El Asma es una Enfermedad Inflamatoria de la Vía Aérea

Presentación del tema: "El Asma es una Enfermedad Inflamatoria de la Vía Aérea"— Transcripción de la presentación:

0 Contents Slide 1 Asthma Is an Inflammatory Disease of the Airways Slide 2 Long-Acting Beta2 Agonists as a Second Therapeutic Agent Slide 3 Potential Masking Effects of Salmeterol on Airway Inflammation in Asthma Slide 4 Montelukast Provided Bronchoprotection without Development of Tolerance Slide 5 Montelukast Provided Protection against AMP Challenge without Development of Tolerance Slide 6 Montelukast Did Not Reduce Rescue Effects of Short-Acting Beta Agonists Slide 7 Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation Slide 8 Montelukast Combined with an ICS Provided Better Control of Inflammation Slide 9 IMPACT Study Objectives Slide 10 Country Participation Slide 11 Inclusion Criteria Slide 12 Study Design Slide 13 Study Endpoints Slide 14 Patient Disposition Slide 15 Baseline Characteristics Slide 16 Montelukast Was as Effective as Salmeterol in Percentage of Patients with No Asthma Attacks Slide 17 Montelukast Was as Effective as Salmeterol in Number of Asthma Attacks Slide 18 Montelukast Was as Effective as Salmeterol in Cumulative Percentage of Patients with an Asthma Attack Slide 19 Montelukast Produced Superior Reduction in Blood Eosinophils Compared with Salmeterol Slide 20 Sputum Substudy: Mean Sputum Eosinophil Counts Slide 21 Sputum Substudy: Mean Sputum Eosinophilic Cationic Protein Slide 22 Montelukast Was as Effective as Salmeterol in Reducing Nocturnal Awakenings from Baseline Slide 23 Montelukast and Salmeterol Demonstrated Similar Use of Medical Resources Slide 24 Pre-Beta2 Agonist FEV1, But Not Post-Beta2 Agonist FEV1, Was Improved with Both Treatments Slide 25 Montelukast Was as Effective as Salmeterol in Asthma-Specific Quality of Life Slide 26 Montelukast Demonstrated Less Drug-Related and Serious Adverse Events Than Salmeterol Slide 27 Adverse Events Reported by 5% of Patients in Either Treatment Group (%) Slide 28 IMPACT Findings References (Investigation of Montelukast as a Partner Agent for Complementary Therapy – Investigación de Montelukast como Agente Asociado para Tratamiento Complementario)

1 El Asma es una Enfermedad Inflamatoria de la Vía Aérea
Recomendaciones de las Guías NIH: Uso regular de medicamentos antiinflamatorios Tratamiento inicial con corticosteroides inhalados a dosis bajas para asma leve persistente Tratamiento adicional para pacientes asmáticos que continuan presentando síntomas a pesar de tomar corticosteroides inhalados, como: Agonistas beta2 de acción prolongada (ABAP) Antagonistas de receptores de leucotrienos (ARLT) Diapositiva 1 En años recientes, el entendimiento del asma como una enfermedad crónica de la vía aérea ha cambiado el enfoque del tratamiento de medicamentos broncodilatadores a medicamentos antiinflamatorios.1 Este manejo se refleja en la guías de tratamiento actuales de los National Institutes of Health que recomiendan tratamiento regular con corticosteroides inhalados para pacientes con asma persistente leve, moderada o severa.2,3 Sin embargo, muchos pacientes asmáticos que continúan experimientando síntomas a pesar del tratamiento crónico con corticosteroides inhalados representan un reto en el manejo para sus médicos.4 El fracaso de los corticosteroides inhalados para lograr el control en todos los pacientes puede explicarse por el hecho de que esos medicamentos no afectan ciertas vías inflamatorias (ej. la vía de los leucotrienos).4 Los manejos actuales para el tratamiento del asma en pacientes que continúan experimentando síntomas mientras toman corticosteroides inhalados incluye el aumentar la dosis de los corticosteroides inhalados o añadir un segundo agente terapéutico como un agonista beta2 de acción prolongada (ABAP) o un antagonista de receptores de leucotrienos oral (ARLT).2 Estos dos manejos concuerdan con las guías de tratamiento actuales, las cuales recomiendan lograr el control clínico del asma con la menor cantidad posible de medicamentos.2 Adaptado de Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention. NHLBI/WHO Workshop Report, National Institutes of Health Publication No , Bethesda, MD, 2002; Global Initiative for Asthma (GINA): Pocket Guide for Asthma Management and Prevention, National Institutes of Health Publication No B, Bethesda, MD, 1998.

2 Agonistas Beta2 de Acción Prolongada como Segundo Agente Terapéutico
Ventajas En estudios clínicos, aumento en eficacia vs. aumento en la dosis de corticosteroides mejorando: Síntomas de asma Función pulmonar Preocupaciones En dos estudios clínicos, desarrollo de tolerancia a los efectos broncoprotectores con la exposición crónica que no parece ser superada por los corticosteroides Riesgo potencial de enmascarar la inflamación subyacente de la vía aérea y empeoramiento del asma Diapositiva 2 Estudios recientes han sugerido que la adición de ABAPs al tratamiento con corticosteroides inhalados es más efectivo para mejorar síntomas y función pulmonar que el aumentar la dosis del corticosteroide inhalado.5-7 Sin embargo, existe preocupación sobre el desarrollo de tolerancia para los efectos broncoprotectores de los ABAPs.8 Estudios en animales han indicado que la tolerancia puede desarrollarse como resultado de contraregulación de los receptores pulmonares adrenérgicos beta2 mediada por exposición crónica a los agonistas beta Aunque se ha postulado que la tolerancia al tratamiento con agonistas beta2 puede prevenirse mediante el uso concomitante de corticosteroides, hasta la fecha estudios pequeños han sugerido que los corticosteroides no parecen ofrecer tal proteccióngon.8,11 Otra preocupación potencial de los ABAPs se relaciona con el riesgo de enmascarar la inflamación subyacente de la vía aérea, la cual puede retrasar el reconocer el empeoramiento del asma, el riesgo de que ésto ocurra puede aumentar cuando el control sintomático ha llevado a uso reducido de corticosteroides.12 Adaptado de Greening AP y cols. Lancet 1994;344: ; Woolcock A y cols. Am J Respir Crit Care Med 1996;153: ; Murray JJ y cols. Allergy Asthma Proc 1999;20(3): ; Yates DH y cols. Am J Respir Crit Care Med 1996;154: ; Kalra S y cols. Chest 1996;109(4): ; McIvor RA y cols. Am J Respir Crit Care Med 1998;158:

