SGA 2003-W-286750-SS Slide 1

Dual Pathways of Asthmatic Inflammation

Montelukast with Inhaled Corticosteroids

SGA 2003-W-286750-SS Slide 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. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Bjermer L Respir Med 2001;95:703-719.

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-286750-SS Slide 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;161:9-16.

20,00010,000

1,000

100

10

1

Eosinophil 103/gsputum

Controlgroup

Mild to moderate

ICSlow-dose(n=10)

ICShigh-dose

(n=15)

OCS(n=10)

OCS ± ICS(n=7)

Severe asthma

p<0.01

p<0.001

p<0.001

p<0.01

In a clinical study of 74 patients

SGA 2003-W-286750-SS Slide 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;165:108-116; 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, 2000:1172-1185.

No Inflammation InflammationAsthma

Leukotrienes: Important in Early Asthma and Throughout the Disease

SGA 2003-W-286750-SS Slide 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-286750-SS Slide 6

Dual Pathways of Inflammation Effects of the CysLT1 Receptor on Inflammatory Cells

EosinophilsLung Macrophage

Smooth- musclecell

PBMC

CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells

Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233.

Monocytes

SGA 2003-W-286750-SS Slide 7

Dual Pathways of Inflammation Expression of the CysLT1 Receptor

Neutrophil

Monocyte

Macrophage

Basophil

Pluripotent hemopoieticstem cell

T CellsEosinophil

B Lymphocyte

CCR3

CD4+CD8+

CD19

M-CSF, GM-CSF, IL-3

LTC4, LTD4, LTE4

LN5

Mast Cell

LTC4

LTD4

LTE4

M-CSFGM-CSF

IL-5IL-3

GM-CSFLTC4

LTD4

LTE4

CD14

IL5Rβ

Represents the CysLT1 receptor

Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233; Mellor et al Proc Natl Acad Sci USA 2001;98:7964-7969

CysLT1R

CD34+

SGA 2003-W-286750-SS Slide 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

Mediatorreceptor

Othermediators

CysLTreceptor CysLT

SGA 2003-W-286750-SS Slide 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-286750-SS Slide 10

Dual Pathways of Inflammation Central Role of CysLTs in Asthma

Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.

Inflammatory Cells (mast cells, eosinophils)

Sensory Nerves

(C fibers)

CysLTsEdema

BloodVessel

Decreased Mucus Transport

EosinophilInflux

Cationic Protein Release,Epithelial-Cell Damage

Contraction and Proliferation

Airway Smooth Muscle

Increased Mucus

Secretion

Airway Epithelium

SGA 2003-W-286750-SS Slide 11

p = NS between groups

Adapted from O’Shaughnessy KM et al Am Rev Respir Dis 1993;147:1472-1476.

18.720

16

12

8

4

0

Urinary LTE4

excretion(ng/mmol

creatinine)

18.4

PlaceboFluticasone propionate

Effect of Inhaled Fluticasone Propionate on Urinary LTE4 Excretion

SGA 2003-W-286750-SS Slide 12

*

*p<0.05 vs. baseline 

Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.

0.3

0.2

0.1

0

Urinary LTE4

(ng/mgcreatinine)

Post-allergen challenge

Baseline

ControlPrednisone

*

Effect of Oral Prednisone on Urinary LTE4 Excretion

SGA 2003-W-286750-SS Slide 13

n=14

Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.

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;149:953-959.

80

70

60

50

40

30

20

10

0

BALlevels(pg/ml)

LTE4LTC4

Before prednisoneAfter prednisone

Eicosanoids in Asthmatics

SGA 2003-W-286750-SS Slide 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;160:1905-1909.

14

12

10

8

6

4

2

0

SputumCysLT 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-286750-SS Slide 15

LABA = long-acting beta2 agonist

Adapted from Currie GP et al Am J Respir Crit Care Med (in press).

Dual Pathways of Inflammation Long-Acting Beta2 Agonists Did Not Have Anti-inflammatory Effects

0

–100

–200

Change ineosinophils

( 106/L)from run-in

ICS + LABA + Montelukast

ICS +LABA ICS

ICS +Montelukast

p<0.05

p<0.05

LTRA montelukast further reduced inflammation when added to ICS

SGA 2003-W-286750-SS Slide 16

*p<0.05 compared with beclomethasone

Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868.

0.12

0.10

0.08

0.06

0.04

0.02

0

Eosinophilcounts(change

from baseline 103/µl)

Placebo Beclomethasone 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-286750-SS Slide 17

block steroid-sensitivemediators

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

CysLTsplay a key role in asthmatic inflammation

Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients

DUAL PATHWAY

SGA 2003-W-286750-SS Slide 18

Dual Pathways of Inflammation Airway Inflammation Correlated with Lung Function and Clinical Control

FEV1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; rS = Spearman’s rank coefficient of correlation; ECP = eosinophilic cationic protein

Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.

0

–0.2

–0.4

–0.6

rS

FEV1

Daily symptomscore

PEFRvariability

–0.51

Absolute eosinophil countsECP concentrations

–0.36

–0.49 –0.51

–0.43

–0.52

SGA 2003-W-286750-SS Slide 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-286750-SS Slide 20

References

Please see notes page.

SGA 2003-W-286750-SS Slide 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

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