Theophylline infusion modulates prostaglandin and leukotriene production in man

Abstract

Although theophylline has been used in the treatment of asthma for decades, it is not a first line choice any more. It is a well-known bronchodilator, but was recently discovered also to be an anti-inflammatory, immunomodulatory and bronchoprotective agent. Therefore we wanted to establish the role of theophylline on prostaglandin and leukotriene production, which plays a part in the pathogenesis of asthma. Theophylline was infused (bolus 5 mg/kg in 15 min and infusion 0.4 mg/kg/h for 1 h 45 min) into healthy volunteers. Thromboxane B 2, prostaglandin E 2 and leukotriene E 4 were measured from the A23187-stimulated whole blood samples and stable metabolites of thromboxane A 2; prostacyclin and leukotriene E 4 were measured from urine. Theophylline increased prostaglandin E 2 production and decreased leukotriene E 4 production ex vivo in whole blood, thus increasing the prostanoid/leukotriene ratio. It did not change thromboxane B 2 production stimulated by either spontaneous clotting or A23187 in the whole blood. Theophylline had hardly any effect on in vivo thromboxane, prostacyclin and leukotriene E 4 production measured as urinary metabolites, 11-dehydro-thromboxane B 2, 2,3-dinor-6-keto-prostaglandin F 1α and leukotriene E 4, respectively. Serum theophylline concentrations were at the lower level of normal therapeutic range during the infusion. The increase in PGE 2 and the decrease in LTE 4 synthesis ex vivo may offer a new explanation for the mode of antiasthmatic action of theophylline. It is notable that this phenomenon occurs at low serum theophylline concentrations. These results confirm the idea that theophylline has an anti-inflammatory and bronchoprotective action and support the use of theophylline as a therapeutic agent in asthmatic patients.