Schlepper M, Thormann J, Schwarz F
Arzneimittelforschung. 1975 Sep;25(9):1452-5.
The widely recognized, negative dromotropic effects of alpha-isopropyl-alpha-[N-methyl-N-homaveratryl)-gamma-aminopropyl]-3-4-dimethoxyphenylacetonitrile (verapamil, Isoptin) on arterio-venous (A-V) nodal conductions were studied using long-term atrial stimulation (AS) in 7 healthy volunteers whose mean age was 30 years. A control group consisting of three of the volunteers who underwent long-term atrial stimulation without medication was established. Since an isolated, well-known drug effect was studied over a long period of time, it was felt that this was an acceptable method for reaching valid pharmacodynamic conclusions. Atrial stimulation was carried out at hourly intervals up to 14-16 h and continued to the highest possible rate without the occurrence of 2nd degree A-V block before and following oral application of verapamil, 240 mg. The stimulus-Q (S-Q) prolongation at increased pace rates was compared to the control. Verapamil retard was tested in a similar course of investigation the following day. The results clearly demonstrated that both forms of verapamil are effective when taken orally. Verapamil acts 2 h after oral application. The peak effectiveness of the drug is found at 5 h and at this point A-V block can occur at low atrial stimulated rates. The effect of verapamil retard is obvious only after 6 h but is still apparent after 14 h and it remains constant with no peak in effectiveness. Characteristics of the resulting regressions allow to distinguish the effect of verapamil on A-V conduction from influences that might be mediated by the diurnal changes in tone of the autonomic nervous system only. The effect of verapamil after oral application is more pronounced with higher heart rates. The pharmacodnaymics of verapamil evaluated with regard to a single well-known pharmacological effect, have not necessarily to be identical with the pharmacokinetics and the bioavailability of the drug.
采用长期心房刺激（AS）方法，对7名平均年龄为30岁的健康志愿者进行研究，以探讨广泛认可的α-异丙基-α-[N-甲基-N-高藜芦基）-γ-氨基丙基]-3,4-二甲氧基苯乙腈（维拉帕米，异搏定）对动静脉（A-V）结传导的负性变传导作用。设立了一个由3名志愿者组成的对照组，他们在未用药的情况下接受长期心房刺激。由于在较长时间内研究的是一种孤立的、众所周知的药物效应，因此认为这是得出有效药效学结论的一种可接受方法。每小时进行一次心房刺激，持续14 - 16小时，并在口服240毫克维拉帕米之前和之后，以尽可能高的速率持续刺激，直至不发生二度A-V阻滞。将心率增加时的刺激-Q（S-Q）延长与对照组进行比较。次日在类似的研究过程中测试了缓释维拉帕米。结果清楚地表明，两种形式的维拉帕米口服均有效。维拉帕米口服后2小时起效。药物的最大效应在5小时出现，此时在低心房刺激率下可能发生A-V阻滞。缓释维拉帕米的作用仅在6小时后明显，但在14小时后仍很明显，且效果保持恒定，无效应峰值。所得到的回归特征使得能够将维拉帕米对A-V传导的作用与仅可能由自主神经系统张力的昼夜变化介导的影响区分开来。口服维拉帕米后，心率越高，其作用越明显。就单一众所周知的药理效应评估的维拉帕米药效学，不一定与该药物的药代动力学和生物利用度相同。
