SGA 2003-W SS Slide 1 Dual Pathways of Asthmatic Inflammation Montelukast with Inhaled Corticosteroids

SGA 2003-W SSSlide 2 Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998; Bjermer L Respir Med 2001;95: Importance of Inflammation in Asthma Asthma is fundamentally a disease of inflammation Inflammation causes bronchoconstriction and airway hyperresponsiveness, resulting in symptoms Treating inflammation first in patients with mild to moderate persistent asthma is an appropriate treatment approach

SGA 2003-W SSSlide 3 Airway Inflammation Persisted Despite Corticosteroid Use ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS Adapted from Louis R et al Am J Respir Crit Care Med 2000;161: ,000 10,000 1, Eosinophil  10 3 /g sputum Control group Mild to moderate ICS low-dose (n=10) ICS high-dose (n=15) OCS (n=10) OCS ± ICS (n=7) Severe asthma p<0.01 p<0.001 p<0.01 In a clinical study of 74 patients

SGA 2003-W SSSlide 4 Leukotrienes Other inflammatory mediators This slide is an artistic rendition. Adapted from Holgate ST, Peters-Golden M J Allergy Clin Immunol 2003;111(1 suppl):S1-S4; Holgate ST et al J Allergy Clin Immunol 2003;111(1 suppl):S18-S36; Henderson WR Jr et al Am J Respir Crit Care Med 2002;165: ; Peters- Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma and Rhinitis. Oxford, UK: Blackwell Science, 2000: No InflammationInflammationAsthma Leukotrienes: Important in Early Asthma and Throughout the Disease

SGA 2003-W SSSlide 5 Suppression of a number of inflammatory mediators –Cytokines –Adhesion molecules –Inducible enzymes Variable effects on inflammatory processes Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48. Dual Pathways of Inflammation Actions of Corticosteroids

SGA 2003-W SSSlide 6 Dual Pathways of Inflammation Effects of the CysLT 1 Receptor on Inflammatory Cells Eosinophils Lung Macrophage Smooth- muscle cell PBMC CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163: Monocytes

SGA 2003-W SSSlide 7 Dual Pathways of Inflammation Expression of the CysLT 1 Receptor Neutrophil Monocyte Macrophage Basophil Pluripotent hemopoietic stem cell T Cells Eosinophil B Lymphocyte CCR3 CD4+ CD8+ CD19 M-CSF, GM-CSF, IL-3 LTC 4, LTD 4, LTE 4 LN5 Mast Cell LTC 4 LTD 4 LTE 4 M-CSF GM-CSF IL-5 IL-3 GM-CSF LTC 4 LTD 4 LTE 4 CD14 IL5Rβ Represents the CysLT 1 receptor Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163: ; Mellor et al Proc Natl Acad Sci USA 2001;98: CysLT 1 R CD34+

SGA 2003-W SSSlide 8 Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48. Dual Pathways of Inflammation Leukotrienes Are Powerful Inflammatory Mediators Mediator receptor Other mediators CysLT receptor CysLT

SGA 2003-W SSSlide 9 Suppress many inflammatory mediators Suppress inflammatory processes –Via the leukotriene pathway –Via the steroid-sensitive pathway LTRAs = leukotriene receptor antagonists Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48. Dual Pathways of Inflammation Actions of LTRAs Leukotrienes are highly specific but catalyze a massive inflammatory cascade

SGA 2003-W SSSlide 10 Dual Pathways of Inflammation Central Role of CysLTs in Asthma Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16: Inflammatory Cells (mast cells, eosinophils) Sensory Nerves (C fibers) CysLTs Edema Blood Vessel Decreased Mucus Transport Eosinophil Influx Cationic Protein Release, Epithelial-Cell Damage Contraction and Proliferation Airway Smooth Muscle Increased Mucus Secretion Airway Epithelium

SGA 2003-W SSSlide 11 p = NS between groups Adapted from O’Shaughnessy KM et al Am Rev Respir Dis 1993;147: Urinary LTE 4 excretion (ng/mmol creatinine) 18.4 PlaceboFluticasone propionate Effect of Inhaled Fluticasone Propionate on Urinary LTE 4 Excretion

SGA 2003-W SSSlide 12 * *p<0.05 vs. baseline Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149: Urinary LTE 4 (ng/mg creatinine) Post-allergen challenge Baseline Control Prednisone * Effect of Oral Prednisone on Urinary LTE 4 Excretion

SGA 2003-W SSSlide 13 n=14 Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149: Oral Prednisone Did Not Suppress CysLT Levels Recovered from BAL Fluid BAL = bronchoalveolar lavage Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149: BAL levels (pg/ml) LTE 4 LTC 4 Before prednisone After prednisone Eicosanoids in Asthmatics

SGA 2003-W SSSlide 14 *p<0.02 vs. normal individuals; **p<0.05 vs. normal individuals Adapted from Pavord ID et al Am J Respir Crit Care Med 1999;160: Sputum CysLT levels (ng/ml) Controls (n=10) 6.4 All patients with asthma (n=26) 9.4* Patients with persistent asthma (n=10) 11.4** Patients with acute attacks (n=12) 13* Effect of ICS on Sputum Leukotriene Levels

SGA 2003-W SSSlide 15 LABA = long-acting beta 2 agonist Adapted from Currie GP et al Am J Respir Crit Care Med (in press). Dual Pathways of Inflammation Long-Acting Beta 2 Agonists Did Not Have Anti-inflammatory Effects 0 –100 –200 Change in eosinophils (  10 6 /L) from run-in ICS + LABA + Montelukast ICS + LABA ICS ICS + Montelukast p<0.05 LTRA montelukast further reduced inflammation when added to ICS

SGA 2003-W SSSlide 16 *p<0.05 compared with beclomethasone Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160: Eosinophil counts (change from baseline  10 3 /µl) PlaceboBeclomethasone Montelukast + beclomethasone Montelukast * <1* Treatment group Dual Pathways of Inflammation LTRA Montelukast Further Reduced Asthmatic Inflammation Complementary therapy that targets dual pathways of inflammation provided better control of inflammation

SGA 2003-W SSSlide 17 block steroid- sensitive mediators blocks the effects of CysLTs Inhaled steroidsMontelukast Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation The slide represents an artistic rendition. Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy 2001;56(suppl 66):7-11. Steroid-sensitive mediators play a key role in asthmatic inflammation CysLTs play a key role in asthmatic inflammation Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients DUAL PATHWAY

SGA 2003-W SSSlide 18 Dual Pathways of Inflammation Airway Inflammation Correlated with Lung Function and Clinical Control FEV 1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; r S = Spearman’s rank coefficient of correlation; ECP = eosinophilic cationic protein Adapted from Louis R et al Am J Respir Crit Care Med 2000;161: –0.2 –0.4 –0.6 rSrS FEV 1 Daily symptom score PEFR variability –0.51 Absolute eosinophil counts ECP concentrations –0.36 –0.49 –0.51 –0.43 –0.52

SGA 2003-W SSSlide 19 CysLTs and steroid-sensitive mediators are two important pathways of inflammation in asthma Corticosteroids do not block the leukotriene- mediated pathway of inflammation Treating dual pathways of inflammation in the airway of asthmatic patients may provide better control of inflammation and effective asthma control Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy 2001;56(suppl 66):7-11. Summary Targeting Dual Pathways of Inflammation Improves Asthma Control

SGA 2003-W SSSlide 20 References Please see notes page.

SGA 2003-W SSSlide 21 Montelukast with Inhaled Corticosteroids Dual Pathways of Asthmatic Inflammation Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. Printed in USA VISIT US ON THE WORLD WIDE WEB AT