Theophylline inhibits late asthmatic reactions induced by toluene diisocyanate in sensitised subjects

Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting b 2 -agonist and an inhaled corticosteroid, and combinations of long-acting b 2 -agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of ''triple-inhaler'' fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called ''bifunctional drugs''. In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/antiinflammatory drugs and bifunctional anti-inflammatory drugs. @ERSpublications Bifunctional drugs offer an exciting new approach to the treatment of asthma and COPD

Section: Bifunctional Bronchodilator/anti-inflammatory Drugsmentioning

confidence: 89%

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Page

Cazzola

2014

“…In two studies on six patients each, theophylline had no significant effect on the increase in methacholine responsiveness following the late asthmatic reaction [65,67]. CRESCIOLI et al [66] observed that in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine compared to placebo and control day. HENDELES et al [69] reported a study involving 15 patients and found a significant inhibition by theophylline of the increase in airway responsivness to histamine, measured 4.5 h after allergen challenge.…”

Section: Effect In Allergen Challenge Studiesmentioning

confidence: 99%

“…Several studies have been performed, and have observed either no or only partial protection against the early response [60][61][62][63][64][65][66][67][68][69]. However, all studies except one observed, a marked protective effect against the late asthmatic reaction following allergen challenge ( fig 2).…”

Section: Effect In Allergen Challenge Studiesmentioning

confidence: 99%

Theophylline in the management of asthma: time for reappraisal?

Barnes¹,

Pauwels²

1994

250

107

T Th he eo op ph hy yl ll li in ne e i in n t th he e m ma an na ag ge em me en nt t o of f a as st th hm ma a: : t ti im me e f fo or r r re ea ap pp pr ra ai is sa al l? ?P.J. Barnes*, R.A. Pauwels** Theophylline is now considered to be a bronchodilator, but it is increasingly recognized that theophylline has other anti-asthma activities, which may be more important. Theophylline, even at low plasma concentrations, inhibits the late asthmatic reaction following allergen challenge. These clinical pharmacological observations are substantiated by experimental animal and in vitro data showing that theophylline has several anti-inflammatory activities relevant to asthma. These include the inhibition of cytokine synthesis and release, the inhibition of inflammatory cell activation and microvascular leakage, and the prevention of airway hyperresponsiveness induced by airway inflammation. Theophylline appears to have immunomodulatory effects, even at relatively low plasma concentrations.Based on these considerations, theophylline can be regarded as a useful alternative to other anti-inflammatory drugs for the chronic treatment of mild to moderate asthma. Theophylline should be used at lower doses to achieve plasma concentrations of 5-10 mg·l -1 , which will avoid the risk of side-effects.Further studies are required to evaluate the role of low-dose theophylline as an adjunct to low-dose inhaled steroids in the management of chronic asthma. It may now be appropriate to re-evaluate the role of theophylline in asthma management.

“…Theophylline, a drug widelyused in asthma therapy for its bronchodilator effects, has been demonstrated at therapeutic concentrations to inhibit the activity of several immunocompetent cells in a number of experimental and clinical situations [10][11][12]. Indeed, there is increasing evidence that theophylline attenuates the LAR to inhaled allergen [13][14][15]. Recently, in our laboratories, this inhibition was achieved at serum concentrations below the conventional range for bronchodilation and was demonstrated to have an immunomodulatory role, possibly through regulation of T-lymphocyte activation [15].…”

mentioning

confidence: 99%

Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics

Jaffar¹,

Sullivan²,

Page³

et al. 1996

Theophylline has been shown by several investigators to attenuate the late asthmatic response (LAR) to inhaled allergen, suggesting that it has antiinflammatory or immunomodulatory properties. We have, therefore, undertaken a double-blind, placebo-controlled study to examine the effects of low-dose theophylline on bronchoalveolar lavage (BAL) and blood T-lymphocyte profile and activation in asthmatics following antigen challenge and the development of a LAR.Peripheral blood and BAL samples were obtained from 17 subjects with mild atopic asthma before and after 6 weeks of treatment with either oral theophylline or placebo. The mean serum theophylline concentration achieved was 6.6 µg·mL -1 , which is below the currently accepted therapeutic range.Following theophylline therapy, there was a significant decrease in the number of BAL lymphocytes compared to placebo. On flow cytometric analysis of BAL cells, a significant loss of CD3+ T-lymphocytes, comprising both CD4+ and CD8+ subsets, was demonstrated. Moreover, there was a decrease in the number of BAL CD4+ T-cells expressing the activation marker very late activation antigen-1 (VLA-1), and an apparent reduction in human leucocyte antigen-DR (HLA-DR). Correspondingly, this was accompanied in the blood by an elevation in the proportion of activated CD4+ T-lymphocytes, in particular those expressing HLA-DR.These findings provide further evidence that theophylline has an anti-inflammatory action in asthma.