Inhaled muscarinic antagonists for respiratory diseases: A review of patents and current developments (2006 2010)

Expert Opinion on Therapeutic Patents

Volumn 21, Issue 10, 2011, Pages 1543-1573

  Prat, Maria ^a   Gavald, Amadeu ^a   Fonquerna, Silvia ^a   Miralpeix, Montserrat ^a  

^a Department of Medicinal Chemistry ^*  (Spain)

Author keywords

Asthma; Chronic obstructive pulmonary disease; Inhalation; Low systemic exposure; Muscarinic M3 antagonist

Indexed keywords

ACLIDINIUM BROMIDE; ALKS 27; AMMONIUM DERIVATIVE; AZABYCICLO DERIVATIVE; AZD 8683; BENZYL DERIVATIVE; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; CHF 5407; CORTICOSTEROID; DARIFENACIN; DAROTROPIUM BROMIDE; EKLIRA; GLYCOPYRRONIUM BROMIDE; GSK 573719; IMIDAFENACIN; IMIDAZOLIDIN 2 ONE DERIVATIVE; IPRATROPIUM BROMIDE; MUSCARINIC M1 RECEPTOR; MUSCARINIC M2 RECEPTOR; MUSCARINIC M3 RECEPTOR; MUSCARINIC RECEPTOR BLOCKING AGENT; OXITROPIUM BROMIDE; PF 3635659; PIPERIDINE DERIVATIVE; PIPERIDINOL ESTER DERIVATIVE; PYRROLIDINOL ESTER DERIVATIVE; QUINUCLIDINOL CARBONATE DERIVATIVE; QUINUCLIDINOL ESTER DERIVATIVE; TIOTROPIUM BROMIDE; TROPANE DERIVATIVE; TROSEC; TROSPIUM CHLORIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

CHRONIC OBSTRUCTIVE LUNG DISEASE; CORTICOSTEROID THERAPY; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG SAFETY; HUMAN; LUNG FUNCTION; NONHUMAN; OVERACTIVE BLADDER; PATENT; PEPTIC ULCER; PLASMA PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN HYDROLYSIS; QUALITY OF LIFE; REVIEW; UNSPECIFIED SIDE EFFECT;

ADMINISTRATION, INHALATION; ADRENERGIC BETA-AGONISTS; ANIMALS; DELAYED-ACTION PREPARATIONS; DRUG DESIGN; DRUG THERAPY, COMBINATION; GLUCOCORTICOIDS; HUMANS; MUSCARINIC ANTAGONISTS; PATENTS AS TOPIC; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 80052996062     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2011.596528     Document Type: Review

References (153)

