Beta 2 agonists

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Beta 2 agonists

Presented by Piyawadee Lertchanaruengrith, MD.

20110930

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  • OH ที่ 3,4 เป็นที่ที่COMT มาทำงานคือย่อย catecholamineReposition OH group ไปที่ 3,5 เปลี่ยนตำแหน่งที่ 3 จาก OH เป็นกลุ่มอื่น
  • ส้ม = แทนที่isopropyl group ด้วยอย่างอื่นเหลือง = เพิ่มขนาด terminal amino group เป็น lipophilic side chain (salmet > ) ป้องกันโดน MAO มาทำลาย  เพิ่ม duration of axn
  • 413 aa residue, 46500 kDa7 transmembrane-spanning alpha helix, 3 intracellular loopRed: bindingGreen: polymorphismBlue: couplingPink: desensitizationOrange: downregulationAWsm m พบ receptor ประมาณ 30-40000 /cell
  • Note: beta2-rec activated MAPK จะไปเติม P ให้ GR  prime GR ให้ไวต่อ steroid-dependent activationนอกจากนี้ยังเพิ่ม translocation GR เข้า nucleus ผ่าน C/EBP alpha
  • Active site อยู่ใน lipid bilayerดังนั้น molecular structure ของยา จึงเป็นตัวกำหนด ว่ายาจะจับ receptor ยังไง Albuterol: ชอบน้ำ ผ่าน extracellular aqueous compartment ไปจับ active site โดยตรง  onset เร็ว แต่ก็ re-equilibrate คือจับ recอ่อนและกระจายกลับ microcirculation เร็ว จึงออกฤทธิ์สั้น 4-6 ชั่วโมงFormoterol: ชอบไขมันกลางๆ ถูก uptake เข้า cell membrane  depot แล้วค่อยๆปล่อยมาจับ active site ออกฤทธิ์ยาว 12 ชั่วโมง (conc dependent) : ก็ยังมีบางส่วน อยู่ใน aqueous phase นอกเซลล์ จึง onset เร็ว Salmeterol: ชอบไขมันที่สุด เข้าไปส่วนใหญ่อยู่ใน cell membrane ภายใน 1 นาที แล้วค่อยขยายไปด้านข้างเข้า active site ถูกปล่อยช้ากว่า จึง onset ช้ากว่า F และยาอื่น: interxnระหว่าง side chain ของมันที่ยาวมากๆ กับ exosite (บริเวณ aaที่เกลียดน้ำมาก อยู่ใน domain ที่ 4)  ทำให้ยาไม่หลุดจาก rec  ออกฤทธิ์นาน (conc independent)0
  • Majority: intermediate agonist พอมี receptor เยอะ จะกลายเป็น full agonistF > 80% rec activation
  • Corticosteroids to beta- increase the transcription of the b2-receptorgene increased expression of b2-receptors at the cellsurface (human lung in vitro and in the nasal mucosa in vivo after application of a topicalnasal corticosteroid (effect with in a few hours)Preventdownregulation of pulmonary b2-receptors and tolerancethat occurs after prolonged b2-agonist administration Reverse the uncoupling of b2-receptors that occurs afterexposure to b2-agonists -This suggests that treatment withinhaled corticosteroids may prevent the development oftolerance to LABA. -Thus, b2-agonists maypreserve the response to b2-agonists in mast cells andneutrophils, which would normally rapidly develop tachy-phylaxis in response to b2-agonists. This would be relevant inthe use of budesonide/formoterol as rescue therapy as theacute effects of formoterol and mast cells and neutrophils maybe preserved by the maintenance treatment with inhaledbudesonide.
