Recent in COPD

Recent in COPD
Gamal Rabie Agmy, MD,FCCP
Professor of Chest Diseases, Assiut university
Presentation1.lnk

LUNG INFLAMMATION
COPD PATHOLOGY
Oxidative
stress Proteinases
Repair
mechanisms
Anti-proteinasesAnti-oxidants
Host factors
Amplifying mechanisms
Cigarette smoke
Biomass particles
Particulates
Source: Peter J. Barnes,
MD
Pathogenesis of COPD

44
Apoptotic Pathways in COPD
Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
Survival
factor Granzyme B Perforin
TNF-α
sFasL
cytoplasm
nucleus
ER Stress
Apoptosome
Apaf 1
Procasp-9
Procasp-9
Casp-9
Casp-8 CAD CAD
ICAD
Casp-8
Procasp-8Procasp-8
FADDBidtBid
Bax
Bak
Cyt C
ER
stress
DNAfragmentation
1
2
4
3
5
?
Fas
COPD Pathogenesis

66
Angiogenesis in COPD
Reprinted from International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in
chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission from Dove Medical Press Ltd.
extravasated
plasma proteins
Inflammatory cells
(Mac, Neu, Epith, Lymph)
Release of angiogenic
mediators
Fibrinogen
products
Inflammation Tissue
hypoxia
Airway
fibrosis
Mechanical
Injury
Increased
blood flow
Vessel growth
Angiogenesis
Vascular remodeling
Up-regulation of
Angiogenic factors
Shear stress
on the endothelium
COPD Pathogenesis

77
Angiogenic and Angiostatic Factors in COPD
 Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL1
– CXCL5
– CXCL8
– CCL2
– VEGF
– bFGF
– Angiopoietin-1
– HGF
– EGF
 Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL10
– CXCL11
Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
COPD Pathogenesis

Disrupted alveolar attachments
Inflammatory exudate in lumen
Peribronchial fibrosis
Lymphoid
follicle
Thickened wall with inflammatory cells
- macrophages, CD8+ cells, fibroblasts
Changes in Small Airways in COPD Patients
Source: Peter J. Barnes,
MD

9
Alveolar wall destruction
Loss of elasticity
Destruction of pulmonary
capillary bed
↑ Inflammatory cells
macrophages, CD8+ lymphocytes
Changes in the Lung Parenchyma in COPD
Source: Peter J. Barnes, MD

10
Normal
Inspiration
Expiration
alveolar attachments
Mild/moderate
COPD
loss of elasticity
Severe
COPD
loss of alveolar attachments
closure
small
airway
Dyspnea
↓ Exercise capacity
Air trapping
Hyperinflation
↓ Health
status
Source: Peter J. Barnes, MD
Air trapping in COPD

Dr.Sarma@works
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CLINICAL FEATURES

Dr.Sarma@works
12
CHRONIC BRONCHITISEMPHYSEMA
1. Mild dyspnea
2. Cough before dyspnea starts
3. Copious, purulent sputum
4. More frequent infections
5. Repeated resp. insufficiency
6. PaCO2 50-60 mmHg
7. PaO2 45-60 mmHg
8. Hematocrit 50-60%
9. DLCO is not that much ↓
10. Cor pulmonalecommon
1. Severe dyspnea
2. Cough after dyspnea
3. Scant sputum
4. Less frequent infections
5. Terminal RF
6. PaCO2 35-40 mmHg
7. PaO2 65-75 mmHg
8. Hematocrit 35-45%
9. DLCO is decreased
10. Cor pulmonalerare.

