Carlo Capristo Montelukast, una molecola buona per tutte le stagioni?
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Transcript of Carlo Capristo Montelukast, una molecola buona per tutte le stagioni?
Carlo Capristo
Montelukast, una molecola buona per
tutte le stagioni?
Leukotrienes
M. Peter-Golden N Engl J Med 2007
EXPRESSION OF THE CYSTEINYL LEUKOTRIENE 1 RECEPTOR IN NORMAL HUMAN LUNG AND PERIPHERAL BLOOD LEUKOCYTES
CysLT1R
CysLT1R
CysLT1R
CysLT1R
CysLT1RCysLT1R
CD34+
CD8+CD4+
CCR3
T Cells
Eosinophil
Neutrophil
Monocyte
IL5R
CD14
LTC4
LTD4
LTE4
Macrophage
LN5
M-CSF
GM-CSFBasophil
B lymphocyte
CD19
M-CSF, GM-CSF, IL-3
LTC4, LTD4, LTE4
PluripotentHaemopoietic
Stem Cell
Partendo dalle linee guida, quali sono le nuove evidenze presenti in
letteratura in tema di…
Asma bronchiale
Asma da sforzo
Wheezing prescolare
Classification and pharmacological treatment of preschool wheezing: changes
since 2008 Brand PLP, ERJ 2014;43:1172
** Brand PL, Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008; 32: 1096–1110.
**
Classification and pharmacological treatment of preschool wheezing: changes
since 2008 Brand PLP, ERJ 2014;43:1172
2013 consensus statement on classification and management of preschool wheezing disorders
Distinction of preschool
wheeze phenotypes
The distinctiondistinction between EVW and MTW is not clear in all patientsnot clear in all patients
SomeSome children retain a consistent pattern consistent pattern of EVW or MTW, but symptom patterns but symptom patterns change over time in many patientschange over time in many patients and their airway pathology remains unclear
Severity and frequency of episodes Severity and frequency of episodes seem to be at least as important to distinguish between children as the distinction between EVW and MTW
Classification and pharmacological treatment of preschool wheezing: changes
since 2008 Brand PLP, ERJ 2014;43:11722013 consensus statement on classification and
management of preschool wheezing disorders
Daily controller therapy
In children with MTW, ICS are the first choice for daily controller therapy
In children with EVW, daily therapy may be considered with either ICS or montelukast if:
- the attacks are severe (requiring hospital admission or systemic corticosteroids);
- or the attacks are frequent;
- or the clinician suspects that interval symptoms are being under reported
Classification and pharmacological treatment of preschool wheezing: changes
since 2008 Brand PLP, ERJ 2014;43:1172
2013 consensus statement on classification and management of preschool wheezing disorders
Daily controller therapy
Any controller therapy should be viewed as a treatment trial, with scheduled follow-up
Discontinue treatment if there has been no benefit
Take favourable natural history into account: - taper down to lowest effective dose, and - discontinue treatment if the child has been symptom-free for 3 months on low-dose therapy
(PREVIA Study). Bisgaard ARCCM 2005;171:315
* **
* **
** *
* **
**
*
** * *
****
***
****
*
*
*
**
**
**
*****
placebo
montelukast
Perc
en
tag
e o
f p
ati
en
ts
wit
h a
n e
xacerb
ati
on
even
t
1.19
0.660.53
1.74
1.10
0.64
0.0
0.5
1.0
1.5
2.0
2.5
Totali (via inalatoria ed orale)
Via Inalatoria Via Orale
Montelukast 4 mg (n=265)
Placebo (n=257)
Cicli di trattamentoconCorticosteroidi
32%
40%
p=0.024
p=0.027
p=0.368
Montelukast Reduces Asthma Exacerbations in2- to 5-Year-Old Children with Intermittent Asthma
