THEOPHYLLINE INFUSION MODULATES PROSTAGLANDIN AND LEUKOTRIENE PRODUCTION IN MAN

Although theophylline has been used in the treatment of asthma for dec ades, it is not a first line choice any more. It is a well-known bronc hodilator, 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 p roduction, which plays a part in the pathogenesis of asthma. Theophyll ine 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 b lood samples and stable metabolites of thromboxane A(2); prostacyclin and leukotriene E-4 were measured from urine. Theophylline increased p rostaglandin E-2 production and decreased leukotriene E-4 production e x vivo in whole blood, thus increasing the prostanoid/leukotriene rati o. It did not change thromboxane B-2 production stimulated by either s pontaneous clotting or A23187 in the whole blood. Theophylline had har dly 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-1 alpha and leukotriene E-4, resp ectively. Serum theophylline concentrations were at the lower level of normal therapeutic range during the infusion. The increase in PGE(2) and the decrease in LTE4 synthesis ex vivo may offer a new explanation for the mode of antiasthmatic action of theophylline. It is notable t hat this phenomenon occurs at low serum theophylline concentrations. T hese results confirm the idea that theophylline has an anti-inflammato ry and bronchoprotective action and support the use of theophylline as a therapeutic agent in asthmatic patients.