Protection against Methacholine Bronchoconstriction  to Assess Relative Potency of Inhaled  β<sub>2</sub>-Agonist

Parameswaran, Krishnan; Inman, Mark D.; Ekholm, Bruce P.; Morris, Marilyn M.; Summers, E.; O’Byrne, Paul M.; Hargreave, Frederick E.

doi:10.1164/ajrccm.160.1.9812035

Cited by 45 publications

(30 citation statements)

References 11 publications

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“…Bel and colleagues 14 showed that salbutamol 200 and 400 mg inhaled through a pMDI were both very efficient in shifting to the right the concentration of histamine or methacholine provoking a fall in FEV 1 of 20% or more (PC 20 ) with a small dose related effect for PC 20 histamine but not for PC 20 methacholine. 14 Inhalation of salbutamol 100-400 mg by MDI produces strong bronchoprotection against methacholine that is, however, weakly proportional to the dose since 80% of protection is already achieved with 100 mg. 15 On the other hand, inhalation of 1600 mg salbutamol dry powder on top of regular treatment with salmeterol (50 mg twice daily) or formoterol (12 mg twice daily) did not increase the bronchoprotection towards methacholine. The inability of a dose of salbutamol similar to the one we used and administered through a dry powder inhaler to further improve the bronchoprotection given by long acting b 2 agonists 16 therefore suggests that, in our study, the ultrasonic nebulisation itself may well reinforce the bronchoprotection obtained with salbutamol.…”

Section: Discussionmentioning

confidence: 92%

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Delvaux¹,

Henket

Lau³

et al. 2004

Thorax

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Background: Inhalation of hypertonic or even isotonic saline during sputum induction may cause bronchospasm in susceptible patients with asthma, despite premedication with 400 mg inhaled salbutamol delivered by pressurised metered dose inhaler (pMDI). The bronchoprotection afforded by additional inhaled salbutamol administered through the ultrasonic nebuliser during sputum induction was investigated. Methods: Twenty patients with moderate to severe asthma underwent sputum induction by inhaling saline 4.5% (or 0.9% if post-bronchodilation forced expiratory volume in 1 second (FEV 1 ) ,65% predicted) for 10 minutes according to two protocols given 1 week apart in random order. At visit A the patients received 400 mg salbutamol administered through a pMDI + spacer 20 minutes before induction while at visit B the premedication was supplemented by 1500 mg nebulised salbutamol inhaled throughout the induction procedure. Both the investigator and the patients were blind to the nebulised solution used. FEV 1 was recorded during sputum induction at 1, 3, 5, and 10 minutes. Sputum cell counts and histamine, tryptase and albumin levels in the supernatants were determined. Results: The mean (SE) maximal reduction in FEV 1 over the 10 minute period of sputum induction was 11.7 (2.8)% at visit A, which was significantly greater than at visit B (2.6 (1.2)%; mean difference 9% (95% CI 2.7 to 15.4), p,0.01). Total and differential sputum cell counts as well as albumin, tryptase, and histamine levels did not differ between the two visits. Conclusion: The addition of inhaled salbutamol through an ultrasonic nebuliser markedly improves bronchoprotection against saline induced bronchoconstriction in patients with moderate to severe asthma undergoing sputum induction without affecting cell counts and inflammatory markers.

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Section: Discussionmentioning

confidence: 92%

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Delvaux¹,

Henket

Lau³

et al. 2004

Thorax

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“…For example, crossover studies of salbutamol Turbuhaler1 and pMDI required 23 patients to assess bronchoprotective effects against methacholine [24], whereas direct assessment of bronchodilation required o40 evaluable patients [7]. Methacholine-induced bronchoconstriction is now widely accepted as a method of increasing the sensitivity of the efficacy end-point in assessing inhaled b 2 -agonists, and was recently validated in a bioequivalence study of HFA and CFC pMDIs [25]. This placebo-controlled crossover study required 18 asthmatic patients to compare 100, 200, and 400 mg doses of salbutamol from the two devices and Finney bioassay showed a potency ratio of 1.08, confirmed using the nonlinear Emax model [15,25].…”

Section: Discussionmentioning

confidence: 99%

Protection against methacholine-induced bronchospasm: salbutamol pMDIversusClickhaler® DPI

Newhouse¹,

Patel²,

Parry-Billings³

2003

Eur Respir J

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Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler1 DPI. M.T. Newhouse, P. Patel, M. Parry-Billings. #ERS Journals Ltd 2003. ABSTRACT: Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy.This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler1) with a reference salbutamol pMDI (Ventolin1). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) v4 mg?mL -1 ) were treated on separate days with 0, 100, 200 or 400 mg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney9s bioassay to test for therapeutic equivalence of the inhalers.Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events).Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler1 dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler. Salbutamol, the b 2 -agonist bronchodilator most commonly used in the treatment of asthma, has been administered using pressurised metered-dose inhalers (pMDIs) and pressurised chlorofluorocarbon (CFC) propellants for the past 30 yrs. Substituting "ozone-friendly" alternatives puts the onus on the pharmaceutical industry to produce cost-effective replacement inhalers and establish that the switch-over from CFC pMDIs does not compromise patient care [1]. Each new device/formulation is a unique combination that must satisfy strict regulatory requirements [2].Pharmaceutical research and development has followed two major pathways: upgrading pMDIs with hydrofluoroalkanes (HFAs) as chlorine-free propellants, and innovative design of efficient dry-powder inhalers (DPIs) [3,4]. The activity of inhaled medications in the lung is determined by the amount of drug entering the lower respiratory tract [5], which is dependent on the mass of particles of y1-5 mm diameter and inspiratory flow velocity through the device [6]. Changes of formulation, humidity, device or handling may alter drug mass or deposition, with implications for both safety and efficacy [7][8][9]. Rapid systemic absorption of inhaled salbutamol occurs mainly at the vascular lung surface and the risk:benefit ratio can change with improved deposition [10]. In-vitro data therefore need the supp...

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“…20,[37][38][39] These methods used bioassay study design and statistical methods to estimate differences in potency and are capable of making these estimates with a high degree of precision. A study by Lötvall and colleagues 9 was the first to use statistical bioassay methodology to estimate the relative potency of levalbuterol and racemic albuterol.…”

Section: What Is the Appropriate Methods For Examining Relative Potencmentioning

confidence: 99%

Is There Any Advantage to Using Levalbuterol in the Treatment of Asthma?

Weinberger¹

2004

Clinical Pulmonary Medicine

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Albuterol has become the most commonly used bronchodilator for relieving symptoms of acute asthma since its introduction in the 1970s. Albuterol is a racemic mixture of R-and S-enantiomers. All bronchodilating activity has been recognized as coming from the R-enantiomer also known as levalbuterol. Levalbuterol has been marketed by Sepracor as the mono-isomer since 1999 under the brand name of Xopenex. Although receiving US Food and Drug Administration approval only as an alternative to racemic albuterol, it has been advertised as a "purified" albuterol, and the company has supported and extensively distributed publications purporting therapeutic advantage to levalbuterol over racemic albuterol. However, critical examination of that literature suggests the methodology used in those studies was inappropriate to examine relative potency of levalbuterol to the racemate for bronchodilator and systemic effect. Published studies of clinical efficacy in emergency rooms and hospital are very limited, and the claims of therapeutic advantage in these settings remain inconclusive. No appropriate studies of use in ambulatory patients were found. Since the cost of levalbuterol is substantially higher than racemic albuterol, there is no compelling justification for routine use of levalbuterol as an alternative to any preservative-free formulation of albuterol. Administration of albuterol by metered dose inhaler is the least expensive formulation and is as effective as by nebulizer, using a valved holding chamber for infants, toddlers, and others where coordination and cooperation are a problem for delivery. Further appropriate study is needed to determine if there is therapeutic advantage of levalbuterol in higherthan-usual doses as might be used in emergency or hospital treatment.

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Protection against Methacholine Bronchoconstriction to Assess Relative Potency of Inhaled β₂-Agonist

Cited by 45 publications

References 11 publications

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Protection against methacholine-induced bronchospasm: salbutamol pMDIversusClickhaler® DPI

Is There Any Advantage to Using Levalbuterol in the Treatment of Asthma?

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Protection against Methacholine Bronchoconstriction to Assess Relative Potency of Inhaled β2-Agonist

Cited by 45 publications

References 11 publications

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma

Protection against methacholine-induced bronchospasm: salbutamol pMDIversusClickhaler® DPI

Is There Any Advantage to Using Levalbuterol in the Treatment of Asthma?

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Product

Resources

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Protection against Methacholine Bronchoconstriction to Assess Relative Potency of Inhaled β₂-Agonist