293
Views
8
CrossRef citations to date
0
Altmetric
Review

Experimental and investigational phosphodiesterase inhibitors in development for asthma

, , , &
Pages 261-266 | Received 05 Sep 2018, Accepted 15 Jan 2019, Published online: 24 Jan 2019

References

  • Global strategy for asthma management and prevention (2018 update). GINA (GLOBAL INITIATIVE FOR ASTHMA); 2018.
  • Carr T, Bleecker E. Asthma heterogeneity and severity. World Allergy Organ J. 2016;9:41.
  • Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–373.
  • Barnes PJ. Novel signal transduction modulator for the treatment of airway diseases. Pharmacol Ther. 2006;109:238–245.
  • Gillissen A. Managing asthma in the real world. Int J Prac. 2004;58:592–603.
  • Chung KF, Caramori G, Adcock IM. Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol. 2009;65:853–858.
  • Palmqvist M, Bruce C, Sjöstrand M, et al. Differential effects of fluticasone montelukast on allergen-induced asthma. Allergy. 2005;60:65–70.
  • Duong M, Gauvreau G, Watson R, et al. The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge. JACI. 2007;119:322–327.
  • Gauvreau GM, Boulet LP, Postma DS, et al. Effect of low-dose ciclesonide on allergen-induced responses in subjects with mild allergic asthma. JACI. 2005;116:285–291.
  • Virchow JC Jr, Walker C, Hafner D, et al. T cells and cytokines in bronchoalveolar lavage fluid after segmental allergen provocation in atopic asthma. AJRCCM. 1995;151:960–968.
  • Voehringer D, Reese TA, Huang X, et al. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J Exp Med. 2006;203:1435–1446.
  • Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118:3546–3556.
  • Risse PA, Jo T, Suarez F, et al. Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype. Am J Physiol Lung Cell Mol Physiol. 2011;300:958–966.
  • Boswell-Smith V, Cazzola M, Page CP. Are PDE4 inhibitors just more theophylline? JACI. 2006;117:1237–1243.
  • Lal D, Manocha S, Ray A, et al. Comparative study of the efficacy and safety of theophylline and doxofylline in patients with bronchial asthma and chronic obstructive pulmonary disease. J Basic Clin Physiol Pharmacol. 2015;5:443–451.
  • Matera MG, Page C, Cazzola M. Doxofylline is not just another theophylline! Int J Chron Obstruct Pulmon Dis. 2017;12:3487–3493.
  • Chung KF. Phosphodiesterase inhibitors in airway disease. E J Phar. 2006;533:110–117.
  • Francis SH, Corbin JD. Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci. 1999;36:275–328.
  • Grandoch M, Roscioni SS, Schmidt M. The role of EPAC proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol. 2010;159:265–284.
  • Page CP, Spina D. Selective PDE inhibitors as novel treatment for respiratory disease. Curr Opin Pharmacol. 2012;12:275–286.
  • Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs. 2003;63:2575–2594.
  • Giembycz MA, Field SK. Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010;4:147–158.
  • Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the chronic obstructive pulmonary disease frequent exacerbator phenotype. Chest. 2013;143:1302–1311.
  • Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007;62:1081–1087.
  • Mokry, J, Urbanova A Medvedova I, et al. Effects of tardafil (PDE5 inhibitor) and roflumilast (PDE 4 inhibitor) on airway reactivity and markers of inflammationin ovalbumin-induced airway hyperresponsiveness in guinea pigs. J Physiol Pharmacol. 2017;68:721–730.
  • Beute J, Lukkes M, Koekoek E, et al. A pathophysiological role of PDE3 in allergic airway inflammation. JCI Insight. 2018;25:3.
  • Fujimura M, Kamio Y, Myou S, et al. Effect of a phosphodiesterase 3 inhibitor, cilostazol, on bronchial hyperresponsiveness in elderly patients with asthma. Int Arch Allergy Immunol. 1997;114:379–384.
