Does the Unfavorable Pharmacokinetic and Pharmacodynamic Profile of the iNOS Inhibitor GW273629 Lead to Inefficacy in Acute Migraine?

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 ni...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2009-03, Vol.49 (3), p.281-290
Main Authors: Van der Schueren, B. J., Lunnon, M. W., Laurijssens, B. E., Guillard, F., Palmer, J., Van Hecken, A., Depré, M., Vanmolkot, F. H., de Hoon, J. N.
Format: Article
Language:English
Subjects:
Adult
Area Under Curve
Female
Half-Life
Humans
iNOS
Male
Migraine Disorders - drug therapy
migraine therapy
Nitrates - blood
Nitric Oxide - blood
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - antagonists & inhibitors
pharmacodynamic assay
pharmacokinetics
Sulfones - pharmacokinetics
Sulfones - pharmacology
Sulfones - therapeutic use
Tyrosine - analogs & derivatives
Tyrosine - blood
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Summary: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 (AUC0–2 [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.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270008329548