Newer approaches in the treatment of asthma

Kamlesh P. Patel, Harsh M. Joshi, Varsha J. Patel

Abstract


Asthma is a worldwide public health problem. The most effective anti-asthmatic drugs - inhaled β2-agonists and glucocorticoids controls asthma in about 90-95% of patients. However, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden. Therefore, reducing glucocorticoids - related adverse effects using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Although glucocorticoids effectively control the inflammatory process in asthma, they have little effect on the lower airway remodeling processes that appear to play a role in the pathophysiology of asthma. Several new drugs developed to target specific components of the inflammatory process in asthma [e.g. anti-IgE antibodies (omalizumab), cytokines and/or chemokines antagonists, immunomodulators, antagonists of adhesion molecules)], have not yet been proven to be particularly effective. Hence, considering the central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising future therapeutic strategies. Some of these new anti-asthmatic treatment approaches may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease. Hence, the development of novel drugs may allow resolution of these changes.


Keywords


Antiasthamatics, Anti-IgE antibodies, Cytokines, Chemokines, Immunomodulators, Glucocorticoids

Full Text:

PDF

References


Martinez FD. Genes, environments, development and asthma: a reappraisal. Eur Respir J 2007;29:179-84.

Rodrigo GJ, Nannini LJ. Comparison between nebulized adrenaline and beta2 agonists for the treatment of acute asthma. A meta-analysis of randomized trials. Am J Emerg Med 2006;24:217-22.

Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2009;(3):CD006922.

U.S. Food and Drug Administration. FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs), February 2010. Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm. Accessed 19 September 2012.

Karagiannidis C, Ruckert B, Hense G, Willer G, Menz G, Blaser K,Schmidt-Weber CB. Distinct leucocyte redistribution after glucocorticoid treatment among difficult-to-treat asthmatic patients. Scand J Immunol 2005;61:187-96.

Forssmann U, Hartung I, Balder R, Fuchs B, Escher SE, Spodsberg N, Dulkys Y. n-Nonanoyl-CC chemokine ligand 14, a potent CC chemokine ligand 14 analogue that prevents the recruitment of eosinophils in allergic airway inflammation. J Immunol 2004;173:3456-66.

Sugimoto H, Shichijo M, Iino T, Manabe Y, Watanabe A, Shimazaki M, Gantner F, Bacon KB. An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J Pharmacol Exp Ther 2003;305:347-52.

Dorsam G, Graeler MH, Seroogy C, Kong Y, Voice JK, Goetzl EJ. Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J Immunol 2003;171:3500-7.

Nguyen C, Teo JL, Matsuda A, Eguchi M, Chi EY, Henderson WR Jr, Kahn M. Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma. Proc Natl Acad Sci USA 2003;100:1169-73.

Quarcoo D, Weixler S, Groneberg D, Joachim R, Ahrens B, Wagner AH, Hecker M, Hamelmann E. Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced air way inflammation and hyperreactivity. J Allergy Clin Immunol 2004;114:288-95.

Djuric SW, BaMaung NY, Basha A, Liu H, Luly JR, Madar DJ et al. 3,5-Bis(trifluoromethyl) pyrazoles: a novel class of NFAT transcription factor regulator. J Med Chem 2000;43:2975-81.

Mueller C, Weaver V, Vanden Heuvel JP, August A, Cantorna MT. Peroxisome proliferator-activated receptor gamma ligands attenuate immunological symptoms of experimental allergic asthma. Arch Biochem Biophys 2003;418:186-96.

Nakano T, Inoue H, Fukuyama S, Matsumoto K, Matsumura M, Tsuda M et al. Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am J Respir Crit Care Med 2006;173:1216-21.

Yang G, Volk A, Petley T, Emmell E, Giles-Komar J, Shang X et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine 2004;28:224-32.

Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993;329:90-5.

Chen Y, Smith ML, Chiou GX, Ballaron S, Sheets MP, Gubbins E, Warrior U, Wilkins J. TH1 and TH2 cytokine inhibition by 3,5- bis(trifluoromethyl)pyrazoles, a novel class of immunomodulators. Cell Immunol 2002;220:134-42.

Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: Systematic review and meta-analysis. Emerg Med J 2007;24:823-30.

Black JL, Armour CL, Johnson PR et al. The action of a potassium channel activator BRL 38227 (lemakalim) on human airway smooth muscle. Am Rev Respir Dis 1990;142:1384-9.

Angus RM, Mecallaum MJ, Hulks G, Thomson NC. Bronchodilator, cardiovascular and cyclic guanylyl monophosphate response to high dose infused atrial natriuretic peptide in asthma. Am Rev Respir Dis 1993;147:1122-5.

Linden A, Hansson L, Andersson A et al. Bronchodilation by an inhaled VPAC(2) receptor agonist in patients with stable asthma. Thorax 2003;58:217-21.

Schacke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index. Mol Cell Endocrinol 2007;275:109-17.

Delhase M, Li N, Karin M. Kinase regulation in inflammatory response. Nature 2000;406:367-8.

Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 2007;1773:1358-75.