  • ไม่เท่ากับ tachyphylaxisซึงคือ ยา x ไปแทนที่ยา Y ที่symp n endings
  • ระยะสั้น คือสีแดงPKAและหรือ ARK ไปเติม P ให้ receptor  receptor จับ B-arrestin  ทำให้ไม่มี receptor จับกับ stimulated Gs protein  limit receptor functionชั่วคราว หายในเวลาเป็นนาทีหลังเอา agonist ออกระยะกลางReceptor ถูก sequestration เข้า cell  เหลือน้อยบน cell surface เข้ามาก็จะถูกเอา P ออก หายในเวลาเป็นชั่วโมงหลังเอา agonist ออก
  • No differences between LOS, admission rate, no of return visit
  • Regular treatment with formoterol combined withbudesonide did not cause any long-term loss of con-trol of asthma. There were no signs of worsening ofdisease or tolerance to the effects of medication withregard to any clinical or functional variable exam-ined, except for a decrease in the effect of formo-terol on peak expiratory flow in the morning afterthe first two days of treatment. The
  • FACET: ICS ไม่ prevent?
  • placebo vstriamcinolone, P,.001; for salmeterolvstriamcinolone, P=.004; and for placebo vssalmeterol, P=.18placebo vstriamcinolone, P=.003; forsalmeterolvstriamcinolone, P=.04; and for placebo vssalmeterol, P=.29
  • นอกจากนี้ SF ดีกว่า F: exacerbation, QOL, symptom-free day, achieve well และ total control ไวและที่ steroid ขนาดต่ำกว่า, change morning PEF มากกว่า
  • morning PEF 70% of baseline on 2 consecutive days;treatment with oral steroids; an increase in inhaled corticosteroids [via a separate inhaler] and/or otheradditional treatment; or hospitalization/ED treatment)
  • Best add-on therapy giving effective response
  • PC20, FeNo, Genotype Arg/Arg (เดิมว่าLABA ดี) – not predict
  • A for ≥12 years of age, B for 5–11 years of ageEIB: but duration of action does not exceed 5 hours with chronic regular use,disguise poorly controlled persistent asthma
  • A for ≥12 years of age, B for 5–11 years of ageEIB: but duration of action does not exceed 5 hours with chronic regular use,disguise poorly controlled persistent asthma
  • - Tremor ลดใน 2 wkหลังให้ต่อเนื่อง (dose-limiting effect)
  • Beta 2 agonists

    1. 1. BETA 2-AGONISTS Piyawadee Lertchanaruengrith, MD 30/09/2011
    2. 2. Topic outlines Structure & Function Relationship Non-bronchodilator Actions of β2–Adrenergic Agonist Clinical Applications Safety issues β2–Adrenergic Agonist in Asthma Guidelines
    3. 3. Structure & Function Relationship
    4. 4. Classification of β2-agonists CATECHOLAMINE NON-CATHECHOLAMINE  Ephedrine  Short-acting non-selective: Metaproterenol, Fenoterol  Epinephrine  Isoproterenol  Short-acting selective: Albuterol, Terbutaline  Long-acting selective: Formoterol, Salmeterol, Arformoterol, Carmoterol, IndacaterolSorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    5. 5. Modification of 3,4- hydroxylgroup on benzene ring Prolonged bronchodilator action Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    6. 6. Increasing the bulk of side chain β2-adrenergic specificityIncreasing duration of bronchodilation Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    7. 7. β2-adrenoreceptor Long arm of chromosome 5 G protein-coupled receptors Distribution  Widely distributed in lung, with high levels in central lung and alveolar region  Airway smooth muscle, epithelial cells, endothelial cells, type II cells  Mast cell, eosinophil, monocyte, alveolar macrophage, dendritic cells Johnson M. JACI 2006;117:18-24.
    8. 8. Intracellular signaling pathway GTP Phosphorylate key regulatory proteinsATP that control muscle tone-Inhibition of Ca2+ release from intracellular store-Reduction of membrane Ca2+ entry-Sequestration of intracellular Ca2+ Relaxation of airway smooth muscle Johnson M. JACI 2006;117:18-24.
    9. 9. Mechanisms of Actions Johnson M. Paediatric respiratory reviews 2001;2:57-62.
