Kaila T, Huupponen R, Karhuvaara S, Havula P, Scheinin M, Iisalo E, Salminen L
Department of Clinical Pharmacology, University of Turku, Finland.
Clin Pharmacol Ther. 1991 Jan;49(1):53-8. doi: 10.1038/clpt.1991.10.
The concentration-effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double-blind, crossover study design. Blockade of cardiac beta-adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR-1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 +/- 0.11 (+/- SD; n = 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac beta-blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The beta-blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.
采用随机、双盲、交叉研究设计，在6名健康年轻志愿者中研究了静脉注射0.25 mg噻吗洛尔（无论是否预先给予100 mg奎尼丁）的浓度-效应关系。通过测定在输注噻吗洛尔前后使心率增加25次/分钟所需的异丙肾上腺素输注剂量比（DR）来评估心脏β-肾上腺素能受体的阻滞情况。在血浆中噻吗洛尔浓度远低于1 ng/ml时，血浆中噻吗洛尔浓度的对数与异丙肾上腺素输注的对数（DR - 1）呈线性相关，平均Pearson相关系数为0.89±0.11（±标准差；n = 24）。异丙肾上腺素输注引起的环磷酸腺苷（cAMP）和去甲肾上腺素血浆水平升高在输注噻吗洛尔后减弱。给予奎尼丁使噻吗洛尔血浆水平和心脏β-阻滞作用增加10%至40%。得出结论：血浆中浓度低于1 ng/ml的噻吗洛尔竞争性拮抗异丙肾上腺素输注的心脏和非心脏效应。给予奎尼丁后噻吗洛尔的效应增强。低血浆水平时出现的β-阻滞可解释局部应用噻吗洛尔的副作用和作用。
