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Calcitonin gene–related peptide–induced vasodilation in the human forearm is antagonized by CGRP 8‐37 : Evaluation of a human in vivo pharmacodynamic model
Author(s) -
Vanmolkot Floris H.M.,
Van der Schueren Bart J.E.P.,
Hoon Jan N.J.M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.11.005
Subject(s) - calcitonin gene related peptide , forearm , medicine , calcitonin , vasodilation , anesthesia , placebo , pharmacodynamics , in vivo , crossover study , endocrinology , pharmacology , pharmacokinetics , receptor , surgery , neuropeptide , pathology , biology , alternative medicine , microbiology and biotechnology
Objectives The aims of this study were to assess the potential of CGRP 8–37 , 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 CGRP 8‐37 (333 ng·min −1 ·dL −1 forearm) to assess inhibition by CGRP 8‐37 . To determine the antagonistic potency of CGRP 8‐37 , 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 CGRP 8‐37 (300, 600, or 1200 ng·min −1 ·dL −1 forearm). In addition, the effect of each dose of CGRP 8‐37 on resting FBF was evaluated. Results CGRP 8–37 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 CGRP 8‐37 , respectively; P < .001). The FBF response during the 20‐minute infusion of CGRP was dose‐dependently inhibited by CGRP 8‐37 (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 CGRP 8‐37 , 300, 600, and 1200 ng·min −1 ·dL −1 forearm, respectively; P < .001). CGRP 8‐37 did not affect resting FBF. Conclusions CGRP 8–37 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