Luis J Nannini. Neumonología. HEEP. Universidad Nacional Rosario.

Presentación del tema: "Luis J Nannini. Neumonología. HEEP. Universidad Nacional Rosario."— Transcripción de la presentación:

1 Luis J Nannini. Neumonología. HEEP. Universidad Nacional Rosario.
Uso de la asociación del corticoide inhalado y del broncodilatador de larga acción en la crisis de asma. Luis J Nannini. Neumonología. HEEP. Universidad Nacional Rosario.

2 Formoterol/Budesonide M & R.
Una estrategia altamente efectiva que adecua la terapia anti inflamatoria en función de la actividad del asma «  si se elige un inhalador combinado que contiene budesonida y formoterol, éste puede ser utilizado para rescate y mantenimiento. Esta estrategia ha demostrado reducir las exacerbaciones y mejorar el control del asma en adultos y adolescentes con dosis realtivamente bajas de tratamiento (Evidence A) » KEY MESSAGE(s) FOR SLIDE : GINA fully endorses the SMART approach with budesonide and formoterol and highlights that it leads to improved asthma control at low doses. It indicates the evidence for this statement is (level A) which is the highest level of evidence possible. GINA 2007; página30

3 Con Bud/Form M&R se usan tanto las dosis de mantenimiento como las de rescate para ajustar el control Medicacion usada por día (mantenimiento + rescate) Bud/Form + SABA a demanda Bud/Form + Bud/Form a demanda Exacerbacion sin exacerbacion Dosis regular de mantenimiento Tiempo (días)

4 Budesonide+Formoterol
Combinación Efectos no genómicos Formoterol Budesonide Neutrofilos Mastocitos Células epiteliales Eosinófilos Linfocitos-Th2 KEY MESSAGES FOR SLIDE : There is good evidence that both components of Symbicort when used as maintenance therapy contribute to the efficacy of Symbicort SMART and there is good evidence that both components when used as reliever therapy contribute to fine tuning overall asthma control/inflammatory control thus preventing asthma exacerbations. Both formoterol & budesonide have both long-lasting and rapid effects that make them well suited to be given for both mainteance and relief. This is not the case for other ICS/LABA combinations. Rápido alivio sintomático/broncoprotección (e.g. Estabilización de los mastocitos) Reduce inflamación por neutrófilos (infecc. Virales y asma) Reduce edema bronquial. Vasoconstricción dentro de 30 min Aumenta la función b2-receptor dentro de 2h Reduce los niveles de eosinófilos y óxido nítrico dentro de 6h. Acción antiinflamatoria anti NFKb Barnes PJ Eur Respir J 2007 (Review)

5 El formoterol atenúa la inflamación de la vía aérea mediada por neutrófilos
500 1000 1500 2000 2500 Formoterol basal A las 4 semanas Plac Basal Plac 4 sem Bud* Basal Bud 4 sem P<0.01 Recuento de neutrófilos (x103/mm3) esputo P<0.005 P<0.5 In a double-blind randomized crossover study, the effects of 4 weeks’ treatment with formoterol 24 µg bid (F; Turbuhaler) compared with placebo (PLC) on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients was evaluated.1 Therapy with budesonide 400 µg bid (BD; Turbuhaler) for 4 weeks was added at the end as the "gold standard" anti-inflammatory effect comparison. Formoterol significantly reduced neutrophil count compared with placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. These data suggest that formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations. 1Maneechotesuwan K, Essilfie-Quaye S, Meah S, et al. Formoterol attenuates neutrophilic airway inflammation in asthma. Chest 2005;128: Maneechotesuwan et al, CHEST 2005 * Bud: budesonide