Dr.Sarma@works
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CHRONIC BRONCHITISEMPHYSEMA
BLUE BLOTTERPINK PUFFER

ALPHA1 ANTITRYPSIN ↓EMPHYSEMA
Specific circumstances of Alpha 1- AT↓include.
• Emphysema in a young individual(< 35)
• Without obvious risk factors (smoking etc)
• Necrotizing panniculitis, Systemic vasculitis
• Anti-neutrophil cytoplasmic antibody (ANCA)
• Cirrhosis of liver, Hepatocellular carcinoma
• Bronchiectasis of undetermined etiology
• Otherwise unexplained liver disease, or a
• Family history of any one of these conditions
• Especially siblings of PI*ZZ individuals.
• Only 2% of COPD is alpha 1- AT ↓

Patterns of Abnormality
Restriction low FEV1 & FVC, high FEV1%FVC
Recorded Predicted SR %Pred
FEV 1 1.49 2.52 -2.0 59
FVC 1.97 3.32 -2.2 59
FEV 1 %FVC 76 74 0.3 103
PEF 8.42 7.19 1.0 117
Obstructive low FEV1 relative to FVC, low PEF, low FEV1%FVC
FEV 1 0.56 3.25 -5.3 17
FVC 1.65 4.04 -3.9 41
FEV 1 %FVC 34 78 -6.1 44
PEF 2.5 8.28 -4.8 30
high PEF early ILD
low PEF late ILD

Patterns of Abnormality
Upper AirwayObstruction low PEF relative to FEV1
FEV 1 2.17 2.27 -0.3 96
FVC 2.68 2.70 0.0 99
FEV 1 %FVC 81 76 0.7 106
PEF 2.95 5.99 -3.4 49
FEV 1 /PEF 12.3
Discordant PEF and FEV1
High PEF versus FEV1 = early interstitial lung disease (ILD)
Low PEF versus FEV1 = upper airway obstruction
Concordant PEF and FEV1
Both low in airflow obstruction, myopathy, late ILD

β2-adrenergic receptors
• High concentration in lung
tissue
• Density in airway smooth
muscle does not change at
different airway levels
• Bronchioles have a
similar density to large
airways.
Muscarinic
(cholinergic) receptors
• In smooth muscle
of all airways
• Higher density
in larger airways
β2-agonists and muscarinic antagonists provide
bronchodilation with complementary modes and
sites of action
Muscarinic antagonists
• Prevent acetylcholine
binding to muscarinic
receptors that make
muscle contract
β2-agonists
• Promote muscle relaxation
by stimulating c-AMP,
providing functional
antagonism to
bronchoconstriction
Barnes PJ. Distribution of receptor targets in the lung. PATS 2004;1:345–51.

Influencing the bronchial tone
Bronchodilation may, therefore, be
obtained either by directly relaxing the
smooth muscle through stimulation of the
b2-AR with b2-AR agonists, or/and by
inhibiting the action of ACh at mAChRs.

Bronchodilators
Indacterol Glycopyrronium bromide
Olodaterol Aclidinium bromide
Vilanterol
Xanthines

Inhibitory NANC (iNANC) system is considered to be
the main neural mechanism mediating ASM relaxation
by releasing of vasoactive intestinal peptide (VIP), VIP
structure-related peptides and nitric oxide (NO) .
On the other hand, excitatory NANC (eNANC) system
mediates bronchial contraction activating the efferent
functions of bronchopulmonary-sensitive sensory
nerves. These nerves release tachykinins, such as
substance P and neurokinin A, which in turn activate
neurokinin-1 (NK-1) and NK-2 receptors located on the
ASM membrane, thus inducing bronchoconstriction

Bronchodilation may, therefore, be
obtained either by directly relaxing the
smooth muscle through stimulation of the
b2-AR with b2-AR agonists, or/and by
inhibiting the action of ACh at mAChRs.
Furthermore, an alternative approach
could be the modulation of the NANC
system.

Global Strategy for Diagnosis, Management and Prevention of COPD
Definition of COPD
◙ COPD, a common preventable and treatable
disease, is characterized by persistent airflow
limitation that is usually progressive and
associated with an enhanced chronic
inflammatory response in the airways and the
lung to noxious particles or gases.
◙ Exacerbations and comorbidities contribute to
the overall severity in individual patients.

