Development of safer xanthine drugs for treatment of obstructive airways disease

Abstract

Antiasthma drug development, for the most part, seems based on three classes of therapeutic agents. Many new sympathomimetic and corticosteroid drugs with increased specificity for the lung have been introduced. The third class of drugs, the xanthines, is still best represented by the prototype drug theophylline. After a brief review of the chemical history of antiasthma xanthines (the first limited attempts to develop novel derivatives 30 to 40 years ago), and some recent structure-activity findings, this article discusses the pharmacology of a selected xanthine derivative, enprofylline (3-propylxanthine). In various experimental systems and in patients, enprofylline shares antiasthmatic effects with theophylline; however, enprofylline is the more potent of the two (>1 to 2 μg/ml plasma are effective concentrations of enprofylline). At present, enprofylline, which lacks diaphragmatic and central nervous system stimulatory actions, has been shown to be at least as clinically efficacious as theophylline in obstructive lung disease. Further work is needed to elucidate the target cells and mechanism(s) of action involved in bronchodilatory and anti-inflammatory effects of the xanthines. Growing numbers of animal and human pharmacologic studies show that enprofylline it without many of theophylline's extrapulmonary effects—in particular the excitatory ones. Perhaps most significantly, enprofylline does not produce central nervous system stimulant behavioral effects, including seizures. If and when enprofylline becomes available as an alternative drug, increased attention will probably be focused on the significance of other theophylline actions (gastric secretion, release of free fatty acids, vasoconstriction, diuresis, etc.) that are not shared by enprofylline. The differences in action profiles can probably be explained by the fact that enprofylline is a poor, and theophylline a potent, antagonist of the purine nucleoside adenosine, which may have a number of inhibitory physiologic functions.