1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532-55 (Pubitemid 47403272)
2. Joss GF. Potential for long-acting muscarinic antagonist in chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2010;19:257-64
3. Gosens R, Zaagsma J, Meurs H, et al. Muscarinic receptor signalling in the pathophysiology of asthma and COPD. Respir Res 2006;7:73-87
4. Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med 2004;117(Suppl 12A):24S-32S
5. Mak JCW, Baraniuk JN, Barnes PJ. Localization of muscarinic receptor subtype mRNAs in human lung. Am J Respir Cell Mol Biol 1992;7:344-8
6. Fryer AD, Jacoby DB. Muscarinic receptors and control of airway smooth muscle. Am J Respir Crit Care Med 1998;158:S154-60 (Pubitemid 28536584)
7. Fisher JT, Vincent SG, Gomeza J, et al. Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors. FASEB J 2004;18:711-13
8. Fernandes LB, Fryer AD, Hirshman CA. M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle. J Pharmacol Exp Ther 1992;262:119-26
9. Sarria B, Naline E, Zhang Y, et al. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol 2002;283:L1125-32 (Pubitemid 35204906)
10. Roffel AF, Elzinga CR, Zaagsma J. Cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors. Eur J Pharmacol 1993;250:267-79
11. Roffel AF, Elzinga CR, Zaagsma J. Muscarinic M3 receptors mediate contraction of human central and peripheral airway smooth muscle. Pulm Pharmacol 1990;3:47-51 (Pubitemid 20187064)
12. Rogers DF. Motor control of airway goblet cells and glands. Respir Physiol 2001;125:129-44 (Pubitemid 32184649)
13. Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther 2003;98:59-69 (Pubitemid 36349761)
14. Lieberman JA III. Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry 2004;6:20-3
15. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 years treatment with tiotropium. Eur Respir J 2002;19:209-16 (Pubitemid 34162819)
16. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19:217-24 (Pubitemid 34162820)
17. Proctor GB. Muscarinic receptors and salivary secretion. J Appl Physiol 2006;100:1103-4 (Pubitemid 43671463)
18. Lee TA, Pickard AS, Au DH, et al. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med 2008;149:380-90
19. Disse B, Reichal R, Speck G, et al. Ba679BR, a novel anticholinergic bronchodilator: preclinical and clinical aspects. Life Sci 1993;52:537-44
20. Calverley PM, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax 2003;58:855-60 (Pubitemid 37239232)
21. Barr RG, Bourbeau J, Camargo CA, et al. Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis. Thorax 2006;61(10):854-62 (Pubitemid 44570305)
22. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-54
23. Peters S, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363(18):1715-26
24. Gavalda A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther 2009;331(2):740-51
25. Sentellas S, Ramos I, Alberti J, et al. Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites. Eur J Pharm Sci 2010;39:283-90
26. Jansat JM, Lamarca R, Garcia Gil E, et al. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Int J Clin Pharmacol Ther 2009;47:460-8
27. Jansat JM, Lamarca R, de Miquel G, et al. Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants. J Clin Pharmacol 2009;49:1239-46
28. Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res 2011;26:55-DOI: 10.1186/1465-9921- 12-55
29. Update on Eklira (aclidinium bromide) for chronic obstructive pulmonary disease (COPD): positive results in a short-term comparative trial and announcement of new Phase III studies. (Press release 20.10. 2009). Available from: http://www.almirall.com/webcorp2/cda/comunicacion-detalle-noticia.jsp?id= 1229. [Last accessed 28 February 2011]
30. Magnussen H, Ribera Llovera A, Kirsten AM, et al. Efficacy and safety of aclidinium bromide 400 ?g BID compared with placebo and tiotropium in patients with moderate to severe COPD. Am J Respir Crit Care Med 2009;181:A4440
31. Almirall strengthens its focus on the twice-daily dosing of Eklira-in Chronic Obstructive Pulmonary Disease (COPD). (Press release 27.01.2010). Available from: http://www.almirall.com/webcorp2/ cda/comunicacion-detalle- noticia.jsp?id=1317#-ednref2. [Last accessed 28 February 2011]
