Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Heart Valve Department, ETB-BISLIFE, Beverwijk, The Netherlands.
Br J Pharmacol. 2024 Jun;181(12):1720-1733. doi: 10.1111/bph.16322. Epub 2024 Feb 6.
Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for migraine treatment. Here, the effect of the monoclonal antibody erenumab on CGRP-induced vasorelaxation was investigated in human isolated blood vessels, as well as the effect of combining erenumab with the small molecule drugs, namely rimegepant, olcegepant, or sumatriptan.
Concentration-response curves to CGRP, adrenomedullin or pramlintide were constructed in human coronary artery (HCA) and human middle meningeal artery (HMMA) segments, incubated with or without erenumab and/or olcegepant. pA or pK values were calculated to determine the potency of erenumab in both tissues. To study whether acutely acting antimigraine drugs exerted additional CGRP-blocking effects on top of erenumab, HCA segments were incubated with a maximally effective concentration of erenumab (3 μM), precontracted with KCl and exposed to CGRP, followed by rimegepant, olcegepant, or sumatriptan in increasing concentrations.
Erenumab shifted the concentration-response curve to CGRP in both vascular tissues. However, in HCA, the Schild plot slope was significantly smaller than unity, whereas this was not the case in HMMA, indicating different CGRP receptor mechanisms in these tissues. In HCA, rimegepant, olcegepant and sumatriptan exerted additional effects on CGRP on top of a maximal effect of erenumab.
Gepants have additional effects on top of erenumab for CGRP-induced relaxation and could be effective in treating migraine attacks in patients already using erenumab as prophylaxis.
已有多种靶向降钙素基因相关肽（CGRP）受体的药物被开发用于偏头痛治疗。本研究旨在研究单克隆抗体依那西普对人离体血管中 CGRP 诱导的血管舒张的作用，以及依那西普与小分子药物利马吉泮、欧立吉林或舒马曲坦联合应用的效果。
构建人冠状动脉（HCA）和人脑膜中动脉（HMMA）节段中 CGRP、肾上腺髓质素或普兰林肽的浓度-反应曲线，在孵育时加入或不加入依那西普和/或欧立吉林。计算 pA 或 pK 值以确定依那西普在两种组织中的效力。为研究急性作用的偏头痛治疗药物是否在依那西普的基础上进一步发挥 CGRP 阻断作用，将 HCA 节段用最大有效浓度的依那西普（3 μM）孵育，用 KCl 预收缩，然后暴露于 CGRP，再加入递增浓度的利马吉泮、欧立吉林或舒马曲坦。
依那西普使两种血管组织中的 CGRP 浓度-反应曲线发生移位。然而，在 HCA 中，Schild 图斜率明显小于 1，而在 HMMA 中则不然，表明这些组织中 CGRP 受体机制不同。在 HCA 中，利马吉泮、欧立吉林和舒马曲坦在依那西普最大效应的基础上对 CGRP 产生额外的作用。
吉泮类药物在依那西普的基础上对 CGRP 诱导的舒张具有额外的作用，并且可能对已经使用依那西普作为预防措施的偏头痛患者的发作有效。