    10. 10. Summary of Structure and Function Relationship ALBUTEROL FORMOTEROL SALMETEROLLipophilicity Hydrophilic Moderately Most lipophilic lipophilicOnset of action Fast Fast DelayedDuration of action Short Long Longβ2-agonist potency Partial agonist Full agonist Partial agonist(Efficacy & receptor (= Terbutaline) (= Isoproterenol, (Less than albuterol)affinity) Fenoterol)Mechanism of action Accesses active site Forms a depot in Rapidly diffuses into directly from the cell membrane and cell membrane to aqueous progressively leach active site extracellular out Exosite compartment (Duration-dose (Duration-dose dependent) independent) Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    11. 11. Summary of Pharmacologic Attributes of Selected β2-agonists β2-agonists Selectivity ratio Onset of action Duration of action (β1:β2 receptors) (minutes) (hours)Isoprenaline 1:1 2-5 < 20 minutesAlbuterol 1:1375 2-3 4-6Fenoterol 1:120 2-4 4-6Terbutaline nd 2-4 4-6Salmeterol 1:85000 30 > 12Formoterol 1:120 2-3 > 12 Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    12. 12. Non-bronchodilator Actions ofβ2–Adrenergic Agonist
    13. 13. Non-bronchodilator actions1. Increased mucociliary clearance - Increased ion & water secretion, ciliary beat frequency - “Conflicting data; ? Clinical importance”2. Suppression of microvascular permeability - 16 normal subjects  histamine inhalation followed by sputum induction by 4.5% hypertonic saline inhalation  formoterol 18 mcg or placebo  sputum β2- macroglobulin - At 30 minutes after formoterol, the effect of histamine was reduced by 50% compared with placebo.3. Inhibition of cholinergic neurotransmission4. Protection of respiratory epithelium against bacteria Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    14. 14. Non-bronchodilator actions5. Inhibition of mediator release: basophil, mast cell, lung tissue - In vitro: Salmeterol blocks release of histamine, LTC4, LTD4, PGD2 from normal human lung tissues which were sensitized by serum of allergic donors - In vitro: Salmeterol blocks TNF- α from human skin mast cell6. Inhibition of function: - Eosinophil – In vitro: Salmeterol reduces plasma ECP after allergen challenge - Macrophage/DC - In vitro: Salbutamol inhibits production of IL-12 - T lymphocyte – In vitro: Salmeterol inhibits production of IFN-γ & IL-4 - Bronchial epithelial cells – In vitro: Formoterol + Budesonide inhibit production of GM-CSF & IL-8 * However, SABA & LABA should not be replaced ICS in terms of anti- inflammatory action * Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    15. 15. Non-bronchodilator actions7. Priming the glucocorticoid receptor - Mitogen-activated protein kinases (MAPKs) pathway – result of prolonged stimulation of β2–adrenergic receptor Barnes PJ. Eur Respir J 2007;29:587-95.
    16. 16. β2-receptor Desensitization Down-regulation of receptor after constant association with agonist molecule Autoregulatory process Develops over days or weeks Mechanisms  Uncoupling of receptor from adenylate cyclase  Internalization of uncoupled receptor  Downregulation Johnson M. JACI 2006;117:18-24.
    17. 17. β2-receptor Desensitization Johnson M. JACI 2006;117:18-24.
    18. 18. β2-receptor Desensitization Downregulation A net loss of cellular receptors  Several mechanisms that are independent of receptor phosphorylation receptor degradation  Transcriptionof β2–receptor gene is required to restore the membrane receptor  Hours of agonist exposure Johnson M. JACI 2006;117:18-24.
    19. 19. β2-receptor Desensitization Effects of β2-receptor Desensitization  Decreased in unwanted receptor stimulation  Tremor: decreases after 2 weeks  Palpitation  Hyperglycemia, hypokalemia ? Loss of bronchodilator response Johnson M. JACI 2006;117:18-24.
    20. 20. SalmeterolObjective: To determine whether regular use of salmeterol reduces the emergencyeffectiveness of albuterolPatient ≥ 17 years, asthma with acute attack, 2 groups (match) 1. Using salmeterol for chronic asthma control (57) 2. Not using salmeterol for chronic asthma control (57)Intervention & 1st : Albuterol 2.5 mg NB every 20 minutes x 3 doses (33 each)control 2nd: Albuterol 5.0 mg NB every 20 minutes x 3 doses (24 each)Primary outcome Change of PEF % predicted before & after each aerosol Korosec M, et al. Am J Med 1999; 107:209-13.
