Acute effects of sumatriptan on aortic blood pressure, stiffness, and pressure waveform.

BACKGROUND AND OBJECTIVES: Sumatriptan, a 5-hydroxytryptamine (HT)(1B/1D) receptor agonist, is an effective acute antimigraine drug. Because of its vasoconstrictor activity, it is contraindicated in patients at high risk for adverse cardiovascular events. Acute antimigraine drugs without vasoconstrictor effects are currently being developed, and sensitive, noninvasive techniques by which to detect drug-induced vascular effects would facilitate their clinical development. The effects of sumatriptan on aortic blood pressure, stiffness, and pressure waveform have not been assessed previously in detail. METHODS: A randomized, placebo-controlled, double-blind, 4-way crossover study was performed in 12 healthy subjects. Each subject received 25, 50, and 100 mg sumatriptan and placebo as single oral doses. Vascular measurements, including oscillometric blood pressure measurement, arterial ultrasound, systolic pulse contour analysis, and aortic pulse wave velocity measurement, were performed at baseline and 30, 90, and 150 minutes after drug administration. RESULTS: Compared with placebo and expressed as weighted mean +/- SD, 100 mg sumatriptan increased aortic systolic blood pressure by 6 +/- 5 mm Hg (P < .01), aortic pulse wave velocity by 0.5 +/- 0.5 m/s (P < .01), and aortic augmentation index by 13% +/- 6% (P < .0001). The increase in aortic systolic blood pressure was larger compared with the increase in brachial systolic blood pressure (P < .0001). Significant vascular effects were already detected after the lowest dose of sumatriptan by systolic pulse contour analysis and arterial ultrasound. CONCLUSION: These findings show that therapeutic doses of sumatriptan acutely increase aortic blood pressure, stiffness, and augmentation index. Noninvasive systolic pulse contour analysis and arterial ultrasound may facilitate detection of drug-induced vascular effects in early clinical trials.

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

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.

Reproducibility of forearm vasodilator response to intra-arterial infusion of calcitonin gene-related peptide assessed by venous occlusion plethysmography.

AIMS: To assess the reproducibility of the forearm blood flow (FBF) response to intra-arterial infusion of calcitonin-gene related peptide (CGRP), measured by venous occlusion plethysmography. In addition, to compare different ways of expressing the FBF response and perform sample size calculations. METHODS: On two separate visits, CGRP (10 ng min(-1) dl(-1) forearm) was infused for 45 min into the brachial artery of six healthy subjects. Reproducibility was assessed by calculating mean difference, repeatability coefficient, within-subject coefficient of variation (WCV) and intraclass correlation coefficient. RESULTS: CGRP increased FBF from 2.8 +/- 0.4 and 3.2 +/- 0.7 (at baseline) to 15.4 +/- 1.4 and 15.2 +/- 1.5 ml min(-1) dl(-1) forearm (at 45 min) on visits 1 and 2, respectively (P < 0.0001 for both visits). Mean difference in FBF at 45 min between both visits was 0.3 ml min(-1) dl(-1) forearm (repeatability coefficient: 4.1 ml min(-1) dl(-1) forearm). This FBF response appeared to be more reproducible when expressed as absolute FBF in the infused arm (WCV 11%) compared with absolute FBF-ratio between both arms (WCV 37%), percentage change from baseline in FBF in the infused arm (WCV 29%) and percentage change from baseline in FBF-ratio (WCV 40%). When expressed as absolute FBF, a sample size of five (95% confidence interval: 2-12) subjects gives 90% power at a type I error probability of 0.05 to detect a 25% shift in FBF response. CONCLUSIONS: Intra-arterial infusion of CGRP results in a forearm vasodilator response which is reproducible between days. This response is most reproducible when expressed as absolute FBF. The presented methodology provides a suitable pharmacodynamic model to assess the in vivo activity of CGRP-receptor antagonists in a small number of subjects.