28
COPDforum is
supported by
Inflammatory Cells in Stable COPD
Gamal Agmy 2-5-2014
Inflammation in COPD

2929
Neutrophils in COPD
Mucoushypersecretion
Serine proteases
Neutrophil
Elastase
Cathepsin G
Proteinase-3

O2
-
MPO
LTB4,IL-8, GRO-
LTB4,IL-8
Adapted from Barnes PJ. N Engl J Med. 2000; 343: 269-280
Adapted from Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688
Emphysema
Severe emphysema
Images courtesy R Buhl.

3030
Sputum Neutrophil Count
Correlates With Declining Lung Function
Reproduced with permission of Thorax from “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are
associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through
Copyright Clearance Center, Inc.
> 30 < 20
100
0
NeutrophilsiniInducedsputum(%)
90
20 – 30
80
60
70
50
40
FEV1 decline (mL/year)
P<0.01

3131
Neutrophils Infiltrating Bronchial
Glands in COPD
Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission from American Thoracic Society.
Copyright © 1997

3232
Reduction in Neutrophil Apoptosis in COPD
Adapted from Brown V, et al. Respir Res. 2009;10:24.
Apoptotic neutrophils
(arrows)
*P<0.05
*P<0.01
MorphologyTunel
NS
HS
COPD
60
50
40
30
20
10
0
Apoptotic
neutrophils [%]
Image courtesyof R Buhl.
NS: nonsmoking controls (n=9) HS:
healthy smoking controls (n=9)
TUNEL: the terminal transferase-
mediated dUTP nick end-labeling method

3333
Alveolar Macrophages in COPD
 Phagocytosis
Cigarette smoke
Wood smoke
Elastolysis
MMP-9,MMP-12
Cathepsins K, L, S
Emphysema
Steroid resistance
NO
ROSONOO-
 HDAC
 Steroid
response
Monocytes
MCP-1
GRO-
Neutrophils
LTB4
IL-8
GRO-
CD8+
Cells
IP-10
Mig
I-TAC
Adapted from Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 from "Alveolar Macrophages as Orchestrators of COPD" by
Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com
Emphysema
Severe emphysema
Images courtesy of R Buhl.
 Numbers
 Secretion

3434
Inflammatory Mediators in COPD – Summary
Cell
Neutrophils
Macrophages
T-cell
Epithelialcell
IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- ,
MCP-1, MMP-9
Granzyme B, perforins, IFN-, TNF-
IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4,
GRO-, MCP-1, ROS, MMP-9
Serine proteases, TNF-, ROS, IL-8, MPO, LTB4
Selected Mediators
Barnes PJ, et al. Eur Respir J. 2003;22:672-888.

3535
Examples of Chemotactic Factors in COPD
Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272.
Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898.
Montuschi P, et al. Thorax. 2003;58:585-588.
 MCP-1
 GRO-
 Elastin
fragments
 LTB4
 IL-8
 GRO-
 Elastin
fragments
 IP-10
 Mig
 I-TAC
Neutrophil Monocyte T-cell

3636
TNF- Has Pro-inflammatory
Actions in COPD
Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission from Biomed Central.
Oxidative stress
Activation of NF-B and AP-1
Activation of proinflammatorymolecules e.g.VCAM-1,ICAM-1 and RAGE
SubcellularROS production
TNF-
Antioxidants
e.g. GSH,
Catalase
Scavenge free radicals,
detoxifycellular
hydrogen peroxideand
inhibit ROS generation
Proinflammation
+
+
+
+
+
+
+
-
-

37
COPDforum is
supported by
Modulation of Inflammation by
Histone Deacetylase (HDAC)
Gamal Agmy 2-5-2014

3838
Decreased HDAC Expression May Promote
Inflammation and Decrease Response to
ICS in COPD
Normal
Histone
acetylation
Stimuli
Steroid
sensitive
Histone
hyperacetylation
nitration
ubiquitination
oxidation
↑TNF
↑IL-8
↑GM-CSF
Stimuli
Steroid
resistant
HAT
TF
HAT
TF
TNF
IL-8
GM-CSF
Glucocorticoid
receptor
COPD
HDAC2
HDAC2
Glucocorticoid
peroxynitrite
Reproduced from Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inflammatory lung diseases,” pp249-265.
Copyright © 2007, with permission from Elsevier.

