April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
INO-8875, an Adenosine A1 Agonist, Lowers Intraocular Pressure Through the Conventional Outflow Pathway
Author Affiliations & Notes
  • N. Kim
    Inotek Pharmaceuticals, Lexington, Massachusetts
  • C. Crosson
    Medical University of South Carolina, Charleston, South Carolina
  • T. Lam
    Covance, Inc., Madison, Wisconsin
  • B. Christian
    Covance, Inc., Madison, Wisconsin
  • C. Busse
    Covance, Inc., Madison, Wisconsin
  • G. Cantone
    Toxikon, Bedford, Massachusetts
  • R. Baumgartner
    Inotek Pharmaceuticals, Lexington, Massachusetts
  • T. McCauley
    Inotek Pharmaceuticals, Lexington, Massachusetts
  • W. McVicar
    Inotek Pharmaceuticals, Lexington, Massachusetts
  • Footnotes
    Commercial Relationships  N. Kim, Inotek Pharmaceuticals, E; C. Crosson, Inotek Pharmaceuticals, C; T. Lam, Inotek Pharmaceuticals, E; B. Christian, Inotek Pharmaceuticals, E; C. Busse, Inotek Pharmaceuticals, E; G. Cantone, Inotek Pharmaceuticals, E; R. Baumgartner, Inotek Pharmaceuticals, E; T. McCauley, Inotek Pharmaceuticals, E; W. McVicar, Inotek Pharmaceuticals, E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3238. doi:https://doi.org/
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      N. Kim, C. Crosson, T. Lam, B. Christian, C. Busse, G. Cantone, R. Baumgartner, T. McCauley, W. McVicar; INO-8875, an Adenosine A1 Agonist, Lowers Intraocular Pressure Through the Conventional Outflow Pathway. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3238. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : INO-8875, a highly selective adenosine A1 agonist, is under development for treatment of ocular hypertension and primary open-angle glaucoma. The mechanism of action by which INO-8875 lowers IOP was evaluated in vitro and ex vivo.

Methods: : INO-8875 was studied in ocular normotensive Dutch-Belted rabbits and Cynomolgus monkeys. INO-8875 was delivered topically (40-50 µL) at 3-1000 µg in monkeys and at 1.5-150 µg in rabbits. IOP was measured using a tonometer. The signaling pathway and the site of action of INO-8875 was investigated in human trabecular meshwork cells by measuring extracellular signal-regulated kinases 1/2 (ERK 1/2) and matrix metallopeptidases-2 (MMP-2) via Western blot. The conventional outflow facility was measured in isolated perfused porcine anterior segments (corneo-scleral shells). An A1 antagonist (cyclopentyltheophylline; CPT) and a MAP-kinase inhibitor (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; U0126) were used to confirm the activity of INO-8875.

Results: : A single topical INO-8875 dose of ≥5 and ≥10 µg significantly reduced IOP in rabbits and monkeys, respectively. The maximum IOP reduction in both species was 20-25% of baseline and occurred at 1-2 hours post-dose. IOP returned to baseline levels between 2-6 hrs post-dose. A large reservoir of drug was present in the trabecular meshwork region. The addition of INO-8875 to cultured human trabecular meshwork cells produced a rapid activation of ERK 1/2 within 10 minutes and the subsequent stimulation of MMP-2 by 2 hours. Both increases in ERK1/2 activation and MMP-2 secretion were blocked by the addition of CPT and U0126. In isolated perfused porcine anterior segments, the outflow facility was significantly increased following INO-8875 (10-7 M) compared to the vehicle treatment.

Conclusions: : These experiments demonstrate that INO-8875, a novel selective adenosine A1 agonist, reduces IOP by increasing the conventional outflow facility. INO-8875 is currently in clinical development.

Keywords: outflow: trabecular meshwork • intraocular pressure • adenosine 
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