Calcitonin gene-related peptide-induced vasodilation in the human forearm is antagonized by CGRP8-37: evaluation of a human in vivo pharmacodynamic model

Clinical Pharmacology and Therapeutics
F H VanmolkotJan N de Hoon

Abstract

The aims of this study were to assess the potential of CGRP8-37, the C-terminal fragment of calcitonin gene-related peptide (CGRP), to inhibit CGRP-induced vasodilation in the human forearm and to evaluate a pharmacodynamic model to aid the clinical development of novel CGRP-receptor antagonists. Forearm blood flow (FBF) responses to intra-arterial CGRP infusions were measured via venous occlusion plethysmography in 21 healthy subjects. Dose response to CGRP was assessed during graded infusion of CGRP (1, 3, and 10 ng.min(-1).dL(-1) forearm; n = 6). After a 90-minute washout period, CGRP infusions were repeated during coinfusion of CGRP8-37 (333 ng.min(-1).dL(-1) forearm) to assess inhibition by CGRP8-37. To determine the antagonistic potency of CGRP8-37, a 4-period, placebo-controlled crossover study was conducted in 6 subjects, in which CGRP (10 ng.min(-1).dL(-1) forearm) was infused for 20 minutes together with placebo or CGRP8-37 (300, 600, or 1200 ng.min(-1).dL(-1) forearm). In addition, the effect of each dose of CGRP8-37 on resting FBF was evaluated. CGRP8-37 significantly inhibited the CGRP-induced increase in FBF compared with placebo (from 3.2 +/- 1.1 mL.min(-1).dL(-1) forearm at baseline to 4.8 +/- 1.0, 7.7 +/- 1.9, ...Continue Reading

Citations

May 21, 2010·Expert Opinion on Investigational Drugs·Michael J M Fischer
Nov 10, 2010·Cephalalgia : an International Journal of Headache·Floris Vanmolkot, Jan de Hoon
Jan 19, 2010·British Journal of Clinical Pharmacology·Simon R SinclairJay N de Hoon
Jan 25, 2008·The Journal of Pharmacology and Experimental Therapeutics·B J Van der SchuerenJ N de Hoon
Jun 27, 2015·British Journal of Clinical Pharmacology·Linde BuntinxJan de Hoon

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