6 78 pacientes. Ataque asma. FEV1= 1.83 (59%)
Salbutamol 2 x 800 µg. Salbutamol 800µg x 2 Formoterol Turbuhaler similar eficacia que salbutamol. A randomised, double-blind, double-dummy, parallel group study was performed in four Australian emergency treatment centres. The study included a total of 78 adult patients FEV1= 1.83 L; 59% predicted with acute asthma. FIGURE 1. Effect of formoterol via Turbuhaler1 (2x18 mcg; o) and salbutamol (2x800 μg; cuadrado negro) via pressurised metered-dose inhaler plus spacer on forced expiratory volume in one second (FEV1), expressed as mean change in % predicted from baseline. First dose administered at baseline; administration of second dose indicated by dotted line. Formoterol Turbuhaler as reliever medication in patients with acute asthma A.R. Rubinfeld*, R. Scicchitano#, A. Hunt", P.J. Thompson+, A. Van Nooten1 and O. Selroose Formoterol 2 x 18 µg Rubinfeld AR. Eur Respir J 2006; 27: 735–741

7 Similares efectos sistémicos que salbutamol.
Formoterol Formoterol salbutamol FIGURE 3. Effect of formoterol via Turbuhaler1 (2x18 mcg) and salbutamol (2x800 mcg) via pressurised metered-dose inhaler plus spacer on mean change in serum potassium. First dose administered at baseline; administration of second dose indicated by dotted line. FIGURE 2. Effect of formoterol via Turbuhaler1 (2x18 mcg) and salbutamol (2x800 mcg) via pressurised metered-dose inhaler plus spacer on mean change in QTc. First dose administered at baseline; administration of second dose indicated by dotted line. Rubinfeld AR.Eur Respir J 2006; 27: 735–741

8 Formoterol 90 μg vs terbutalina 10 mg.
O = Terbutalina. Dif significativas K+ y pulso Fig. 1. –Mean serum potassium values after administration of study drug. Patients were administered formoterol (90 mcg; +) or terbutaline (10 mg; #) on six occasions during a 3-h period at time points of 0, 30, 60, 120, 150 and 180 min. The vertical lines indicate administration of formoterol/terbutaline (- - -), methylprednisolone (—) was administered at 90 min. Fig. 3. – Geometric mean forced expiratory volume in one second (FEV1) values after administration of study drug. Patients were administered formoterol (90 mcg) or terbutaline (10 mg) on six occasions during a 3-h period at time points of 0, 30, 60, 120, 150 and 180 min. The vertical lines indicate administration of formoterol/terbutaline (- - -), methylprednisolone (—) was administered at 90 min. Fig. 2. –Mean pulse values after administration of study drug. Patients were administered formoterol (90 mg; +) or terbutaline (10 mg; #) on six associations during a 3-h period at time points of 0, 30, 60, 120, 150 and 180 min. The vertical lines indicate administration of formoterol/terbutaline (- - -), methylprednisolone (—) was administered at 90 min. bpm: beats per minute. El potasio y el pulso fueron significativamente diferentes entre formot y terbutalina. El pulso después de los 40 min en terbut pasó de 100 y nunca bajó en 6 hs, en tanto formoterol a la primer dosis bajó y nunca pasó de 100. J. Malolepszy Eur Respir J 2001; 18: 928–934

