Resistance to Theophylline Therapy

Abstract

In a recent clinical trial theophylline was given to 312 patients with smell loss (hyposmia) and over 50% improved. While all patients exhibited lower levels of parotid saliva cAMP and cGMP prior to treatment lack of improvement among all patients raised questions about drug efficacy. To investigate reasons for response lack analysis of changes in smell function and in parotid saliva cAMP and cGMP resulted in separation of patients into two groups ‐ those who improved in smell function (responders) and those who did not (non‐responders). Analysis of saliva cAMP and cGMP levels in responders demonstrated significant improvement in smell function and significantly higher levels of both cyclic nucleotides above baseline whereas among non‐responders there was little change from baseline in either smell function or saliva cyclic nucleotides. While plasma theophylline increased in both groups plasma theophylline among responders was consistently higher than among non‐responders and significantly higher as theophylline dose increased. These results indicate that some patients with smell loss treated with theophylline are resistant to the drug and may explain some aspects of decreased response to its use in improving smell function. Mechanism(s) of this resistance is unclear but could relate to individual genetic differences, differences in drug metabolism or apoptotic changes related to drug responsiveness.