Skip to main content

Bifunctional Drugs for the Treatment of Respiratory Diseases

  • Chapter
  • First Online:
Pharmacology and Therapeutics of Asthma and COPD

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

Abstract

Over the last decade, there has been a steady increase in the use of fixed dose combinations for the treatment of a range of diseases, including cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed dose combinations, including combinations of a long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS), and combinations of LABAs and long-acting muscarinic receptor antagonists (LAMAs). There are now also “triple inhaler” fixed dose combinations (containing a LABA, LAMA and ICS) under development and already being made available in clinical practice, with the first such triple combination having been approved in India. The use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule that we have called “bifunctional drugs”. In this review we have discussed the state of the art of bifunctional drugs that can be categorized as bifunctional bronchodilators, bifunctional bronchodilator/anti-inflammatory drugs, bifunctional anti-inflammatory drugs and bifunctional mucolytic and anti-inflammatory drugs.

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

Access this chapter

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

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adcock IM, Caramori G, Chung KF (2008) New targets for drug development in asthma. Lancet 372:1073–1087

    Article  CAS  PubMed  Google Scholar 

  • Ahmedat AS, Warnken M, Juergens UR et al (2012) β2-adrenoceptors and muscarinic receptors mediate opposing effects on endothelin-1 expression in human lung fibroblasts. Eur J Pharmacol 691:218–224

    Article  CAS  PubMed  Google Scholar 

  • Arakida Y, Suwa K, Ohga K et al (1998) In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors. J Pharmacol Exp Ther 287:633–639

    CAS  PubMed  Google Scholar 

  • Baba K, Sakakibara A, Yagi T et al (2001) Effects of theophylline withdrawal in well-controlled asthmatics treated with inhaled corticosteroid. J Asthma 38:615–624

    Article  CAS  PubMed  Google Scholar 

  • Bardin PG, Dorward MA, Lampe FC et al (1998) Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol 45:387–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes N, Grape S, Fox JC, Fitzgerland M, Snell N, Pavord ID, Jeffery P, Qui Y, Singh D, Antczak A, Nizankowska-Mogilnicka E (2010) Effects of low dose inhaled theophylline (ADC 4022) co-administered with budesonide on inflammatory markers and lung function in patients with COPD. American Thoracic Society Abstract, Annual Conference

    Google Scholar 

  • Barrett EG, Rudolph K, Royer C et al (2010) A novel mutual prodrug of salmeterol and desisobutrylciclesonide attenuates acute bronchoconstriction in the absence of cardiovascular side-effects in ragweed sensitized and naive dogs [abstract]. Am J Respir Crit Care Med 181:A4249

    Google Scholar 

  • Bateman ED, Hurd SS, Barnes PJ et al (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31:143–178

    Article  CAS  PubMed  Google Scholar 

  • Bateman ED, Kornmann O, Ambery C et al (2013) Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther 26:581–587

    Article  CAS  PubMed  Google Scholar 

  • Boswell-Smith V, Cazzola M, Page CP (2006a) Are PDE4 inhibitors just more theophylline? J Allergy Clin Immunol 117(6):1237–1243

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Boulet L-P, Lemière C, Gauvreau G et al (2009) Safety, pharmacodynamics and pharmacokinetics of TPI 1020 in smokers with asthma. Respir Med 103:1159–1166

    Article  PubMed  Google Scholar 

  • Boulet L-P, FitzGerald JM, Levy ML et al (2012) A guide to the translation of the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J 39:1220–1229

    Article  PubMed  Google Scholar 

  • Brunnée T, Engelstätter R, Steinijans VW, Kunkel G (1992) Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J 5:982–985

    PubMed  Google Scholar 

  • Bryan SA, O’Connor BJ, Matti S et al (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2149–2153

    Article  CAS  PubMed  Google Scholar 

  • Calverley PMA, Rabe KF, Goehring U-M et al (2009) Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 374:685–694

    Article  CAS  PubMed  Google Scholar 

  • Calzetta L, Page CP, Spina D et al (2013) Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 346:414–423

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Campos HS, Xisto DG, Oliveira MB et al (2006) Protective effects of phosphodiesterase inhibitors on lung function and remodelling in a murine model of chronic asthma. Braz J Med Biol Res 39:283–287