9 Revisión de Sears, ERJ 2008 Comparing asthma-related mortality with formoterol vs. non-LABA in the overalldataset, the a priori primary outcome of this study, there were 8 deaths among 49,906 formoterol-randomized patients and 2 among 18,098 non-LABA randomized patients (rates per 1000 treatment-years, 0.34 vs. 0.22; RR 1.57, 95% CI ) (Table 1). * Rate ratio and exact confidence intervals for asthma, cardiac ,“other” or any death (for formoterol vs. non-LABA) as calculated using StatXact (Cytel Inc., Cambridge, USA) [27]. † Two salbutamol as needed-randomized patients in the RELIEF study (SD ) who suffered a cardiac-related death actually were exposed to formoterol as needed: one erroneously received formoterol instead of salbutamol at start of treatment, and one used salbutamol for 5 weeks then exchanged medication with a formoterol-randomized patient and died 2 days later; the physician could not determine which drug was used before death. When applying a worst-case approach and re-assigning these two deaths to formoterol, the resulting 10 vs. 7 cardiac-deaths gives rates per TTY of 0.43 vs and a rate ratio (95% CI) for cardiac death of 0.56 ( ) for formoterol vs. non-LABA. ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; TTY = 1,000 treatment-years; SABA = short-acting β2-agonist There were eight asthma-related deaths (0.34 per 1000 patient-years) among 49,906 formoterol-randomized patients (92% using ICS), and two (0.22 per 1000 patient-years) among 18,098 patients (83% using ICS) not randomized to formoterol (RR 1.57, 95% CI ) which was not statistically significant. Asthma-related SAEs (>90% of which were hospitalizations) were significantly lower among formoterol-randomized patients (0.75% vs. 1.10%; RR 0.68, 95% CI 0.57- 0.81). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9 vs 18 vs 36 mcg). There was no statistically significant difference in cardiac mortality (RR 0.34, 95% CI ) or non-cardiac, non-asthma-related mortality (RR 2.35, 95% ) in formoterol-randomized when compared to non- LABA-treated patients. All-cause mortality was similar (RR 0.95, 95% CI ). In 3 the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1000 patient-years) among 46,003 formoterolrandomized patients and one (0.14 per 1000 patient-years) among 13,905 patients not randomized to formoterol (RR 2.32, 95% CI ) which was also not statistically significant. Conclusions: There were few asthma-related or cardiac-related deaths among patients randomized to formoterol, and all differences were not statistically significant compared with non-LABA-randomized patients. However, despite data on over 68,000 patients, the power is insufficient to conclude no increased mortality with formoterol. Cardiac-related SAEs were not increased, and asthma-related SAEs were significantly reduced with formoterol.

10 Formoterol un agonista total. Estudios in vitro.
Bronquio humano Br conejo FORMOTEROLREVIEW 2006 Figure 1. Relaxation by formoterol, terbutaline, and salmeterol of the human bronchus. Tone was induced by carbachol (0.5 mol/L). The data are the mean
SE of 7 to 10 experiments. Reprinted with permission of the European Journal of Pharmacology from Ka¨llstro¨m et al.21 Copyright 1994 Macmillan Publishers Ltd. Figure 2. Salmeterol inhibits formoterol-induced relaxation of guinea pig airway tissue. Guinea pig tracheal smooth muscle was contracted with 1-mol/L carbachol. Cumulative concentration-response curves are shown. The data are the mean
SE from 26 and 7 experiments, respectively. Reprinted with permission of Pharmacology and Toxicology from Jeppsson et al.24 Copyright 1992 Blackwell Publishing Ltd. Berger W. Ann Allergy Asthma Immunol. 2006;97:24–33.

11 Diferencias significativas intragrupo * p= 0,000035 y # :p= 0,0001.
Nannini LJ. RAMR 2001.

12 Mayor efecto del salbutamol sobre formoterol que a la inversa
145,6 45,7 Nannini LJ. RAMR 2001.

13 Budesonide+Formoterol
Combinación Efectos no genómicos Formoterol Budesonide Neutrofilos Mastocitos Células epiteliales Eosinófilos Linfocitos-Th2 KEY MESSAGES FOR SLIDE : There is good evidence that both components of Symbicort when used as maintenance therapy contribute to the efficacy of Symbicort SMART and there is good evidence that both components when used as reliever therapy contribute to fine tuning overall asthma control/inflammatory control thus preventing asthma exacerbations. Both formoterol & budesonide have both long-lasting and rapid effects that make them well suited to be given for both mainteance and relief. This is not the case for other ICS/LABA combinations. Rápido alivio sintomático/broncoprotección (e.g. Estabilización de los mastocitos) Reduce inflamación por neutrófilos (infecc. Virales y asma) Reduce edema bronquial. Vasoconstricción dentro de 30 min Aumenta la función b2-receptor dentro de 2h Reduce los niveles de eosinófilos y óxido nítrico dentro de 6h. Acción antiinflamatoria anti NFKb Barnes PJ Eur Respir J 2007 (Review)

