AIMS: Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. METHODS:Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min-1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298. RESULTS: L-758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (-0.49 to +0.49) ml 100 ml-1 min-1, 1. 0 (-3.2 to +5.2) mmHg and 1.9 (-5.9 to +9.7) beats min-1, respectively. Twenty-four hours after 1.43 mg of L-758,298, there was approximately 34-fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml-1. L-758 298 was generally well tolerated without serious adverse events. CONCLUSIONS: Substance P induced forearm vasodilatation is mediated by the endothelial cell NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.
RCT Entities:
AIMS: Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. METHODS: Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min-1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298. RESULTS:L-758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (-0.49 to +0.49) ml 100 ml-1 min-1, 1. 0 (-3.2 to +5.2) mmHg and 1.9 (-5.9 to +9.7) beats min-1, respectively. Twenty-four hours after 1.43 mg of L-758,298, there was approximately 34-fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml-1. L-758 298 was generally well tolerated without serious adverse events. CONCLUSIONS:Substance P induced forearm vasodilatation is mediated by the endothelial cell NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.
Authors: M S Kramer; N Cutler; J Feighner; R Shrivastava; J Carman; J J Sramek; S A Reines; G Liu; D Snavely; E Wyatt-Knowles; J J Hale; S G Mills; M MacCoss; C J Swain; T Harrison; R G Hill; F Hefti; E M Scolnick; M A Cascieri; G G Chicchi; S Sadowski; A R Williams; L Hewson; D Smith; E J Carlson; R J Hargreaves; N M Rupniak Journal: Science Date: 1998-09-11 Impact factor: 47.728
Authors: J M Lundberg; T Hökfelt; J Kewenter; G Pettersson; H Ahlman; R Edin; A Dahlström; G Nilsson; L Terenius; K Uvnäs-Wallensten; S Said Journal: Gastroenterology Date: 1979-09 Impact factor: 22.682
Authors: R M Navari; R R Reinhardt; R J Gralla; M G Kris; P J Hesketh; A Khojasteh; H Kindler; T H Grote; K Pendergrass; S M Grunberg; A D Carides; B J Gertz Journal: N Engl J Med Date: 1999-01-21 Impact factor: 91.245