3 Efectos Potencialmente Enmascaradores del Salmeterol sobre la Inflamación de la Vía Aérea en Asma
Conteo promedio (DE) de eosinófilos en expectoración una semana antes de la exacerbación* p=0.006 25 19.9 (17.6) 20 Eosinófilos (% de leucocitos totales en expectoración) 15 9.3 (29.8) 10 5 Slide 3 Estudio doble ciego, de dos periodos, con asignación al azar, controlado, cruzado, utilizando reducción escalonada de corticosteroides inhalados, dirigido a determinar la extensión en la que la inflamación desarrollada (medida por eosinofilia en expectoración) antes de una exacerbación de asma fue clínicamente aparente.12 Después de un periodo inicial de una semana, 13 pacientes con asma que requirieron beclometasona a altas dosis (1500 µg/día) o budesonida fueron asignados al azar para recibir salmeterol 50 µg dos veces al día o placebo además del tratamiento con corticosteroide inhalado. Después de una semana de este régimen para establecer valores iniciales, los pacientes fueron sometidos a reducción escalonada de los corticosteroides inhalados para determinar la extensión en la que se desarrollaba inflamación (reflejada en eosinófilos en expectoración) antes de que una exacerbación de asma fuera clínicamente aparente. Después de un periodo de restablecimiento de al menos cuatro semanas a la dosis original de corticosteroides, con un curso inicial de 1 semana de prednisolona 30 mg diarios si la exacerbación era más que leve, los pacientes fueron entonces cruzados al régimen alterno para reducción de corticosteroides.12 En la semana previa a una exacerbación, los conteos de eosinófilos en expectoración fueron significativamente mayores en el brazo de salmeterol que en el brazo placebo; ej., 19.9% ± 17.6% del conteo de leucocitos totales en expectoración durante el tratamiento con salmeterol contra 9.3% ± 29.8% durante el tratamiento con placebo (p=0.006), mientras que las puntuaciones de síntomas, FEM, uso de agonistas beta2 y VEF1 permanecieron estables.12 Estos datos indican que el uso de salmeterol permitió que los pacientes toleraran un mayor grado de inflamación sin aumento de síntomas o disminución de la función pulmonar, y por lo tanto, retrasó el reconocimiento del empeoramiento del asma inducido por la disminución de un corticosteroide inhalado.12 Salmeterol 50 µg dos veces al día (n=13) Placebo (n=13) Estudio doble ciego, cruzado en 13 pacientes con asma que requirieron altas dosis (1500 mg) de beclometasona o budesonida inhaladas. Adaptado de McIvor RA y cols. Am J Respir Crit Care Med 1998;158:

4 Montelukast Proporcionó Broncoprotección sin Desarrollo de Tolerancia
Montelukast (n=97) 80 Salmeterol (n=94) 70 p=0.002 p=0.015 Cambio en mediana a partir del inicio en disminución % máxima en VEF1 (%) 60 50 40 30 20 Slide 4 Este estudio de 10 semanas, multicéntrico, con asignación al azar, doble ciego, evaluó el efecto del tratamiento con montelukast o salmeterol en aerosol en broncoconstricción inducida por ejercicio en adultos de 15 a 45 años de edad con asma crónica. Después de un periodo inicial de 2 semanas con placebo, 191 pacientes con VEF1 65% en reposo y disminución en el VEF1 20% después de reto estandarizado con ejercicio en dos ocasiones durante el periodo inicial, fueron asignados al azar para recibir montelukast (tableta de 10 mg a la hora de acostarse) o salmeterol (2 inhalaciones dos veces al día de un inhalador de 50 g). At clinic visits, FEV1 was measured before and at intervals after an exercise challenge.13 The graph shows the median change from baseline in the maximum percentage decrease in FEV1 after exercise. By Day 3, both treatments had produced a similar reduction in maximum percentage decrease in FEV1. Thereafter, the improvement in bronchoprotective effect was maintained in the montelukast group, while a loss in bronchoprotective effect was observed in the salmeterol group. At Weeks 4 and 8, the percentage change in maximum percentage decrease in FEV1 was significantly greater in the montelukast group compared with the salmeterol group (p=0.015 and p=0.002, respectively). A similar relationship was seen for time to recovery (time for FEV1 to return to within 5% of pre-challenge value): the effect of salmeterol diminished after the initial visit, while the effect of montelukast was maintained.13 The results of this study demonstrated that long-term administration of montelukast, but not salmeterol, provided consistent bronchoprotection at 4 and 8 weeks of therapy without the development of tolerance.13 10 Días 1-3 Semana 4 Semana 8 Estudio de 10 semanas, con asignación al azar, doble ciego en 191 pacientes con asma crónica y broncoconstricción inducida por ejercicio documentada. Después de un periodo inicial de 2 semanas con placebo, los pacienbtes fueron asignados al azar a montelukast 10 mg una vez al día o salmeterol 50 mg 2 inhalaciones dos veces al día por 8 semanas. Adaptado de Edelman JM y col. Ann Intern Med 2000;132:

