title: The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs.
abstract: OBJECTIVE
  Keratoconjunctivitis sicca (KCS) is characterized by inflammation and decreased production of tears containing increased levels of cytokines. The release occurs in the setting of conjunctival and lacrimal gland inflammation, potentially mediated by the interaction between lymphocyte function-associated antigen (LFA)-1, a cell surface protein found on lymphocytes, and its cognate ligand intercellular adhesion molecule (ICAM)-1. SAR 1118 is a novel LFA-1 antagonist and may be an effective therapeutic agent for the treatment of KCS. The following studies were performed to assess the in vitro activity of SAR 1118 and to evaluate the clinical efficacy of topical SAR 1118 for the treatment of idiopathic canine KCS.
  
  
  METHODS
  Pharmacodynamics were assessed by measuring the ability of SAR 1118 to inhibit Jurkat T-cell binding with recombinant human ICAM-1 and to inhibit cytokine release from human peripheral blood mononuclear cells (PBMCs) stimulated by staphylococcal enterotoxin B. For the assessment of clinical efficacy, 10 dogs diagnosed with idiopathic KCS were treated with SAR 1118 1% topical ophthalmic solution three times daily for 12 weeks. Schirmer's tear test (STT) was used to measure tear production.
  
  
  RESULTS
  SAR 1118 demonstrated concentration-dependent inhibition of Jurkat T-cell attachment, inhibition of lymphocyte activation, and release of inflammatory cytokines, particularly the Th1, Th2, and Th17 T-cell cytokines IFN-γ, IL-2, and IL-17F, respectively. Mean STT values increased from 3.4 mm during week 1 to 5.8 mm at week 12 (P < 0.025). No SAR 1118-related adverse events were observed.
  
  
  CONCLUSIONS
  SAR 1118 appears to be an effective anti-inflammatory treatment for KCS. Additional studies are warranted to establish the efficacy of SAR 1118 for the treatment of KCS in humans.
authors.affiliation: School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA. murphyc@corl.vetmed.wisc.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murphy
authors.forename: Ellison
authors.initials: E
authors.lastname: Bentley
authors.forename: Paul E
authors.initials: PE
authors.lastname: Miller
authors.forename: Kim
authors.initials: K
authors.lastname: McIntyre
authors.forename: Gary
authors.initials: G
authors.lastname: Leatherberry
authors.forename: Richard
authors.initials: R
authors.lastname: Dubielzig
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Giuliano
authors.forename: Cecil P
authors.initials: CP
authors.lastname: Moore
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Phillips
authors.forename: Peter B
authors.initials: PB
authors.lastname: Smith
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Prescott
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Randall
authors.initials: R
authors.lastname: Scagliotti
authors.forename: Doug
authors.initials: D
authors.lastname: Esson
authors.forename: Tom
authors.initials: T
authors.lastname: Gadek
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004283:Dog Diseases / Q000175:diagnosis / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019169:Jurkat Cells / Q000378:metabolism; D007638:Keratoconjunctivitis Sicca / Q000188:drug therapy / Q000662:veterinary*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D008297:Male; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D009883:Ophthalmic Solutions; D018799:Intercellular Adhesion Molecule-1