title: TOWARDS A TREATMENT FOR DIABETIC RETINOPATHY: Intravitreal Toxicity and Preclinical Safety Evaluation of Inducible Nitric Oxide Synthase Inhibitors.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: *Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas; and †Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: B Cameron
authors.initials: BC
authors.lastname: Carr
authors.forename: Caitlyn E
authors.initials: CE
authors.lastname: Emigh
authors.forename: Lea D
authors.initials: LD
authors.lastname: Bennett
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Pansick
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Chan
authors.initials: C
authors.lastname: Nguyen
mesh_terms: D000578:Amidines / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001596:Benzylamines / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity*; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D007429:Intraocular Pressure / Q000187:drug effects; D058449:Intravitreal Injections / Q000009:adverse effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D006146:Guanidines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine