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Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD.
Chest. 2010 09; 138(3):595-604.Chest

Abstract

BACKGROUND

Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.

METHODS

Nineteen patients with COPD (FEV(1)/FVC ratio < 0.7; FEV(1) < 60%) completed a double-blind randomized crossover trial of tiotropium 18 microg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).

RESULTS

Mean +/- SEM for age and FEV(1) were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV(1) (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.

CONCLUSIONS

Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result.

Authors+Show Affiliations

Asthma and Allergy Research Group, University of Dundee, Ninewells Hospital & Medical School, Dundee, Scotland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20418370

Citation

Williamson, Peter A., et al. "Paradoxical Trough Effects of Triple Therapy With Budesonide/formoterol and Tiotropium Bromide On Pulmonary Function Outcomes in COPD." Chest, vol. 138, no. 3, 2010, pp. 595-604.
Williamson PA, Short PM, Clearie KL, et al. Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD. Chest. 2010;138(3):595-604.
Williamson, P. A., Short, P. M., Clearie, K. L., Vaidyanathan, S., Fardon, T. C., Howaniec, L. J., & Lipworth, B. J. (2010). Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD. Chest, 138(3), 595-604. https://doi.org/10.1378/chest.10-0247
Williamson PA, et al. Paradoxical Trough Effects of Triple Therapy With Budesonide/formoterol and Tiotropium Bromide On Pulmonary Function Outcomes in COPD. Chest. 2010;138(3):595-604. PubMed PMID: 20418370.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD. AU - Williamson,Peter A, AU - Short,Philip M, AU - Clearie,Karine L, AU - Vaidyanathan,Sriram, AU - Fardon,Thomas C, AU - Howaniec,Laura J, AU - Lipworth,Brian J, Y1 - 2010/04/23/ PY - 2010/4/27/entrez PY - 2010/4/27/pubmed PY - 2010/10/15/medline SP - 595 EP - 604 JF - Chest JO - Chest VL - 138 IS - 3 N2 - BACKGROUND: Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD. METHODS: Nineteen patients with COPD (FEV(1)/FVC ratio < 0.7; FEV(1) < 60%) completed a double-blind randomized crossover trial of tiotropium 18 microg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol). RESULTS: Mean +/- SEM for age and FEV(1) were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV(1) (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only. CONCLUSIONS: Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result. SN - 1931-3543 UR - https://www.unboundmedicine.com/medline/citation/20418370/Paradoxical_trough_effects_of_triple_therapy_with_budesonide/formoterol_and_tiotropium_bromide_on_pulmonary_function_outcomes_in_COPD_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-3692(10)60472-2 DB - PRIME DP - Unbound Medicine ER -