Bisgaard H et al. - Am J Respir Crit Care Med 2005; 171: 315–322
Studio MOSAICDisegno
Visite
Mese
Run-in placebo
Montelukast 5 mg una volta al giorno*+ placebo-fluticasone x2/die
Fluticasone 100 µg x2/die + placebo-montelukast una volta al giorno
Periodo I
Periodo II
6
12
8
5
-1 4
4
0
321
ß-agonistaoß-agonista+ 1 farmaco di controllo
*I pazienti che compivano 15 anni di età, passavano al dosaggio di montelukast 10mg alla Visita 5
Garcia ML et al. Pediatrics 2005;116(2):360-369
N= 495
N= 499
Studio MOSAICObiettivo Primario
ENDPOINT PRIMARIO: Variazione dal basale della percentuale di giorni senza interventi di
soccorso per asma (Rescue Free Days-RFD) (assunzione di ß-agonisti a breve durata d’azione, CS per via sistemica, altri farmaci di soccorso o utilizzo di risorse sanitarie – visite ambulatoriali, visite in PS, ricoveri ospedalieri)
Garcia ML et al. Pediatrics 2005;116(2):360-369
Studio MOSAICRisultati
86.784.0
0
20
40
60
80
100
Montelukast 5 mg (n=482)
Fluticasone 200 mcg (n=484)
Analisi intention to treat modificata (MITT)
Montelukast è risultato NON INFERIORE al fluticasone sull’endpoint primario nei 12 mesi di
trattamento
Giorni senza interventi di soccorso, media(%)
Garcia ML et al. Pediatrics 2005;116(2):360-369
Studio MOSAICRisultati sulla velocità di crescita staturale
7.0
6.5
6.0
5.5
5.0
Mesi4 8 12
Montelukast 5 mg (n=481)
Fluticasone 200 mcg (n=482)
Velocità di crescita media(cm/anno)
p=0.018
Garcia ML et al. Pediatrics 2005;116(2):360-369
Montelukast As An Episode Modifier in the Treatment of Infrequent Episodic Asthma in Children
TRATTAMENTO A BREVE TERMINECON MONTELUKAST IN BAMBINI
CON ASMA INTERMITTENTE: UNO STUDIORANDOMIZZATO E CONTROLLATO
Pre-EmptRobertson CF et al
Am J Respir Crit Care Med 2007;175:323-329
Studio PRE-EMPTDisegno
0 2
Settimane
52 settimane o 5 episodi trattati
Montelukast 4 mg or 5 mg* una volta al giorno con episodi di URTI** o asma
per un minimo di 1 settimana e un max di 20 giorni
Placebo una volta al giornocon episodi di URTI** o asma
per un minimo di 1 settimana e un max di 20 giorni
Beta-agonistial bisogno
Periodo IRun-in
Periodo IITrattamento attivo in doppio cieco
*4 mg per I bambini di 2-5 anni di età, 5 mg per I bambini di 6-14 anni
**URTI = Upper Respiratory Tract Infections generalmente seguite da asma
n=107
n=113
Robertson CF et al. Am J Respir Crit Care Med 2007;175:323-329
Studio PRE-EMPTObiettivo Primario
Obiettivo dello studio era valutare se un trattamento
intermittente con montelukast, introdotto ai primi segni di un
episodio acuto di asma o di infezione virale delle vie aeree superiori,
potesse modificare la severità dell’episodio stesso
Endpoint primario era l’utilizzo non programmato di risorse
sanitarie correlate al trattamento degli episodi asmatici acuti (visite
mediche non programmate,visite pediatriche specialistiche, ricorso
al pronto soccorso e ospedalizzazioni)(HRU*)
Robertson CF et al. Am J Respir Crit Care Med 2007;175:323-329*Healthcare Resource Utilization
Il trattamento a breve termine con MONTELUKAST ha ridotto significativamente l’utilizzo di risorse sanitarie correlate al trattamento degli episodi asmatici acuti
30.1
39.9
0
5
10
15
20
25
30
35
40
45
Montelukast (n=97) Placebo (n=105)
p=0.008
-24%-24%
Episodicon HRU(%)
Robertson CF et al. Am J Respir Crit Care Med 2007;175:323-329
Il trattamento a breve termine con MONTELUKAST ha ridotto significativamente l’HRU, i sintomi, i giorni di assenza da scuola
dei bambini e quelli di assenza da lavoro dei genitori
