Schaffler Klaus, Seibel Klaus, Thomsen Mikael, Edwards Martin
Human Pharmacodynamic Research, Munich, Germany.
Arzneimittelforschung. 2004;54(3):187-91. doi: 10.1055/s-0031-1296957.
Extensive pre-clinical investigations have shown that the tricyclic compound ReN1869 ((R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid, CAS 170149-99-2) is a potent H1-antagonist with pronounced antinociceptive properties. In this human phase-I trial the effect of different acute and multiple doses of ReN1869 on capsaicin induced neurogenic inflammation and hyperalgesia was investigated. Twenty-one healthy male subjects were enrolled in this randomised, double-blind, three-period, crossover trial design--consisting of acute and one week b.i.d. oral administration of 25 and 50 mg doses of ReN1869 and matching placebo--separated by 3 week washout periods. Capsaicin solution (1%) (INCI: Capsicum frutescens--containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) was applied in an occlusive mode for 30 min on the skin of the back in all three acute and subchronic medication periods to induce neurogenic inflammation. When the nociceptive laser pulses were applied to the capsaicin pre-treated skin, ReN1869 exerted a highly significant reduction of the pain response--as predominantly detected by suppression of the (central) P2-component in the laser-induced somatosensory evoked potentials (LSEPs) from Vertex-EEG. The primary efficacy endpoint, the N1/P2 peak to peak amplitude, was significantly reduced with the administration of ReN1869--primarily by a suppression of the P2-component of the LSEP. This suppression was dose-dependent and was more pronounced after a one week treatment (subchronic mode) with ReN1869 than after the first dose (acute mode). In contrast to the (central) P2-component there was no significant effect on the (peripheral) N1-component of the LSEPs taken from capsaicin-treated skin. As ReN1869 had no significant effect when the laser pulses were applied to normal skin, and the compound's effect was mainly restricted to the (central) P2-component, when LSEPs were taken from capsaicin treated skin, it can be concluded that ReN1869 exerts its positive effect to reduce capsaicin-induced hyperalgesia by a primarily central mechanism.
广泛的临床前研究表明，三环化合物ReN1869（(R)-1-(3-(10,11-二氢-5H-二苯并[a,d]环庚烯-5-亚基)-1-丙基)-3-哌啶羧酸，CAS 170149-99-2）是一种具有显著抗伤害感受特性的强效H1拮抗剂。在这项人体I期试验中，研究了不同急性和多次剂量的ReN1869对辣椒素诱导的神经源性炎症和痛觉过敏的影响。21名健康男性受试者参与了这项随机、双盲、三阶段、交叉试验设计，包括急性和为期一周的每日两次口服25毫克和50毫克剂量的ReN1869以及匹配的安慰剂，各阶段之间间隔3周的洗脱期。在所有三个急性和亚慢性用药阶段，将辣椒素溶液（1%）（成分表：辣椒（Capsicum frutescens），含有来自辣椒（Capsicum annuum annuum）的辣椒素类物质，CAS 84603-55-4）以封闭方式涂抹于背部皮肤30分钟，以诱导神经源性炎症。当对辣椒素预处理的皮肤施加伤害性激光脉冲时，ReN1869显著降低了疼痛反应，主要通过抑制顶点脑电图的激光诱发体感诱发电位（LSEP）中的（中央）P2成分来检测。主要疗效终点，即N1/P2峰峰值振幅，在给予ReN1869后显著降低，主要是通过抑制LSEP的P2成分。这种抑制呈剂量依赖性，在ReN1869治疗一周（亚慢性模式）后比首次给药（急性模式）后更明显。与（中央）P2成分不同，对取自辣椒素处理皮肤的LSEP的（外周）N1成分没有显著影响。由于当激光脉冲施加于正常皮肤时ReN1869没有显著作用，且该化合物的作用主要局限于从辣椒素处理皮肤获取LSEP时的（中央）P2成分，因此可以得出结论，ReN1869主要通过中枢机制发挥其减轻辣椒素诱导的痛觉过敏的积极作用。
