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LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 2004 Jul;24(7):596-602 PMID: 15196302

Pubmed ID

15196302

Abstract

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

Author List

Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F

Authors

Frederick G. Freitag DO Associate Professor in the Neurology department at Medical College of Wisconsin
Paul L. Ornstein PhD Associate Professor in the School of Pharmacy department at Medical College of Wisconsin




Scopus

2-s2.0-2342483183   119 Citations

MESH terms used to index this publication - Major topics in bold

Acute Disease
Adult
Analysis of Variance
Chi-Square Distribution
Female
Humans
Isoquinolines
Male
Middle Aged
Migraine Disorders
Receptors, AMPA
Receptors, Kainic Acid
Tetrazoles
jenkins-FCD Prod-300 626508253d14e4184314fb9f66322a03a5906796