14 Barnes PJ. Eur Respir J 2006; 27: 413–426
Efectos no genómicos Membrana No clásica sin RG Barnes PJ. Eur Respir J 2006; 27: 413–426

15 Acción vasoconstrictora, no genómica de ICS.
Fluticasona 880 µg Figure 3. Comparative vasoconstrictive efficacy of three inhaled corticosteroids in 10 corticosteroid-naive subjects with asthma. Mean (SE). *p < 0.05 versus respective baseline. Noncumulative dose–response curves. Note greater vasoconstrictor efficacy of budesonide and fluticasone than beclomethasone. Reprinted by permission from Reference 10. Figure 2. Effect of 880 μg fluticasone proprionate on airway mucosal blood flow (Q˙ aw) in 10 healthy (normal) subjects and 10 corticosteroidnaive subjects with mild asthma during a 90-minute period. Mean (SE). BSL indicates baseline. Note higher baseline and greater vasoconstrictive response in subjects with asthma. Reprinted by permission from Reference 9. Wanner A. Proc Am Thorac Soc Vol 1. pp 235–238, 2004

16 ¿Cómo producen vasocontricción en menos de 5 minutos?
FIGURE 3. Proposed mechanism of the acute vasoconstrictor effect of inhaled corticosteroids in the airway. Corticosteroids facilitate the noradrenergic (sympathetic) neuromuscular signal transmission by rapidly (within 5 min) inhibiting the extraneuronal monoamine transporter (EMT) in vascular smooth muscle cells Horwath G, Wanner A. Eur Respir J 2006; 27: 172–187

17 Restablece la broncodilatación post inspiración (In vitro).
Figure 2. Cumulative data for FFIR in control and dexamethasone-treated canine TSM strips. Dexamethasone-treated strips demonstrated a greater increase in FFIR (ΔFFIR) than did control strips when comparing FFIR posttreatment to pretreatment (ΔFFIR = 6.6 % ± 2.70 % versus 0.52 % ± 0.72 % respectively, p = 0.029). Figure 4. MKP-1 and HSP27 expression in dexamethasone-treated canine TSM cells. After 1 h of incubation in 4 μM dexamethasone (Dex) TSM cells demonstrated a significant increase in MKP-1 expression (relative to β-actin), as compared to control (Con) cells (1.69 ± 0.23 versus Con = 1.00, p=0.040). Although HSP27 phosphorylation (relative to total HSP27) was unchanged at 1 h incubation, by 2 h there was significantly less HSP27 phosphorylation in cells incubated in dexamethasone compared to control cells (0.54 ± 0.10 versus Con = 1.00, p=0.041). Molecular weights: HSP27, total and phosphorylated ~ 27 kD; MKP-1, β-actin ~ 40 kD. * p<0.05 MKP1 inhibe a p38 mitogen-activated protein kinase MAKP. Lakser OJ. ERJ November 2008

18 Características de los efectos no genómicos de los ICS.
Comienzo rápido (30 min) corta duración (<60 min). Dosis dependiente. Sin transcripción ni síntesis proteica. Visibles en células anucleadas (plaq, eritrocitos y epermatozoides). Los esteroides sin acceso celular también logran respuesta. It is important to understand, however, that these effects are not solely alternative to the genomic effects. Very useful in this matter is the definition of nongenomic effects recently given by Lösel and Wehling: “Any action that does not directly and initially influence gene expression, but rather drives more rapid effects such as the activation of signaling cascades” (Lösel R, Wehling M. Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol 2003;4:46–56.) Acciones sobre sistemas de segundo mensajeros como: (Ca2+, adenosine, monophosphate, inositol trisphosphate, protein kinase C) to alter cellular processes LJ Nannini