32. Almirall and Forest announce positive results from the ATTAIN Phase III study of aclidinium bromide and the Phase IIb studies with the fixed dose combination with formoterol in moderate to severe COPD patients. (Press release 04.01.2011). Available from: http://www. almirall.es/webcorp2/cda/comunicacion- detalle-noticia.jsp?id=1442. [Last accessed 28 February 2011]
33. Barman M, Larson R. The effect of glycopyrrolate on norturnal gastric secretion in peptic ulcer patients. Am J Med Sci 1963;246:325-8
34. Mirakhur R, Dundee J. Glycopyrrolate: pharmacology and clinical use. Anaesthesia 1983;38:1195-204 (Pubitemid 14243293)
35. Viletti G, Bergamaschi M, Bassani F, et al. Pharmacological assessment of the duration of action of glycopyrrolate vs. tiotropium and ipratropium in guinea pig and human airways. Br J Pharmacol 2006;148:291-8 (Pubitemid 43801176)
36. Beleta J, Ramos I, Vilella D, et al. In vitro M3/M2 kinetic selectivity of aclidinium and glycopyrrolate. Am J Respir Crit Care Med 2010;181:A4258
37. Gavalda A, Otal R, Llupia J, et al. In vivo studies of aclidinium bromide and glycopyrrolate to assess bronchodilatory activity and potential to induce dry mouth. Am J Respir Crit Care Med 2010;181:A4448
38. Overend T, Fukuchi Y, Flemale A, et al. Dose ranging study to assess the efficacy and tolerability of NVA237, a once daily long-acting muscarinic antagonist in patients with COPD. Eur Respir J 2008;32(Suppl 52):630s
39. Fogarty C, Hattersley H, Di Scala L, et al. A randomized, double-blind, placebo-controlled, multi-center, two-period crossover study to investigate the bronchodilatory effect of NVA237 50?g inhaled once daily in patients with COPD. Am J Respir Crit Care Med 2010;181:A4437
40. Clinical trials.gov. A service of the US National Institutes of Health. Search of NVA-237: a study to assess the safety, tolerability and efficacy of NVA237 versus placebo (GLOW 1). Available from: http://www.clinicaltrials. gov/ct2/show/NCT01005901? term=NVA237&rank=9. [Last accessed 28 February 2011]
41. Clinical trials.gov. A service of the US National Institutes of Health. Search of NVA-237: 1-year study to assess the efficacy, safety and tolerability of NVA237 in Chronic Obstructive Pulmonary Disease (COPD) (GLOW 2). Available from: http://www.clinicaltrials. gov/ct2/show/NCT00929110? term=NVA237&rank= 6. [Last accessed 28 February 2011]
42. Alkermes, Inc. Terminates feasibility pact with indevus pharmaceuticals, Inc.-DJ. Available from: http://www.reuters.com/ finance/stocks/keyDevelopments? symbol=ALKS.O&pn=6. [Last accessed 28 February 2011]
43. Oleson L, Turncliff RZ, Silverman B, et al. ALKS 27 (Trospium inhalation powder) improves lung function following single administration in subjects with COPD. Am J Respir Crit Care Med 2010;181:A4457
44. Wan Z, Laine DI, Yan H, et al. Discovery of (3-endo)-3-(2-cyano-2,2- diphenylethyl)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD. Bioorg Med Chem Lett 2009;19:4560-2
45. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: GSK233705. Available from: http:// clinicaltrials.gov/ct2/results? term=GSK233705. [Last accessed 28 February 2011]
46. GSK Annual report 2009. Available from: http://www.gsk.com/investors/ reps09/GSK-Report-2009-full.pdf. [Last accessed 28 February 2011]
47. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: GSK533719. Available from: http://www.clinicaltrials.gov/ct2/results? term=GSK573719. [Last accessed 28 February 2011]
48. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: AZD8683. Available from: http:// clinicaltrials.gov/ct2/results? term=NCT01205269. [Last accessed 28 February 2011]
49. Cazzola M, Segreti A, Matera MG. Novel bronchodilators in asthma. Curr Opin Pulm Med 2010;16:6-12
50. Pfizer Pipeline as of 27 September 2010. Available from: http://media.pfizer.com/ files/research/pipeline/2010-0927/pipeline-2010-0927. pdf. [Last accessed 28 February 2011]
51. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: AZD8683. Available from: http://www.clinicaltrials. gov/ct2/show/NCT01033487. [Last accessed 28 February 2011]
52. Villetti G, Pastore F, Bergamaschi M, et al. Bronchodilator activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5- trifluorophenyl)methyl]amino] carbonyl] oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1- azoniabicyclo[2.2.2]octane bromide (CHF5407), a potent, long-acting, and selective muscarinic M3 receptor antagonist. Pharmacol Exp Ther 2010;335:622-35