    21. 21. P = 0.1346% 62% 58% P < 0.00139% Salmeterol vs control Salmeterol vs control P = 0.37 P = 0.81 Korosec M, et al. Am J Med 1999; 107:209-13.
    22. 22. Formoterol FACETObjective: To evaluate the effects of adding inhaled formoterol to both lower andhigher doses of the inhaled glucocorticoid budesonidePatient 852 patients with asthma (FEV1 at baseline ≥ 50%) at least 6 months, 18-70 years, treat with ICSIntervention & Run-in period: BUD 800 µg BID x 4 wkcontrol Random to 4 groups: 1. BUD 100 µg BID x 1 year 2. BUD 100 µg BID + Formoterol 12 µg BID x 1 year 3. BUD 400 µg BID x 1 year 4. BUD 400 µg BID + Formoterol 12 µg BID x 1 yearPrimary outcome Rates of severe and mild exacerbations of asthma per patient per year Pauwels RA, et al. NEJM 1997;337:1405-11.
    23. 23. • Formoterol groups, am PEF was higher during the first daysof treatment than subsequently (i.e., after day 3; P <.001)• ? Limited tolerance to bronchodilating effect of formoterol during theearly phase of regular treatment  little or no clinical significance. Pauwels RA, et al. NEJM 1997;337:1405-11.
    24. 24. LABAs: Desensitization Occurs in Formoterol, but not Salmeterol FACET study  Little or no clinical significance  ICSs did not prevent tolerance Hypothesis?  Agonist occupancy: Full (Formoterol), Partial (Salmeterol)  Salmeterol may maintain functional –receptor through persistent elevation of gene transcription. Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
    25. 25. Clinical Applications
    26. 26. Clinical Applications SABAs  Regular schedule or as-needed LABAs  Monotherapy or combination with ICSs  Reduction or stop ICSs if LABAs were added  Add-on LABAs or double dose ICSs  ICS + LABAs or ICS + Montelukast
    27. 27. BAGSObjective: To compare the effects of regularly scheduled use of inhaled albuterolwith those of albuterol used only as-neededPatient 255 mild asthma patients (12-55 years, FEV1 ≥ 70%, PC20 ≤ 16 mg/ml), no ICS for 6 weeksIntervention & Run-in period: no ICS x 6 weeksControl Albuterol MDI 2 puff qid daily (µg/d) + as-needed x 16 weeks (126/116) Placebo MDI 2 puff qid daily + Albuterol as-needed x 16 weeks (129/114) Withdrawal period: Placebo X 4 weeksPrimary outcome Morning peak expiratory flow Drazen JM et al. NEJM 1996;335:841-7.
    28. 28. Morning PEF did not change significantly during the treatment period in the scheduled or the as-needed treatment groups (P = 0.71)As-needed use Drazen JM et al. NEJM 1996;335:841-7
    29. 29. LABA Monotherapy vs Continued Therapy With ICS in Patients With Persistent Asthma: A Randomized Controlled Trial SOCObjective: To examine the effectiveness of salmeterol as replacement therapy inpatients whose asthma is well controlled by low-dose TAPatient 164 patients, 12-65 years, well controlled persistent asthma (FEV1 > 80%, PEF variability ≤ 20%) during a 6-week run-in period of treatment with TA 400 µg BIDIntervention 1. Triamcinolone MDI 400 µg BID X 16 weeks (54) 2. Salmeterol MDI 42 µg BID X 16 weeks (54)Control Placebo MDI 2 puffs BID X 16 weeks (56)Primary outcome Change in morning PEF from the final week of the run-in period (week 6) to the final week of the randomized treatment period (week 22). Lazarus SC, et al. JAMA 2001;285:2583-93
    30. 30. AM PEF, increased in salmeterol and triamcinolone groups and decreased initially then increased in placebo group(no statistically significant differences either within or among 3 groups) Lazarus SC, et al. JAMA 2001;285:2583-93
