Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial

BACKGROUND: Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist. METHODS: Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 μg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV(1). Salbutamol 100, 200 and 400 μg (cumulative dose) was then given at 5-minute intervals and FEV(1 )was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve. RESULTS: The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68%) lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV(1 )and dose of methacholine given (p = 0.001). CONCLUSION: The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Protein kinase A enhances lipopolysaccharide-induced IL-6, IL-8, and PGE2 production by human gingival fibroblasts

<p>Abstract</p> <p>Objective</p> <p>Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. Interleukin (IL)-6, IL-8, and the chemical mediator prostaglandin E₂(PGE₂) are known to play important roles in inflammatory responses and tissue degradation.</p> <p>Recently, we reported that the protein kinase A (PKA) inhibitor H-89 suppresses lipopolysaccharide (LPS)-induced IL-8 production by human gingival fibroblasts (HGFs). In the present study, the relevance of the PKA activity and two PKA-activating drugs, aminophylline and adrenaline, to LPS-induced inflammatory cytokines (IL-6 and IL-8) and PGE₂by HGFs were examined.</p> <p>Methods</p> <p>HGFs were treated with LPS from <it>Porphyromonas gingivalis </it>and H-89, the cAMP analog dibutyryl cyclic AMP (dbcAMP), aminophylline, or adrenaline. After 24 h, IL-6, IL-8, and PGE₂levels were evaluated by ELISA.</p> <p>Results</p> <p>H-89 did not affect LPS-induced IL-6 production, but suppressed IL-8 and PGE₂production. In contrast, dbcAMP significantly increased LPS-induced IL-6, IL-8, and PGE₂production. Up to 10 μg/ml of aminophylline did not affect LPS-induced IL-6, IL-8, or PGE₂production, but they were significantly increased at 100 μg/ml. Similarly, 0.01 μg/ml of adrenaline did not affect LPS-induced IL-6, IL-8, or PGE₂production, but they were significantly increased at concentrations of 0.1 and 1 μg/ml. In the absence of LPS, H-89, dbcAMP, aminophylline, and adrenaline had no relevance to IL-6, IL-8, or PGE₂production.</p> <p>Conclusion</p> <p>These results suggest that the PKA pathway, and also PKA-activating drugs, enhance LPS-induced IL-6, IL-8, and PGE₂production by HGFs. However, aminophylline may not have an effect on the production of these molecules at concentrations used in clinical settings (8 to 20 μg/ml in serum). These results suggest that aminophylline does not affect inflammatory responses in periodontal disease.</p

THE THEOPHYLLINE-ERYTHROMYCIN INTERACTION

Since its publication in 1976, the original report of an interaction between erythromycin and theophylline by Cummin, Kozak, and Gillman has generated considerable interest and controversy. Many studies with considerably different designs have been performed to address this question. Those studies that most closely simulate the clinical setting suggest that a 7- to 10-day course of concurrent theophylline and erythromycin therapy will result in variable changes in theophylline clearance. It may be that as many as 25% of patients, especially when maintained with serum theophylline concentrations at the upper portion of the therapeutic range, display elevations in serum theophylline concentrations that might lead to clinical symptoms of theophylline toxicity. There has been a suggestion, based on the mean changes in several studies, that the interaction may lead to a 25% increase in serum theophylline concentrations; however, it is clear that there may be a much larger increase in some patients. This toxicity can be anticipated and avoided if careful attention is paid to monitoring the serum theophylline concentrations of such high-risk patients when erythromycin therapy is contemplated as an addition to theophylline therapy. Other macrolide antibiotics may display interactions with theophylline, which may be due in part to the ability of the various antibiotics to form complexes with isoenzymes of the cytochromes P-450. The growing impression of the importance of mycoplasma in asthmatics and the introduction of new macrolides onto the market make the appreciation of this possible interaction of extreme importance to primary care and chest physicians