19 Efectos de los C sobre MLB
Disminuye Ca++ intracelular. Manifestaciones de receptores muscarínicos. Desensibilización de receptores β2. Aumenta: adenilciclasa y relajación. Aumenta nro de receptores β2. Aumenta actividad de la bomba Na+/K+. Lung, (6): p Br J Pharmacol, (4): p Gen Pharmacol, (2): p Br J Pharmacol, (1): p J Clin Invest, (1): p Am J Physiol, (1 Pt 1): p. L41-6. Br J Pharmacol, (5): p

20 Ttratamiento al inicio de respuesta tardía
El efecto temprano de la budesonida reduce la respuesta asmática tardía Budesonida 800 µg VEF1 (L) Placebo 4 * * * * * 3 2 Ttratamiento al inicio de respuesta tardía The effect of budesonide used in the relief of allergen symptoms has shown no effect on the immediate asthmatic response, however budesonide significantly reduces the late phase allergic reaction – an event that is thought to develop as a result of the increased inflammation. This highlights one aspect of the value of budesonide given in response to symptoms. Paggiaro PL, Dente FL, Morelli MC, et al. Postallergen inhaled budesonide reduces late asthmatic response and inhibits the associated increase of airway responsiveness to methacholine in asthmatics. Am J Crit Care Med 1994;149:1447–51. * p<0.05 1 -2 -1 1 2 3 4 5 6 7 8 9 10 Tiempo (horas) Paggiaro et al 1994

21 3000 μg Flutic+2400 Salb+504 Iprat/hr vs Hidrocort 500 mg
3000 μg Flutic+2400 Salb+504 Iprat/hr vs Hidrocort 500 mg. Duración: 3 hs. Todos los pacientes FEV1 Basal < 1 litro 250 x 2 FP x 4 Cada 10 m Figure 3. FEV1 values (% predicted) after the administration of FP or HYD in patients with FEV1 at presentation less than 1 L (left panel) or 1 L or more (right panel). Data points are mean values, and the brackets represent 95% confidence intervals. *p < 0.01; **p < *p < 0.05; **p < 0.01 *p < 0.01; **p < 0.001 N= 54 y 52. FEV1 B=29.5% GJ Rodrigo AJRCCM junio2005

22 Curva Kaplan Meier de ptes con alta.
(FEV1<1 L) p<0.0003 P<0.004 Figure 2. Kaplan-Meier estimated curves showing the percentage of patients in the FP and HYD groups who obtained the discharge threshold during the treatment time. Log-rank test, p < Figure 4. Kaplan-Meier estimated curves showing the percentage of patients with baseline FEV1 less than 1 L in the FP and HYD groups who obtained the discharge threshold during the treatment time. Log-rank test, p < Rodrigo GJ. AJRCCM 2005; 171: 1231–1236

23 Bud & Form 2+4+4 de 160/4.5 µg en 60 min (tolerancia y seguridad).
14 asmáticos tratados con Symbic. Inhalan 10 dosis adicionales en total son 1920/54 en un día. No hubo diferencias clínicamente relevantes Ankerst J. Pulm Pharm & Ther 2003;16:

