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.
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ADMA and NG-monomethyl-l-arginine (but not symmetric dimethylarginine) are NOS inhibitors and can be important regulators of NOS activity in vivo.
“Notably, ADMA and NG-monomethyl-l-arginine (but not symmetric dimethylarginine) are NOS inhibitors and can be important regulators of NOS activity in vivo (566, 963).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [963]
Cites
Nitric oxide: physiology, pathophysiology, and pharmacology.
Moncada, S., Palmer, R. M., & Higgs, E. A. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06663-3 · Cited by 15,525 · see citing works
(2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200406-710st · Cited by 3,203 · see citing works
Association between mitochondrial dysfunction and severity and outcome of septic shock
Brealey, D. A., Brand, M. P., Hargreaves, I. P., Heales, S., Land, J. M., Smolenski, R. T., Davies, N. A., Cooper, C. E., & Singer, M. (2002) · The Lancet · doi:10.1016/s0140-6736(02)09459-x · Cited by 1,505 · see citing works
Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.
Stamler, J. S., Jaraki, O., Osborne, J., Simon, D. I., Keaney, J., Vita, J., Singel, D., Valeri, C. R., & Loscalzo, J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.16.7674 · Cited by 1,238 · see citing works
Guidelines for Controlled Trials of Drugs in Migraine: Second Edition
International Headache Society Clinical Trials Subcommittee, Tfelt-Hansen, P., Block, G., Dahlöf, C., Diener, H.-C., Ferrari, M., Goadsby, P., Guidetti, V, Jones, B., Lipton, R., et al. (2000) · Cephalalgia · doi:10.1046/j.1468-2982.2000.00117.x · Cited by 698 · see citing works
Ho, T. W., Mannix, L. K., Fan, X. F., Assaid, C., Furtek, C. I., Jones, C. J., Lines, C. R., & Rapoport, A. M. (2007) · Neurology · doi:10.1212/01.wnl.0000286940.29755.61 · Cited by 464 · see citing works
The Nitric Oxide Synthase Family of Proteins
Sessa, W. C. (2008) · Journal of Vascular Research · doi:10.1159/000159039 · Cited by 458 · see citing works
Tsikas, D. (2005) · Free Radical Research · doi:10.1080/10715760500053651 · Cited by 357 · see citing works
A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks
Thomsen, L. L., Kruuse, C. R., Iversen, H. K., & Olesen, J. (1994) · European Journal of Neurology · doi:10.1111/j.1468-1331.1994.tb00053.x · Cited by 328 · see citing works
Sarchielli, P., Alberti, A., Codini, M., Floridi, A., & Gallai, V. (2000) · Cephalalgia · doi:10.1046/j.1468-2982.2000.00146.x · Cited by 264 · see citing works
Nitric oxide synthase inhibition in migraine
Lassen, L., Ashina, M., Christiansen, I. S., Ulrich, V., & Olesen, J. (1997) · The Lancet · doi:10.1016/s0140-6736(97)80021-9 · Cited by 252 · see citing works
Nuclear factor‐κB as a molecular target for migraine therapy
Reuter, U., Chiarugi, A., Bolay, H., & Moskowitz, M. A. (2002) · Annals of Neurology · doi:10.1002/ana.10159 · Cited by 183 · see citing works
Akerman, S., Williamson, D. J., Kaube, H., & Goadsby, P. J. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704842 · Cited by 176 · see citing works
Giovannoni, G., Land, J. M., Keir, G., Thompson, E. J., & Heales, S. (1997) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456329703400212 · Cited by 163 · see citing works
Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine
Lassen, L. H., Thomsen, L. L., & Olesen, J. (1995) · Neuroreport · doi:10.1097/00001756-199507310-00003 · Cited by 162 · see citing works
FROST, M. T., Halliwell, B. B., & Moore, K. P. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3450453 · Cited by 151 · see citing works
Increased Nitric Oxide in Exhaled Gas as an Early Marker of Lung Inflammation in a Model of Sepsis
Stewart, T. E., Valenza, F., Ribeiro, S. P., Wener, A. D., VOLGYESI, G. A., Mullen, J. B., & Slutsky, A. S. (1995) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.151.3.7533602 · Cited by 140 · see citing works
Nitric oxide in primary headaches