53. Chiesi 2009 R&S Pipeline. Available from: http://www.chiesigroup.com/ web/guest/traguardi-e-pipeline. [Last accessed 28 February 2011]
54. Argenta Discovery: http://www. argentadiscovery.com/about/ clientstestimonials. htm [Last accesed 1 March 2011]
55. Astra Zeneca Annual Report and Form 20-F Information 2009: http://www. astrazeneca-annualreports.com/2009/ directors-report/therapy-area-review/resp- and-inflamm/index.html [Last accesed 1 March 2011]
56. Argenta Discovery Ltd. Bicyclo[2.2.1] hept-7-ylamine derivatives and their uses. WO2007017670; 2007
57. Argenta Discovery Ltd. Bicyclor[2.2.1] hept-7-ylamine derivatives as muscarinic M3 receptor modulators. WO2008096094; 2008
58. Argenta Discovery Ltd. Cyclic amine derivatives and their uses. WO2007068929; 2007
59. Argenta Discovery Ltd., Astra Zeneca AB. Bicyclo[[2.2.1]hept-2-ylamine derivates and their use. WO2008149053; 2008
60. Pfizer Research and Development Company, N.V./S.A. Oxa- and thia-diazole muscarinic receptor antagonists. WO9730994; 1997
61. Saunders J, Cassidy M, Freedman SB, et al. Novel quinuclidine-based ligands for the muscarinic cholinergic receptor. J Med Chem 1990;33(4):1128-38 (Pubitemid 20115414)
62. Argenta Discovery Ltd. Azole and thiazole derivatives and their use. WO2007017669; 2007
63. Argenta Discovery Ltd. Oxazole and thiazole derivatives and their uses. WO2008096093; 2008
64. Argenta Discovery Ltd. Oxazole and thiazole derivatives and their uses 2. WO2008096128; 2008
65. Argenta Discovery Ltd., Astra Zeneca AB. 2-(9H-Xanthen-9-yl)-oxazol derivatives as M3 muscarinic receptor antagonists for the treatment of asthma and chronic obstructive lung disease. WO2009098455; 2009
66. Argenta Discovery Ltd., Astra Zeneca AB. Nitrogen containing heterocyclic compounds useful as M3-receptor modulators. WO2008023157; 2008
67. Argenta Discovery Ltd. Heterocyclic derivatives as M3 muscarinic receptors. WO2008099186; 2008
68. Argenta Discovery Ltd., Astra Zeneca AB. Heterocyclic compounds used in the treatment of diseases where enhanced M3 receptor activation is implicated. WO2010018352; 2008
69. Astra Zeneca AB., Argenta Discovery Ltd. Azonia bicycloalkanes as M3 muscarinic acetylcholin receptor antagonists. WO2009098453; 2009
70. Pharmacia & Upjohn AB. Arylcycloalkane carboxylic esters, their use, pharmaceutical compositions and preparation. WO199804517; 1998
71. Astra Zeneca AB. Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists. WO2008059245; 2008
72. Astra Zeneca AB., Argenta Discovery Ltd. Quinuclidine derivatives as muscarinic M3 receptor antagonists. WO2009138707; 2009
73. Astra Zeneca AB., Argenta Discovery Ltd. Quinuclidine derivatives and their use as muscarinic receptor antagonists for the treatment of asthma and chronic obstructive pulmonary disease (COPD). WO2009139709; 2009
74. Astra Zeneca AB. Quinuclidinol derivatives as muscarinic receptor antagonists. WO2008075005; 2008
75. Argenta Discovery Ltd., Astra Zeneca AB. 1-Aza-bicyclo[2.2.2]octane derivatives useful as muscarinic receptor antagonists. WO2009153536; 2009
76. Astra Zeneca AB., Argenta Discovery Ltd. Quinuclidine derivatives and their use as muscarinic receptor antagonists. WO2009139710; 2009
77. Almirall Prodesfarma S.A. Novel quinuclidine derivatives and medicinal compositions containing the same. WO2001004118; 2001
78. Almirall Prodesfarma A.G. Novel quinuclidine derivatives and medicinal compositions containing the same. WO2002053564;2002
79. Almirall Prodesfarma S.A. New quaternized quinuclidine esters. WO2005090342; 2005
80. Astra Zeneca AB. New muscarinic receptor antagonists. WO2006112778; 2006
81. Astra Zeneca AB. New alkyl esters of cyclic amino alcohols with muscarinic M3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder. WO2007123465; 2007
82. Astra Zeneca AB. Novel compounds 514. WO2008059239; 2008
83. Astra Zeneca AB. Piperldinum compounds for treatment of obstructive pulmonary diseases (COPD). WO2008075006; 2008
84. Glaxo Group Ltd. Muscarinic acetylcholine receptor antagonists. WO2006005057; 2006
85. Glaxo Group Ltd. M3 muscarinic acetylcholine receptor antagonists. WO2007016650; 2007
86. Glaxo Group Ltd. M3 muscarinic acetylcholine receptor antagonists. WO2007016639; 2007
87. Laine DI, Wan Z, Yan H, et al. Design, synthesis and structure-activity relationship of tropane muscarinic acetylcholine receptor antagonists. J Med Chem 2009;52(16):5241-52
