The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men

Authors


Dr Bart J. Van der Schueren, Center for Clinical Pharmacology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Tel.: +32 (0)1634 2020
Fax: +32 (0)1634 2050
E-mail: bart.vanderschueren@uz.kuleuven.be

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Telcagepant (MK-0974, Merck & Co., Inc.), an oral calcitonin gene-related peptide (CGRP) antagonist, is effective in treating acute migraine headache. Although CGRP receptor antagonists seem devoid of direct vasoconstrictor activity, animal research suggests a role for CGRP in nitroglycerin (NTG) induced vasodilation. Pulse wave analysis and high resolution ultrasound are sensitive techniques to investigate cardiovascular responses to drugs in vivo in humans.

WHAT THIS STUDY ADDS

• This study shows that telcagepant, at a supra-therapeutic dose for the treatment of acute migraine headache, has no clinically relevant effect on NTG-induced haemodynamic changes in healthy male volunteers. There is also no measurable vasoconstrictor effect of telcagepant as such in both the central and peripheral vascular bed. The results of the present study support the favourable cardiovascular safety profile of telcagepant and indicate that CGRP is not involved in NTG-induced vasodilation in humans.

AIMS To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG).

METHODS Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI).

RESULTS The aortic AIx following NTG decreased by −18.50 (−21.02, −15.98) % after telcagepant vs. −17.28 (−19.80, −14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated.

CONCLUSIONS Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.

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