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Pretreatment with Albuterol versus Montelukast for Exercise-Induced Bronchospasm in Children Raissy HH, Harkins M, Kelly F, Kelly HW Pharmacotherpay 2008 Mar;28(3):287-94. doi: 10.1592/phco.28.3.287. Paul Khaper, PGY-2 2/18/2015 More than 10 percent of the general population and up to 90 percent of persons previously diagnosed with asthma have experienced exercise-induced bronchospasm S/S: coughing, wheezing, and chest tightness with exercise; however, many athletes will present with nonspecific symptoms, such as fatigue and impaired performance. Peak about five to 10 minutes after vigorous exercise Pathophysiology-> the underlying pathogenesis is poorly understood, but nitric oxide, leukotrienes, expression of mast cell genes, and epithelial shedding into the airway lumen are potentially factors in etiology Cys-LTs – cysteinyl leukotrienes LTC4, LTD4, LTE4 have been detected in exhaled breath condensate in children with asthma and reported to be higher in patients with exercise induced Albuterol rescue inhaler 15 minutes before exercise. Lasts approximately 2 hours. ?inflammatory component of EIB? ?compliance? ?duration of action? ?long term relief? What about athletes with prolonged exercise regimens, playing multiple times a day, tournaments, *not all patients with EIB have asthma* Leukotriene receptor antagonist Multiple studies suggesting children taking montelukast have significant protection against EIB (1) Evidence of protection after 3 days of treatment with Montelukast (2) Maximum effect of Montelukast occurs 12 hours after administration, persists up to 24 hours 3 day tx with montelukast lowers Cys-LT [ ] Long term use of montelukast reduces EIB by 2050% 2007 FDA approved montelukast for prevention of EIB in asthmatic patients >15yo (3,4) P – children/adolescents with EIB with poorly controlled symptoms I – use of alternative pretreatment medication C – use of singulair instead of albuterol for pretreatment of EIB O – better prevention of EIB associated symptoms This is the first clinical trial comparing the protective effects of montelukast with albuterol Study subjects had mild-moderate asthma (193) Prospective, randomized, double-blind, crossover study Prospective, randomized, double-blind, crossover clinical trial was conducted from November 1, 2005–April 30, 2007. Patients aged 7–17 years with physician-diagnosed mild to moderate asthma for at least 6 months in addition to self-reported exercise-induced . Long term controller meds were allowed to be continued Exclusion->history of cardiac dysfunction unable to perform exercise challenge or spirometry used montelukast for asthma management had upper respiratory infection in the previous 4 weeks used oral corticosteroids in the previous 3 months. Study consisted of 4 visits: screening, baseline, study visit 1, study visit 2 Screening and baseline visits: EIB was assessed Patients were required to have a positive exercise challenge, defined as a 15% or greater decrease in FEV1 at both the screening and baseline visits (1-14 days later) to qualify the end of the baseline visit, eligible patients were randomly assigned to receive either montelukast capsules 5–10 mg (depending on age) or matching placebo capsules to be taken Every night for 3-7 days. Study Visit 1 : was scheduled 3–7 days later . At this visit, exhaled breath condensate was measured, and baseline spirometry was performed. Patients who had received montelukast were then instructed to use 2 puffs of a placebo metered-dose inhaler (MDI) 15 min before exercise challenge. patients who had received placebo used 2 puffs (90 µg/puff) of an albuterol MDI 15 minutes before the exercise challenge. At the end of study visit 1, patients were crossed over to the alternative therapy and scheduled for study visit 2. All visits were scheduled for 7:30 A.M. (± 30 min), so the exercise challenge could be performed approximately 12 hours (± 30 min) after the last dose of montelukast Study Visit 2: Cross over Exercise Challenge: Pre-exercise spirometry was performed 5 minutes before the challenge. exercise challenge was performed on a treadmill. Workload was increased until 80–90% of the maximum heart rate (220 minus age) was achieved in the first 2 minutes, and exercise was sustained for 6 minutes. Spirometry was performed immediately after exercise (time 0) and at 5, 10, 15, 20, 30, and 60 minutes. A