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Carlo Capristo Montelukast, una molecola buona per tutte le stagioni?

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Presentazione sul tema: "Carlo Capristo Montelukast, una molecola buona per tutte le stagioni?"— Transcript della presentazione:

1 Carlo Capristo Montelukast, una molecola buona per tutte le stagioni?

2 Leukotrienes M. Peter-Golden N Engl J Med 2007

3 EXPRESSION OF THE CYSTEINYL LEUKOTRIENE 1 RECEPTOR IN NORMAL HUMAN LUNG AND PERIPHERAL BLOOD LEUKOCYTES CysLT 1 R CD34 + CD8 + CD4 + CCR3 T Cells Eosinophil Neutrophil Monocyte IL5R  CD1 4 LTC 4 LTD 4 LTE 4 Macrophage LN5 M-CSF GM-CSF Basophil B lymphocyte CD19 M-CSF, GM-CSF, IL-3 LTC 4, LTD 4, LTE 4 Pluripotent Haemopoietic Stem Cell

4 Partendo dalle linee guida, quali sono le nuove evidenze presenti in letteratura in tema di…  Asma bronchiale  Asma da sforzo  Wheezing prescolare

5 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43:1172 significant new evidence 1)Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. wheeze patterns in young children vary over time and with treatment distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. 2)The consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. 3)Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, episodic viral wheeze with frequent or severe episodes 3)Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported.

6 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43:1172 4)Any controller therapy should be viewed as a treatment trial 4)Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. 5)The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. 6)Oral corticosteroids are not indicated in mild-to- moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients 6)Oral corticosteroids are not indicated in mild-to- moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients.

7 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. *

8 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43: consensus statement on classification and management of preschool wheezing disorders Distinction of preschool wheeze phenotypes distinction not clear in all patients  The distinction between EVW and MTW is not clear in all patients  Someconsistent pattern but symptom patterns change over time in many patients  Some children retain a consistent pattern of EVW or MTW, but symptom patterns change 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

9 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43: 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

10 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43: 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

11 Classification and pharmacological treatment of preschool wheezing: changes since 2008 Brand PLP, ERJ 2014;43: consensus statement on classification and management of preschool wheezing disorders Treatment of acute episodes  Oral corticosteroids are not indicated in preschool children with an exacerbation of viral wheeze who do not need to be admitted to hospital  Oral corticosteroids are indicated only in preschool children admitted to hospital with very severe wheeze; even in this group, evidence to support the use of prednisolone is not robust

12 (PREVIA Study). Bisgaard ARCCM 2005;171:315 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * placebo montelukast Percentage of patients with an exacerbation event

13 Totali (via inalatoria ed orale) Via InalatoriaVia Orale Montelukast 4 mg (n=265) Placebo (n=257) Cicli di trattamento con Corticosteroidi 32% 40% p=0.024 p=0.027 p=0.368 Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent Asthma Bisgaard H et al. - Am J Respir Crit Care Med 2005; 171: 315–322

14 MONTELUKAST, confrontato con il fluticasone, nel controllo dell’asma, in bambini dai 6 ai 14 anni con asma lieve: lo studio MOSAIC MOntelukast Study of Asthma In Children Garcia ML, et al Pediatrics 2005; 116(2):

15 Studio MOSAIC Disegno Visite Mese Run-in placebo Montelukast 5 mg una volta al giorno* + placebo-fluticasone x2/die Fluticasone 100 µ g x2/die + placebo-montelukast una volta al giorno Periodo I Periodo II ß-agonista o ß-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): N= 495 N= 499

16 Studio MOSAIC Obiettivo 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):

17 Studio MOSAIC Risultati 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):

18 Studio MOSAIC Risultati sulla velocità di crescita staturale Mesi 4812 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):

19 Montelukast As An Episode Modifier in the Treatment of Infrequent Episodic Asthma in Children TRATTAMENTO A BREVE TERMINE CON MONTELUKAST IN BAMBINI CON ASMA INTERMITTENTE: UNO STUDIO RANDOMIZZATO E CONTROLLATO Pre-Empt Robertson CF et al Am J Respir Crit Care Med 2007;175:

20 Studio PRE-EMPT Disegno 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 giorno con episodi di URTI** o asma per un minimo di 1 settimana e un max di 20 giorni Beta-agonisti al bisogno Periodo I Run-in Periodo II Trattamento 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:

