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- Title
Calcitonin gene–related peptide–induced vasodilation in the human forearm is antagonized by CGRP<sub>8-37</sub>: Evaluation of a human in vivo pharmacodynamic model<sup>*</sup>.
- Authors
Vanmolkot, Floris H. M.; Van der Schueren, Bart J. E. P.; de Hoon, Jan N. J. M.
- 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.Clinical Pharmacology & Therapeutics (2006) 79, 263–273; doi: 10.1016/j.clpt.2005.11.005
- Subjects
PHARMACODYNAMICS; CALCITONIN gene-related peptide; VASODILATION; PLETHYSMOGRAPHY; BLOOD circulation; FOREARM; BRACHIAL artery
- Publication
Clinical Pharmacology & Therapeutics, 2006, Vol 79, Issue 3, p263
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.11.005