    31. 31. P=.18 P=.29 P=.001 P=.003 P=.04 P=.004Salmeterol group had more treatment failures and asthma exacerbations than the triamcinolone group Lazarus SC, et al. JAMA 2001;285:2583-93
    32. 32. P = .0012.4%[0.0-10.6%] Greater increases in median sputum eosinophils Patients with well-controlled persistent asthma by low doses of TA cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control Monotherapy could not be recommended in persistent asthma−0.1%[−0.7% - 0.3%] Lazarus SC, et al. JAMA 2001;285:2583-93
    33. 33. ICS Reduction and Elimination in Patients With SLICPersistent Asthma Receiving Salmeterol Lemanske RF, Jr, et al. JAMA 2001;285;2594-603.Objective: To determine whether ICS can be reduced or eliminated in patients withpersistent asthma after adding LABAPatient: 175 patients, 12-65 years with persistent asthma that was uncontrolled (FEV1≤ 80%, PEF variability >20%) during a 6-week run-in period of treatment with TA 400 µg BIDIntervention & Salmeterol induction phase (2 wk)Control 1. TA 400 µg BID + Placebo BID (21)  Group I 2. TA 400 µg BID + Salmeterol 42 µg BID(154)  Group II TA Reduction Phase (8 wk) 1. Group I: TA 200 µg BID + Placebo BID (19)  Placebo-minus 2. Group II: TA 400 µg BID + Salmeterol 42 µg BID (74)  Salmeterol- plus 3. Group II: TA 200 µg BID + Salmeterol 42 µg BID (74)  Salmeterol- minus TA Elimination Phase (8 wk) 1. Placebo-minus: Placebo TA + Placebo (18) 2. Salmeterol-plus: TA 400 µg BID + Salmeterol 42 µg BID (71) 3. Salmeterol-minus: Placebo TA + Salmeterol 42 µg BID (71)Primary outcome: Time to asthma treatment failure in patients receiving salmeterol
    34. 34. Reduction phase: RR of treatment failure Elimination phase: RR of treatment failurefor patients in salmeterol-minus group in salmeterol-minus group compared withcompared with salmeterol-plus group was salmeterol-plus group was 4.3 (2.0-9.2), (P2.2 (0.5-9.2) (P =.27) = .001) ICSs could safely undergo 50% reduction , but could not have ICSs eliminated Lemanske RF, Jr, et al. JAMA 2001;285:2594-603.
    35. 35. GOALObjective: To determine proportion of patients who achieved well-controlledasthma with salmeterol/fluticasone combination compared with fluticasone alonePatient 3421 patients, 12 years, asthma 6 months, reversibility of 15%, smoking pack years < 10 years, uncontrolled asthma 2 out of 4 weeks during run-in period 3 strata (ICS in 6 months prior to randomisation): Stratum 1: Corticosteroid-naïve (S/F 550;F 548) Stratum 2: 500 µg Beclomethasone or equivalent (S/F 578;F 585) Stratum 3: >500 – 1000µg Beclomethasone or equivalent (S/F 579;F 576) Bateman ED, et al. AJRCCM 2004;170:836-44.
    36. 36. Study design for Strata 1 and 2 Phase I 8- week control assessment Phase II 4- week control assessment Seretide 50/500 & oral prednisolone Seretide 50/500 or FP 500 Seretide 50/250 or FP 250 Step 3 Seretide 50/100 or FP 100 Step 2 Step 1Visit 1 2 3 4 5 6 7 8 9Week -4 0 4 12 24 36 48 52 56 Bateman ED, et al. AJRCCM 2004;170:836-44.
    37. 37. Study design for Stratum 3 Phase I 8- week control assessment Phase II 4- week control assessment Seretide 50/500 & oral prednisolone Seretide 50/500 or FP 500 Seretide 50/250 or FP 250 Step 2 Step 1Visit 1 2 3 4 5 6 7 8 9Week -4 0 4 12 24 36 48 52 56 Bateman ED, et al. AJRCCM 2004;170:836-44.
