Efficacy of theophylline and its N-7-substituted derivatives in experimentally induced bronchial asthma in the guinea-pig.

: A study has been made of the bronchospasmolytic actions of theophylline and some ot its N-7-substituted derivatives administered by i.v infusion in anaesthetized guinea pigs, in which experimental bronchial asthma was induced by i.v. administration of histamine, 5-hydroxytryptamine and bradykinin. Bronchoconstriction was measured as changes in tidal volume, airflow rate, intrapleural pressure fluctuations and respiratory frequency. Dynamic lung compliance and pulmonary resistance was computed and recorded simultaneously. In addition blood pressure and heart rate were recorded. Theophylline, proxyphylline, diprophylline and etophylline when given alone had hardly an effect on lung function; relatively high doses of the drugs caused a fall in blood pressure and an increase in heart rate. Acephylline infusion in relatively high doses produced a decrease of dynamic lung compliance and an increase of pulmonary resistance. Some animals died. Theophylline, proxyphylline, diprophylline and etophylline were effective in reducing the mediator-induced bronchoconstriction. Protective effects correlated considerably (R = 0.75-0.82) with the plasma concentrations. The magnitude of these protective effects increased with the plasma concentration. Effective doses of proxyphylline, diprophylline and etophylline were much higher than those of theophylline. Acephylline was completely inactive in reversing the mediator-induced bronchoconstriction. At relatively high doses it increased the bronchoconstrictive effects of the mediators. It is concluded that diprophylline, proxyphylline and etophylline, like theophylline, are highly effective bronchospasmolytics, but does of the individual drugs must be adjusted according to the derivative used. Theophylline is by far the most effective of the four compounds. On the basis of this study and recent pharmacokinetic data in man the therapeutic value of acephylline in asthmatics seems doubtful.