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.
RCT Entities:
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.
Authors: Ruth Fricker; Christiane Hesse; Johanna Weiss; Yorki Tayrouz; Michael M Hoffmann; Kristina Unnebrink; Ulrich Mansmann; Walter E Haefeli Journal: Br J Clin Pharmacol Date: 2004-08 Impact factor: 4.335
Authors: L Pradier; E Habert-Ortoli; L Emile; J Le Guern; I Loquet; M D Bock; J Clot; L Mercken; V Fardin; C Garret Journal: Mol Pharmacol Date: 1995-02 Impact factor: 4.436