    Article  CAS  PubMed  Google Scholar 

  • Cazzola M, Matera MG (2014) Triple combinations in chronic obstructive pulmonary disease – is three better than two? Expert Opin Pharmacol 15:2475–2478

    Article  CAS  Google Scholar 

  • Cazzola M, Molimard M (2010) The scientific rationale for combining long acting β2 agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 23:257–267

    Article  CAS  PubMed  Google Scholar 

  • Cazzola M, Floriani I, Page CP (2010) The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta analysis of induced patient data. Pulm Pharm Ther 23:135–144

    Article  CAS  Google Scholar 

  • Cazzola M, Page CP, Calzetta L, Matera MG (2012a) Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 64:450–504

    Article  CAS  PubMed  Google Scholar 

  • Cazzola M, Page CP, Calzetta L, Matera MG (2012b) Emerging anti-inflammatory strategies for COPD. Eur Respir J 40:724–741

    Article  CAS  PubMed  Google Scholar 

  • Cazzola M, Segreti A, Matera MG (2013a) New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. Drug Des Devel Ther 7:1201–1208

    Article  PubMed  PubMed Central  Google Scholar 

  • Cazzola M, Lopez-Campos JL, Puente-Maestu L (2013b) The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J 42:885–887

    Article  CAS  PubMed  Google Scholar 

  • Chan S, Yan C (2011) PDE1 isozymes, key regulators of pathological vascular remodeling. Curr Opin Pharmacol 11:720–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charan NB (2001) Does sildenafil also improve breathing? Chest 120:305–306

    Article  CAS  PubMed  Google Scholar 

  • Church MK (2010) Efficacy and tolerability of rupatadine at four times the recommended dose against histamine- and platelet-activating factor-induced flare responses and ex vivo platelet aggregation in healthy males. Br J Dermatol 163:1330–1332

    Article  CAS  PubMed  Google Scholar 

  • Crescioli S, Spinazzi A, Plebani M et al (1991) Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. Ann Allergy 66:245–251

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Dawson R, Diacon A (2013) PA-824, moxifloxacin and pyrazinamide combination therapy for tuberculosis. Expert Opin Investig Drugs 22:927–932

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fabbri LM, Calverley PMA, Izquierdo-Alonso JL et al (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 374:695–703

    Article  CAS  PubMed  Google Scholar 

  • Flexner C, Saag M (2013) The antiretroviral drug pipeline: prospects and implications for future treatment research. Curr Opin HIV AIDS 8:572–578

    Article  CAS  PubMed  Google Scholar 

  • Ford PA, Durham AL, Russell REK et al (2010) Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137:1338–1344

    Article  CAS  PubMed  Google Scholar 

  • Foster RW, Rakshi K, Carpenter JR, Small RC (1992) Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor AH 21–132 in healthy volunteers during a methacholine challenge test. Br J Clin Pharmacol 34:527–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franciosi LG, Diamant Z, Banner KH et al (2013) Efficacy and safety of RPL 554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med 1:714–727

    Article  CAS  PubMed  Google Scholar 

  • Gauvreau GM, Boulet L-P, Cockcroft DW et al (2014) OX40L blockade and allergen-induced airway responses in subjects with mild asthma. Clin Exp Allergy 44(1):29–37. doi:10.1111/cea.12235

    Article  CAS  PubMed  Google Scholar 

  • Giembycz MA (2005) Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 5:238–244

    Article  CAS  PubMed  Google Scholar 

  • Giembycz MA, Maurice DH (2014) Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease. Curr Opin Pharmacol 16:89–107

    Article  CAS  PubMed  Google Scholar 

  • Goodman & Gilman (2005) The pharmacological basis of therapeutics. In: Brunton LL, Lazo JS, Parker KL (eds), 11th edn. McGraw Hill, pp 717–736

    Google Scholar 

  • Grootendorst DC, Gauw SA, Benschop N et al (2003) Efficacy of the novel phosphodiesterase 4 inhibitor BAY 19–8004 on lung function and airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). Pulm Pharmacol Ther 16:115–120

