Schäfers R F, Karl I, Mennicke K, Daul A E, Philipp T, Brodde O E
Department of Nephrology and Hypertension, University of Essen, Germany.
Br J Clin Pharmacol. 1999 Jan;47(1):59-66. doi: 10.1046/j.1365-2125.1999.00854.x.
To study whether desensitization occurs after long-term administration of the 1-adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen.
In a double-blind, randomized design 10 young, healthy males received ketotifen (2 x 1 mg day(-1) p.o.) or placebo for 3 weeks with xamoterol (2 x 200 mg day(-1) p.o.) administered concomitantly during the last 2 weeks. 'l1-adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline-induced tachycardia was measured as a mixed beta1-/beta2-adrenoceptor-mediated effect.
The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. 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 QS2c (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 QS2c 0.13 (-0.22; 0.48)).
In humans xamoterol is a partial beta1-adrenoceptor agonist with positive chrono- and inotropic effects at rest and antagonistic properties under conditions of beta-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of beta1-adrenoceptor desensitization. Ketotifen does not change the beta-adrenoceptor mediated responses of xamoterol after chronic dosing.
研究长期给予β1 - 肾上腺素能受体部分激动剂扎莫特罗后是否会发生脱敏现象，若发生，酮替芬是否会对其产生影响。
采用双盲、随机设计，10名年轻健康男性接受酮替芬（每日口服2次，每次1 mg）或安慰剂治疗3周，在最后2周同时给予扎莫特罗（每日口服2次，每次200 mg）。通过运动诱发的心动过速和异丙肾上腺素诱发的心率校正机电收缩期（QS2c）缩短来评估β1 - 肾上腺素能受体介导的反应；异丙肾上腺素诱发的心动过速作为β1 - /β2 - 肾上腺素能受体介导的混合效应进行测量。
扎莫特罗的首剂显著增加静息心率和收缩压，并显著缩短QS2c。治疗2周后扎莫特罗的末次剂量仍产生相同反应。酮替芬未影响扎莫特罗对静息血流动力学的这些作用。扎莫特罗的首剂使运动和异丙肾上腺素诱发的心动过速（平均剂量比±标准误均值：1.20±0.05和2.46±0.23）以及异丙肾上腺素诱发的QS2c缩短（剂量比3.59±0.68）出现右移。扎莫特罗治疗2周后这种右移更为明显。扎莫特罗治疗2周后的这种额外右移不受酮替芬影响（安慰剂和酮替芬之间对数转换剂量比的平均差异（95%可信区间）：运动性心动过速0.001（-0.03；0.04）；异丙肾上腺素性心动过速0.03（-0.15；0.21）；异丙肾上腺素诱发的QS2c缩短0.13（-0.22；0.48））。
在人体中，扎莫特罗是一种β1 - 肾上腺素能受体部分激动剂，在静息时具有正性变时和变力作用，在β - 肾上腺素能受体刺激条件下具有拮抗特性。长期给药后这些作用维持良好，无β1 - 肾上腺素能受体脱敏迹象。酮替芬在长期给药后不改变扎莫特罗的β - 肾上腺素能受体介导的反应。
