Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers

Aims To study whether desensitization occurs after long-term administration of the beta(1)-adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. Methods In a double-blind, randomized design 10 young, healthy males receiv ed ketotifen (2 x 1 mg day(-1) p.o.) of placebo for 3 weeks with xamoterol (2 x 200 mg day(-1) p.o.) administered concomitantly during the last 2 week s. B1 adrenoceptor mediated responses were assessed as exercise-induced tac hycardia and isoprenaline-induced shortening of heart rate corrected electr omechanical systole (QS(2)c); isoprenaline-induced tachycardia was measured as a mixed beta(1)-/beta(2)-adrenoceptor-mediated effect. Results The first dose of xamoterol significantly increased resting heart r ate and systolic blood pressure and significantly shortened QS(2)c. The las t dose of xamoterol after 2 weeks of treatment still produced the same resp onses. Ketotifen did not influence these effects of xamoterol on resting ha emodynamics. The first dose of xamoterol caused a rightward shift of the ex ercise- and isoprenaline-induced tachycardia (mean dose ratios +/- s.e.mean : 1.20 +/- 0.05 and 2.46 +/- 0.23) and the isoprenaline-evoked shortening o f QS(2)c (dose ratio 3.59 +/- 0.68). This rightward shift was even more pro nounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference ( 95% CI) of log transformed dose ratios between placebo and ketotifen: exerc ise tachycardia 0.001 (-0.03; 0.04); isoprenaline tachycardia 0.03 (-0.15, 0.21); isoprenaline induced shortening of QS(2)c 0.13 (-0.22, 0.48)). Conclusions In humans xamoterol is a partial beta(1)-adrenoceptor agonist w ith positive chrono- and inotropic effects at rest and antagonistic propert ies under conditions of beta-adrenoceptor stimulation. These effects were w ell maintained after chronic dosing with no signs of beta(1)-adrenoceptor d esensitization. Ketotifen does not change the beta-adrenoceptor mediated re sponses of xamoterol after chronic dosing.