5 Montelukast Proporcionó Protección contra Reto con AMP sin Desarrollo de Tolerancia
0.5 1.0 1.5 2.0 2.5 Día 1 (Primera dosis) Semana 2 (última dosis) NS p<0.05 0.0 Montelukast + CSI Salmeterol + CSI PC20 doubling dose difference vs. placebo (pooled) Slide 5 Adenosine monophosphate (AMP) challenge causes bronchoconstriction due to release of inflammatory mediators from primed mast cells.14 This was a randomised, placebo-controlled, single-blind, double-dummy, crossover study. Enrolled patients (n=20) had asthma that was not optimally controlled on >400 mg/day of inhaled corticosteroid (budesonide n=5, beclomethasone n=14, fluticasone n=1). Eligible patients had persistent asthma symptoms requiring 2 puffs per day of beta2 agonist and had 10% diurnal variability in PEF. Patients were also required to be responsive to AMP challenge testing by demonstrating a PC20 (dose producing a reduction in FEV1 of 20%) of <200 mg/mL before the run-in period. Patients were randomised to receive inhaled salmeterol 50 mg twice daily plus placebo tablet or montelukast 10 mg daily plus placebo inhaler for 2 weeks. Before each active treatment phase and at crossover, patients had a 1-week period with a placebo inhaler and placebo tablets. Patients continued their usual inhaled corticosteroid therapy throughout. Data from patients with >90% compliance over the course of the study were considered evaluable.14 AMP challenge testing was performed at the end of the 1-week run-in and crossover washout placebo periods, and after each 2-week active treatment period. Testing was also performed after the first dose of active therapy (i.e., 12 hours after the dose of salmeterol and 24 hours after the first dose of montelukast). AMP was administered in doubling cumulative doses at 5-minute intervals until a reduction in FEV1 of 20% was recorded. The PC20 was calculated using a computer-assisted curve-fitting package and interpolation of the log dose-response curve. The graph shows the doubling dose difference vs. the pooled placebo value.14 The mean PC20 with placebo treatment (pooled run-in periods) was 47.5 mg/mL. The PC20 was significantly greater (p<0.05) after the first dose of montelukast (114.1 mg/mL) and after 2 weeks of treatment (94.2 mg/mL) compared with placebo. With salmeterol treatment, the PC20 was significantly greater than with placebo after the first dose (160.1 mg/mL) but was not significantly different from placebo after 2 weeks (70.1 mg/mL). Salmeterol, but not montelukast, was shown to exhibit significant (p<0.05) tolerance between the first-dose and last-dose protection against AMP bronchial challenge.14 The results of this study showed that the bronchoprotective effects of montelukast were maintained with continuing treatment, while tolerance developed to the effects of salmeterol.14 Estudio con asignación al azar, controlado con placebo, ciego sencillo, doble dummy, cruzado en 20 pacientes con asma persistente no controlada con un ICS. Para cada periodo de tratamiento activo de 2 semanas, los pacientes recibieron montelukast 10 mg o salmeterol 50 mg dos veces al día además de su ICS usual. El reto con adenosin monofosfato (AMP) se realizó después de la primera dosis del medicamento en estudio y al final del periodo de 2 semanas de tratamiento. Adaptado de Wilson AM y cols. Chest 2001;119:

6 Montelukast No Redujo los Efectos de Rescate del Agonista Beta de Acción Corta
100 p<0.001 p=NS p<0.001 98 p=NS p=NS p0.05 VEF1 (% predicho) después de rescate con salbutamol 96 94 92 Slide 6 This was a 6-week randomised, double-blind, double-dummy, placebo-controlled study of 122 non-smoking adult patients aged years with chronic asthma poorly controlled on inhaled corticosteroids and a documented history of exercise-induced asthma. During a 2-week run-in period, patients received fluticasone 100 mg twice daily. They were then randomised to receive, in addition to fluticasone, montelukast 10 mg once daily, inhaled salmeterol 50 mg twice daily, or placebo for 4 weeks. FEV1 was measured before and after an exercise challenge at baseline and weeks 1 and 4. Patients received rescue albuterol (180 mg) 15 minutes after the exercise challenge, and FEV1 was monitored for 30 minutes. After 30 minutes, a second dose of albuterol was administered and the FEV1 assessment repeated.15,16 The figure shows the primary efficacy measure, maximum FEV1 percent predicted, following rescue bronchodilation with albuterol at baseline and after 4 weeks of treatment. Patients who received montelukast combined with fluticasone for 4 weeks showed no significant attenuation in FEV1 response after rescue therapy compared with baseline (95% CI for least squares mean change from baseline –0.4, 3.3). Likewise, there was no significant attenuation of response to short-acting beta-agonist in the patients receiving placebo + fluticasone (95% CI for least squares mean change from baseline –0.6, 3.0). In contrast, patients who received salmeterol combined with fluticasone experienced a significantly reduced response to albuterol rescue at week 4 (95% CI for least squares mean change from baseline –5.8, -1.9). There was a significant difference between the montelukast + fluticasone and salmeterol + fluticasone groups (p<0.001) and between the placebo + fluticasone and salmeterol + fluticasone groups in mean change from baseline at week 4 in maximum FEV1 percent predicted, while there was no significant difference between the montelukast + fluticasone and placebo + fluticasone groups (p=0.830). 15,16 Exploratory analyses included the area under the post-exercise curve of percentage change in FEV1-time (AUC) until recovery to pre-exercise FEV1. Compared with salmeterol, montelukast produced a significantly greater improvement from baseline to week 4 in AUC (p=0.006).15,16 The results showed that montelukast permitted greater and more rapid rescue bronchodilation with albuterol than did salmeterol. This advantage was due to loss of albuterol effect with continued use of salmeterol. Compared with salmeterol, montelukast provided substantial protection against exercise-induced asthma that did not diminish over time.15 Inicial Semana 4 Inicial Semana 4 Inicial Semana 4 Placebo + fluticasona (n=38) Montelukast + fluticasona (n=36) Salmeterol + fluticasona (n=34) Estudio de 6 semanas con asignación al azar, doble ciego, doble dummy en 122 pacientes adultos con asma crónica pobremente controlada con esteroides inhalados y antecedentes documentados de asma inducida por ejercicio. Después de un periodo inicial de 2 semanas, se asignó al azar a los pacientes para recibir montelukast 10 mg una vez al día, salmeterol inhalado 50 mg dos veces al día, o placebo por 4 semanas además de fluticasona. Adaptado de Corren J y cols, Poster #K37 presentado en la reunión annual de ATS, Mayo 18-23, 2001, San Francisco, CA, EUA .

7 Montelukast Combinado con un Esteroide Afecta la Vía Doble de la Inflamación
Los cisteinil leucotrienos tienen un papel clave en la inflamación asmática Los mediadores sensibles a los esteroides tienen un papel clave en la inflamación asmática Los esteroides NO inhiben la formación de cisteinil leucotrienos en la vía aérea de los pacientes asmáticos Montelukast Esteroides inhalados Slide 7 Glucocorticoids are thought to be effective in controlling asthma by increasing or decreasing the transcription of genes coding for various inflammatory mediators. Examples of these mediators include cytokines, nitric oxide synthase, cyclo-oxygenase, and phospholipase.17,18 However, steroids do not inhibit the formation of cysteinyl leukotrienes in the airways of asthmatic patients.19 Cysteinyl leukotrienes are inflammatory mediators that play an important role in asthma.20,21,22 Montelukast is a selective LTRA, and thus blocks the inflammatory effects of cysteinyl leukotrienes. When administered in combination, montelukast and an inhaled steroid have been shown to have a complementary anti-inflammatory effect, as demonstrated by reduction in blood eosinophils.23 bloquea los mediadores sensibles a los esteroides bloquea los efectos de los cisteinil leucotrienos VIA DOBLE

