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Safety, tolerability, pharmacokinetics, and effects on human experimental pain of the selective ionotropic glutamate receptor 5 (iGluR5) antagonist LY545694 in healthy volunteers.

Abstract
The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization.
AuthorsKarin L Petersen, Smriti Iyengar, Amy S Chappell, Evelyn D Lobo, Haatem Reda, William R Prucka, Steven J Verfaille
JournalPain (Pain) Vol. 155 Issue 5 Pg. 929-936 (May 2014) ISSN: 1872-6623 [Electronic] United States
PMID24486883 (Publication Type: Journal Article, Randomized Controlled Trial)
CopyrightCopyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Excitatory Amino Acid Antagonists
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Topics
  • Adult
  • Cross-Over Studies
  • Double-Blind Method
  • Excitatory Amino Acid Antagonists (adverse effects, pharmacokinetics, therapeutic use)
  • Female
  • Healthy Volunteers
  • Humans
  • Isoquinolines (adverse effects, pharmacokinetics, therapeutic use)
  • Male
  • Pain (drug therapy)
  • Prodrugs (adverse effects, pharmacokinetics, therapeutic use)
  • Tetrazoles (adverse effects, pharmacokinetics, therapeutic use)
  • Treatment Outcome
  • Young Adult

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