The efficacy and tolerability of inhaled salmeterol and individually dose-titrated, sustained-release theophylline in patients with reversible airways disease

doi:10.1016/S0954-6111(05)80008-3

Respiratory Medicine

Volume 88, Issue 8, September 1994, Pages 599-607

https://doi.org/10.1016/S0954-6111(05)80008-3 Get rights and content

In a double-blind, double-dummy, cross-over, multicentre study, 141 patients with moderate reversible airways disease were randomized to receive either 50 μg salmeterol via a metered dose inhaler or individually dose-titrated oral theophylline, both twice daily for a 2-week period. Just over half (n=77) the patients had received theophylline before, but 64 patients were new to theophylline therapy. Efficacy was based on lung function data and symptom scores. Salmeterol produced significantly higher increase in mean morning peak expiratory flow (PEF) of 161 min⁻¹ (P<0.001; 95% Confidence Interval (CI); 8–24 1 min⁻¹) and mean evening PEF of 15 1 min⁻¹ (p<0·001; 95% CI; 7–22 1min⁻¹) compared with theophylline therapy. Further analysis of the data revealed that the increase in PEF with salmeterol compared with theophylline was highest in a sub-group of patients new to theophylline therapy. Patients on salmeterol had significantly less night-time awakenings than those on theophylline (P=0·011) and significantly less daytime symptoms (P=0·017). There was also a significant increase in the number of nights (P=0·013) and days (P<0·001) on salmeterol when no additional salbutamol was required compared with theophylline. Theophylline produced a higher incidence of adverse events compared with salmeterol. The results of this study show that inhaled salmeterol is more effective and better tolerated than individually dose-titrated oral theophylline over a 2-week study period in patients with moderate asthma.

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Comparison of salmeterol/fluticasone propionate (FP) combination with FP+sustained release theophylline in moderate asthma patients
2008, Respiratory Medicine
Citation Excerpt :
To date, no study has directly compared the effect of salmeterol and theophylline as add-on therapies to ICS; a meta-analysis of studies directly comparing the efficacy and safety of salmeterol and theophylline has demonstrated that salmeterol is significantly superior to theophylline with respect to improving morning and evening peak expiratory flow (PEF), reducing daytime and night-time symptoms, reducing rescue medication use and reducing adverse events that lead to withdrawal of patients from the studies.11 The well-documented superiority of the combination of ICS plus LABA for the treatment of asthma has led to this form of therapy being recommended by the current international asthma guidelines (Global Initiative for Asthma)2 as the first-choice treatment option for patients with moderate-to-severe persistent asthma; this option is preferred to increasing the dose of the ICS or using sustained release theophylline (SR-T) or a leukotriene modifier as add-on therapy to ICS.12–14 Despite this recommendation, and the fact that theophylline requires careful dose titration due to its relatively narrow therapeutic index, theophylline is widely used in clinical practice in Japan.
To compare the efficacy and safety of the salmeterol/fluticasone propionate combination product with concurrent sustained release theophylline plus fluticasone propionate in adult Japanese patients with persistent asthma.
Multicentre, randomised, double-blind, double-dummy, parallel-group study.
Three hundred and eighty-three asthmatic patients receiving sustained release theophylline 200–400 mg/day entered the study and were randomised to receive either salmeterol/fluticasone propionate combination (SFC) 50 μg/250 μg+1 placebo tablet, fluticasone propionate 250 μg+1 sustained release theophylline 200 mg (SR-T+FP), twice daily for 8 weeks.
The adjusted mean change morning peak expiratory flow (PEF) over 8 weeks was 29.8 L/min in the SFC group and 16.3 L/min in the SR-T+FP group, with a treatment difference of 13.4 L/min (p=0.0004). SFC improved evening PEF, FEV₁, ${\dot{V}}_{50}$ and ${\dot{V}}_{25}$ at the completion of treatment to a greater extent than SR-T+FP (all p<0.05). A higher percentage of patients on SFC were symptom free (p=0.0286) and rescue free (ns) than those on SR-T+FP. There was not a statistically significant difference between treatments in symptom scores. Both treatments were well tolerated.
The finding that SFC was associated with greater improvements in lung function than SR-T+FP, a commonly employed treatment for asthmatic patients in Japan, suggests that SFC should be the preferred therapeutic option in these patients.
Asthma
2002, Lancet
Citation Excerpt :
Theophylline is effective in asthma and has some anti-inflammatory activity.108 It is less effective than the long-acting β agonists109 however, and its narrow therapeutic window and interactions with other drugs make it a less attractive option. More selective phosphodiesterase inhibitors have been developed110 but have not yet shown clear benefit over theophylline.
Asthma is one of the commonest chronic diseases of affluent societies. The striking increase in prevalence of asthma over recent decades and the rarity of this disease in less affluent populations confirms the importance of environmental factors in the cause of asthma—although which environmental factors are responsible is still not clear. Family studies show that genetic factors are also important in determining individual susceptibility to asthma, with results of genetic studies suggesting that there are many genes with moderate effects rather than a few major genes. Asthmatic airways show inflammation and remodelling, with CD4+ helper cells, mast cells, and eosinophils characterising the inflammatory response. Inhaled corticosteroids remain the cornerstone of treatment with the addition of long-acting β agonists as the next step if symptoms continue. Leukotriene antagonists, the only new drugs to reach the market in the past decade, have modest effects. However, a better understanding of the mechanisms underlying asthma and the genetic and environmental factors that predispose individuals to asthma should lead to better preventative strategies and new therapeutic approaches.
Beta-agonist drugs in the treatment of bronchial asthma
2000, Archivos de Bronconeumologia
Nocturnal asthma: Effect of salmeterol on quality of life and clinical outcomes
1999, Chest
To evaluate the effect of salmeterol on asthma-specific quality of life in patients experiencing significant nocturnal symptoms.
Randomized, double-blind, placebo-controlled, multicenter clinical trial.
Allergy/respiratory care clinics.
Nonsmokers ≥ 12 years of age with nocturnal asthma symptoms on at least 6 of 14 days during screening and ≥ 15% decrease in peak expiratory flow (PEF) from baseline on nocturnal awakening at least once during screening.
Salmeterol, 42 μg, or placebo twice daily. Patients were allowed to continue theophylline, inhaled corticosteroids, and “as-needed” albuterol.
Outcome measures included Asthma Quality of Life Questionnaire (AQLQ) global and individual domain scores, FEV₁, PEF, nighttime awakenings, asthma symptoms, and supplemental albuterol use. Mean change from baseline for the global and domain AQLQ scores was significantly greater (p ≤ 0.005) with salmeterol compared with placebo. At week 12, salmeterol significantly (p < 0.001 compared with placebo) increased mean change from baseline in FEV₁, morning and evening PEF, percentage of symptom-free days, percentage of nights with no awakenings due to asthma, and the percentage of days and nights with no supplemental albuterol use. Significant improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline (p < 0.05).
These results provide evidence that validates the role of salmeterol in improving quality of life in patients with moderate persistent asthma who exhibited nocturnal asthma symptoms and supports the efficacy of salmeterol compared with that of placebo (ie,“ as-needed” albuterol).
Long-term treatment of asthmatic patients with salmeterol vs slow-release theophylline
1998, Respiratory Medicine
The aim of the present multicentre, open, randomized, parallel group study was to evaluate the efficacy and safety of salmeterol versus theophylline in asthmatic patients. A total of 112 patients were randomized: 56 received inhaled salmeterol (50 μg twice daily) and 50 oral dose titrated theophylline twice daily. The study lasted 12 months. The efficacy of both drugs was evaluated for the first 3 months of the study and the safety for a further 9 months. Spirometric measurements were carried out for the total duration of the study. Salmeterol showed a greater and more significant efficacy than theophylline in reducing both day- and night-time symptoms (P<0·001) and in reducing additional salbutamol requirement (P<0·001). The subjective assessment of efficacy by physicians and patients was in favour of salmeterol from the first month of treatment (P<0·001). Both drugs improved the quality of life as measured by the specific questionnaire ‘Living with Asthma’ with no significant differences. The total number of adverse events was slightly higher in the theophylline group compared with salmeterol (18 vs 9; P n.s.). Both salmeterol and theophylline increased morning and evening PEFR with no significant difference. FEV₁ and FVC increased in both groups of patients; the difference between the effects of the two treatments was not statistically significant at 12 months. Our study suggests that salmeterol has higher efficacy and safety than theophylline in long-term treatment of asthmatic patients.