8 Cambio a partir del inicio en conteo de eosinófilos sanguíneos
Montelukast Combinado con un CSI Proporciona un Mejor Control de la Inflamación 0.12 p<0.05 p<0.05 0.10 Cambio a partir del inicio en conteo de eosinófilos sanguíneos (x103/L) 0.08 0.06 0.04 0.02 Slide 8 Eosinophils are key effector cells in the inflammatory response in asthma.2 This was a 20-week randomised, double-blind, double-dummy clinical study of 642 adults (aged 15 years) with chronic asthma incompletely controlled with inhaled beclomethasone 200 mg twice daily during the 4-week run-in period. Eligible patients were then randomised to receive one of the following treatments for 16 weeks: Montelukast 10 mg + inhaled beclomethasone 200 mg twice daily Placebo tablet + inhaled beclomethasone 200 mg twice daily Montelukast 10 mg + placebo inhaler Placebo tablet + placebo inhaler Baseline blood eosinophil counts were comparable in the four treatment groups (0.22–0.23 × 103/µL). Over the 16-week treatment period, there was a significant increase in eosinophil counts in the beclomethasone group compared with the group receiving montelukast + beclomethasone (p=0.011).23 Montelukast (n=201) Beclometasona (n=200) Placebo (n=48) Montelukast + beclometasona (n=193) Estudio clínico de 20 semanas, doble ciego, doble dummy en 642 adultos ( 15 años de edad) con asma crónica no controlada con corticosteroides inhalados. Adaptado de LaViolette M y cols. Am J Respir Crit Care Med 1999;160:

9 Determinar el perfil de tolerabilidad de ambos tratamientos
Objetivos del Estudio Evaluar la eficacia de 48 semanas de tratamiento con montelukast vs. salmeterol inhalado administrado concomitantement con fluticasona inhalada en el porcentaje de pacientes con al menos un ataque de asma como punto final primario Determinar el perfil de tolerabilidad de ambos tratamientos Slide 9 The objective of the IMPACT study was to assess the efficacy and tolerability of 48 weeks of treatment with montelukast versus salmeterol concomitantly administered with inhaled fluticasone on the primary endpoint of percent of patients with at least one asthma attack and to determine the tolerability profile of both treatments over the 48- week treatment period.4,16 Adaptado de Bjermer L y cols. Respir Med 2000;94:

10 Se incluyeron 1490 pacientes
Participación por Países Investigadores de 37 países* Se incluyeron 1490 pacientes Slide 10 The IMPACT study is the largest and longest-running clinical study to compare the effects of an LTRA combined with an inhaled corticosteriod with a LABA combined with an inhaled corticosteriod. IMPACT enrolled patients at 148 asthma centers in 37 countries throughout Europe, Latin America, the Middle East, Africa, and the Asia-Pacific region. A total of 1490 patients were randomised to study medication for a duration of almost one year.16 *Países participantes en amarillo

11 Criterios de Inclusión
15–65 años de edad 1 año con antecedentes de síntomas intermitentes o persistentes incluyendo disnea, sibilancias, opresión torácica, tos o expectoración VEF1 50–90% del valor predicho Mejoría en VEF1 o FEM de 12% después de agonista beta2 Uso regular de corticosteroides por 8 semanas antes de la visita 1 Nivel mínimo predefinido de síntomas diurnos (puntuación bisemanal 56) y uso de agonista beta2 (promedio 1 inhalación/día) Tratamiento actual del asma sólo con agonista beta2 de acción corta y corticosteroide inhalado No fumador por 6 meses antes del estudio Slide 11 IMPACT enrolled male and female patients according to the following main inclusion criteria:4,16 Aged 15 to 65 years History of 1-year duration of intermittent or persistent symptoms including dyspnea, wheezing, chest tightness, cough, or sputum production FEV1 between 50 and 90% of the predicted value Reversible airway obstruction (demonstrated by an improvement of 12% in FEV1 or peak expiratory flow rate (PEFR) after beta2 agonist administration) on at least two occasions at visits 1, 2, or 3 A predefined minimum daytime asthma symptom score (bi-weekly score of 56) and use of an average of 1 puff per day of a beta2 agonist Regular use of inhaled corticosteroid for 8 weeks prior to visit 1 (defined as 200–1000 µg/day of beclomethasone, budesonide, or triamcinolone, or 100–500 µg/day of fluticasone, not missing more than five days in the previous 8-week period before visit 1) Current asthma treatment consisting only of short-acting beta agonist and inhaled corticosteroid (budesonide µg/day or equivalent) Currently a non-smoker and has been a non-smoker for 6 months prior to visit 1, with a smoking history of 12 pack-years. Adaptado de Bjermer L y cols. Respir Med 2000;94:

12 Diseño del Estudio Periodo I Periodo II Fluticasona 200 µg/día
Montelukast 10 mg/día + fluticasona 200 µg/día + PS PM + PS n=743 Salmeterol 100 µg/día + fluticasona 200 µg/día + PM Slide 12 IMPACT was a 52-week, randomised, double-blind, double-dummy, parallel-group, multicentre study with a four-week run-in period (Period I) and a 48-week, double-blind treatment period (Period II).4 Patients taking an inhaled corticosteroid but with abnormal pulmonary function and daytime symptoms received open-label fluticasone propionate (100 µg twice daily via Discus® dry-powder inhaler) during Period I. During the last two weeks of Period I, single-blind montelukast placebo and salmeterol placebo were added. Patients who continued to be uncontrolled (based on FEV1, PEFR, beta-agonist use, and daytime symptoms) were then randomised to one of two treatment groups in a double- blind fashion: Active montelukast (10 mg tablet once daily at bedtime) added to fluticasone mg/day and salmeterol placebo Active salmeterol (50 µg twice daily via a pMDI) added to fluticasone 200 mg/day and montelukast placebo. Visita Semana -4 – PM = placebo demontelukast; PS = placebo de salmeterol Adaptado de Bjermer L y cols. Respir Med 2000;94:

