Theophylline produces over-additive relaxation of canine tracheal smooth muscle when combined with beta-agonists: The dose-response relationship

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

“…As evidenced by the pIC 50 values here obtained, the concentrations of theophylline required to relax the gastrointestinal regions are higher the ones achieved in plasma following in vivo administration of the drug in several animal species [44–46], the rabbit included [47–49]. Interestingly, this is also the case for the in vitro mean effective concentrations of theophylline required to produce bronchodilation in horses [10], dogs [11,12], cats [50], pigs [13], as well as in man [14,51]. However, many factors may influence the pharmacokinetic behaviour of a drug and its final distribution in tissues, and there is experimental evidence to suggest that theophylline’s concentrations at cellular level are higher the ones detected in plasma.…”

“…Besides the relaxing effect of theophylline on the respiratory tissues in several animal species [9–14], man included [15–17], which underlies the clinical bronchodilator properties of the drug, a relaxing effect has been also demonstrated on gastrointestinal smooth muscle tissues. In particular, in vitro and in vivo studies have shown that theophylline relaxes the lower oesophageal sphincter (LOS) in man [18], opossum [19,20] and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig.…”

“…Regardless of its narrow therapeutic index and the risk of adverse effects, theophylline was not withdrawn from the therapeutic practice; on the contrary, the drug has gained increasing interest after the quite recently documented anti-inflammatory and immuno-modulatory properties [1][2][3] which may contribute to the efficacy of the drug in patients with chronic obstructive pulmonary disease [4,5]. How-ever, the administration of the drug may be accompanied by more or less serious adverse effects including gastrointestinal disorders, such as gastro-oesophageal reflux, vomiting, stomach cramps and diarrhoea [6][7][8].Besides the relaxing effect of theophylline on the respiratory tissues in several animal species [9][10][11][12][13][14], man included [15][16][17], which underlies the clinical bronchodilator properties of the drug, a relaxing effect has been also demonstrated on gastrointestinal smooth muscle tissues. In particular, in vitro and in vivo studies have shown that theophylline relaxes the lower oesophageal sphincter (LOS) in man [18], opossum [19,20] This study investigates the effect of theophylline along the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced by the combined application of its three major metabolites.…”

Effects of Salmeterol in Patients with Persistent Asthma Receiving Inhaled Corticosteroid plus Theophylline

“…A combination therapy with salmeterol and theophylline might be beneficial. Several studies have indicated that the combination treatment with β 2 -adrenergic agonists plus theophylline was more effective in bronchodilation or the relaxation of airway smooth muscle than in single treatments with either of them in asthmatic patients or experimental animals [15,16,17]. In patients with chronic obstructive pulmonary disease, a combination therapy with salmeterol and theophylline provided significantly greater physiological and clinical improvements than a monotherapy with either agent alone [18, 19].…”

What role for theophylline?

“…If they are adequately informed and closely followed, a trial of theophylline in the mid to slightly lower therapeutic range (12)(13)(14)(15) jg/ml) is important for those in whom dyspnoea gradually assumes total dominion over their lives. (2) Severe asthmatic patients in whom oral corticosteroids are being used or may be otherwise necessary.…”