88. Glaxo Group Ltd. Muscarinic acetylcholine receptor antagonists. WO2007022351; 2007
89. Laine DI, McCleland B, Thomas S, et al. Discovery of novel 1-azoniabicyclo [2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009;52(8):2493-505
90. Glaxo Group Ltd. Novel M3 muscarinic acetylcholine receptor antagonists. WO2006055553; 2006
91. Glaxo Group Ltd. Novel M3 muscarinic acetylcholine receptor antagonists. WO2006055503; 2006
92. Jin J, Budzik B, Wang Y, et al. Discovery of biphenylpiperazines as novel and long-acting muscarinic acetylcholine receptor antagonists. J Med Chem 2008;51(19):5915-18
93. Glaxo Group Ltd. Novel muscarinic acetylcholine receptor antagonists. WO2006065788; 2006
94. Glaxo Group Ltd. Novel M3 muscarinic acetylcholine receptor antagonists. WO2007018508; 2007
95. Glaxo Group Ltd. Quaternary ammonium salts of fused heteroaromatic amines as novel muscarinic acetylcholine receptor antagonists. WO2006065755; 2006
96. Glaxo Group Ltd. Novel M3 muscarinic acetylcholine receptor antagonists. WO2007018514; 2007
97. Pfizer Ltd. Novel compounds active as muscarinic receptor antagonists. WO2009034432; 2009
98. Pfizer Ltd. Azetidine derivatives as muscarinic receptor antagonists. WO2008035157; 2008
99. Pfizer Ltd. Carboxamide derivatives as muscarinic receptor antagonists. WO2007034325; 2007
100. Pfizer Ltd. Novel compounds active as muscarinic receptor antagonists. WO2010007552; 2010
101. Pfizer Ltd. Novel compounds active as muscarinic receptor antagonists. WO2010007561; 2010
102. Novartis AG. Pyrrolinidium derivatives as M3 muscarinic receptors. WO2006066928; 2006
103. Novartis AG. Quaternary ammonium salts as M3 antagonists. WO2006066929; 2006
104. Almirall Prodesfarma S.A. New pyrrolidinium derivatives. WO2003087094; 2003
105. Novartis AG. Quinuclidine derivatives and their use as muscarinic M3 receptor antagonists. WO2006048225; 2006
106. Chiesi Farmaceutici S.p.A. Azole derivatives with antimuscarinic activity. WO2006066924; 2006
107. Peretto I, Forlani R, Fossati C, et al. Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1). J Med Chem 2007;50(7):1571-83 (Pubitemid 46564378)
108. Peretto I, Fossati C, Giardina GAM, et al. Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 2). J Med Chem 2007;50(7):1693-7 (Pubitemid 46564390)
109. Chiesi Farmaceutici S.p.A. Quinuclidine derivatives as M3 antagonists. WO2008012290; 2008
110. Konzett H, Rossler F. Versuchsanordnung zu Untersuchungen an der Bronchialmuskulatur. Naunyn-Schmiedebergs Arch Exp Pathol Pharm 1940;195:71-4
111. Peretto I, Petrillo P, Imbimbo BP. Med Res Rev 2009;29(6):867-902
112. Chiesi Farmaceutici S.p.A. Quinuclidine carbonate derivatives and medicinal composition thereof. WO2010015324; 2010
113. Laboratorios Almirall S.A. Novel methods. WO2008101591; 2008
114. Chiesi Farmaceutici S.p.A. Alkaloid aminoester derivatives and medicinal composition thereof. WO2010072338; 2010
115. Boehringer Ingelheim Pharma GmbH & Co. KG. Novel crystalline forms of tiotropium bromide. WO2006117299; 2006
116. Boehringer Ingelheim Pharma GmbH & Co. KG. Crystalline form of tiotropium bromide and urea. WO2008058968; 2008
117. Mitsubishi Tanabe Pharma Corp. Novel nitrogenated heterocyclic compound. WO2007013421, EP1939183A1; 2007
118. Mitsubishi Tanabe Pharma Corp. Novel nitrogenated heterocyclic compounds. JP2007031325; 2007
119. Thomson Reuters Integrity. Entry Number 446138. Drug Data Rep 2007;29(4):320
120. Ono Pharmaceutical Co., Ltd. Tropane compound and pharmaceutical composition containing the same as active ingredient. WO2007086554; 2007
121. Ono Pharmaceutical Co. Ltd. JP2009091250; 2009
122. Thomson Reuters Integrity. Entry Number 458664. Drug Data Rep 2007;29(8):711
123. Kyorin Pharmaceutical Co., Ltd. Muscarinic receptor antagonist. WO2010113952; 2010
124. Thomson Reuters Integrity. Entry Number 712220. Drug Data Rep Abst 2011;33:1
125. Ranbaxy Laboratories Ltd. Muscarinic receptor antagonists. WO2007110782; 2007
126. Astellas Pharma, Inc. Aza-bridged-ring compound. WO2008096870; 2008
127. Nuada LLC. Compounds and methods of use thereof. WO2006063010; 2006
128. Rohatagi S, Luo Y, Shen L, et al. Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther 2005;12:201-9 (Pubitemid 40825123)