3939
Pulmonary HDAC Levels Decrease
With COPD Severity
Adapted from Ito K, et al. N Engl J Med. 2005;352:1967-1976.
S = COPD Stage
0
.5
1.0
1.5
2.0
Non-
smoker
N=11
P<0.001
HDAC2expression(vs.laminA/C)
P=0.04
P<0.001
P<0.001
S4
N=6
S0
N=9
S1
N=10
S2
N=10
■
■
■
■
■

4040
Inflammation Leads to Small
Airway Narrowing
 Acute and chronic inflammation suspected to contribute to COPD-related
small airway narrowing
 Airway narrowing leads to airway obstruction
 Narrowing results from several factors:
– Collagen deposition and increased lymphoid follicles in outer airway wall
– Mucosal thickening of airway lumen
– Inflammatory exudate in airway lumen
Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.

4141
Inflammation and Airway Destruction
Normal COPD
Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary
disease," pp709-721. Copyright © 2004, with permission from Elsevier.

4242
Exacerbations of Chronic Bronchitis
and Inflammatory Cell Types
Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931.
Barnes PJ. N Engl J Med. 2000;343:269-280.
COPD Exacerbation
Eosinophils
Eosinophils
T-Cells
Neutrophils
Cells Predominant in:
Induced sputum
Biopsy
Neutrophils
Inflammation in
COPD

4343
Clinical Impact of Inflammation in COPD
Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission from Biomed Central.
Increased Airway Inflammation
Increased mucous production
Airway wall thickening
Airway wall oedema
Bronchoconstriction
Airway narrowing
V’/Q’ MismatchingHyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure

4444
Inflammation:
Clinical Consequences
Systemic
 Nutritional abnormalities and weight loss
 Hypoxaemia
 Skeletal muscle dysfunction
 Cardiovascular disease
 Depression
 Osteoporosis
 Anaemia
Agusti AG, et al. Eur Respir J. 2003;21:347-360.
Agusti AG. Proc Am Thorac. 2006;3:478-483.
Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185.
Pulmonary
 Dyspnoea
 Cough
 Sputum production
 Exacerbations

Influencing The Cellular Components
Of Inflammation
Phosphodiesterase Inhibitors
The PDE4 isoenzyme is a major therapeutic target
because it is the predominant isoenzyme in the majority
of inflammatory cells, including neutrophils, which are
implicated in the pathogenesis of COPD. Inhibition of
PDE4 in inflammatory cells influences various specific
responses, such as the production and/or release of pro-
inflammatory mediators including cytokines and active
oxygen species , with a well-documented efficacy in
animal models of COPD .

Of Inflammation
Phosphodiesterase Inhibitors
Oral PDE4 inhibitors: roflumilast; GRC-3886;
ELB353; GRC 4039; MEM1414; oglemilast;
OX914; ASP3258; TAS-203; Zl-n-91; NIS-
62949; tetomilast
Inhaled PDE4 inhibitors; GSK256066;
SCH900182; Compound 1; tofimilast;
AWD12-281; UK500001
PDE3/4 inhibitors: RPL554
PDE4/7 inhibitors: TPI 1100

Of Inflammation
Adenosine receptors Agonist
Some evidence suggests the involvement of adenosine
receptors in inflammation. Four subtypes (A1, A2A, A2B, A3) of
adenosine receptors have been characterized. The anti-
inflammatory effect of adenosine is due to a short-term
activation of A2A receptor that elevates cAMP and,
consequently, modulates key pro-inflammatory neutrophil
functions such as superoxide generation, degranulation and
adhesion. Furthermore, adenosine A2A receptor activation
induces a shift in the profile of lipid mediator production from
leukotrienes to prostaglandin E2.This shift may contribute to
prevent the subsequent neutrophil-elicited inflammatory
events

