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Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers
Author(s) -
Schäfers Rafael F.,
Karl Ingeborg,
Mennicke Kirsten,
Daul Anton Erich,
Philipp Thomas,
Brodde OttoErich
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00854.x
Subject(s) - isoprenaline , ketotifen , tachycardia , medicine , heart rate , anesthesia , placebo , endocrinology , blood pressure , asthma , stimulation , alternative medicine , pathology
Aims To study whether desensitization occurs after long‐term administration of the β 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 received ketotifen (2×1 mg day −1 p.o.) or placebo for 3 weeks with xamoterol (2×200 mg day −1 p.o.) administered concomitantly during the last 2 weeks. β 1 ‐adrenoceptor mediated responses were assessed as exercise‐induced tachycardia and isoprenaline‐induced shortening of heart rate corrected electromechanical systole (QS 2 c); isoprenaline‐induced tachycardia was measured as a mixed β 1 ‐/β 2 ‐adrenoceptor‐mediated effect.Results The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS 2 c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise‐ and isoprenaline‐induced tachycardia (mean dose ratios±s.e.mean: 1.20±0.05 and 2.46±0.23) and the isoprenaline‐evoked shortening of QS 2 c (dose ratio 3.59±0.68). This rightward shift was even more pronounced 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: exercise 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 β 1 ‐adrenoceptor agonist with positive chrono‐ and inotropic effects at rest and antagonistic properties under conditions of β‐adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of β 1 ‐adrenoceptor desensitization. Ketotifen does not change the β‐adrenoceptor mediated responses of xamoterol after chronic dosing.