Thomsen, L. L., & Olesen, J. (2001) · Current Opinion in Neurology · doi:10.1097/00019052-200106000-00009 · Cited by 131 · see citing works
Gastric Stasis in Migraine: More Than Just a Paroxysmal Abnormality During a Migraine Attack
Aurora, S. K., Kori, S. H., Barrodale, P. M., McDonald, S. A., & Haseley, D. R. (2006) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2006.00311.x · Cited by 128 · see citing works
Increased Nitric Oxide in Exhaled Gas as an Early Marker of Lung Inflammation in a Model of Sepsis
Stewart, T. E., Valenza, F., Ribeiro, S. P., et al. (1995) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm/151.3_pt_1.713 · Cited by 118 · see citing works
Volans, G. N. (1978) · Clinical Pharmacokinetics · doi:10.2165/00003088-197803040-00004 · Cited by 105 · see citing works
Origins of Breath Nitric Oxide in Humans
Dillon, W. C., Hampl, V., Shultz, P. J., Rubins, J. B., & Archer, S. L. (1996) · CHEST Journal · doi:10.1378/chest.110.4.930 · Cited by 89 · see citing works
ALDERTON, W. K., Angell, A. D. R., Craig, C., Dawson, J., Garvey, E. P., Moncada, S., Monkhouse, J., Rees, D. D., Russell, L. J., Russell, R. J., et al. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706168 · Cited by 89 · see citing works
The Hypotensive Effect of L-Arginine Is Associated With Increased Expired Nitric Oxide in Humans
Mehta, S., Stewart, D. J., & Levy, R. D. (1996) · CHEST Journal · doi:10.1378/chest.109.6.1550 · Cited by 73 · see citing works
Lamb, N. J., Quinlan, G. J., WESTERMAN, S. T., Gutteridge, J. M. C., & Evans, T. W. (1999) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.160.3.9810048 · Cited by 71 · see citing works
D’Amico, D., Ferraris, A., Leone, M., Catania, A. P., Carlin, A., Grazzi, L., & Bussone, G. (2002) · Cephalalgia · doi:10.1046/j.1468-2982.2002.00304.x · Cited by 67 · see citing works
Intravenous nitrate vasodilators and exhaled nitric oxide
Marczin, N., Riedel, B., Royston, D., & Yacoub, M. H. (1997) · The Lancet · doi:10.1016/s0140-6736(05)62953-4 · Cited by 63 · see citing works
Sarchielli, P., Floridi, A., Mancini, M. L., Rossi, C. R., Coppola, F., Baldi, A., Pini, L. A., & Calabresi, P. (2006) · Cephalalgia · doi:10.1111/j.1468-2982.2006.01164.x · Cited by 57 · see citing works
Detection of nitric oxide in exhaled air during administration of nitroglycerinin vivo
Persson, M. G., Agvald, P., & Gustafsson, L. E. (1994) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1994.tb14812.x · Cited by 55 · see citing works
Exhaled nitric oxide as a marker for organic nitrate tolerance.
Husain, M., Adrie, C., Ichinose, F., Kavosi, M., & Zapol, W. M. (1994) · Circulation · doi:10.1161/01.cir.89.6.2498 · Cited by 51 · see citing works
Lipopolysaccharide-induced increase in plasma nitrotyrosine concentrations in rats
Kamisaki, Y., Wada, K., Ataka, M., Yamada, Y., Nakamoto, K., Ashida, K., & Kishimoto, Y. (1997) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(97)00052-5 · Cited by 45 · see citing works
Validation of a new instrument for determining migraine prevalence
Tom, T., Brody, M., Valabhji, A., Turner, L. C., Molgaard, C. A., & Rothrock, J. (1994) · Neurology · doi:10.1212/wnl.44.5.925 · Cited by 43 · see citing works
Dear, G. J., Plumb, R. S., Sweatman, B. C., Parry, P. S., Roberts, A. D., Lindon, J. C., Nicholson, J. K., & Ismail, I. M. (2000) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)00401-1 · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Human models of migraine — short-term pain for long-term gain
Ashina, M., Hansen, J. M., Dunga, B. Ó. Á., & Olesen, J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.137 · Cited by 242 · see citing works
Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications
Casas, A. I., Dao, V. T.-V., Daiber, A., Maghzal, G. J., Di Lisa, F., Kaludercic, N., Leach, S., Cuadrado, A., Jaquet, V., Seredenina, T., et al. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6433 · Cited by 136 · see citing works
CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation
Meßlinger, K., Lennerz, J. K., Eberhardt, M. J., & Fischer, M. J. M. (2012) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2012.02212.x · Cited by 130 · see citing works
Felice, M. D., Ossipov, M. H., Wang, R., Dussor, G. O., Lai, J., Meng, I. D., Chichorro, J. G., Andrews, J. S., Rakhit, S., Maddaford, S. P., et al. (2010) · Brain · doi:10.1093/brain/awq159 · Cited by 128 · see citing works
Pearls and pitfalls in human pharmacological models of migraine: 30 years' experience
Ashina, M., Hansen, J. M., & Olesen, J. (2013) · Cephalalgia · doi:10.1177/0333102412475234 · Cited by 100 · see citing works
Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache
Høivik, H. O., Laurijssens, B. E., Harnisch, L. O., Twomey, C. K., Dixon, R. M., Kirkham, A. J. T., Williams, P. M., Wentz, A., & Lunnon, M. W. (2010) · Cephalalgia · doi:10.1177/0333102410370875 · Cited by 90 · see citing works
Self-citationPharmacology and Clinical Drug Candidates in Redox Medicine
Dao, V. T.-V., Casas, A. I., Maghzal, G. J., Seredenina, T., Kaludercic, N., Robledinos-Anton, N., Di Lisa, F., Stocker, R., Ghezzi, P., Jaquet, V., et al. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6430 · Cited by 88 · see citing works
Little, J. W., Doyle, T. M., & Salvemini, D. (2010) · Amino Acids · doi:10.1007/s00726-010-0633-0 · Cited by 83 · see citing works
Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects
Lukács, M., Tajti, J., Fülöp, F., Toldi, J., Edvinsson, L. I., & Vécsei, L. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170712163437 · Cited by 78 · see citing works
Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies
Meng, I. D., Dodick, D., Ossipov, M. H., & Porreca, F. (2011) · Cephalalgia · doi:10.1177/0333102411402367 · Cited by 70 · see citing works
Dieterle, A., Fischer, M. J. M., Link, A., Neuhuber, W., & Meßlinger, K. (2010) · Cephalalgia · doi:10.1177/0333102410375725 · Cited by 56 · see citing works
Potential mechanisms of prospective antimigraine drugs: A focus on vascular (side) effects
Chan, K. Y., Vermeersch, S., Hoon, J. N. J. M. D., Villalón, C. M., & MaassenVanDenBrink, A. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.12.001 · Cited by 53 · see citing works
Redox Mechanisms in Migraine: Novel Therapeutics and Dietary Interventions
Ferroni, P., Barbanti, P., Della‐Morte, D., Palmirotta, R., Jirillo, E., & Guadagni, F. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7260 · Cited by 49 · see citing works
Chemical Mediators of Migraine: Preclinical and Clinical Observations
Gupta, S. K., Nahas, S. J., & Peterlin, B. L. (2011) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2011.01929.x · Cited by 45 · see citing works
Drugs targeting nitric oxide synthase for migraine treatment
Barbanti, P., Egeo, G., Aurilia, C., Fofi, L., & Della‐Morte, D. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.918953 · Cited by 44 · see citing works
Feistel, S., Albrecht, S., & Meßlinger, K. (2013) · The Journal of Headache and Pain · doi:10.1186/1129-2377-14-93 · Cited by 34 · see citing works
Challenges in developing drugs for primary headaches
Schytz, H. W., Hargreaves, R. J., & Ashina, M. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.005 · Cited by 32 · see citing works
Michaličková, D., Šíma, M., & Slanař, O. (2020) · Physiological Research · doi:10.33549/physiolres.934276 · Cited by 32 · see citing works
Grände, G., Nilsson, E., & Edvinsson, L. I. (2012) · Cephalalgia · doi:10.1177/0333102412468340 · Cited by 31 · see citing works
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Dao, V. T.-V., Elbatreek, M. H., Fuchß, T., Grädler, U., Schmidt, H. H. H. W., Shah, A. M., Wallace, A. V., & Knowles, R. G. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_382 · Cited by 29 · see citing works
Galeotti, N., & Ghelardini, C. (2013) · Phytomedicine · doi:10.1016/j.phymed.2013.03.007 · Cited by 27 · see citing works