  • Bardin PG, Dorward MA, Lampe FC, et al. of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol. 1998;45:3873–3891.
  • Howell RE. Jenkins L P and Howell D E. Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther. 1995;275:703–709.
  • Clayton RA, Dick CA, Mackenzie A, et al. The effect of selective phosphodiesterase inhibitors, alone andin combination, on a murinemodel of allergic asthma. Respir Res. 2004;5:4.
  • Fujimura M, Kamio Y, Saito M, et al. Bronchodilator and bronchoprotective effects of cilostazol in humans in vivo. Ajrccm. 1995;151:222–225.
  • Myou S, Fujimura M, Kamio Y, et al. Bronchodilator effects of intravenous olprinone, a phosphodiesterase 3 inhibitor, with and without aminophylline in asthmatic patients. BJCP. 2003;55:341–346.
  • Hirota K, Yoshioka H, Kabara S, et al. A comparison of the relaxant effects of olprinone and aminophylline on methacholine-induced bronchoconstriction in dogs. Anesth Analg. 2001;93:230–233.
  • Myou S, Fujimura M, Kamio Y, et al. Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. AJRCCM. 1999;160:817–820.
  • Hori M, Iwama T, Asakura Y, et al. NT-702 (parogrelil hydrochloride, NM702),a novel and potent phosphodiesterase 3 inhibitor, suppress the asthmatic response in guinea pigs, with both bronchodilating and anti-inflammatoryeffects. E J Phar. 2009;15:63–69.
  • Kroegel C, Foerster M. Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs. 2007;16:109–124.
  • Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008;15:308–315.
  • St John AL, Abraham SN. Innate immunity and its regulation by mast cells. J Immunol. 2013;1:4458–4463.
  • Kawamatawong T. Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases. J Thorac Dis. 2017;9:1144–1154.
  • Global Initiative for Chronic Obstructive Lung Disease(GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2019 update). GOLD (Global Initiative for Chronic Obstructive Lung Disease). 2019.
  • Schalkwyk Van E, Strydom K, Williams Z. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. JACI. 2005;116:292–298.
  • Luo J, Yang L, Yang J, et al. Efficacy and safety of phosphodiesterase 4 inhibitors in patients with asthma: a systematic review and meta-analysis. Respirology. 2018;23:467–477.
  • Kumar RK, Herbert C, Thomas PS, et al. Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. J Pharmacol Exp Ther. 2003;307:349–355.
  • Bateman ED, Goehring UM, Richard F, et al. Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma. J Allergy Clin Immunol. 2016;138:142–149.
  • Dastidar SG, Ray A, Shirumalla R, et al. Pharmacology of a novel, orally active PDE4 inhibitor. Pharmacology. 2009;83:275–286.
  • Leaker BR, Singh D, Ali FY, et al. The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma. BMC Pulm Med. 2014;14:166.
  • Kwak HJ, Nam JY, Song JS, et al. Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model. Eur J Pharmacol. 2012;685:141–148.
  • Deng YM, Xie QM, Tang HF, et al. Effects of ciclamilast, a new PDE 4 PDE4 inhibitor, on airway hyperresponsiveness, PDE4D expression and airway inflammation in a murine model of asthma. Eur J Pharmacol. 2006;547:125–135.
  • Lu S, Liu N, Dass SB, et al. Randomized, placebo-controlled study of a selective PDE4 inhibitor in the treatment of asthma. Respir Med. 2009;103:342–347.
  • Giembycz MA. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2001;10:1361–1379.
  • Aoki M, Yamamoto S, Kobayashi M, et al. Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs. J Pharmacol Exp Ther. 2001;297:165–173.
  • Singh D, Leaker B, Boyce M, et al. A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients. Pulm Pharmacol Ther. 2016;40:1–6.
  • Southworth T, Kaur M, Hodgson L, et al. Anti-inflammatory effects of the phosphodiesterase type 4 inhibitor CHF6001 on bronchoalveolar lavage lymphocytes from asthma patients. Cytokine. 2018;18:30255–30262.
