Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).
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.
Rao
Vidhya R
VR
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
Prescott
Elizabeth
E
Shelke
Namdev B
NB
Trivedi
Ruchit
R
Thomas
Peter
P
Struble
Craig
C
Gadek
Tom
T
O'Neill
Charles A
CA
Kompella
Uday B
UB
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
D016169:Lymphocyte Function-Associated Antigen-1; D009883:Ophthalmic Solutions
FASEB J. 2003 Jan;17(1):76-8
12475915
Mediators Inflamm. 2000;9(5):243-8
11200365
Exp Diabetes Res. 2007;2007:95103
18274606
Am J Pathol. 1995 Sep;147(3):642-53
7545873
FASEB J. 2004 Sep;18(12):1450-2
15231732
Free Radic Biol Med. 2000 Jun 15;28(12):1717-25
10946213
Clin J Am Soc Nephrol. 2006 Mar;1(2):281-7
17699218
Microvasc Res. 2005 May;69(3):135-41
15896355
Am J Pathol. 2001 Jan;158(1):147-52
11141487
Curr Diabetes Rev. 2007 Feb;3(1):3-14
18220651
Cardiovasc Hematol Disord Drug Targets. 2009 Sep;9(3):222-9
19619127
Methods Enzymol. 1990;186:729-42
2172726
Surv Ophthalmol. 2002 Aug;47 Suppl 1:S41-52
12204700
Inflammation. 2003 Oct;27(5):281-91
14635785
Invest Ophthalmol Vis Sci. 2000 Apr;41(5):1153-8
10752954
Optometry. 2007 Nov;78(11):574-81
17976619
Am J Pathol. 2000 May;156(5):1733-9
10793084
Curr Eye Res. 1998 Feb;17(2):218-21
9523102
Optometry. 2004 Mar;75(3):183-8
15058700
FASEB J. 2002 Mar;16(3):438-40
11821258
Arch Ophthalmol. 2009 Mar;127(3):245-51
19273785
Diabetes. 2004 Nov;53(11):2950-9
15504976
Science. 2002 Jun 28;296(5577):2391-4
12089442
Am J Pathol. 2002 Feb;160(2):501-9
11839570
Semin Immunopathol. 2008 Apr;30(2):65-84
18340447
Ophthalmology. 2003 Sep;110(9):1677-82
13129861
J Clin Invest. 1996 Jun 15;97(12):2883-90
8675702
Science. 2002 Feb 8;295(5557):1086-9
11834839
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10836-41
10485912
Exp Eye Res. 2006 Jan;82(1):179-82
16202408
Br J Ophthalmol. 2007 Apr;91(4):538-45
16943230
Ophthalmology. 2009 Jan;116(1):73-9
19118698
Am J Ophthalmol. 2003 Jul;136(1):122-35
12834680
Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4547-52
17003451
Diabetes. 2007 Feb;56(2):373-9
17259381
Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1149-60
16505053
Eur J Pharmacol. 2005 Mar 28;511(2-3):191-8
15792788
Am J Ophthalmol. 2001 Nov;132(5):760-76
11704039