13 Puntos Finales del Estudio
Punto final primario Porcentajede pacientes con al menos un ataque de asma. Un ataque de asma fue definido como empeoramiento del asma que requirió: Visita no programada al consultorio del médico Visita no programa al servicio de emergencias Visita no programada al hospital Tratamiento con corticosteroide oral, intravenoso o intramuscular Puntos finales secundarios incluídos Conteo de eosinófilos de sangre periférica, calidad de vida específica para asma, despertares nocturnos, utilización de recursos para cuisaso de la salud y FEM matutino Slide 13 In IMPACT, the primary endpoint was the percentage of patients with at least one asthma attack. An asthma attack was defined as treatment with a course of oral corticosteroids or an unscheduled visit to the doctor’s office, emergency room, or hospitalisation. An indication for systemic steroid treatment was based upon either objective criterion as increase in symptoms or lung function deterioration, or according to judgment by the investigator. Patients were instructed to contact their doctor if their PEFR was 30% below baseline on three consecutive mornings or if symptoms increased the need for beta2-agonist use (at intervals <3 hours).4 Secondary objectives of the study included peripheral blood eosinophil counts, asthma- specific quality of life, nocturnal awakenings, healthcare resource utilisation, and morning PEFR. In addition the study compared the tolerability profiles of montelukast and salmeterol in combination with inhaled fluticasone.4 Además, el estudio comparó los perfiles de tolerabilidad de montelukast y salmeterol en combinación con fluticasona inhalada Adaptado de Bjermer L y cols. Respir Med 2000;94:

14 Disposición de los Pacientes
Los pacientes fueron reclutados en 37 países Asignación al azar (N=1490) Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) Completaron el estudio (n=622) Suspendieron (n=125) Evento adverso 38 Retiro consentimiento 22 Desviación de protocolo 15 Pérdida seguimiento Término de sitio Mudanza paciente Falta de eficacia Otras razones Completaron el estudio (n=633) Suspendieron (n=110) Evento adverso Retiro consentimiento 22 Desviación de protocolo 15 Pérdida seguimiento 12 Término de sitio 4 Mudanza paciente Falta de eficacia Otras razones Slide 14 Of the 1490 randomised patients, 747 received montelukast added to fluticasone, while 743 received salmeterol added to fluticasone. Reasons for discontinuation of study medication are shown on the slide. ‘Other reasons’ include patient unwilling, non- compliance, private reasons, and miscellaneous problems with the study drug or visits.16 ‘Otras razones’ incluye pacientes poco dispuestos, falta de apego, razones privadas y problema misceláneos con el medicamento en estudio o las visitas.

15 Características Iniciales
Género (%) Masculino Femenino Edad promedio (años) VEF1 promedio (% predicho) Reversibilidad promedio VEF1 (%) VEF1 promedio pre-agonista beta(L) VEF1 promedio post-agonista beta(L) FEM AM promedio (L/min) Promedio despertares nocturnos (por semana) Uso diario promedio de agonista beta (inhalaciones/día) Conteo promedio de eosinófilos sanguíneos (x103/L) Pacientes con rinitis alérgica (%) Montelukast + fluticasona (n=747) 41.2 71.3 18.4 2.4 2.8 384.0 2.6 3.3 0.3 61.7 Salmeterol + fluticasona (n=743) 41.0 72.7 18.8 2.5 2.9 388.7 3.3 0.3 60.4 Slide 15 Patient characteristics at baseline were similar in the two treatment groups. Approximately 50% of the patients were men and the mean age was 41 years. The patients in this study had mean FEV1 of approximately 72% predicted, an FEV1 reversibility of approximately 18% and used about 3 puffs per day of inhaled beta agonist to relieve symptoms. Allergic rhinitis is a common comorbid condition with asthma;24 in the IMPACT study, approximately 60% of patients had allergic rhinitis.16

16 Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743)
Montelukast* Fue tan Efectivo como Salmeterol** en Porcentaje de Pacientes Sin Ataques de Asma p=NS 100 79.9% 80.9% 80 Pacientes sin ataques de asma (%) 60 40 20 Slide 16 The figure shows the percentage of patients who had no asthma attacks during the double-blind treatment phase. During 48 weeks of treatment, 79.9% of patients in the montelukast + fluticasone group had not experienced any asthma attacks compared with 80.9% in the salmeterol + fluticasone group (p=0.638).16 The risk ratio (montelukast / salmeterol) at week 48 was 1.05 (with a 95% confidence interval [CI] of 0.86, 1.29). As the upper limit of the 95% CI was less than 1.33, montelukast + fluticasone was considered as effective as salmeterol + fluticasone. These results show that montelukast combined with fluticasone was as effective as salmeterol combined with fluticasone, with respect to the proportion of patients experiencing no asthma attacks. Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado

17 Montelukast. Fue tan Efectivo como Salmeterol
Montelukast* Fue tan Efectivo como Salmeterol** en el Número de Ataques de Asma La distribución de ataques de asma no mostró diferencia entre grupos de tratamiento 100 Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) 80 Pacientes (%) 60 40 Slide 17 The figure shows the distribution of patients according to the number of asthma attacks they had during 48 weeks of treatment. In both treatment groups, approximately 80% of patients experienced no asthma attacks and 14% had only one asthma attack. Less than 1% of patients had four or more attacks (in each treatment group, the maximum number of attacks experienced was six). There were no significant differences between treatment groups.16 These results show that montelukast combined with fluticasone was as effective as salmeterol combined with fluticasone, with respect to the number of asthma attacks experienced during treatment. 20 1 2 3 4 Número de ataques de asma *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado. Máximo de 6 ataques en cada grupo de tratamiento.

18 Montelukast. Fue tan Efectivo como Salmeterol
Montelukast* Fue tan Efectivo como Salmeterol** en Porcentaje Acumulado de Pacientes con un Ataque de Asma 25 Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) Proporción de pacientes con ataque de asma(%) 20 15 10 p=NS 5 Slide 18 The figure shows Kaplan-Meier curves of cumulative percentage of patients with an asthma attack. There was no significant difference between treatment groups (log rank test p=0.599).16 These results show that montelukast combined with fluticasone was as effective as salmeterol combined with fluticasone, with respect to time to first asthma attack. 10 20 30 40 50 Semanas a partir de la asignación al azar *10 mg mg fluticasona, ** 100 mg mg fluticasona.

19 Montelukast + fluticasona (n=604) Salmeterol + fluticasona (n=610)
Montelukast* Produjo Reducción Superior en Eosinófilos Sanguíneos Comparado con Salmeterol** Montelukast + fluticasona (n=604) Salmeterol + fluticasona (n=610) -0.04 (0.01) -0.01 (0.01) -0.05 -0.04 -0.03 -0.02 -0.01 p=0.006 Cambio Promedio (EE) a partir del inicio en el conteo de eosinófilos sanguíneos (x103/ L) a la Semana 48 Slide 19 The figure shows the mean change from baseline in peripheral blood eosinophil counts. In all forms of asthma, there is evidence to implicate eosinophils as key effector cells of the inflammatory response.2 Montelukast + fluticasone produced a significantly greater reduction from baseline in blood eosinophils compared with salmeterol + fluticasone (p=0.006, at Week 48).16 At baseline the blood eosinophil count was 0.3x103/L in both treatment groups. At Week 48, counts were reduced by –0.04x103/L in the montelukast + fluticasone group and –0.01x103/L in the salmeterol + fluticasone group. These results show that montelukast combined with fluticasone provided superior control of asthmatic inflammation compared with salmeterol combined with fluticasone, with respect to reduction in blood eosinophils. *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado. Los valores son los cambios promedio en mínimos cuadrados a partir del inicio. El valor P es para diferencia entre grupos. Modelo ANCOVA incluyendo tratamiento y centro como factor e inicio como covarianza. Valor inicial = 0.3 x103/mL en ambos grupos de tratamiento.