    Article  CAS  PubMed  Google Scholar 

  • Grootendorst DC, Gauw SA, Verhoosel RM et al (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62:1081–1087

    Article  PubMed  PubMed Central  Google Scholar 

  • Guimaraes IH, Padilha GDA, Lopes-Pacheco M et al (2014) Therapy with a new phosphodiesterase 4 and 5 inhibitor in experimental elastase-induced emphysema (abstract). Am J Respir Crit Care Med 189:A6557

    Google Scholar 

  • Harbinson PL, MacLeod D, Hawksworth R et al (1997) The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 10:1008–1014

    Article  CAS  PubMed  Google Scholar 

  • Huang Z-B, Zhao S-S, Huang Y et al (2013) Comparison of the efficacy of lamivudine plus adefovir versus entecavir in the treatment of lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Clin Ther 2013 35(12):1997–2006. doi:10.1016/j.clinthera.2013.10.002

    CAS  Google Scholar 

  • Huang L, Shan W, Zhou Q et al (2014) Design synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Bioorg Med Chem Lett 24:249–253

    Article  CAS  PubMed  Google Scholar 

  • Hughes AD, Jones LH (2011) Dual-pharmacology muscarinic antagonist and β2-agonist molecules for the treatment of chronic obstructive pulmonary disease. Future Med Chem 3:1585–1605

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kasaian MT, Marquette K, Fish S et al (2013) An IL-4/IL-13 dual antagonist reduces lung inflammation, airway hyperresponsiveness, and IgE production in mice. Am J Respir Cell Mol Biol 49:37–46

    Article  CAS  PubMed  Google Scholar 

  • Kau AL, Korenblat PE (2014) Anti-interleukin 4 and 13 for asthma treatment in the era of endotypes. Curr Opin Allergy Clin Immunol 14(6):570–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kew KM, Seniukovich A (2014) Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev (3):CD010115

    Google Scholar 

  • Kidney J, Dominguez M, Taylor M et al (1995) Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 151:1907–1914

    Article  CAS  PubMed  Google Scholar 

  • Kita T, Fujimura M, Myou S et al (2009) Effects of KF19514, a phosphodiesterase 4 and 1 inhibitor, on bronchial inflammation and remodeling in a murine model of chronic asthma. Allergol Int 58:267–275

    Article  PubMed  Google Scholar 

  • Lagente V, Naline E, Guenon I et al (2004) A nitric oxide-releasing salbutamol elicits potent relaxant and anti-inflammatory activities. J Pharmacol Exp Ther 310:367–375

    Article  CAS  PubMed  Google Scholar 

  • Leckie MJ, ten Brinke A, Khan J et al (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2144–2148

    Article  CAS  PubMed  Google Scholar 

  • Lim S, Tomita K, Caramori G et al (2001) Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 164:273–276

    Article  CAS  PubMed  Google Scholar 

  • Liu A, Huang L, Wang Z et al (2013) Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD. Bioorg Med Chem Lett 23:1548–1552

    Article  CAS  PubMed  Google Scholar 

  • Magnussen H, Disse B, Rodriguez-Roisin R, Kirsten A, Waltz H, Tetzlaff K, Towse L, Finnegan H, Dahl R, Decramer M, Chanez P, Wouters EFM, Calverley PMA (2014) Withdrawal of inhibited glucocorticosteroids of COPD. N Engl J Med 371(14):1285–1294

    Article  PubMed  CAS  Google Scholar 

  • Manzini S, Perretti F, Abelli L et al (1993) Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs. Eur J Pharmacol 249:251–257

    Article  CAS  PubMed  Google Scholar 

  • Matera MG, Rogliani P, Calzetta L, Cazzola M (2014) Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs 74:1983–1992

    Article  CAS  PubMed  Google Scholar 

  • McDonald JD, Doyle-Eisele M, Kuehl PJ et al (2012) GS-5759, a novel bi-functional phosphodiesterase 4 inhibitor and long-acting β2-adrenoreceptor agonist: evaluation of its bronchodilator and anti-inflammatory pharmacology in non-human primates [abstract]. Am J Respir Crit Care Med 185:A5698