129. Rennard S, Donohue J, Bateman E, et al. Efficacy and safety of the novel, long-acting antimuscarinic, aclidinium bromide, in COPD patients in a phase III study: ACCLAIM/COPD II. Am J Respir Crit Care Med 2009;179:A6178
130. Jones PW, Agusti A, Chanez P, et al. A phase III study evaluating aclidinium bromide, a novel long-acting antimuscarinic, in patients with COPD: ACCLAIM/COPD I. Am J Respir Crit Care Med 2009;179:A6180
131. Magnussen H, Ribera A, Kirsten AM, et al. Efficacy and safety of aclidinium bromide 400 ?g BID compared with placebo and tiotropium in patients with moderate to severe COPD. Am J Respir Crit Care Med 2010;181:A4440
132. Bos IS, Gosens R, Zuidhof AB, et al. Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. Eur Respir J 2007;30:653-61 (Pubitemid 351194824)
133. Milara J, Serrano A, Peiro T, et al. Aclidinium partially prevents human lung fibroblast activation in vitro. Am J Respir Crit Care Med 2011;183:In press
134. Milara J, Peiro T, Serrano A, et al. Cigarette smoke-induced fibroblast activation is attenuated by aclidinium in vitro. Am J Respir Crit Care Med 2011;183:In press
135. Kawashima K, Fujii T. Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci 2008;106:167-73 (Pubitemid 351366333)
136. Gosens R, Zaagsma J, Meurs H, et al. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res 2006;7:73
137. Kaplan A. Effect of tiotropium on quality of life in COPD: a systematic review. Prim Care Respir J 2010;19:315-25
138. Global strategy for diagnosis, management, and prevention of COPD. Available from: http://www.goldcopd. com/Guidelineitem.asp? l1=2&l2= 1&intId=989. [Last accessed 28 February 2011]
139. Cazzola M, Di Marco F, Santus P, et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004;17:35-9 (Pubitemid 37468407)
140. van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26:214-22 (Pubitemid 41079064)
141. Vogelmeier C, Kardos P, Harari S, et al. Formoterol and tiotropium both improve lung function in stable COPD patients, with some additional benefit when given together. Respir Med 2008;102:1511-20
142. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545-55 (Pubitemid 351650535)
143. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: QVA149. Available from: http:// clinicaltrials.gov/ct2/results? term=QVA149 [Last accessed 28 February 2011]
144. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: tiotropium+olodaterol. Available from: http://clinicaltrials.gov/ct2/ results? term=tiotropium+olodaterol [Last accessed 28 February 2011]
145. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: aclidinium+formoterol. Available from: http://clinicaltrials.gov/ct2/ results? term=aclidinium+formoterol [Last accessed 28 February 2011]
146. Clinicaltrials.gov, a service of the U.S. National Institutes of Health. Search of: GSK573719+Vilanterol. Available from: http://clinicaltrials.gov/ct2/ results? term=GSK-573719+%2B+vilanterol+ [Last accessed 19 May 2011]
147. Jacoby DB, Yost BL, Kumaravel B, et al. Glucocorticoid treatment increases inhibitory M(2) muscarinic receptor expression and function in the airways. Am J Respir Cell Mol Biol 2001;24:485-91 (Pubitemid 32324738)
148. Johnson M. Corticosteroids: potential beta2-agonist and anticholinergic interactions in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:320-5 (Pubitemid 41566943)
149. Um SW, Yoo CG, Kim YW, et al. The combination of tiotropium and budesonide in the treatment of chronic obstructive pulmonary disease. J Korean Med Sci 2007;22:839-45
150. Choi J, Na J, Kim Y. The effect of tiotropium and inhaled corticosteroid combination therapy in chronic obstructive pulmonary disease (COPD) and chronic obstructive bronchial asthma (COBA) associated with irreversible pulmonary function. Am J Respir Crit Care Med 2007;175:A130
151. FDAs Recommendations: long-acting beta agonists (LABA) in asthma. Available from: http://www.hkresp.com/ index.php/administrator/123-copd- andasthma/ 712-2010-junjul-fdasrecommendations- long-acting-betaagonists- laba-in-asthma [Last accessed 28 February 2011]
152. Ray NC, Alcaraz L. Muscarinic antagonist-beta-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review. Expert Opin Ther Patents 2009;19:1-12
153. Almirall: 2010 financial results in line with guidance. Available from: http:// www.almirall.es/webcorp2/contentFiles/1464/en/Almirall-2010-financial- results-in-line-with-guidance.pdf [Last accessed 28 February 2011]