Affiliation:
1. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands
2. Heart Valve Department ETB‐BISLIFE Beverwijk The Netherlands
3. Department of Neurosurgery Erasmus University Medical Center The Netherlands
4. Novartis Pharma AG Basel Switzerland
5. Amgen Inc Thousand Oaks California USA
Abstract
AbstractBackground and PurposeMultiple 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.Experimental ApproachConcentration–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. pA2 or pKb 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.Key ResultsErenumab 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.Conclusions and ImplicationsGepants 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.
Funder
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
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