positive exercise challenge was defined as a decrease in FEV1 from the preexercise value by at least 15%. Patients were instructed to withhold their short-acting b2-agonist and cromolyn for 6 hours and long-acting b2-agonist for 12 hours before the exercise challenge. Exhaled Breath Condensate – collected at beginning of visits 1 and 2. Cys- LT concentration measured by specific enzyme immunoassay The exhaled breath condensate was collected and analyzed in all of the qualified patients and the last 11 patients with a negative exercise challenge Primary Outcome - maximum change in FEV1 after exercise Secondary Outcomesarea under the curve for FEV1 (expressed as percentage decrease from baseline FEV1) in the first 60 minutes (AUC0–60) after exercise proportion of patients in whom exerciseinduced bronchospasm was prevented. 91 pts recruited 13 lost to follow up/other reasons 78 completed screening test, 13 of whom had EIB 11 of 13 completed study 100% adherence to study Pretreatment with albuterol had greater efficacy than pretreatment with montelukast in prevention of EIB The FEV1 AUC 0-60 after exercise was signficantly smaller with albuterol compared montelukast 100% pts using albuterol pretreatment had prevention of EIB symptoms 55% of those taking montelukast had prevention of symptoms. Cys-LT concentrations did not significantly differ between patients receiving montelukast and patients receiving placebo. Pts with a negative exercise challenge test had lower Cys-LT compared with EIB pts, but difference was not statistically significant (p=0.08) No correlation between severity of EIB or response to Montelukast and Cys-LT [ ] Study was designed to assess protective effect of Montelukast against EIB at 12 hours after ingestion (max effect) Pts were allowed to continue taking B2 agonists previously prescribed Limitations: 11pt study. Difficult to get patients for EIB and go through study (tests). Helpful to do a cross-over study for this topic. Question of every cross over study does the manner/timing of giving medications have any effect on patient response Was there enough time for washout period? No long term effects studies of montelukast, studies have shown optimal long term efficacy of montelukast up to 8 weeks No studies with patients who have had failure with –beta 2 agonists Decreased protection over time due to increased sensitivity to exercise long term B2 agonists Montelukast use in Adults, no significant studies since FDA approval in 2007. Clinical use 2008 Feb;121(2):383-9. Epub 2007 Nov 5. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. Stelmach I1, Grzelewski T, Majak P, Jerzynska J, Stelmach W, Kuna P. Regular antiasthma treatment with inhaled glucocorticosteroids (ICSs) and leukotriene modifiers alleviates exercise-induced bronchoconstriction in children.4, 5 and 6 In contrast with bronchodilators, which children often forget to take as needed, these medications do not have to be taken immediately before the exercise, and they modify airway hyperresponsiveness Children 6 to 18 years of age with atopic asthma were randomized to a 4-week, placebo-controlled, double-blind trial. Patients were randomly allocated to receive: daily 200 mcg budesonide (twice daily, 100 mcg per dose) + 9 mcg formoterol (twice daily, 4.5 mcg per dose; n = 20); 200 mcg budesonide + 5 or 10 mg montelukast (once daily at bedtime; n = 20); 5 or 10 mg montelukast (n = 20); 200 mcg budesonide (n = 20); or placebo (n = 20). A standardized treadmill exercise challenge was performed before and after treatment. Put under 4 week treatment then exercise challenged All modalities improved EIB vs placebo but The protection effect of monotherapy with montelukast and combined therapy of montelukast with budesonide on EIB was greater than that of other 2 active treatment groups. Prolonged effect of montelukast in asthmatic children with EIB. Pediatric Pulmonology 2005;39:162-6. Kim JH, Lee SY, Kim et al 2. Montelukast versus Salmeterol in patients with asthma and EIB. J Allergy Clin Immunology 1999;104:547-53. Villaran C, O’Neill SJ, Helbling A et al 3. Effects of a Leukotriene receptor antagonist on exhaled Leukotriene E4 and prostanoids in children with asthma. J Allergy Clin Immunology 2006;118:347-53 Montuschi P, Mondino C, Koch P, Barnes PJ 4. Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast. J Asthma 2007;44:213-17. Philip G, Villaran C, Pearlman DS, Loeys T 1.