title: Does the unfavorable pharmacokinetic and pharmacodynamic profile of the iNOS inhibitor GW273629 lead to inefficacy in acute migraine?
abstract: The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.
authors.affiliation: Center for Clinical Pharmacology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. bart.vanderschueren@uz.kuleuven.be
authors.forename: B J
authors.initials: BJ
authors.lastname: Van der Schueren
authors.forename: M W
authors.initials: MW
authors.lastname: Lunnon
authors.forename: B E
authors.initials: BE
authors.lastname: Laurijssens
authors.forename: F
authors.initials: F
authors.lastname: Guillard
authors.forename: J
authors.initials: J
authors.lastname: Palmer
authors.forename: A
authors.initials: A
authors.lastname: Van Hecken
authors.forename: M
authors.initials: M
authors.lastname: Depré
authors.forename: F H
authors.initials: FH
authors.lastname: Vanmolkot
authors.forename: J N
authors.initials: JN
authors.lastname: de Hoon
mesh_terms: D000328:Adult; D019540:Area Under Curve; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: C409003:GW 273629; D009566:Nitrates; D013450:Sulfones; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II