Of Inflammation
Adenosine receptors A2a Agonists
CGS21680; ATL146e; UK371,104; GW328267X;
regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP

Of Inflammation
Adhesion molecules
Inflammatory processes in COPD are coupled to an increased
recruitmentof neutrophilsto the lung in response to a release of IL-8
and leukotriene B4 (LTB4) by activated epithelial cells and
macrophages . Migration of inflammatory cells from the vascular
compartment to the surrounding tissue is partly regulated by
selectins (L-, P- and E-selectin). Selectins mediate transient adhesive
interactions pertinent to inflammation through the recognition of the
carbohydrate epitope, sialyl Lewisx (sLex), expressed on circulating
leukocytes. The rapid turnover of selectin--ligand bonds mediates the
cell tethering and rolling in shear flow. Several studies suggest that
selectins are involved in the inflammatory processes of COPD .
Therefore, targeting these molecules might reduce the inflammation
in COPD

Of Inflammation
Drugs that interfere with adhesion molecules
Carbohydrate-based inhibitors: sLex antagonists
(bimosiamose); heparins and heparinoids (PGX-
100, PGX-200); synthetic glycomimetic molecule
(GMI-1070) mAb inhibitors: EL246

Influencing The Inflammatory mediators
1-TNF-a
2-Chemokines
3-NF-kB
4-p38 MAPK and MK2
5-PI3K
6-LTB4
7-PPAR

Targeting protease activity at the
enzymatic level

Drugs that may have indirect anti-
inflammatory actions
Reversing glucocorticoid resistance :
Activation of HDAC2: theophylline;
curcumin; resveratrol
Inhibition of P-glycoprotein
Inhibition of MIF

THE PRIMARY PHYSIOLOGIC
IMPAIRMENT IN COPD IS
Rabe K et al. PATS 2006;3:270–5.
AIRFLOW LIMITATION

COPD is caused by inhaled noxious agents,
with lung damage leading to airflow
limitation
Inhaled noxious agents
(e.g. cigarette smoking, pollutants)
Obstruction and airflow limitation
Lung damage
Small airway disease:
Airway narrowing
and fibrosis
Mucus
hypersecretion
(chronic
bronchitis)
Parenchymal
destruction:
Loss of alveolar
attachments, decrease
in elastic recoil
(emphysema)
GOLD 2014

Eur Respir Rev 2006; 15: 99, 37–41
The physiological hallmark of COPD is
expiratoryflow limitation.
Expiratory flow limitation in patients with COPD
Air trapping
Dyspnea
(breathlessness)
Exercise
intolerance
Hyperinflation
Reduced health-
related quality of
life (HRQoL)

Obstruction and airflow limitation lead to
dyspnea and exercise intolerance
Narrowingof
peripheral airways
Decreased FEV1
Progressive
Air Trapping and
Hyperinflation Inspiratory capacity
reduced
Dyspnea and Limitation of
Exercise capacity
1. GOLD 2014; 2. Rabe. PATS 2006

Air trapping and associated hyperinflation
provide a mechanistic link between the
physiological impairment and the
characteristic symptoms of COPD

Air Trapping and Hyperinflation
• Air trapping and associated
hyperinflationprovide a mechanistic
link between the physiological
impairment and the characteristic
symptoms of COPD, such as :
1. Dyspnea (breathlessness)
2. Exercise intolerance
3. Reduced health-related quality of life
Proc Am Thorac Soc Vol 3. pp 185–189, 2006

Relationship between static lung
volumes and disease severity.
• Gas trapping and lung
hyperinflation were
shown to occur even
in the earliest stages
of COPD and
increased
exponentially with
severity of airway
obstruction
Expert Rev. Respir. Med. 6(6), 651–662 (2012)
RV: Residual volume

