The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs.

PURPOSE: 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. METHOD: 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.

Distribution and amount of pigment within the ciliary body and iris of dogs with blue and brown irides.

OBJECTIVE: Compare the amount and distribution of pigment in normal canine eyes with blue and brown irides. ANIMAL STUDIED: Eighteen mixed-breed dogs euthanized for population control. PROCEDURES: Intact globes were removed immediately following euthanasia. Iris color was noted, and globes were evaluated histologically to determine the distribution of pigment. High magnification (x400) digital images were taken of the dorsal and ventral ciliary processes (CP) of 13 eyes with blue irides and 13 eyes with brown irides. Low magnification (x20) images were taken of the dorsal and ventral portions of the ciliary body (CB) of 14 eyes with blue irides and 14 eyes with brown irides. The images were digitally analyzed to determine the percent of the CP and CB that were pigmented in the high and low magnification images, respectively. RESULTS: Eyes with brown irides contained abundant melanin pigment around the CB musculature. This pigment was absent in eyes with blue irides, and the difference was statistically significant (P = 0.001) when digitally analyzed using the low magnification images. Iris color did not have a significant (P = 0.34) impact on the amount of melanin within the CP, as determined using the high magnification images. CONCLUSIONS: Compared to eyes with brown irides, eyes with blue irides lack pigment around the CB musculature, but contain comparable amounts of pigment in the CP.