    Google Scholar 

  • McNamara A, Steinfeld T, Pulido-Rios MT et al (2012) Preclinical efficacy of THRX-200495, a dual pharmacology muscarinic receptor antagonist and β2-adrenoceptor agonist (MABA). Pulm Pharmacol Ther 25:357–363

    Article  CAS  PubMed  Google Scholar 

  • Meurs H, Dekkers BG, Maarsingh H et al (2013a) Muscarinic receptors on airway mesenchymal cells: novel findings for an ancient target. Pulm Pharmacol Ther 26:145–155

    Article  CAS  PubMed  Google Scholar 

  • Meurs H, Oenema TA, Kistemaker LE, Gosens R (2013b) A new perspective on muscarinic receptor antagonism in obstructive airways diseases. Curr Opin Pharmacol 13:316–323

    Article  CAS  PubMed  Google Scholar 

  • Minoguchi K, Kohno Y, Oda N et al (1998) Effect of theophylline withdrawal on airway inflammation in asthma. Clin Exp Allergy 28(Suppl 3):57–63

    CAS  PubMed  Google Scholar 

  • Myou S, Fujimura M, Kamio Y et al (1999) Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. Am J Respir Crit Care Med 160:817–820

    Article  CAS  PubMed  Google Scholar 

  • Nair P, Pizzichini MM, Kjarsgaard M et al (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360:985–993

    Article  CAS  PubMed  Google Scholar 

  • Nair P, Gaga M, Zervas E et al (2012) Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 42:1097–1103

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Norris V, Ambery C (2013) Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. Pulm Pharmacol Ther 26:574–580

    Article  CAS  PubMed  Google Scholar 

  • Ochiai K, Takita S, Kojima A et al (2013) Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Bioorg Med Chem Lett 23:375–381

    Article  CAS  PubMed  Google Scholar 

  • Page CP (2010) Doxophylline: a “novophylline”. Pulm Pharmacol Ther 23:231–234

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Pera T, Penn RB (2014) Crosstalk between beta 2-adrenoceptor and muscarinic acetylcholine receptors in the airway. Curr Opin Pharmacol 16:72–81

    Article  CAS  PubMed  Google Scholar 

  • Persson CG (1985) On the medical history of xanthines and other remedies for asthma: a tribute to HH Salter. Thorax 40:881–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phillips G, Salmon M (2012) Bifunctional compounds for the treatment of COPD. Annu Rep Med Chem 47:209–222

    Article  CAS  Google Scholar 

  • Profita M, Bonanno A, Montalbano AM et al (2012) β2 long-acting and anticholinergic drugs control TGF-β1-mediated neutrophilic inflammation in COPD. Biochim Biophys Acta 1822:1079–1089

    Article  CAS  PubMed  Google Scholar 

  • Profita M, Albano GD, Riccobono L, Di Sano C, Montalbano AM, Gagliardo R, Anzalone G, Bonanno A, Pieper MP, Gjomarkaj M (2014) Increased levels of Th17 cells are associated with non-neuronal acetylcholine in COPD patients. Immunobiology 219:392–401

    Article  CAS  PubMed  Google Scholar 

  • Provins L, Christophe B, Danhaive P et al (2007) Dual M3 antagonists–PDE4 inhibitors. Part 2: synthesis and SAR of 3-substituted azetidinyl derivatives. Bioorg Med Chem Lett 17:3077–3080

    Article  CAS  PubMed  Google Scholar 

  • Rahman I, MacNee W (2012) Anti oxidant pharmacological therapies for COPD. Curr Opin Pharmacol 12:256–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rieder F, Siegmund B, Bundschuh DS et al (2013) The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice. PLoS One 8:e56867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocco PR, Momesso DP, Figueira RC et al (2003) Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury. Eur Respir J 22:20–27

    Article  CAS  PubMed  Google Scholar 

  • Saint-Martin F, Dumur JP, Pérez I, Izquierdo I (2004) A randomized, double-blind, parallel-group study, comparing the efficacy and safety of rupatadine (20 and 10 mg), a new PAF and H1 receptor-specific histamine antagonist, to loratadine 10 mg in the treatment of seasonal allergic rhinitis. J Investig Allergol Clin Immunol 14:34–40

    CAS  PubMed  Google Scholar 

  • Seguin RM, Ferrari N (2009) Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs 18:1505–1517