Improve
exercise
tolerance
GOLD guidelines state that effective
management should aim to:
The GOLD guideline recommends long-acting
bronchodilators as first-line maintenance
treatment in COPD.
Eur Respir Rev 2006; 15: 99, 37–41
Relieve
symptoms
(dyspnea)1 2 Improve
HRQoL3

Bronchodilators address airflow limitation by
targeting bronchoconstriction and reducing
air trapping
GOLD 2014

Bronchodilators improves airflow limitation
by targeting bronchoconstriction and
reducing air trapping
BronchodilatorsBronchodilators
Smooth muscle relaxation
Increased
mucociliary
clearance
Reduced
hyperinflation Improved respiratory muscle function
Improve emptying of the lungs
GOLD 2014
Chest 2001;120;258-270

V
BD
 Air flowDeflation
 Improvement in flow – FEV1
 Improvement in volumes – FVC and IC
Bronchodilator therapy deflates the
lung
BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;
FVC= forced vital capacity; IC = inspiratory capacity

Bronchodilators work by:
Eur Respir Rev 2006; 15: 99, 37–41
Relievedyspnea by
deflating the lungs
Allowingimprovedlung
emptying with each
breath
Improvementin
exercise tolerance
Reduces the
elastic load on the
inspiratory
muscles.

The GOLD guidelinesrecommend
bronchodilators
• The GOLD guidelines recommend
bronchodilators,such as β2-agonists,
anticholinergic agents and methyl
xanthines, for first line symptom
control, and long-acting
bronchodilators for first-line
maintenancetreatment in COPD
Proc Am Thorac Soc Vol 3. pp 185–189, 2006

Bronchodilators are the cornerstone
of COPD treatment
• Target air flow limitation,
bronchodilatingby altering airway
smooth muscle tone
• Improve emptying of the lung
• Reduce hyperinflation at rest and
during exercise
GOLD 2014

Indacaterol once daily
β2-agonist
Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes post-dose.1 and
sustained bronchodilation over 24 hours.2
1-Balint, et al. Int J COPD 2010;5:311–8.
2- Vogelmeieret al. Respiratory Research 2010, 11:135

1.2
1.3
1.4
1.5
1.6
Placebo
(n=88)
Salmeterol/
fluticasone
(n=88)
Salbutamol
(n=86)
Indacaterol
150 µg
(n=85)
Indacaterol
300 µg
(n=87)
LSmeanofFEV1(L)
Data are least squares mean (LSM) with standard errors of the mean at 5 minutes post-dose
**
*** ***
***
Balint, et al. Int J COPD 2010;5:311–8.
Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes
post-dose
INSURE: INdacaterol: Starting qUickly and Remaining Effective in COPD
***p<0.001,
**p<0.01 versus placebo
N= 89 patients

Data are LSM±SE.
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Indacaterol 150 µg
Indacaterol 300 µg
Tiotropium
Placebo
1.65
1.60
1.55
1.50
1.45
1.40
1.35
1.30
†
†
†
†
†
† †
†
Time post-dose
(hours)
FEV1(L)
Vogelmeieret al. Respiratory Research 2010, 11:135
Indacaterol provided sustained
bronchodilation over 24 hours
INTIME: INdacaterol & TIotropium: Measuring Efficacy
p<0.001 for indacaterol (150 and 300 µg) vs placebo at each timepoint, p<0.001 for indacaterol 150 µg vs
tiotropium at 5 and 15 minutes, †p<0.05 for indacaterol 300 µg vs tiotropium, p<0.05 for tiotropium vs placebo at
each timepoint
n= 153 patients

Renard D, et al. 2011 Respir Res; 12:54
• Pooled analysis of 11 placebo-controlled studies
• Aim: determine Optimal Indacaterol dosage
• Primary endpoint: trough FEV1 with a duration of at
least 14 days.
• n=7,476 COPD patients
• Patients received Indacaterol 18.75-600 µg o.d.

