title: Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).
abstract: OBJECTIVE
  To determine the pharmacokinetics of SAR 1118, a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1, after administration of ophthalmic drops in normal rats, and to determine its pharmacologic activity by assessing the inhibition of retinal leukostasis and vascular leakiness in a streptozotocin (STZ)-induced diabetic retinopathy model.
  
  
  METHODS
  The ocular pharmacokinetics of SAR 1118 were studied in rats after a single topical dose of (14)C-SAR 1118 (1 mg/eye; 40 μCi; 15.5 μL). SAR 1118 concentration time profiles in plasma and ocular tissues were quantified by liquid scintillation counting (LSC). The pharmacologic activity of SAR 1118 eye drops administered thrice daily for 2 months at 1% (0.3 mg/eye/d) and 5% (1.5 mg/eye/d) was assessed in an STZ-induced diabetic rat model by determining retinal leukostasis and blood-retinal barrier breakdown. Diabetic rats treated with periocularly administered celecoxib microparticles served as the positive control, and vehicle-treated rats served as the negative control.
  
  
  RESULTS
  A single dose of 6.5% (14)C-radiolabeled SAR 1118 ophthalmic drops delivered retinal drug levels greater than 1 μM in less than 30 minutes and sustained levels greater than 100 nM for 8 hours. SAR 1118 eye drops significantly reduced leukostasis and blood-retinal barrier breakdown in a dose-dependent manner.
  
  
  CONCLUSIONS
  SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Vidhya R
authors.initials: VR
authors.lastname: Rao
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Prescott
authors.forename: Namdev B
authors.initials: NB
authors.lastname: Shelke
authors.forename: Ruchit
authors.initials: R
authors.lastname: Trivedi
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Craig
authors.initials: C
authors.lastname: Struble
authors.forename: Tom
authors.initials: T
authors.lastname: Gadek
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D018921:Leukostasis / Q000517:prevention & control; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D008297:Male; D018613:Microscopy, Confocal; D009883:Ophthalmic Solutions / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D009883:Ophthalmic Solutions
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