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Clin Pharmacol Ther. 2006 Mar;79(3):263-73. Epub 2006 Feb 7.

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

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1
Center for Clinical Pharmacology, University Hospital Gasthuisberg (Katholieke Universiteit Leuven), Leuven, Belgium. floris.vanmolkot@med.kuleuven.be

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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, and 12.3 +/- 3.8 mL.min(-1).dL(-1) forearm versus 3.1 +/- 0.7 mL.min(-1).dL(-1) forearm to 3.8 +/- 0.6, 5.2 +/- 1.5, and 8.5 +/- 3.0 mL.min(-1).dL(-1) forearm for placebo and CGRP8-37, respectively; P < .001). The FBF response during the 20-minute infusion of CGRP was dose-dependently inhibited by CGRP8-37 (area under the curve, 200 +/- 51 mL.dL(-1) forearm for placebo versus 181 +/- 23, 160 +/- 40, and 132 +/- 56 mL.dL(-1) forearm for CGRP8-37, 300, 600, and 1200 ng.min(-1).dL(-1) forearm, respectively; P < .001). CGRP8-37 did not affect resting FBF.

CONCLUSIONS:

CGRP8-37 inhibits CGRP-induced vasodilation in the human forearm without affecting resting FBF. Venous occlusion plethysmography combined with brachial artery administration of CGRP provides a suitable pharmacodynamic model to aid the clinical development of CGRP-receptor antagonists.

PMID:
16513450
DOI:
10.1016/j.clpt.2005.11.005
[Indexed for MEDLINE]
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