Van der Schueren B J, Rogiers A, Vanmolkot F H, Van Hecken A, Depré M, Kane S A, De Lepeleire I, Sinclair S R, de Hoon J N
Center for Clinical Pharmacology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
J Pharmacol Exp Ther. 2008 Apr;325(1):248-55. doi: 10.1124/jpet.107.133868. Epub 2008 Jan 23.
The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.
本研究的目的是确定参与辣椒素诱导人体皮肤血管舒张的介质，并评估一种用于降钙素基因相关肽（CGRP）受体拮抗剂早期临床评价的药效学模型。使用激光多普勒灌注成像技术，在22名受试者中测量了前臂皮肤对局部应用辣椒素的皮内血流（DBF）反应。评估了动脉内给予CGRP（8-37）（1200 ng·min⁻¹·dl⁻¹前臂）、吲哚美辛（5 μg·min⁻¹·dl⁻¹前臂）和N（G）-单甲基-L-精氨酸（L-NMMA；0.2 mg·min⁻¹·dl⁻¹前臂）以及口服阿瑞匹坦（375 mg）对辣椒素诱导的皮肤血管舒张的影响。此外，还研究了DBF对辣椒素反应的昼夜变化。CGRP（8-37）抑制了辣椒素诱导的DBF增加：输注侧为217（145, 290）%，未输注侧为370（254, 486）% [平均值（95% CI）；p = 0.004]。相比之下，吲哚美辛、L-NMMA、阿瑞匹坦以及评估时间均未影响DBF对辣椒素的反应。因此，辣椒素诱导的人体前臂皮肤血管舒张主要由CGRP介导，而非由血管舒张性前列腺素、一氧化氮或P物质介导。对辣椒素的反应不显示昼夜节律。提出了一种药效学模型，用于在人体体内评估CGRP受体拮抗剂。
