What needs to be changed in the naural course?

What are the clinical and experimental effects of the drugs?

Do the cohort studies reflect the experimental effects?

Why is there a difference between experimental effects of treatment and cohort studies ?

Question 1What needs to be changed in the naural course?

What do we want to prevent?

• Loss of lung fuctions• Remodelling• Inflammation• Asthma attacks• Low quality of life

Natural course of asthma

Initiation and chronicityfactors

Initiation factors

Initiation

Chronicityfactors

Remission factors

Fernando D Martinezwww.thelancet.com Vol 368 , 2006

FD Martinez Lancet , 2006

• Persistent asthma starts early in life

• Children with persistent asthma have low lung functions

• Low lunfctions are settled in early childhood and does not deteroriate further

Remodelling

Normal bronchus Severe asthmaThickened BM

Normal bronchusCollagen stain

Severe asthmaThickened BMCollagen stain

M.L.K. Tang et al. / Pharmacology & Therapeutics 112 (2006) 474–488

Does Remodelling Start before Asthma Symptoms ?

Bronchus of a 4 year old child who died of asthma

PAEDIATRIC RESPIRATORY REVIEWS (2002) 3, 315±320

Does Remodelling Start before Asthma Symptoms ?

• Histological changes in bronchi of children who died of asthma attack, that resembles changes seen in adults

• Bronchial biopsy findings in children who later develop asthma

• Development of remodelling in children who are unresponsive to inhaled steroid treatment

• Correlation of lung functions and remodelling

• Early wheezers should be treated before established asthma symptoms

Pohunek P, Eur Respir J 1997;Martinez FD N Engl J Med 1995; 332: 133±138. Merkus PJFM. Am Rev Respir Dis 1993; 148: 1484±1489. 35 .

Soru 2

What are the clinical and experimental effects of the drugs?

Effects of Inhale steroids on the consequences of asthma

İnhale steroid reduces

BALBronchial mucosaSputum

• Barnes PJ, Adcock IM: Ann Intern Med 2003, 139(5 Pt 1):359-370.

Glococorticoids

INHIBIT

• Barnes PJ, Adcock IM: Ann Intern Med 2003, 139(5 Pt 1):359-370.

glucocortikoids

Barnes PJ, Chung KF, Page CP: Inflammatory mediators of asthma: an update. Pharmacol Rev 1998, 50(4):515-596. 32

Fluticasone

İnhibits• IL-13• IL-5In peripheral blood CD4+ T cell culturesIncreases synthesis of • IL-10

Peek EJ, et al Am J Respir Cell Mol Biol 2005, 33(1):105-111

Beclametasone and Fluticasone

Inhibit• T cell proliferation• IL-5• GM-CSF expression

Powell N, Till SJ, Kay AB, Corrigan CJ: Clin Exp Allergy 2001, 31(1):69-76

Flunisolide

• In cultured sputum cells• Inhibit TGFβ release• Increase MMP-9

(Profita et al., 2004).

Inhaled steroids

Can stop and even reverse structural changes Decreases reticular basal membrane thickness and fibroblast activity.

Hoshino, M.et al. J Allergy Clin Immunol 102, 783–788.

Hoshino, M.,et al . Clin Exp Allergy 28, 568–577.

Hoshino M et al. Clin Rev Allergy Immunol 27, 59–64.

Inhaled steroids inhibits microvascular angiogenic remodelling

• Pla

B N Feltis Thorax 2007;62:314–319.

Placebo

Plasebo

Placebo IKSIKS

IKS

VEGFVEGFRVascular endothelial growth factor inhibition

Inhaled steroids

• Anti-mitogenic for airway smooth muscle • Anti-mitogenic on normal basement

membrane• Can not exhibit the same effect on collagen• Can not be effective after fibrosis

development.

Bonacci, et al Clin Exp Pharmacol Physiol 30, 324–328. Bonacciet al Br J Pharmacol 138, 1203–1206.

Steroids in effective in the presence of collagen

Basal membraneAirway smooth muscle cellsAfter 48 hrs

Collagen depositionAirway smooth muscle cellsAfter 48 hrs

Collagen depositionAirway smooth muscle cellsAfter 7 days

Bonacci JV British Journal of Pharmacology (2006) 149, 365–373.

Inhibits cell proliferation

Ekshale Sistenil Lökotrienler ile Bazal Membran ilişkisi

Lex C et al. Respiratory Research 2006, 7:63

Montelukast (+)

Montelukast (-)

Question 3

Do the cohort studies reflect the experimental effects?

No evidence that inhale steroids reduces asthma at 10 Devulapalli C,Carlsen K et al

0-2 years IKSn=29

0-2 years no IKSn=56

P values Remission at 2 years n=12

Male (%) 58.6 73.2 0.17 91.7

Parental atopy(%)

48.3 35.7 0.23 87.5

Atopic dermatitis at 2 years (%)

48.3 42.9 0.63 41.7

Hospital admissions(%)

65.5 36.4 0.01 -----

No of hospital admissions

1.3 0.5 0.01 ------

Severity score 7.5 4.5 0.01 ---

STARTBusse et al J Allergy Clin Immunol 2008

Budesonide 200 or 400 mcg/day

+regular asthma treatment

Placebo +regular treatment

0 1 2 3 4 5

Double blind phase Open phase

Budesonide 200 or 400 mcg/day

+regular asthma treatment

7241 5-66 aged Mild persistent asthma

(Busse et J Allergy Clin Immunol 2008;121:1167-74.)

In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

Question 4

Why is there a difference between experimental effects of treatment and cohort studies ?

Why are cohorts different?

• Early treatment----- how early?• Are the dose and duration of medication

adequate ?• Are all the cohorts have standardised

methods?