Indacaterol 300 μg provide optimal
bronchodilation, particularly in patients
with severe disease.
Renard D, et al. 2011 Respir Res; 12:54
Ranking of efficacy by dose

1.31 1.31
1.28
1.43
1.38
1.32
1.45
1.48
1.43
1.15
1.2
1.25
1.3
1.35
1.4
1.45
1.5
After 1 day Week 12 Week 52
†††
***
†††
***†
***
***
***
*
TroughFEV1(L)
Placebo (n=364) Formoterol 12 μg b.i.d. (n=373)
Indacaterol 300 μg o.d. (n=383)
Indacaterol 300 µg provides significant
improvement in trough FEV1 over 52 weeks,
superior to Formoterol
*p<0.05, ***p<0.001 vs placebo; †p<0.05, †††p<0.001 vs Formoterol
Dahl et al. Thorax 2010;65:473–9.
100 ml
110 ml20 ml

*p<0.05, ***p<0.001 vs placebo; †††p<0.001 for difference vs tiotropium; ‡p=0.008 for difference vs
indacaterol 150 μg
Once Daily Indacaterol Pooled Analysis
Clinical efficacy in COPD-Patients with severe
dyspnoea (mMRC>2)
Mahler et al. ERS Annual Congress 2012

Indacaterol reduces breathlessness as
indicated by improvements in TDI score
at all assessments points
Data are LSM and 95% confidence intervals
***p<0.001 versus placebo, †p<0.05, †††p<0.001 versus tiotropium
n= 326 360 355 363 309 349 343 353342 372 367 367 324 353 348 360
***
***
***
***
***
***
***
***
***
††† ††† ***
***
†
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Week 4 Week 8 Week 12 Week 26
TDItotalscore
Placebo Tiotropium 18 µg o.d. Indacaterol 150 µg o.d. Indacaterol 300 µg o.d.
TDI = transition dyspnea index
Donohue JF et al. Am J Respir Crit Care Med 2010;182:155–62.

Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Indacaterol 300 μg dose was superior
compared to the twice-daily β2-agonists

Indacaterol 300 μg dose was superior
compared to the twice-daily β2-agonists
Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Differences between active and placebo treatments in TDI total score after6 months (pooled data). 1
Patient numbers were 602 (Indacaterol 150 μg QD), 651 (Indacaterol 300 μg QD ), 317 (formoterol 12 μg
BID), 320 (tiotropium 18 μg QD ), 279 (salmeterol 50 μg BID) and 823 (placebo). 1
Data are least square means and 95% CI.1
Dotted line indicates the MCID (minimum clinically important difference) vs. placebo.

Indacaterol 300 µg increases % of days without
rescue medication use over 52 weeks, compared
with placebo and Formoterol
***p<0.001 vs placebo; ††p=0.007 vs formoterol
***
68%
improvement
Over 52 weeks
Dayswithnorescueuse(%)
70
60
50
40
30
20
10
0
34.8%
52.1% 58.3%
Placebo (n=364) Formoterol 12 μg b.i.d. (n=373)
Indacaterol 300 μg o.d. (n=383)
***
††
Dahl et al. Thorax 2010;65:473–9.

Effect of Indacaterol on
exercise endurance and
lung hyperinflation in COPD
INABLE 1: Indacaterol: endurance, exercise-based, and lung evaluation 1.
Respiratory Medicine (2011) 105, 1030-1036

Exercise endurance study
INABLE-1 study design
Indacaterol 300 μg o.d. Indacaterol300 μg o.d.
PlaceboPlacebo
Screening Treatment 1 Washout Treatment 2
3 weeks 3 weeks 3 weeks
• Double-blind, placebo-controlled, two-period
crossover study
• 90 patients randomized
• The primary efficacy variable was exercise endurance time after 3 weeks
of treatment, measured through constant-load cycle ergometry testing
performed at 75% of the peak work rate in a screening incremental exercise
test.