Nel gruppo trattato con MONTELUKAST confrontato con il gruppo placebo:
Utilizzo totale di risorse
sanitarie**
Risvegli notturni per episodio*
Giorni di lavoro persi dai
genitori* *Assenze da scuola**
Sintomi*
-40
-35
-30
-25
-20
-15
-10
-5
0
MONTELUKAST
-14%
-28.5%
-8.6%
-37% -33%
Robertson CF et al. Am J Respir Crit Care Med 2007;175:323-329
* p<0.05 ** p<0.01
Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing
Bacharier: JACI 2008; 122: 1127
238 children with moderate- to- severe intermittent wheezing aged 12 to 59 months
7 days of either budesonide i.s. (1 mg twice daily)
montelukast (4 mg daily) placebo
in addition to albuterol with each identified respiratory tract illness
randomized, double-blind, placebo-controlled 12- month trial
Thanks D. PeroniThanks D. Peroni
Exercise-induced bronchoconstriction in children: Exercise-induced bronchoconstriction in children: Montelukast attenuates the immediate-phase and late-phaseMontelukast attenuates the immediate-phase and late-phase
responses responses
• 22 atopic 22 atopic asthmatic asthmatic children aged 7 children aged 7 to 16 years with to 16 years with EIA EIA
• Montelukast Montelukast compared with compared with placebo for 1 placebo for 1 week week
CK. Naspitz - JACI 2003CK. Naspitz - JACI 2003
Exhaled breath condensate cysteinylleukotrienes are increased in children
withexercise-induced bronchoconstriction
S. Carraro JACI 2005
BUD/FOR 100/4.5µg bid BUD 200µg + Montelukast BUD 200µg Montelukast Placebo for 4 weeks
EFFECT OF DIFFERENT ANTIASTHMATIC TREATMENTS ON EXERCISE-INDUCED BRONCHOCONSTRICTION IN CHILDREN WITH
ASTHMA MyLinh Duong JACI 2012
100 ch with exercise-induced asthma (EIA)
Lack of tolerance to the protective effect of montelukast in exercise-
inducedbronchoconstriction in children
F.M. de Benedictis-A.F. Capristo Eur Respir J 2006
Percentuale di protezione clinica ottenuta nel tempo con MONTELUKAST
46
66 64
60
7
0
10
20
30
40
50
60
70
80
90
100
Giorno 3 Giorno 7 Giorno 28
Montelukast Placebo
Pro
tezi
on
e c
lin
ica (
% d
i p
azie
nti
)
F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295
Update on the use of montelukast in pediatric
asthmaCONCLUSIONS
Currently, ICSs are recognized as the preferred longterm control therapy in children with persistent asthma, with leukotriene receptor antagonists Positioned as an alternative choice or as an adjunct treatmentin patients not completely controlled.
Firstline treatment with montelukast appears possible and reasonable for preschool children because a high percentage of them do not have the immunologic features of allergic asthma and may not respond to Prophylactic therapy with ICSs.
C. Capristo and A. L. Boner Allergy and Asthma Proc. 2006
Update on the use of montelukast in pediatric asthma
CONCLUSIONS
The use of montelukast is particularly effective in children with exercise-induced asthma, a condition observed in almost all asthmatic children even in preschool age.
Finally, the currently available pharmaceutical forms dosage of 5 mg/day for children 6–14 years old, 4 mg of chewable tablets for a dosage of 4 mg/day for children 2–5 years of age, and a 4-mg granular formulationfor a dosage of 4 mg /day for babies between 6 months and 2 years of age.These prescriptions cover all age ranges of asthmatic children who might clinically benefit from this drug.
C. Capristo and A. L. Boner Allergy and Asthma Proc. 2006
GRAZIE PER
L’ATTENZIONE
20142014
12-13 Dicembre 201412-13 Dicembre 2014