21 Studio PRE-EMPT Obiettivo 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: *Healthcare Resource Utilization

22 Il trattamento a breve termine con MONTELUKAST ha ridotto significativamente l’utilizzo di risorse sanitarie correlate al trattamento degli episodi asmatici acuti Montelukast (n=97)Placebo (n=105) p= % Episodi con HRU (%) Robertson CF et al. Am J Respir Crit Care Med 2007;175:

23 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: -14% -28.5% -8.6% -37% -33% Robertson CF et al. Am J Respir Crit Care Med 2007;175: * p<0.05 ** p<0.01

24 Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing Bacharier: JACI 2008; 122: 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. Peroni

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36 Exercise-induced bronchoconstriction in children: Montelukast attenuates the immediate-phase and late-phase responses 22 atopic asthmatic children aged 7 to 16 years with EIA22 atopic asthmatic children aged 7 to 16 years with EIA Montelukast compared with placebo for 1 weekMontelukast compared with placebo for 1 week CK. Naspitz - JACI 2003

37 Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction S. Carraro JACI 2005

38  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 ch with exercise-induced asthma (EIA)

39 Assenza del fenomeno di tolleranza nei confronti dell’effetto protettivo di MONTELUKAST nella broncocostrizione indotta dall’esercizio nei pazienti pediatrici F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295

40 Disegno dello studio Studio multicentrico, in doppio cieco, randomizzato, controllato con placebo, a gruppi paralleli, su 32 pazienti tra 6 e 12 anni affetti da asma di grado lieve-moderato, con FEV1 pari almeno al 75% di quello previsto e una riduzione del FEV1 di almeno il 12% rispetto al basale dopo un esercizio standardizzato. I pazienti sono stati randomizzati a Montelukast 5 mg o placebo, una volta al giorno, per 4 settimane. F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295

41 Obiettivo dello studio Lo scopo dello studio era esaminare l’effetto preventivo del Montelukast nella broncocostrizione indotta dall’esercizio a diversi intervalli di tempo durante 4 settimane di trattamento F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295

42 MONTELUKAST ha ridotto la caduta percentuale di FEV 1 a diversi intervalli temporali BasaleGiorno 3Giorno 7Giorno 28 Caduta percentuale di FEV 1 (%) F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295 p<0.05 p<0.01p<0.05

43 Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children F.M. de Benedictis-A.F. Capristo Eur Respir J 2006

44 Percentuale di protezione clinica ottenuta nel tempo con MONTELUKAST Protezione clinica (% di pazienti) F.M. de Benedictis et al Eur Respir J 2006; 28: 291–295

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46 Montelukast Administered in the Morning or Evening to Prevent Exercise-Induced Bronchoconstriction in Children M. Pajaron-Fernandez Pediatric Pulmonology 2006

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49 Summary of Recent Evidence for Therapies Used for Bronchiolitis

50 A RANDOMIZED TRIAL OF MONTELUKAST IN RESPIRATORY SYNCYNTIAL VIRUS POST BRONCHIOLITIS Bisgaard - AJRCCM 2003; 167: lattanti (3-36 mesi) ospedalizzati per bronchiolite da RSV Montelukast 5 mg/die o placebo per 28 giorni entro 7 giorni dall’ insorgenza dei sintomi % giorni liberi da sintomi p=0.015

51 Study Of Montelukast for theTreatment of Respiratory Symptom of Post-RSV-Bronchiolitis in Children. Bisgaard H et al – AJRCCM 2008

52 3-24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV-bronchiolitis and testing positive for RSV. Patients (n=979) were randomized to placebo, montelukast 4 or 8 mg/day for 4 weeks (Period-I) and 20 weeks (Period-II). montelukast did not improve respiratory symptoms of post-RSV- bronchiolitis in children. Study Of Montelukast for theTreatment of Respiratory Symptom of Post-RSV-Bronchiolitis in Children. Bisgaard H et al – AJRCCM 2008

53 A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation. J Pediatr 2010;156(5): Montelukast riduce il numero di episodi di wheezing post-bronchiolite da RSV attraverso la riduzione della degranulazione eosinofila.

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55 Update on the use of montelukast in pediatric asthma CONCLUSIONS 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 treatment in 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

56 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 formulation for 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

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