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The efficacy and tolerability of inhaled salmeterol and individually dose-titrated, sustained-release theophylline in patients with reversible airways disease*

Lancet

Lancet

Lancet

J Allergy Clin Immunol

The acceptability of two different oral bronchodilators, a comparison

Am Rev Resp Dis

An open, multicentre, cross-over comparison of albuterol controlled release tablets and individually titrated slow release theophylline in the treatment of childhood asthma

Am Rev Respir Dis

A multicentre study of a new controlled release formulation of salbutamol (salbutamol CR) compared with a titrated dose of slow-release theophylline (Theodur) in the treatment of chronic obstructive airways disease

Bull Eur Physiophathol Respir

Comparison between salbutamol controlled-release tablets and slow release theophylline tablets in the management of chronic obstructive airways disease

Bull Eur Physiopathol Respir

Comparison of oral, controlled release salbutamol (CR-A) and theophylline (T) in the treatment of chronic asthma

J Allergy Clin Immunol

A comparison of salbutamol controlled-release tablet (Volmax SCR) with slow release theophylline at individually titrated doses in the treatment of childhood asthma

Eur Respir J

Bronchodilator activity of salmeterol—a long acting β2 adrenoceptor agonist

Br J Pharmacol

The design of salmeterol, a long acting β2 adrenoceptor agonist

Br J Pharmacol

Salmeterol—a new long acting β2 adrenoceptor agonist comparison with salbutamol in adult asthmatic patients

Thorax

Inhaled salmeterol—a new long acting β2 adrenoceptor agonist produces sustained bronchodilation in asthmatic patients without causing tachyphylaxis

Am Rev Respir Dis

Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis

Am Rev Respir Dis

A twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients

Eur Respir J

Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients

Thorax

Bronchodilator activity of salmeterol—a long acting β₂ adrenoceptor agonist

The design of salmeterol, a long acting β₂ adrenoceptor agonist

Salmeterol—a new long acting β₂ adrenoceptor agonist comparison with salbutamol in adult asthmatic patients

Inhaled salmeterol—a new long acting β₂ adrenoceptor agonist produces sustained bronchodilation in asthmatic patients without causing tachyphylaxis