20 Montelukast + fluticasona Salmeterol + fluticasona
Subestudio de Expectoración: Conteos Promedio de Eosinófilos en Expectoración p=0.0279 p=NS 1.8 1.8 p=0.004 1.52 1.6 1.5 Conteo promedio de eosinófilos en expectoración 1.4 1.2 0.92 1.0 0.8 0.6 0.4 Slide 20 The Sputum Substudy involved all patients participating in the IMPACT study at centres in Finland. Patients provided sputum samples at study baseline (visit 3), and at weeks 8 (visit 4) and 24 (visit 6) of the double-blind treatment period. Sputum was induced by inhalation of 5 ml of 3% NaCl solution, using an ultrasonic nebulizer for 15 minutes. Subjects were pre-treated with 200 mg salbutamol by inhalation. PEF values were measured before and after induction to ensure safety of the procedure. Subjects were asked to cough during and after inhalation. Sputum samples were collected in empty containers. If PEF fell by more than 15% or troublesome symptoms appeared, patients were treated with 200 mg of inhaled salbutamol. Sputum sample handling at each centre: sputum samples were transferred to Petri dishes and examined against a dark surface. The more viscous parts were collected, using forceps, and mixed. Part of each sample was used to make two smears, which were air dried (not frozen). The rest of each sample was transferred into a pre-weighted tube and frozen at -20ºC. Sputum analysis in the laboratory: frozen sputum samples and the air-dried slides were sent for further analysis. Samples were processed using a method previously described and validated.25,26 Briefly, each sample was thawed and treated with a mucolytic agent and a detergent. After incubation for one hour, cells were lysed and markers inside and outside the cells released and solubilised. The sputum supernatant was separated from cell debris by centrifugation. Thawed sputum supernatant concentrations (mg/L) of eosinophil-activation marker, eosinophil cationic protein (ECP), and a marker of neutrophil activation, myeloperoxidase (MPO), were determined. ECP and MPO concentrations were determined using commercially available immunoassay kits. The air-dried slides were stained using eosin and methylene blue. A sample was considered to be adequate, and to originate from the lower airways, if it contained macrophages and fewer than 50% of squamous epithelial cells. All analyses were conducted by investigators unaware of the clinical characteristics of the subject. 0.2 0.0 Inicial* (n=25) Semana 24* (n=24) Inicial* (n=16) Semana 24* (n=14) Montelukast + fluticasona Salmeterol + fluticasona Este análisis de expectoración fue realizado en todos los pacientes participantes en el estudio IMPACT en centros finlandeses. *Las muestras de expectoración se indujeron mediante inhalación de solución NaCl nebulizada al inicio (visita 3) y semanas 8 (visita 4) y 24 (visita 6). Todas las muestras fueron analizadas en un laboratorio central.

21 Montelukast + fluticasona Salmeterol + fluticasona
Subestudio de Expectoración: Proteína Catiónica Eosinofílica Promedio en Expectoración p=NS 2000 4000 6000 8000 10,000 12,000 14,000 10,222 8073 13,768 10,235 p=0.05 PCE Promedio en Expectoración (g/L) Slide 21 See notes from Slide 20. Inicial* (n=23) Semana 24* (n=23) Inicial* (n=16) Semana 24* (n=13) Montelukast + fluticasona Salmeterol + fluticasona Este análisis de expectoración fue realizado en todos los pacientes participantes en el estudioIMPACT en centros finlandeses. *Las muestras de expectoración se indujeron mediante inhalación de solución NaCl nebulizada al inicio (visita 3) y semanas 8 (visita 4) y 24 (visita 6). Todas las muestras fueron analizadas en un laboratorio central.

22 Montelukast + fluticasona (n=618) Salmeterol + fluticasona (n=624)
Montelukast* Fue tan Efectivo como Salmeterol** en la Reducción de Despertares Nocturnos a partir del Inicio 4.0 3.5 p0.001 p0.001 3.0 Número promedio de despertares nocturnos por semana 2.55 2.51 2.5 2.0 1.5 1.0 0.61 0.45 0.5 Slide 22 The figure shows the mean change from baseline in nocturnal awakenings due to asthma per week. This analysis was performed on a subset of patients with nocturnal asthma (defined as nocturnal awakenings 2 nights/week during the 2 weeks prior to randomisation). There was no significant difference between treatment groups (p=0.375, overall treatment period).16 At baseline, patients in the montelukast + fluticasone group experienced an average 2.55 awakenings per week compared with 2.51 per week in the salmeterol + fluticasone group. At Week 48, the mean number of awakenings per week was 0.61 and 0.45 in the two treatment groups, respectively. In both treatment groups, the reduction from baseline was statistically significant (p0.001 at Week 48). These results show that there was no significant difference between the two treatments for nocturnal awakenings. 0.0 Inicial Semana 48 Inicial Semana 48 Montelukast + fluticasona (n=618) Salmeterol + fluticasona (n=624) *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado. Los valores P se derivan de prueba T para cambio intragrupo a partir del inicio diferente a cero. Análisis realizado en subgrupo de pacientes con asma nocturna (definida como despertares nocturnos 2 noches/semana durante las 2 semanas previas a la asignación al azar).

