asthma Network; Auckland, New Zealand: 2014
2. Bousquet J, Khaltaev N. Global surveillance, prevention and control of chronic respiratory diseases. A comprehensive approach. Global Alliance against Chronic Respiratory Diseases, World Health Organization; Geneva: 2007
3. Burden of COPD. World Health Organization, Geneva. 2005. Available from: http://www.who. int/respiratory/copd/burden/en/ [Last accessed 23 March 2015]
4. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2015. Available from: http://www.goldcopd.org/ [Last accessed 17 April 2015]
5. From the global strategy for asthma management and prevention, global initiative for asthma (GINA). 2015. Available from: http://www.ginasthma.org/ [Last accessed 17 April 2015]
6. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; Bethesda, MD: U.S: 2007
7. Long-acting beta-agonists (LABAs): new safe use requirements. Food and Drug Administration, Silver Spring, MD; 2011. Available from: http://www.fda. gov/Drugs/DrugSafety/ucm201003.htm [Last accessed 17 April 2015]
8. Weiss ST, Litonjua AA, Lange C, et al. Overview of the pharmacogenetics of asthma treatment. Pharmacogenomics J 2006;6(5):311-26
9. Lima JJ. Do genetic polymorphisms alter patient response to inhaled bronchodilators? Expert Opin Drug Metab Toxicol 2014;10(9):1231-40
10. Ortega VE. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management. Clin Genet 2014;86(1):12-20
11. Chung LP, Waterer G, Thompson PJ. Pharmacogenetics of beta2 adrenergic receptor gene polymorphisms, longacting beta-agonists and asthma. Clin Exp Allergy 2011;41(3):312-26
12. Ortega VE, Hawkins GA, Moore WC, et al. Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting beta agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir Med 2014;2(3):204-13
13. Kim WJ, Oh YM, Sung J, et al. Lung function response to 12-week treatment with combined inhalation of long-acting beta2 agonist and glucocorticoid according to ADRB2 polymorphism in patients with chronic obstructive pulmonary disease. Lung 2008;186(6):381-6
14. Mochizuki H, Nanjo Y, Kawate E, et al. Beta2-adrenergic receptor haplotype may be associated with susceptibility to desensitization to long-acting beta2-agonists in COPD patients. Lung 2012;190(4):411-17
15. Barnes PJ. Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995;152(3):838-60
16. Cazzola M, Page CP, Calzetta L, et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012;64(3):450-504
17. Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999;104(2 Pt 2):S42-6
18. Baker JG, Proudman RG, Hill SJ. Salmeterol's extreme beta2 selectivity is due to residues in both extracellular loops and transmembrane domains. Mol Pharmacol 2015;87(1):103-20
19. Nijkamp FP, Engels F, Henricks PA, et al. Mechanisms of beta-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev 1992;72(2):323-67
20. Billington CK, Penn RB. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res 2003;4(1):2
21. Lohse MJ. Molecular mechanisms of membrane receptor desensitization. BiochimBiophys Acta 1993;1179(2):171-88
22. Hardin AO, Lima JJ. Beta 2-adrenoceptor agonist-induced downregulation after short-term exposure. J ReceptSignalTransductRes 1999;19(5):835-52
23. Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med 1998;158(5 Pt 3):S146-S53
24. Shore SA, Moore PE. Regulation of betaadrenergic responses in airway smooth muscle. Respir Physiol Neurobiol 2003;137(2-3):179-95
25. McGraw DW, Liggett SB. Molecular mechanisms of beta2-adrenergic receptor function and regulation. Proc Am Thorac Soc 2005;2(4):292-6; discussion 311-2
26. Rabe KF, Jorres R, Nowak D, et al. Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis 1993;147(6 Pt 1):1436-41
27. Anderson GP, Linden A, Rabe KF. Why are long-acting beta-adrenoceptor agonists long-acting? Eur Respir J 1994;7(3):569-78
28. Szczuka A, Wennerberg M, Packeu A, et al. Molecular mechanisms for the persistent bronchodilatory effect of the beta 2-adrenoceptor agonist salmeterol. Br J Pharmacol 2009;158(1):183-94
29. Green SA, Rathz DA, Schuster AJ, et al. The Ile164 beta(2)-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s). Eur J Pharmacol 2001;421(3):141-7
30. Rong Y, Arbabian M, Thiriot DS, et al. Probing the salmeterol binding site on the beta 2-adrenergic receptor using a novel photoaffinity ligand, [(125)I] iodoazidosalmeterol. Biochemistry 1999;38(35):11278-86