Indacaterol improves exercise
endurance time (in mins)
5
8
10
11
12
Day 1 Week 3
Data are LSM and standard errors
*p=0.011, ***p<0.001
Exerciseendurancetime(mins)
Indacaterol 300 µgPlacebo
8.07
9.75
Δ 1.68 ***
7.92
9.77
Δ 1.85 *
9
7
6

Indacaterol improves inspiratory
capacity
1.5
2.1
2.5
Day 1 Week 3
*p=0.04, **p=0.002
End-exerciseinspiratorycapacity(L)
Indacaterol300 µgPlacebo
1.98
2.17
Δ 190 mL *
1.94
2.22
Δ 280 mL **
2.3
1.9
1.7

Indacaterol improves bronchodilation
1.4
1.7
1.9
Day 1 –
75 min post-dose
Week 3 –
60 min pre-dose
Resting FEV1 was a secondary endpoint
***p<0.001
RestingFEV1(L)
Indacaterol 300 µgPlacebo
1.56
1.79
Δ 0.23 ***
1.53
1.73
Δ 0.20 ***
1.8
1.6
1.5
1.59
1.84
Δ 0.25 ***
Week 3 –
75 min post-dose

Indacaterol has a good overall
safety & tolerability profile
• In terms of safety, Indacaterol 300 μg demonstrated
good overall safety and tolerability profile.
• The overall rate of adverse events (AEs) was
comparable between Indacaterol and placebo, with
nearly all AEs reported being mild or moderate in
severity.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.

Indacaterol has a good overall
safety & tolerability profile
• In a 52-week study that compared Indacaterol 300
and 600 μg once daily with Formoterol and placebo,
Indacaterol was also well tolerated, with a safety
profile that indicated minimal impact on QTc
interval and systemic β2-mediated events.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.

Breezhaler®: Easy-to-use device for
effective drug delivery

Breezhaler® has lower airflow
resistance than other inhalers
0
20
40
60
80
100
120
0 2 4 6 8 10
Inspiratory effort (kPa)
Flowrate(L/min)
Breezhaler 2.2  10-2 kPa1/2 L-1 min
Diskus 2.7  10-2 kPa1/2 L-1 min
Turbuhaler 3.4  10-2 kPa1/2 L-1 min
Handihaler 5.1  10-2 kPa1/2 L-1 min
Singh D et al. ATS 2010 (poster)

Conclusion
• COPD is caused by inhaled noxious
agents, with lung damage leading to
airflow limitation
• Air trapping and associated
hyperinflationprovide a mechanistic
link between the physiological
impairment and the characteristic
symptoms of COPD

Conclusion
• The GOLD guideline recommends
long-acting bronchodilators as first-
line maintenance treatment in COPD.
• Bronchodilatorsaddress airflow
limitation by targeting
bronchoconstriction and reducing air
trapping.

Conclusion
• LABAs
– Improve lung function.
– Improve health statusrelated quality of life.
– Reduce exacerbations in symptomatic
patients with moderate-to-severeCOPD.
– Provide a significant relief from exercise and
Dyspnea.
• There is a need for novel once-daily
LABA with fast onset of action and
superior efficacy over existing
bronchodilators.

Conclusion
• Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes post-
dose and sustained bronchodilation
over 24 hours.
• Indacaterol 300 μg provide optimal
bronchodilation, particularly in patients
with severe disease.
• Indacaterol 300 µg provides significant
improvement in trough FEV1 over 52
weeks

Conclusion
• Indacaterolreduces breathlessness as
indicated by improvements in TDI
score at all assessments points
• Indacaterol 300 μg dose was superior
compared to the twice-daily β2-
agonists
• Indacaterol 300 µg increases % of days
without rescue medication use over 52
weeks

Conclusion
• Indacaterolimproves exercise
endurance time
• Indacaterolimproves inspiratory
capacity
• Indacaterol improves bronchodilation
• Indacaterolhas a good overall safety &
tolerability profile
• Breezhaler® is an Easy-to-use device for
effective drug delivery

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