Towards a treatment for diabetic retinopathy: Intravitreal toxicity and preclinical safety evaluation of inducible nitric oxide synthase inhibitors

B. Cameron Carr, Caitlyn E. Emigh, Lea D. Bennett, Andrew D. Pansick, David G. Birch, Chan Nguyen

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background: The purpose of this study is to determine the maximum tolerated dose of a single intravitreal injection of aminoguanidine and 1400W, 2 inhibitors of inducible nitric oxide synthase, in rabbit eyes. Inhibition of inducible nitric oxide synthase has already been shown to be beneficial in various animal models of diabetic eye disease. Methods: Groups of 4 New Zealand white rabbits were injected with balanced salt solution in the right eye and a single dose of either aminoguanidine (5, 1, 0.25 mg) or 1400W (2 mg and 0.4 mg) in the left eye. Toxicity was assessed by slit-lamp and fundus examination, intraocular pressure and pachymetric measurements, and electrophysiologic and histologic analysis. Results: Eyes injected with high doses of aminoguanidine (5 mg) or 1400W (2 mg) demonstrated severe retinal vascular attenuation and infarction. Lower doses of intravitreal aminoguanidine (1 mg) and 1400W (0.4 mg) caused no significant toxic ocular effects in rabbit eyes. Conclusion: If the difference in vitreal volume between rabbit eyes and human eyes is taken into account, aminoguanidine (2.7 mg) and 1400W (1 mg) would be reasonable intravitreal doses to test for safety and efficacy in early clinical trials.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalRetina
Volume37
Issue number1
DOIs
StatePublished - 2017

Keywords

  • 1400W
  • Aminoguanidine
  • Diabetic retinopathy
  • Inducible nitric oxide synthase
  • iNOS inhibitor
  • Intravitreal toxicity
  • Nitric oxide

ASJC Scopus subject areas

  • Ophthalmology

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