31. Kohout TA, Lefkowitz RJ. Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. MolPharmacol 2003;63(1):9-18
32. Nishikawa M, Mak JC, Barnes PJ. Effect of short-and long-acting beta 2-adrenoceptor agonists on pulmonary beta 2-adrenoceptor expression in human lung. Eur J Pharmacol 1996;318(1):123-9
33. Scola AM, Chong LK, Chess-Williams R, et al. Influence of agonist intrinsic activity on the desensitisation of beta2-adrenoceptor-mediated responses in mast cells. Br J Pharmacol 2004;143(1):71-80
34. January B, Seibold A, Whaley B, et al. beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. J Biol Chem 1997;272(38):23871-9
35. Duringer C, Grundstrom G, Gurcan E, et al. Agonist-specific patterns of beta 2-adrenoceptor responses in human airway cells during prolonged exposure. Br J Pharmacol 2009;158(1):169-79
36. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med 2004;140(10):802-13
37. Knobil K, Yancey S, Kral K, et al. Salmeterol multi-center asthma research trial (SMART): results from an interim analysis. Chest 2003;124(4 Suppl):335S
38. Jackson CM, Lipworth B. Benefit-risk assessment of long-acting beta2-agonists in asthma. Drug Saf 2004;27(4):243-70
39. Kemp JP, DeGraff AC Jr, Pearlman DS, et al. A 1-year study of salmeterol powder on pulmonary function and hyperresponsiveness to methacholine. J Allergy Clin Immunol 1999;104(6):1189-97
40. Rosenthal RR, Busse WW, Kemp JP, et al. Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Chest 1999;116(3):595-602
41. Wong AG, O'Shaughnessy AD, Walker CM, et al. Effects of long-acting and short-acting beta-agonists on methacholine dose-response curves in asthmatics. Eur Respir J 1997;10(2):330-6
42. Verberne AA, Hop WC, Creyghton FB, et al. Airway responsiveness after a single dose of salmeterol and during four months of treatment in children with asthma. J Allergy Clin Immunol 1996;97(4):938-46
43. Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992;327(17):1198-203
44. Repsher LH, Anderson JA, Bush RK, et al. Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 1984;85:34-8
45. Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med 2003;97(9):1014-20
46. Masoli M, Weatherall M, Ayling J, et al. The 24 h duration of bronchodilator action of the salmeterol/fluticasone combination inhaler. Respir Med 2005;99(5):545-52
47. Verberne AA, Hop WC, Bos AB, et al. Effect of a single dose of inhaled salmeterol on baseline airway caliber and methacholine-induced airway obstruction in asthmatic children. JAllergy ClinImmunol 1993;91(1 Pt 1):127-34
48. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995;346(8969):201-6
49. Fuglsang G, Vikre-Jorgensen J, Agertoft L, et al. Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma. PediatrPulmonol 1998;25(5):314-21
50. Lee DK, Jackson CM, Currie GP, et al. Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Br J Clin Pharmacol 2003;56(5):494-500
51. van Veen A, Weller FR, Wierenga EA, et al. A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists. PulmPharmacol Ther 2003;16(3):153-61
52. Storms WW, Bird S, Firriolo KM. The effect of rescue short-acting beta-agonist bronchodilatation in patients on montelukast or salmeterol. J Allergy Clin Immunol 2001;107:S316
53. Nelson HS, Berkowitz RB, Tinkelman DA, et al. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am J RespirCrit Care Med 1999;159(5 Pt 1):1556-61
54. Wilding P, Clark M, Thompson CJ, et al. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997;314(7092):1441-6
55. Boulet LP, Cartier A, Milot J, et al. Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids. Eur Respir J 1998;11(5):1091-7
56. Kalra S, Swystun VA, Bhagat R, et al. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol [see comments]. Chest 1996;109(4):953-6
57. Giuntini CG, Paggiaro PL. Present state of the controversy about regular inhaled beta-agonists in asthma. Eur Respir J 1995;8(5):673-8
58. Inman WH, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969;2(7615):279-85
59. Sears MR. Relationships between asthma mortality and treatment. Ann Allergy 1993;70(5):425-6
60. Pearce N, Beasley R, Crane J, et al. End of the New Zealand asthma mortality epidemic. Lancet 1995;345(8941):41-4
61. Beasley R, Pearce N, Crane J, et al. Withdrawal of fenoterol and the end of the New Zealand asthma mortality epidemic. Int Arch Allergy Immunol 1995;107(1-3):325-7
62. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-6
63. Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996;335(12):841-7
64. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15-26
65. Mann M, Chowdhury B, Sullivan E, et al. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 2003;124(1):70-4
66. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170(8):836-44
67. Masoli M, Weatherall M, Holt S, et al. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 2005;60(9):730-4
68. Ducharme FM, Ni Chroinin M, Greenstone I, et al. Addition of longacting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev 2010(5):CD005535
69. Ducharme FM, Ni Chroinin M, Greenstone I, et al. Addition of longacting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010(4):CD005533
70. Roth M, Johnson PR, Rudiger JJ, et al. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002;360(9342):1293-9
71. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002;19(1):182-91
72. McIvor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158(3):924-30
73. Finkelstein FN. Risks of salmeterol? N Engl J Med 1994;331(19):1314
74. Castle W, Fuller R, Hall J, et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306(6884):1034-7
75. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting beta(2)-adrenergic receptor agonists. Pediatrics 2011;128(5):e1147-54
76. Levenson M. Long-Acting Beta-Agonists and Serious Asthma-Related Events Meta-Analysis. 2008. Food and Drug Administration, Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee; Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee. 2008. Available from: http://www.fda.gov/ ohrms/dockets/ac/08/slides/2008-4398s1-04-Levensosn.pdf [Last accessed 22 September 2011]
77. Bisgaard H. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 2003;36(5):391-8
78. Cates C. The safety of regular longacting beta2-agonists in children with asthma: an overview of Cochrane reviews. Paediatr Respir Rev 2013;14(1):25-6
79. Wells KE, Peterson EL, Ahmedani BK, et al. The relationship between combination inhaled corticosteroid and long-acting beta-agonist use and severe asthma exacerbations in a diverse population. J Allergy Clin Immunol 2012;129(5):1274-9
80. Rodrigo GJ, Moral VP, Marcos LG, et al. Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review. Pulm Pharmacol Ther 2009;22(1):9-19
81. Briefing Information for the March 19, 2015 Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee (PADAC) and Drug Safety and Risk Management Advisory Committee (DSaRM). Food and Drug Administration, Silver Spring, MD; 2015. Available from: http://www.fda. gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/ ucm438378.htm [Last accessed 17 April 2015]
82. Wechsler ME, Castro M, Lehman E, et al. Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med 2011;184(11):1247-53
83. Bailey W, Castro M, Matz J, et al. Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone. Curr Med Res Opin 2008;24(6):1669-82
84. Guo JJ, Tsai K, Kelton CM, et al. Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: a retrospective cohort study. Ann Allergy Asthma Immunol 2011;106(3):214-22
85. Sadatsafavi M, Lynd LD, Marra CA, et al. Dispensation of long-acting beta agonists with or without inhaled corticosteroids, and risk of asthma-related hospitalisation: a population-based study. Thorax 2014;69(4):328-34
86. Briefing Information for the March 10-11, 2010 Joint Meeting of the Pulmonary-Allergy Drugs Advisory Committee and Drug Safety and Risk Management Committee. Food and Drug Administration, Silver Spring, MD; 2010. Available from: http://www.fda. gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ Pulmonary-AllergyDrugsAdvisoryCommittee/ ucm202692.htm [Last accessed 17 April 2015]
87. Sears MR. The FDA-mandated trial of safety of long-acting beta-agonists in asthma: finality or futility? Thorax 2013;68(2):195-8
88. Kobilka BK, Dixon RA, Frielle T, et al. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. ProcNatlAcad Sci USA 1987;84(1):46-50
89. Hawkins GA, Tantisira K, Meyers DA, et al. Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. AmJRespirCrit Care Med 2006;174(10):1101-9
90. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. ProcNatlAcadSci USA 2000;97(19):10483-8
91. Panebra A, Wang WC, Malone MM, et al. Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes. PLoS ONE 2010;5(7):e11819
92. Reihsaus E, Innis M, MacIntyre N, et al. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell MolBiol 1993;8(3):334-9