  • Mariotti F, Govoni M, Lucci G, et al. Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers. Int J Chron Obstruct Pulmon Dis. 2018;13:3399–3410.
  • Myou S, Fujimura M, Kurashima K, et al. Effect of aerosolized administration of KF19514, a phosphodiesterase 4 inhibitor, on bronchial hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea-pigs. CEA. 2000;30:713–718.
  • Kita T, Fujimura M, Myou S, et al. Effects of KF19514, a phosphodiesterase 4 and 1 inhibitor, on bronchial inflammation and remodeling in a murine model of chronic asthma. Allergol Int. 2009;58:267–275.
  • Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013;1:714–727.
  • Singh D, Abbott-Banner K, Bengtsson T, et al. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. ERJ. 2018;52:5.
  • Calzetta L, Page CP, Spina D, et al. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther. 2013;346:414–423.
  • Nicholson CD, Shahid M, Bruin J, et al. Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma. J Pharmacol Exp Ther. 1995;274:678–687.
  • Aljanabi M, Khatib S, Gharaibeh NS. Does sildenafil improve ventilatory function in asthmatic subjects? Breathe (Sheff). 2017;13:113–116.
  • Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (viagra), in animal models of airways disease. Am J Respir Crit Care Med. 2004;169:227–234.
  • Mostafa T. Useful implications of low-dose long-term use of PDE-5 inhibitors. Sex Med Rev. 2016;4:270–284.
  • Lee FP, Chao PZ, Wang HW. Vardenafil inhibiting parasympathetic function of tracheal smooth muscle. J Chin Med Assoc. 2018;81:631–635.
  • Richalet JP, Gratadour P, Robach P, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. AJRCCM. 2005;171:275–281.
  • Bloom TJ, Beavo JA. Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants. Proc Natl Acad Sci USA. 1996;93:14188–14192.
  • Miró X, Pérez-Torres S, Palacios JM, et al. Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs. Synapse. 2001;40(1):201–214.
  • Smith SJ, Cieslinski LB, Newton R, et al. Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol. 2004;66:1679–1689.
  • Nakata A, Ogawa K, Sasaki T, et al. Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors. Clin Exp Immunol. 2002;128:460–466.
  • Chevalier E, Lagente V, Dupont M, et al. Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma. ERJ. 2012;39:582–588.
  • Johnstone TB, Smith KH, Koziol-White CJ, et al. PDE8 is expressed in human airway smooth muscle and selectively regulates cAMP signaling by β2-adrenergic receptors and adenylyl cyclase 6. Am J Respir Cell Mol Biol. 2018;58:530–541.
  • Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995;75:725–748.
  • van Staveren WC, Glick J, Markerink-van Ittersum M, et al. Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J Neurocytol. 2002;31:729–741.
  • Diederen RM, La Heij EC, Markerink-van Ittersum Μ, et al. Selective blockade of phosphodiesterase types 2, 5 and 9 results in cyclic 3‘5ʹ guanosine monophosphate accumulation in retinal pigment epithelium cells. Br J Ophthalmol. 2007;91:379–384.
  • Bloom TJ. Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle. Can J Physiol Pharmacol. 2002;80:1132–1135.
  • Nagasaki S, Nakano Y, Masuda M, et al. Phosphodiesterase type 9 (PDE9) in the human lower urinary tract: an immunohistochemical study. BJU Int. 2012;109:934–940.
  • Tajima T, Shinoda T, Urakawa N, et al. Phosphodiesterase 9 (PDE9) regulates bovine tracheal smooth muscle relaxation. J Vet Med Sci. 2018;80:499–502.
  •  Kew KM, Dahri K. Cochrane Database Syst Rev. 2016;(1):CD011721.
  • Wells JM, Jackson PL, Viera L, et al. A Randomized, placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease. AJRCCM. 2015;192:934–942.
  • Calverley PM, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176:1541–1561.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.