    38. 38. 70% 78% 75% 71% 69% 62% 65% 60% 52% 47% 51% 33% Well-controlled asthma: SFC versus FP Phase I: stratum 1 p = 0.039, strata 2 and 3 p < 0.001Cumulative phase I and phase II: stratum 1 p = 0.003, strata 2 and 3 p < 0.001 Bateman ED, et al. AJRCCM 2004;170:836-44.
    39. 39. Well Controlled Asthma% of patients with a SeretideWell-controlled week 100 FP 80 77% 60 68% 40 20 0 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week All patients Bateman ED, et al. AJRCCM 2004;170:836-44.
    40. 40. 50% 44% 40% 42% 28% 32% 29% 31% 16% 20% 19% 8% Totally controlled asthma: SFC versus FP Phase I: all strata p < 0.001Cumulative phase I and phase II: all strata p < 0.001 Bateman ED, et al. AJRCCM 2004;170:836-44.
    41. 41. FACETObjective: To evaluate the effects of adding inhaled formoterol to both lower andhigher doses of the inhaled glucocorticoid budesonidePatient 852 patients with asthma (FEV1 at baseline ≥ 50%) at least 6 months, 18-70 years, treat with ICSIntervention & Run-in period: BUD 800 µg BID x 4 wkcontrol Random to 4 groups: 1. BUD 100 µg BID x 1 year 2. BUD 100 µg BID + Formoterol 12 µg BID x 1 year 3. BUD 400 µg BID x 1 year 4. BUD 400 µg BID + Formoterol 12 µg BID x 1 yearPrimary outcome Rates of severe and mild exacerbations of asthma per patient per year Pauwels RA, et al. NEJM 1997;337:1405-11.
    42. 42. 1 2 3 4 Pauwels RA, et al. NEJM 1997;337:1405-11.
    43. 43. • FEV1 increased significantly in all groups during the run-in period • FEV1 increased further with the addition of formoterol • The higher dose of budesonide was associated with a significantly higher FEV1 than the lower dosePatients who have persistent symptoms despite treatment with ICSs, the addition of formoterol to BUD  Increasing dose of ICSs might be a more appropriate initial therapeutic step in patients with repeated severe exacerbations Pauwels RA, et al. NEJM 1997;337:1405-11.
    44. 44. Objectives: To investigate whether budesonide/formoterol for maintenance andreliever therapy could reduce asthma exacerbations.Patient 341 children, 4-11 years, with asthma ≥ 6 months, prebronchodilator FEV1 60-100% and 12% reversibility, uncontrolled with ICSIntervention & 1. SMART: BUD/Formoterol 80/4.5 µg OD + BUD/FormoterolControl additional inhalations for symptom relief (≤ 7 as-needed inhalation/day) x 12 months (118) 2. Fixed combination: BUD/Formoterol 80/4.5 µg OD + Terbutaline 0.4 mg for rescue medication X 12 months (117) 3. Fixed-dose budesonide: BUD 320 µg OD + Terbutaline 0.4 mg for rescue medication x 12 months (106)Primary outcome Time to first exacerbation Bisgaard H, et al. Chest 2006;130:1733-43.
    45. 45. 38% 26% 14% SMART significantly prolonged the time to first exacerbationvs fixed-dose combination (p < 0.001) or fixed-dose budesonide (p = 0.02) Bisgaard H, et al. Chest 2006;130:1733-43.
    46. 46. Bisgaard H, et al. Chest 2006;130:1733-43.