24 Seguimiento 12 hs. Significación estadística; pero no clínica.
Ankerst J. Pulm Pharm & Ther 2003;16:

25 FEV1 (% de cambio desde basal)
Budes/formot 1280/36 µg vs salbutamol 1600µg en ataque asma (n=104) FEV1= 43%. Bud/formot Salbutamol FEV1 (% de cambio desde basal) 45 40 35 30 25 20 A critical issue underpinning the SMART concept is the use of Symbicort for relief of symptoms. It has previously been shown that Symbicort is a fast-acting bronchodilator, providing rapid relief that patients actually feel following metacholine-induced bronchoconstriction1. The true test of the effectiveness of any reliever medication is how it performs in the acute setting. The study by Balanag et al2 in 104 patients with acute asthma seeking emergency room attention shows that Symbicort is as effective as salbutamol in relieving bronchospasm and thereby confirms its status as an effective reliever medication. 1Van der Woude HJ et al. Pulm Pharmacol Ther 2004; 17: 89-95 2Balanag VM et al. Pulm Pharmacol Ther (submitted). Mean percentage change from baseline in forced expiratory volume in 1 s (FEV1) following administration of budesonide/formoterol (320/9 mcg, two inhalations) or salbutamol (100 mg, eight actuations). Study drug was administered at -5 and 0 min. Baseline mean FEV1 (measured as and l in the budesonide/formoterol and salbutamol groups, respectively), was measured before the first intake of study treatment. Baseline FEV1 was measured before the first intake of study treatment. No significant between-group difference was observed at any timepoint. Study drug (budesonide/formoterol [320/9 mg, two inhalations] or salbutamol [100 mg, eight actuations]) was administered at -5 and 0 min. 15 10 5 30 60 90 120 150 180 Tiempo luego de la administración (minutos) Balanag VM et al. Pulm Pharm & Ther 19 (2006) 139–147

26 Sin diferencias en [K+]; pero si en el pulso.
V.M. Balanag et al. / Pulmonary Pharmacology & Therapeutics 19 (2006) 139–147. Figura 3 (a) Mean serum potassium. No significant between-group difference was observed for average or minimum serum potassium values. (b) Pulse rate. Mean difference in pulse rate for budesonide/formoterol vs. salbutamol: -4.6 bpm. (c) QTc. No significant between-group difference was observed for average QTc interval. All data are shown over the 3-h treatment period. Study drug (budesonide/formoterol [320/9 mg, two inhalations] or salbutamol [100 mg, eight actuations]) was administered at -5 and 0 min. Balanag VM et al. Pulm Pharm & Ther 19 (2006) 139–147

27 Ante falta de respuesta a salbutamol.
Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol ED Bateman*1, L Fairall1, DM Lombardi2 and R English1 Abstract Background: To compare the efficacy and safety of budesonide/formoterol (Symbicort®) with formoterol (Oxis®) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β2-agonist therapy. Methods: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg), were randomized to receive either budesonide/ formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg]) or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]). The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. Results: FEV1 increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. Conclusion: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a shortacting β2-agonist. Mean increase in FEV1 from baseline eFiitghuerr efo 2rmoterol or budesonide/for mino ptaetrioenl ts treated with Mean increase in FEV1 from baseline in patients treated with either formoterol or budesonide/formoterol. At screening (t = -20 minutes), salbutamol 400 μg was administered to all patients to establish their relative refractoriness to β2-agonist therapy. Patients in the formoterol group received formoterol 9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes (total dose 36 μg). Patients treated with budesonide/ formoterol received budesonide/formoterol 320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes (total dose 1280/36 μg). The timing of study drug administration is shown by vertical dotted lines on the figure. Patients received oral prednisolone 60 mg 90 minutes after the last administration of study drug. Bateman ED. Respiratory Research 2006, 7:13

28 ¿Dos aplicaciones de baja dosis ICS?
Bateman ED. Respiratory Research 2006, 7:13

29 ¿Cómo diseñaría el ensayo clínico para captar las ventajas del CI ?
4 dosis de bud 200 cada 20 min serían 3200bud y 72formoterol Budesonide/Formoterol Modificado de Bateman 2006

30 Muchos interrogantes Relación costo/beneficio (farmacoeconomía)
Administración secuencial y sinergia. Flujos inspiratorios bajos en ataque grave. Nueva presentación en aerosol. Taquifilaxia reversible. Efecto sobre recaídas tempranas.

