外周神经激肽-1受体拮抗剂SLV317在健康个体中的动力学与动态变化

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals.

作者信息

Hesse Christiane, Luntz Steffen P, Siedler Heike, Unnebrink Kristina, Mikus Gerd, de Bruijn Marianne, Zondag Edu, de Vries Michiel, Seibert-Grafe Monika, Haefeli Walter E

机构信息

Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Medical Faculty, University of Heidelberg, Germany.

出版信息

Br J Clin Pharmacol. 2006 Apr;61(4):414-9. doi: 10.1111/j.1365-2125.2006.02590.x.

DOI:10.1111/j.1365-2125.2006.02590.x

PMID:16542202

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1885038/

Abstract

AIMS

To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317.

METHODS

In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method.

RESULTS

Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001).

CONCLUSIONS

This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.

摘要

目的

研究神经激肽-1受体拮抗剂SLV317的药代动力学及其在手背静脉中的药效学作用。

方法

在一项随机、双盲、安慰剂对照的交叉研究中，19名健康男性单次口服SLV317或安慰剂。采集血样分析SLV317的血浆浓度，并采用手静脉顺应性方法评估对P物质的静脉舒张反应的抑制情况。

结果

口服250mg SLV317溶液耐受性良好，47±3分钟内平均血浆峰浓度（±标准误）为77±9ng/ml-1；平均半衰期为9.9±1.6小时。在用去氧肾上腺素预收缩的手静脉中，分别在给予SLV317或安慰剂之前，局部输注P物质导致平均静脉舒张率为56±8%和49±6%（P=0.91）。SLV317对P物质诱导的静脉舒张有显著抑制作用，而安慰剂无作用（P<0.001）。SLV317的最大拮抗作用平均为95±8%，在1.47±0.24小时后观察到。相应地，给予SLV317后的平均效应曲线下面积[278±67%h-1；95%置信区间（CI）198,358]与安慰剂（49±12%h-1；95%CI -24,122；P<0.001）相比显著更高。