    47. 47. Objective: To compare efficacy and safety of salmeterol/fluticasone 50/100 µg BIDwith fluticasone 200 µg BID in children uncontrolled on low dose ICS.Patient 584 children,4–11 yrs, with a clinical history of asthma for at least 6 months, reversibility in FEV1 ≥ 15%, currently receiving BDP 400 µg/day or equivalentIntervention & Run-in period: FP 100 µg BID x 4 wk  not controlled ≥ 2 wk Control Randomization 1. Salmeterol/fluticasone (SFC) 50/100 µg BID x 12 wk (160) 2. Fluticasone propionate (FP) 200 µg BID x 12 wk (161)Primary outcome Mean change from baseline in morning PEF over 12 wk de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
    48. 48. Mean change differences between 2 groups: 7.06±3.01 (95% CI 1.7-13.5)(p = 0.012) de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
    49. 49. SFC is as effective as FP, at half the dose of ICS de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
    50. 50.  At least one adverse event  SFC: 87 (58%) subjects  FP: 86(56%) subjects Most common: headache and nasopharyngitis Serious adverse events  SFC group (2%): laryngotracheitis(1), asthma exacerbation (1) and concussion (1)  FP group (2%): wound infection (1), asthma exacerbation (1) and gastritis (1)  None of which were assessed as related to study de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
    51. 51. PACTObjective: To compare the effectiveness of fluticasone monotherapy, fluticasone +salmeterol, and montelukast in achieving asthma controlPatient 285 children, 6-14 years, mild-moderate persistent asthma symptoms, FEV1 ≥ 80%, PC20 ≤ 12.5 mg/mL, not on controller medications ≥ 2 weeks before randomizationIntervention & Run-in period: Placebo + Albuterol MDI x 2-4 weeksControl Randomization x 48 weeks 1. Fluticasone monotherapy: Fluticasone 100 µg BID (96) 2. PACT combination: Fluticasone 100 µg/salmeterol 50 µg in morning and salmeterol 50 µg evening (94) 3. Montelukast monotherapy: Montelukast 5 mg in the evening (95)Primary outcome Percent of asthma control days during the 48-week treatment period Sorkness C, et al. JACI 2007;119:64-72.
    52. 52. % ACD-F 64.2%-C 59.6%-M 52.5% Sorkness C, et al. JACI 2007;119:64-72.
    53. 53. Sorkness C, et al. JACI 2007;119:64-72.
    54. 54. • Improvements ACD: Both F & C > M• FEV1, FEV1/FVC, max bronchodilator response, ENO: F > C• Favor fluticasone monotherapy in treating Sorkness C, et al.children with mild-moderate persistent asthma with FEV1 ≥ 80% JACI 2007;119:64-72.
    55. 55. BADGERSObjectives: To assess frequency of differential responses to 3 step-up treatmentsin children who had uncontrolled asthma while receiving low-dose ICSsPatient 182 children, 6 -17 years, uncontrolled asthma while receiving Fluticasone 100 µg BIDIntervention Triple-crossover study (random order) x 16 weeks:& Control 1. ICS step-up: Fluticasone 250 µg BID 2. LABA step-up: Fluticasone 100 µg BID + Salmeterol 50 µg of a BID 3. LTRA step-up: Fluticasone 100 µg BID + Montelukast 5 or 10 mg ODPrimary Differential response:outcome - Oral prednisone (Total prednisone received during the period was ≤180 mg) - Asthma-control days (Annualized asthma-control days during the final 12 weeks was increased ≥ 31 days - FEV1 (FEV1 at the end ≥ 5%) Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
    56. 56. 54% 32% P = 0.004 52% 34% P = 0.02 Similar LABA vs LTRA: LABA vs ICS: Relative probability Relative probability of best response 1.6 of best response 1.7 (1.1-2.3);p = 0.004 1.7 (1.2-2.4);p=0.002Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
    57. 57. BADGERS Higher childhood ACT scores (> 19) predict best response to LABA step-up Race  Hispanic & non-hispanic white: best response to LABA  Black: best response to LABA or ICS equally LABA step-up was significantly more likely to provide the best response. Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
    58. 58. Safety issues
    59. 59. SMARTObjectives: To compare the safety of salmeterol xinafoate or placebo added tousual asthma carePatient 26,355 patients, > 12 years, asthma (Clinical judgment), no LABA, no β-blockerIntervention Salmeterol MDI 42 µg BID + Usual care x 28 weeksControl Placebo MDI BID + Usual care + Usual care x 28 weeksPrimary outcome Respiratory-related deaths, or life-threatening experiences Nelson H, et al. Chest 2006;129:15-26.
    60. 60. Nelson H, et al. Chest 2006;129:15-26.