31 Muchas Gracias

32 Symbicort SMART: efecto en las exacerbaciones severas luego de días de asma no controlados
% de pacientes con exacerbaciones de asma posteriores al día de asma no controlado según uso de rescate The COMPASS clinical trial was a 6-month, double-blind, randomised double-dummy study conducted at 235 centres in 16 countries. Following a 2-week run-in period patients were randomised to receive either Symbicort SMART, fixed-dose Seretide (pMDI) or fixed-dose Symbicort, both with SABA (Bricanyl) as needed, for the 6-month treatment period. Patient flow: Enrolled patients: 4399 - Eligibility criteria not fulfilled: 932 - Adverse event: 17 - Lost to follow-up: 29 - Other reason(s): 86 Randomised: 3335 - Not treated or no data on treatment: 14 - Discontinued: 149 - Eligibility criteria not fulfilled: 21 - Adverse events: 34 - Lost to follow-up: 25 - Other reason(s): 69 Completers: 3172 The withdrawal rate was not different between treatment groups. Kuna P, et al. Int J Clin Pract 2007;In Press. AHEAD: Bousquet et al. Respir Med 2007;101:2437

33 Conclusiones Estudio AHEAD
Symbicort SMART vs dosis máximas de Seretide + SABA : Reduce la incidencia de exacerbaciones severas en un 21%, y de internaciones y tratamientos de urgencia en un 31% Proteje contra las exacerbaciones severas luego de días de asma no controlados Permite que los pacientes reciban la mitad de la dosis de CI durante los días de asma controlada y un 38% menos en total al final de 6 meses de tratamiento. AHEAD: Bousquet et al. Respir Med 2007;101:2437

34 …¿Por qué funciona este esquema? Acción de la Budesonida
Ajuste temprano de la dosis ante los primeros signos de empeoramiento Incremento de la dosis y la frecuencia durante los empeoramientos

35 …¿Por qué funciona este esquema? Acción de la Budesonida
Ajuste temprano de la dosis ante los primeros signos de empeoramiento Incremento de la dosis y la frecuencia durante los empeoramientos

36 Flunisolide+salbutamol+ipratropio (1000, 400 , 84 µg) cada 10 min x 3 hs

37 Redujo internaciones en los más graves (PEF basal < 30%)
Rodrigo G. CHEST 2003; 123:1908–1915

38 Efectos vasculares en la vía respiratoria de sujetos con asma
Efectos vasculares en la vía respiratoria de sujetos con asma. Rápido, mediano y largo plazo. FIGURE 2. Rapid (#), delayed ("), and long-term (+) vascular effects of inhaled corticosteroids in the airway of patients with asthma. Effects are spaced vertically on the y-axis simply to facilitate reading. Horwath G, Wanner A. Eur Respir J 2006; 27: 172–187

39 Clasificación de Mannheim. Alemania, septiembre 1998
B. Indirecto A. Directo Generando sistemas de 2º mensajeros, cambios en flujo iónico y activación de vías para quinasas. I. Inespecífico: no mediado por receptor. Efecto sobre la membrana celular. Anafilaxia- lesión medular FIG. 1. Mannheim classification of nongenomic steroid actions. Dotted arrows indicate a hypothetical category with no example yet known. Other arrows indicate examples for categories with given examples, which are explained in the text. In addition to the short time frame in which the effects occur, these characteristics include: (1) a different pharmacologic profile, because the effects are insensitive to transcriptional and protein synthesis inhibitors; (2) action on nonnucleated cells, such as platelets, erythrocytes, and spermatozoa; and (3) the ability of steroid analogs (such as bovine serum albumin-conjugated steroid molecules) that cannot access the intracellular compartment to elicit a response (Schulz M, Schneider S, Lottspeich F, Renkawitz R, Eggert M. Identification of nucleolin as a glucocorticoid receptor interacting protein. Biochem Biophys Res Commun 2001;280:476–480.). II. Específico: involucra al GR. GR clásico intracelular. eNOS. Isquemia miocárdica y cerebral. GR no clásico. Efectos neurofisiológicos J Clin Endocrinol Metab 85: 2072–2075,2000