23 Montelukast. y Salmeterol
Montelukast* y Salmeterol** Demostraron Utilización Similar de Recursos Médicos Uso de recursos médicos (% pacientes) Uso de corticosteroidesa Llamadas al consultorio del médico Visita no programada al médicob Visita al servicio de Emergencias Hospitalización Montelukast + fluticasona (n=747) 15.8 16.1 11.0 2.8 0.7 Salmeterol + fluticasona (n=743) 14.4 12.7 10.8 2.8 0.9 Slide 23 The table shows the percentage of patients who used medical resources during the 48-week treatment period. In the group receiving montelukast + fluticasone, 118 patients (15.8%) took oral, intramuscular, intravenous, or rectal corticosteroids compared with 107 (14.4%) in the group receiving salmeterol + fluticasone. A total of 120 patients (16.1%) in the montelukast + fluticasone group and 94 patients (12.7%) in the salmeterol + fluticasone group phoned their doctor’s office, while 82 patients (11.0%) in the montelukast + fluticasone group and 80 patients (10.8%) in the salmeterol + fluticasone group made an unscheduled visit to their doctor or medical specialist. Twenty-one patients (2.8%) in each of the treatment groups visited the emergency room, while 5 (0.7%) and 7 (0.9%) patients, respectively, were hospitalised.16 *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado. aOral, intramuscular, intravenoso o rectal. bAl médico especialista o visita no programada (médico or no médico)

24 El VEF1 Pre-Agonista Beta2, Pero no el VEF1 Post-Agonista Beta2, Mejoró con Ambos Tratamientos*
3.5 p=NS p=NS p0.001 p0.001 3 2.82 2.80 2.85 2.82 2.66 2.55 2.44 2.46 VEF1 Promedio (L) 2.5 2 1.5 1 0.5 Slide 24 The slide shows absolute mean values for pre– and post–beta2-agonist FEV1 at baseline and at Week 48 in the two treatment groups. Pre–beta2-agonist FEV1 showed a small but statistically significant increase from baseline at week 48 in both treatment groups (p0.001). In the montelukast + fluticasone group, pre–beta2-agonist FEV1 increased from 2.44 L at baseline to 2.55 L at Week 48, while in the salmeterol + fluticasone group pre–beta2-agonist FEV1 increased from 2.46 L at baseline to 2.66 L at Week 48. At Week 48, there was a significant difference between the montelukast + fluticasone and salmeterol + fluticasone groups in mean change from baseline in pre–beta2-agonist FEV1 (0.11 L and 0.19 L, respectively, p0.001). There was no significant difference in post–beta2-agonist FEV1 between baseline and Week 48 in either treatment group. In the montelukast + fluticasone group, post–beta2-agonist FEV1 was 2.82 L at baseline and 2.80 L at Week 48 (p>0.05), while in the salmeterol + fluticasone group post–beta2-agonist FEV1 was 2.85 L at baseline and 2.82 L at Week 48. At Week 48, there was no significant difference between the montelukast + fluticasone and salmeterol + fluticasone groups in mean change from baseline in post–beta2-agonist FEV1 (2.80 L and 2.82 L, \respectively).16 Inicial Semana 48 Inicial Semana 48 Inicial Semana 48 Inicial Semana 48 Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) Montelukast + fluticasona (n=747) Salmeterol + fluticasona (n=743) *Como se demuestra mediante cambio promedio en mínimos cuadrados a partir del inicio a la semana 48. Abordaje por intención de tratar modificado. Los valores de P se derivan de prueba T para cambio intra grupo a partir del inicio diferente a cero.

25 Cambio promedio a partir del inicio (puntuación)
Montelukast* Fue tan Efectivo como Salmeterol** en Calidad de Vida Específica para Asma Montelukast + fluticasona (n=581) Salmeterol + fluticasona (n=581) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 General Limitación en actividad Función emocional Estímulos ambientales Síntomas p=NS 0.71 0.76 0.79 0.85 0.67 0.70 0.72 Cambio promedio a partir del inicio (puntuación) Slide 25 This figure shows the mean change from baseline in asthma-specific quality of life scores over the 48-week treatment period. The Asthma Quality of Life Questionnaire consists of 32 questions, which are grouped into four domains: activity limitations, emotional function, exposure to environmental stimuli, and asthma symptoms.28 All domains were rated on a 7-point scale from 1–7, with low scores indicating a low quality of life and high scores indicating a high quality of life. A change from baseline of 0.5 is considered to be the minimal important difference in quality-of-life score.29 The overall quality-of-life score may be estimated from the mean score for all questions. In both treatment groups, patients had a significant increase (p0.001) from baseline in overall asthma-specific quality-of-life score at week 48, with no significant difference between treatments. The mean overall score at baseline was 4.7 in both treatment groups, while the mean score at Week 48 was 5.60 in the montelukast + fluticasone group and 5.65 in the salmeterol + fluticasone group.16 In each of the individual domains (activity limitations, emotional function, exposure to environmental stimuli, and asthma symptoms), both treatments produced improvements from baseline of more than 0.5 points. These results show that montelukast combined with fluticasone was as effective as salmeterol combined with fluticasone, with respect to improvement in asthma-specific quality of life. *10 mg mg fluticasona, ** 100 mg mg fluticasona. Abordaje por intención de tratar modificado. Los valores son el cambio promedio en mínimos cuadrados a partir del inicio para el periodo de tratamiento en general. El valor P es para diferencia entre grupos. Modelo ANCOVA incluyendo tratamiento y centro como factor e inicio como covarianza. Puntuación general = puntuación promedio para todos los puntos del cuestionario. 0.5 representa la diferencia importante mínima en la puntuación del Cuestionario de Calidad de Vida (Juniper EF y cols. J Clin Epidemiol 1994;47:81-87.)

26 Montelukast* Demostró Menos Eventos Adversos Relacionados con el Medicamento y Eventos Adversos Serios que Salmeterol** 1 evento adverso EA relacionado con el medicamento*** EA serio Suspensión debido a EA Montelukast + fluticasona (n=747) % 71.0 6.3 4.6 5.2 Salmeterol + fluticasona (n=743) % 72.4 10.0 7.4 4.6 Valor p p=NS 0.010 0.022 Slide 26 This table summarises adverse-event data in the two treatment groups. There was no significant difference between treatments in the proportion of patients reporting one or more adverse events. However, patients in the montelukast + fluticasone group experienced a significantly lower (p=0.010) incidence of drug-related adverse events compared with patients in the salmeterol + fluticasone group (6.3% and 10.0%, respectively) and a significantly lower (p=0.022) incidence of serious adverse events (4.6% and 7.4%, respectively). There was no significant difference in the proportion of patients who discontinued treatment due to adverse events.16 These results show that while both treatments were generally well tolerated, montelukast combined with fluticasone was associated with a lower risk of drug-related and serious adverse events compared with salmeterol combined with fluticasone. *10 mg mg fluticasona, ** 100 mg mg fluticasona. ***Determinado por el investigador como posible, probable o definitivamente relacionado con el medicamento

