Klausner M A, Ventura D F, Coelho J, Mullane J F, Irwin C, Hitzenberger G, Magometschnigg D, Kaik G, Garg D C, Weidler D J
Ayerst Laboratories, New York, NY 10017.
J Clin Pharmacol. 1988 Jun;28(6):495-504. doi: 10.1002/j.1552-4604.1988.tb03166.x.
The selectivity of the beta-adrenoceptor blockade produced by single oral doses of cetamolol, atenolol, and nadolol was compared in normal male subjects. Study 1 established the dose at which each drug provides equivalent beta-1 blockade. Beta-1 blockade was estimated using the degree of inhibition of the increased heart rate (HR) response to graded exercise. Cetamolol (30 mg), atenolol (100 mg), and nadolol (80 mg) all attenuated the HR response to a comparable extent. This result established that the dose ratio of cetamolol:atenolol:nadolol of 1.00:3.33:2.67 provides equipotent beta-1 blockade. This ratio of doses was used in Studies 2 and 3 to evaluate the antagonism of beta-2-mediated responses to titrated doses of intravenous isoproterenol (ISO) by low and high doses of each drug. Beta-2 blockade was assessed using the attenuation of ISO-induced reductions in diastolic blood pressure (DBP) in Study 2 and ISO-induced increases in specific airway conductance (sGAW) in Study 3. For within drug comparisons, antagonism of the HR increase induced by ISO (a response mediated by both beta-1 and beta-2 receptors) was also examined. Treatments included cetamolol (15 and 60 mg), atenolol (50 and 200 mg), and nadolol (40 and 160 mg in Study 2; 40 mg only in Study 3). All drugs tested suppressed the HR, DBP, and sGAW responses to ISO, and this blockade was dose dependent. Cetamolol and nadolol produced approximately equipotent beta-1 blockade, whereas cetamolol at both doses produced a less potent beta-2 blockade. Atenolol antagonized ISO effects on all parameters less than either cetamolol or nadolol. Quantitative cardioselectivity indices revealed that cetamolol 60 mg was the most cardioselective and nadolol 40 mg the least. Data from the three studies demonstrate that cetamolol is cardioselective relative to nadolol and that, in contrast to atenolol, cardioselectivity appears to increase at the higher dose.
在正常男性受试者中比较了单次口服西他洛尔、阿替洛尔和纳多洛尔产生的β-肾上腺素能受体阻滞的选择性。研究1确定了每种药物产生等效β-1阻滞的剂量。使用对分级运动时心率（HR）增加反应的抑制程度来评估β-1阻滞。西他洛尔（30毫克）、阿替洛尔（100毫克）和纳多洛尔（80毫克）对HR反应的减弱程度相当。这一结果确定了西他洛尔：阿替洛尔：纳多洛尔剂量比为1.00：3.33：2.67时可产生等效的β-1阻滞。在研究2和3中使用该剂量比来评估每种药物的低剂量和高剂量对静脉注射异丙肾上腺素（ISO）滴定剂量所介导的β-2反应的拮抗作用。在研究2中，使用ISO诱导的舒张压（DBP）降低的减弱情况评估β-2阻滞；在研究3中，使用ISO诱导的比气道传导率（sGAW）增加的减弱情况评估β-2阻滞。对于药物内比较，还研究了ISO诱导的HR增加（一种由β-1和β-2受体介导的反应）的拮抗作用。治疗药物包括西他洛尔（15毫克和60毫克）、阿替洛尔（50毫克和200毫克）以及纳多洛尔（研究2中为40毫克和160毫克；研究3中仅为40毫克）。所有受试药物均抑制了对ISO的HR、DBP和sGAW反应，且这种阻滞呈剂量依赖性。西他洛尔和纳多洛尔产生的β-1阻滞效力大致相当，而西他洛尔的两个剂量产生的β-2阻滞效力较弱。阿替洛尔对所有参数的ISO效应的拮抗作用均小于西他洛尔或纳多洛尔。定量心脏选择性指数显示，60毫克西他洛尔的心脏选择性最高，40毫克纳多洛尔的心脏选择性最低。三项研究的数据表明，相对于纳多洛尔，西他洛尔具有心脏选择性，并且与阿替洛尔不同，心脏选择性似乎在较高剂量时增加。