Galeotti, N., & Ghelardini, C. (2012) · Neurotherapeutics · doi:10.1007/s13311-012-0151-8 · Cited by 16 · see citing works
Lackovic, J., Jeevakumar, V., Burton, M. D., Price, T. J., & Dussor, G. O. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.1366-22.2023 · Cited by 15 · see citing works
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Vécsei, L., Lukács, M., Tajti, J., Fülöp, F., Toldi, J., & Edvinsson, L. I. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180530114534 · Cited by 15 · see citing works
Jordan, P., Costa, A. D. A., Specker, E., Popp, O., Volkamer, A., Piske, R., Obrusnik, T., Kleissle, S., Stuke, K. D., Rex, A., et al. (2023) · PLoS ONE · doi:10.1371/journal.pone.0278325 · Cited by 14 · see citing works
Karsan, N. (2024) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001412 · Cited by 14 · see citing works
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Cady, R. J., Shade, C. L., & Cady, R. K. (2012) · Drugs · doi:10.2165/11641120-000000000-00000 · Cited by 12 · see citing works
Effects of substance P on headache induction and arterial dilation in healthy adults
Al‐Khazali, H. M., Christensen, R. H., Gozalov, E., Hakimzadeh, Z., Melchior, A. G., Domínguez-Moreno, R., Ashina, M., & Ashina, H. (2025) · Cephalalgia · doi:10.1177/03331024251336132 · Cited by 11 · see citing works
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Pellesi, L. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2236545 · Cited by 11 · see citing works
der Schueren, B. V., Verbrugge, F. H., Verbesselt, R., Hecken, A. V., Depré, M., & Hoon, J. N. J. M. D. (2010) · Cephalalgia · doi:10.1177/0333102410365105 · Cited by 6 · see citing works
Self-citationTfelt‐Hansen, P. C. (2010) · The Journal of Headache and Pain · doi:10.1007/s10194-010-0232-1 · Cited by 5 · see citing works
Touati‐Jallabe, Y., Tintillier, T., Mauchauffée, E., Boucher, J., Leroy, J., Ramassamy, B., Hamzé, A., Mezghenna, K., Bouzekrini, A., Verna, C., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.201900659 · Cited by 2 · see citing works
Mauchauffée, E., Leroy, J., Chamcham, J., Ejjoummany, A., Maurel, M., Nauton, L., Ramassamy, B., Mezghenna, K., Boucher, J., Lajoix, A., et al. (2023) · Molecules · doi:10.3390/molecules28135085 · Cited by 1 · see citing works
Hansen, J. M., & Ashina, M. (2017) · doi:10.1002/9781118967225.ch20
THE PROFILE OF THE LEVEL OF ENDOGENOUS NO IN MIGRAINE SUFFERERS
Saleh, A. Y., Machfoed, H., & Kuntoro, K. (2017) · Folia Medica Indonesiana · doi:10.20473/fmi.v52i4.5478
Potential treatment targets and the experience with triptans
Gupta, S. K. (2013) · doi:10.2217/ebo.13.250
Human Migraine Laboratories: Validating Phenotypes, Biomarkers, and Precision Medicine
Pellesi, L., & Ashina, M. (2025) · Springer eBooks · doi:10.1007/978-3-031-86923-5_9
Emerging pharmacological targets in migraine therapy: CGRP and beyond
Atraszkiewicz, D., & Dahiya, D. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1924544
- 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.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Universitair Ziekenhuis Leuven (BE)
- ORCID
- Palmer, J.
- Venue
- The Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2009-03
- Volume
- 49
- Issue
- 3
- Pages
- 281-290
- ISSN
- 0021-9754 (ISSN-L)
- 0091-2700
- 1552-4604
- OpenAlex
- W2007452676
- Cited by
- 39
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2020: 3 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 4
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Migraine and Headache Studies
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Intracranial Aneurysms: Treatment and Complications
- Keywords
- iNOS inhibitors, acute migraine, pharmacokinetics, pharmacodynamics, nitric oxide, exhaled nitric oxide, nasal nitric oxide, nitrotyrosine, treatment efficacy
- MeSH terms
- Adult, Female, Half-Life, Humans, Male, Migraine Disorders, Nitrates, Nitric Oxide, Sulfones, Tyrosine, Area Under Curve, Nitric Oxide Synthase Type II
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