    61. 61. Asthma history and current nocturnal symptoms indicate greater disease severity at baseline in the African-American subgroup Nelson H, et al. Chest 2006;129:15-26.
    62. 62. SeretideSalmeterolFormoterolSymbicort Kramer JM. NEJM 2009;360(16):1592-5.
    63. 63. FDA Committee 2008Age group Single agent Combination4-11 years • Benefits did not • Benefits outweighed the risks outweigh the risks (paucity of for salmeterol/fluticasone (Slim randomized majority) data)Adolescent • Benefits did not out- • Adult: Benefits of combi-& adult weigh the risks nation products outweighed the • Label risks (unanimously for Advair - Against using LABAs as &with 1 abstention for monotherapy Symbicort) - LABAs should be added to • Adolescent: Benefits ICSs only when ICSs alone outweighed the risks for both proved inadequate for Products (Substantial majority) asthma control Kramer JM. NEJM 2009;360(16):1592-5.
    64. 64. Chowdhury BA, Pan GD. NEJM 2010;362(13):1169-71.
    65. 65. Asthma guidelines: β2-agonist• EPR 3: 2007• GINA 2010• GINA under five• PRACTALL
    66. 66. SABAs are the most effective medication for relieving acutebronchospasm.Therapy of choice for relief of acute symptoms and prevention of EIB.Regularly scheduled, daily, chronic use of SABA is not recommended.Increasing use of SABA treatment or using SABA >2 days a week forsymptom relief (not prevention of EIB) generally indicates inadequatecontrol of asthma. SABA
    67. 67. LABAs are not to be used as monotherapy for long-term control.LABAs are used in combination with ICSs for long-term control andprevention of symptoms in moderate or severe persistent asthma (≥ step3 care in children ≥ 5 years of age and adults) -- ? increased risk ofsevere exacerbations associated with the daily use of LABA. - For patients ≥5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS  increasing the ICS dose = adding LABA. - For patients ≥5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care  combination of LABA and ICS is the preferred therapy.LABA may be used before exercise to prevent EIB.The use of LABA for the treatment of acute symptoms is not currentlyrecommended. LABA
    68. 68. 2009 SABAs are the most effective bronchodilatorsand the preferred reliever treatment in children ≤ 5 years. LABAs cannot be recommended in this age group.
    69. 69. 2010
    70. 70. GINA 2010 SABAs LABAsDrug of choice for relief bronchospasm LABAs should not be used asduring exacerbation monotherapyPrevention of EIB Most effective when combined with ICSs Preferred treatment when medium dose of ICSs alone fails to achieve control LABAs + ICSs may also be used to prevent EIB and may provide longer protection than SABAs
    71. 71. Treatment of choice for intermittent and acute asthma episodes in children, very young children and for preventing EIB. Salbutamol, terbutaline, and formoterol have a favorable safety and efficacy profile in patients aged 2–5 yearsBacharier LB, et al. Allergy 2008;63:5-34. SABA
    72. 72. Children > 2 years of ageBacharier LB, et al. Allergy 2008;63:5-34.
    73. 73. Add-on controller therapy to ICS for partially controlled or uncontrolled asthma. Efficacy is not well documented in children in contrast to adults, and use should be evaluated carefully. Safety concerns suggest that use should be restricted to add-on therapy to ICS when indicated. Combination products of LABA and ICS may be licensed for use in children over 4–5 years, however, the effect of LABAs or combination products has not yet been adequately studied in young children under 4 years.Bacharier LB, et al. Allergy 2008;63:5-34. LABA
    74. 74. Take-home messages Catecholamine structure has been modified to achieve greater β2 selectivity and a better pharmacologic profile. Non-bronchodilator actions can be beneficial in the treatment of asthma, including glucocorticoid receptor priming. SABAs are the drugs of choice for treating acute asthma symptoms and exacerbations and for preventing EIB.
    75. 75. Take-home messages LABAs are useful in combination with inhaled corticosteroids for long-term control of asthma but should not be used as monotherapy. Further studies are needed to definitively determine whether the addition of LABAs to ICSs increases the risk of serious asthma outcomes
    76. 76. Thank youfor your attention

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