CROSS TOLERANCE: DECREASED RENAL RESPONSE TO THEOBROMIN AND THEOPHYLLIN IN RABBITS TOLERANT TOWARD CAFFEIN

The close chemical relationship of the methylated xanthines used in therapeutics, suggests, in view of their similarity in action, the possibility of crossed tolerance existing between the different members. A fact that adds further to the possibility of crossed tolerance existing between these methylated xanthines is the common fate of demethylization occurring in the body. To determine the presence or absence of crossed toleration it is necessary to study the comparative response to a common action. Caffein, theobromin and theophyllin share most equally in the power to cause increased formation of urine. This action offers a rather definite means of determining comparative tissue response and becomes the action of choice for study. It has been shown (1) that the toleration of caffein developed in rabbits includes a decreased renal response toward the drug. It remains to determine the minimal effective diuretic doses of theobromin and theophyllin in caffein tolerant rabbits and compare them with the doses required to produce similar results in control rabbits. EXPERIMENTAL METHOD Rabbits were made tolerant toward caffein by giving subcu-taneous injections of the drug, six days each week, with doses increasing from 50 to 90 mgm. per kilogram. After a period of approximately four months of such injections a rabbit re-quires somewhat more than double the dose necessary in a control rabbit to produce an increased flow of urine (1). Rena