93. Green SA, Turki J, Bejarano P, et al. Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. AmJ RespirCell MolBiol 1995;13(1):25-33
94. Brodde OE, Leineweber K. Beta2-adrenoceptor gene polymorphisms. Pharmacogenet Genomics 2005;15(5):267-75
95. Green SA, Cole G, Jacinto M, et al. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 1993;268(31):23116-21
96. Parola AL, Kobilka BK. The peptide product of a 5' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. J Biol Chem 1994;269(6):4497-505
97. McGraw DW, Liggett SB. Coding block and 5 leader cistron polymorphisms of the beta2-adrenergic receptor. Clin Exp Allergy 1999;29(Suppl 4):43-5
98. McGraw DW, Forbes SL, Kramer LA, et al. Polymorphisms of the 5' leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest 1998;102(11):1927-32
99. Ambrose HJ, Lawrance RM, Cresswell CJ, et al. Effect of beta2-adrenergic receptor gene (ADRB2) 3' untranslated region polymorphisms on inhaled corticosteroid/long-acting beta2-adrenergic agonist response. Respir Res 2012;13:37
100. Panebra A, Schwarb MR, Swift SM, et al. Variable-length poly-C tract polymorphisms of the beta2-adrenergic receptor 3'-UTR alter expression and agonist regulation. Am J Physiol Lung Cell MolPhysiol 2008;294(2):L190-L95
101. Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term beta agonist use: influence of beta (2) adrenoceptor polymorphism. Thorax 2000;55(9):762-7
102. Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta (2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162(1):75-80
103. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364(9444):1505-12
104. Tan S, Hall IP, Dewar J, et al. Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics [see comments]. Lancet 1997;350(9083):995-9
105. Aziz I, Hall IP, McFarlane LC, et al. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 1998;101(3):337-41
106. Lipworth BJ, Hall IP, Tan S, et al. Effects of genetic polymorphism on ex vivo and in vivo function of beta2-adrenoceptors in asthmatic patients. Chest 1999;115(2):324-8
107. Lipworth BJ, Hall IP, Aziz I, et al. Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short-and long-acting beta2-agonist therapy. Clin Sci (Lond) 1999;96(3):253-9
108. Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism. Chest 2000;118(2):321-8
109. Sims EJ, Lipworth BJ. Concomitant occasional use of salbutamol influences bronchoprotective responsiveness afforded by formoterol in patients with the glycine-16 genotype. Eur J Clin Pharmacol 2004;59(11):791-5
110. Lee DK, Jackson CM, Bates CE, et al. Cross tolerance to salbutamol occurs independently of beta2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol. Thorax 2004;59(8):662-7
111. Lee DK, Currie GP, Hall IP, et al. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 2004;57(1):68-75
112. Blake KV, Hossain J, Lima J. B2-agonist promoted desensitization following treatment with salmeterol. In: Whites and african americans homozygous for ARG OR GLY at ADRB2 CODON 16. C22 asthma therapy. Am J Respir Crit Care Med 2012;185:A3954
113. Green RH, Brightling CE, McKenna S, et al. Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness. Eur Respir J 2006;27(6):1144-51
114. Bonini M, Permaul P, Kulkarni T, et al. Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide. Am J Respir Crit Care Med 2013;188(12):1407-12
115. Bleecker ER, Yancey SW, Baitinger LA, et al. Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006;118(4):809-16
116. Bleecker ER, Lawrance RM, Ambrose HJ, et al. Beta2-adrenergic receptor gene polymorphisms: Is Arg/Arg genotype associated with serious adverse events during treatment with budesonide and formoterol in one pressurized metered-dose inhaler (BUD/FM pMDI) within racial groups? Am J Respir Crit Care Med 2008;177:A775
117. Yancey SW, Klotsman M, Ortega HG, et al. Acute and chronic lung function responses to salmeterol and salmeterol plus fluticasone propionate in relation to Arg16Gly beta(2)-adrenergic polymorphisms. Curr Med Res Opin 2009;25(4):1011-18
118. Wechsler ME, Kunselman SJ, Chinchilli VM, et al. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotypestratified, randomised, placebocontrolled, crossover trial. Lancet 2009;374(9703):1754-64
119. Wechsler ME, Lehman E, Lazarus SC, et al. beta-Adrenergic receptor polymorphisms and response to salmeterol. Am JRespirCrit Care Med 2006;173(5):519-26