27 Eventos Adversos* Reportados por 5% de los Pacientes en Cualquiera de los Grupos de Tratamiento(%)
Infección de vías respiratorias superiores Asma Cefalea Faringitis Enfermedad similar a influenza Bronquitis Tos Rinitis alérgica Sinusitis Montelukast + fluticasona (n=747) 27.6 22.6 12.0 11.9 9.8 5.9 5.6 5.4 5.1 Salmeterol + fluticasona (n=743) 28.0 22.2 12.5 11.3 9.6 6.6 4.6 5.8 4.7 Slide 27 The table summarises the incidence (%) of adverse events reported by at least 5% of patients in either treatment group, regardless of relationship to study medication. There were no notable differences between the treatment groups in the incidence of these adverse events.16 These results show that both treatments were generally well tolerated. * Sin importar la relación con el medicamento en estudio

28 Hallazgos Tratamiento combinado con montelukast y fluticasona inhalada
Fue tan efectivo como el tratamiento combinado con salmeterol Demonstró efectos antiinflamatorios superiores comparado con la adición de salmeterol (como se demuestra por la reducción en conteos de eosinófilos sanguíneos y en expectoración) Ambos tratamientos proporcionaron control efectivo del asma comparados con el inicio Ambos tratamientos fueron bien tolerados en general, con menos eventos adversos relacionados con el medicamento y eventos adversos serios en el grupo montelukast + fluticasona comparado con salmeterol + fluticasona Slide 28 The results of the IMPACT study have shown that adding montelukast to inhaled fluticasone was as effective as adding salmeterol to inhaled fluticasone with respect to the proportion of patients experiencing asthma attacks, the number of asthma attacks reported, and the time to first asthma attack. Adding montelukast to fluticasone provided better control of asthmatic inflammation compared with adding salmeterol to fluticasone, as demonstrated by the reduction in peripheral blood eosinophils. With regard to other study endpoints, montelukast added to fluticasone was as effective as salmeterol added to fluticasone with respect to nocturnal awakenings due to asthma, post–beta2-agonist FEV1, and asthma-specific quality of life, while salmeterol added to fluticasone increased pre–beta-agonist FEV1 and AM PEF more than montelukast added to fluticasone. Both treatments were generally well tolerated, with significantly lower incidences of drug- related (p=0.010) and serious (p=0.022) adverse events with montelukast combined with fluticasone compared with salmeterol combined with fluticasone.

29 References 1. Bjermer L. History and future perspectives of treating asthma as a systemic and small airways disease. Respir Med 2001;95: 2. National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention. NHLBI/WHO Workshop Report. Publication No Bethesda, MD: National Institutes of Health, 2002. 3. National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998. 4. Bjermer L, Bisgaard H, Bousquet J et al. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: Design and rationale of a randomised, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial). Respir Med 2000;94: 5. Greening AP, Ind PW, Northfield M et al, on behalf of Allen & Hanburys Limited UK Study Group. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344: 6. Woolcock A, Lundback BO, Ringdal N et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153: 7. Murray JJ, Church NL, Anderson WH et al. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Allergy Asthma Proc 1999;20: 8. Yates DH, Kharitonov SA, Barnes PJ. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled β2-agonist. Am J Respir Crit Care Med 1996;154: 9. Nishikawa M, Mak JCW, Shirasaki H et al. Differential down-regulation of pulmonary β1- and β2-adrenoceptor messenger RNA with prolonged in vivo infusion of isoprenaline. Eur J Pharmacol (Mol) 1993;247: 10. Nishikawa M, Mak JCW, Shirasaki H et al. Long-term exposure to norepinephrine results in down-regulation and reduced mRNA expression of pulmonary β-adrenergic receptors in guinea pigs. Am J Respir Cell Mol Biol 1994;10:91-99. 11. Kalra S, Swystun VA, Bhagat R et al. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effects of salmeterol. Chest 1996;109(4): 12. McIvor RA, Pizzichini E, Turner MO et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998;158: 13. Eldeman JM, Turpin JA, Bronsky EA et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Ann Intern Med 2000;132: 14. Wilson AM, Dempsey OJ, Sims EJ et al. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001;119: 15. Corren J, Firriolo K, Ghannam A et al. The effect of add-on therapy with montelukast or salmeterol on exercise-induced asthma exacerbations and recovery following rescue short-acting beta-agonist. Poster #K37 presented at the American Thoracic Society annual meeting, May 18-23, 2001, San Francisco, CA, USA. 16. Data on file, MSD_______. 17. Barnes PJ. Mechanism of action of glucocorticoids in asthma. Am J Respir Crit Care Med 1996; 154:S21-S27. 18. Robinson D, Hamid Q, Ying S et al. Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon- cytokine gene expression. Am Rev Respir Dis 1993;148: 19. Csoma Z, Kharitonov SA, Balint B et al. Increased leukotrienes in exhaled breath condensate in childhood asthma. Am J Respir Crit Care Review 2002;166: 20. Claesson HE, Dahlen SE. Asthma and leukotrienes: Antileukotrienes as novel anti-asthmatic drugs. J Intern Med 1999;245: 21. Henderson WR. Role of leukotrienes in asthma. Ann Allergy 1994;72: 22. Diamant Z, Sampson AP. Anti-inflammatory mechanisms of leukotriene modulators. Clin Exp Allergy 1999;29: 23. LaViolette M, Malmstrom K, Lu S et al for the Montelukast/Beclomethasone Additivity Group. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160: Referencias Ver página de notas de archivo de Power Point para referencias.

30 Referencias (continuación)
References (continued) 24. Corren J. Allergic rhinitis and asthma: How important is the link? J Allergy Clin Immunol 1997;99:S781-S786. 25. Metso T, Rylilä P, Peterson C et al. Granulocyte markers in induced sputum in patients with respiratory disorders and healthy persons obtained by two sputum-processing methods. Respir Med 2001;95:48-55. 26. Rylilä P, Metso T, Petäys T et al. Eosinophilic airway inflammation as an underlying mechanism of undiagnosed prolonged cough in primary healthcare patients. Respir Med 2002;96:52-58. 27. O´Connell JM, Baird LI, Campbell AH. Sputum eosinophilia in chronic bronchitis and asthma. Respiration 1978;35:65-72. 28. Juniper EF, Guyatt GH, Epstein RS et al. Evaluation of impairment of health related quality of life in asthma: Development of a questionnaire for use in clinical trials. Thorax 1992;47:76-83. 29. Juniper EF, Guyatt GH, Willan A et al. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol 1994;47:81-87. Ver página de notas de archivo de Power Point para referencias.