    Article  CAS  PubMed  Google Scholar 

  • Singh D, Petavy F, Macdonald AJ et al (2010) The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 11:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Spiess C, Bevers J III, Jackman J et al (2013) Development of a human IgG4 bispecific antibody for dual targeting of interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokines. J Biol Chem 288:26583–26593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spina D, Landells LJ, Page CP (1998) The role of theophylline and phosphodiesterase isoenzyme inhibitors as anti-inflammatory drugs. Clin Exp Allergy 28(Suppl 3):24–34

    CAS  PubMed  Google Scholar 

  • Spinelli A, Fanelli A, Gorini M et al (1991) Control of breathing in patients with chronic pulmonary obstructive disease: response to bamiphylline. Respiration 58:241–248

    Article  CAS  PubMed  Google Scholar 

  • Stempel DA, Stoloff SW, Carranza Rosenzweig JR et al (2005) Adherence to asthma controller medication regimens. Respir Med 99:1263–1267

    Article  CAS  PubMed  Google Scholar 

  • Sullivan P, Bekir S, Jaffar Z et al (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 343:1006–1008

    Article  CAS  PubMed  Google Scholar 

  • Tannheimer SL, Sorensen EA, Haran AC et al (2012) Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells. Pulm Pharmacol Ther 25:178–184

    Article  CAS  PubMed  Google Scholar 

  • Tannu SA, Renzetti LM, Tare N et al (2010) Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors. Br J Pharmacol 161:1329–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tapadar SR, Das M, Chaudri AD, Basak S, Mahopatra AR (2014) The effect of acebrofylline vs sustained release theophylline in patients with COPD – A comparative study. J Clin Diagn Res 8(9):MC11–MC14

    PubMed  PubMed Central  Google Scholar 

  • Toward TJ, Smith N, Broadley KJ (2004) Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Care Med 169:227–234

    Article  Google Scholar 

  • Turner DL, Ferrari N, Ford WR et al (2010) TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs. Eur J Pharmacol 641:213–219

    Article  CAS  PubMed  Google Scholar 

  • van der Molen T, Cazzola M (2012) Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J 21:101–108

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • van Meir H, Kenter GG, Burggraaf J et al (2014) The need for improvement of the treatment of advanced and metastatic cervical cancer, the rationale for combined chemo-immunotherapy. Anticancer Agents Med Chem 14(2):190–203. doi:10.2174/18715206113136660372

    Article  PubMed  CAS  Google Scholar 

  • Vestbo J, Hurd SS, Agustí AG et al (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 187:347–365

    Article  CAS  PubMed  Google Scholar 

  • Wedzicha JA (2013) Dual PDE3/4 inhibition: a novel approach to airway disease? Lancet Respir Med 1:669–670

    Article  PubMed  Google Scholar 

  • Wenzel S, Ind PW, Otulana BA et al (2010) Inhaled pitrakinra, an IL-4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma [abstract]. Eur Respir J 36:P3980

    Google Scholar 

  • Wenzel S, Ford L, Pearlman D et al (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368:2455–2466

    Article  CAS  PubMed  Google Scholar 

  • Wielders PL, Ludwig-Sengpiel A, Locantore N et al (2013) A new class of bronchodilator improves lung function in COPD: a trial with GSK961081. Eur Respir J 42:972–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yick CY, Zwinderman AH, Kunst PW et al (2013) Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthma versus controls. Eur Respir J 42:662–670

    Article  CAS  PubMed  Google Scholar 

  • Zheng JP, Wenb FQ, Bai CX, Wan HY, Kang J, Chen P, Yao WJ, Ma LJ, Xia L, Raitieri L, Sardina M, Gao Y, Wang BS, Zhong NS, On Behalf of the PANTHEON Study Group (2014) Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2(3):187–194. doi:10.1016/S2213-2600(13)70286-8

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clive Page .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Page, C., Cazzola, M. (2016). Bifunctional Drugs for the Treatment of Respiratory Diseases. In: Page, C., Barnes, P. (eds) Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, vol 237. Springer, Cham. https://doi.org/10.1007/164_2016_69

Download citation

Publish with us

Policies and ethics