120. Manoharan A, Griffin B, Lipworth J, et al. beta-Adrenergic receptor Gly16Arg polymorphism and impaired asthma control in corticosteroid-treated asthmatic adults. Ann Allergy Asthma Immunol 2015;114(5):421-3
121. Palmer CN, Lipworth BJ, Lee S, et al. The arginine-16 beta 2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006;61(11):940-4
122. Basu K, Palmer CN, Tavendale R, et al. Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroidtreated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol 2009;124(6):1188-94
123. Lipworth BJ, Basu K, Donald HP, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond) 2013;124(8):521-8
124. Zuurhout MJ, Vijverberg SJ, Raaijmakers JA, et al. Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting beta2-agonists: results of the PACMAN cohort. Pharmacogenomics 2013;14(16):1965-71
125. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010;362(11):975-85
126. Iordanidou M, Paraskakis E, Tavridou A, et al. G894T polymorphism of eNOS gene is a predictor of response to combination of inhaled corticosteroids with long-lasting beta2-agonists in asthmatic children. Pharmacogenomics 2012;13(12):1363-72
127. Park HW, Tantisira KG, Weiss ST. Pharmacogenomics in asthma therapy: where are we and where do we go? Annu Rev Pharmacol Toxicol 2015;55:129-47
128. Konno S, Hizawa N, Makita H, et al. The effects of a Gly16Arg ADRB2 polymorphism on responses to salmeterol or montelukast in Japanese patients with mild persistent asthma. Pharmacogenet Genomics 2014;24(5):246-55
129. McGeachie MJ, Wu AC, Chang HH, et al. Predicting inhaled corticosteroid response in asthma with two associated SNPs. Pharmacogenomics J 2013;13(4):306-11
130. Xu HM, Sun XW, Qi T, et al. Multivariate dimensionality reduction approaches to identify gene-gene and gene-environment interactions underlying multiple complex traits. PLoS One 2014;9(9):e108103
131. Edwards TL, Lewis K, Velez DR, et al. Exploring the performance of Multifactor Dimensionality Reduction in large scale SNP studies and in the presence of genetic heterogeneity among epistatic disease models. Hum Hered 2009;67(3):183-92
132. Rosenborg J, Larsson P, Tegner K, et al. Mass balance and metabolism of [(3)H] Formoterol in healthy men after combined i.v. and oral administrationmimicking inhalation. Drug Metab Dispos 1999;27(10):1104-16
133. DrugBank: Formoterol. DrugBank. Canadian Institutes of Health Research. Available from: http://www.drugbank.ca/ drugs/DB00983 [Last accessed 29 June 2015]
134. Anwar MM, El-Haggar RS, Zaghary WA. Salmeterol Xinafoate. Profiles Drug Subst Excip Relat Methodol 2015;40:321-69
135. Cazzola M, Testi R, Matera MG. Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet 2002;41(1):19-30
136. Harrell AW, Siederer SK, Bal J, et al. Metabolism and disposition of vilanterol, a long-acting beta(2)-adrenoceptor agonist for inhalation use in humans. Drug Metab Dispos 2013;41(1):89-100
137. Keller CS, Gonzales A, Fleuriet KJ. Retention of minority participants in clinical research studies. West J Nurs Res 2005;27(3):292-306
138. Wang WC, Pauer SH, Smith DC, et al. Targeted transgenesis identifies Galphas as the bottleneck in beta2-adrenergic receptor cell signaling and physiological function in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2014;307(10):L775-80
139. Whalen EJ, Foster MW, Matsumoto A, et al. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 2007;129(3):511-22
140. Strom BL, Buyse M, Hughes J, et al. Data sharing, year 1-access to data from industry-sponsored clinical trials. N Engl J Med 2014;371(22):2052-4
141. Zou J, Zheng MW, Li G, et al. Advanced systems biology methods in drug discovery and translational biomedicine. Biomed Res Int 2013;2013:742835
142. Oresic M, Vidal-Puig A, Hanninen V. Metabolomic approaches to phenotype characterization and applications to complex diseases. Expert Rev Mol Diagn 2006;6(4):575-85
143. Meyers DA, Bleecker ER, Holloway JW, et al. Asthma genetics and personalised medicine. Lancet Respir Med 2014;2(5):405-15
144. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372(9):793-5
145. Hall IP. Should we use ADRB2 variation to stratify asthma treatment? Lancet Respir Med 2014;2(3):169-71
146. Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med 2011;364(26):2473-5
147. Ortega VE, Hawkins GA, Peters SP, et al. Pharmacogenetics of the beta 2-adrenergic receptor gene. Immunol Allergy Clin North Am 2007;27(4):665-84; vii