oxt-328 and Disease-Models--Animal

Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the concanavalin A (Con A) acute DED model: we injected all lacrimal glands with Con A weekly under ultrasound guidance, which prolonged DED to >3 weeks, and thoroughly assessed efficacy with tear break-up time (TBUT), tear osmolarity, Schirmer test, and tear lactoferrin levels. Rabbits with DED (n = 8-10 eyes per group) were treated topically with PS or vehicle 3×/day for 21days. PS restored TBUT, tear osmolarity, and lactoferrin levels (P < 0.0001-0.04) to normal but did not significantly improve the results of the Schirmer test. PS showed no side effects and was much more efficacious than cyclosporine or lifitegrast. In the cornea, PS suppressed the activation of nuclear factor kappa-B, the levels of transforming growth factor beta, interleukin-1 beta, interleukin-6, and interleukin-8, and the levels of matrix metalloproteinase (MMP)-1 and MMP-9, and MMP activity. Levels of prostaglandin E

Topics: Administration, Ophthalmic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Chronic Disease; Concanavalin A; Cytokines; Dinoprostone; Disease Models, Animal; Dry Eye Syndromes; Humans; Lactoferrin; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Organophosphorus Compounds; Osmolar Concentration; Rabbits; Sulindac; Tears

Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model.. LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration.. PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with <14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S.. Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways.

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Bone Resorption; Cartilage; Cyclooxygenase 2; Disease Models, Animal; Female; Hydrogel, Polyethylene Glycol Dimethacrylate; Inflammation; Interleukin-10; Interleukin-6; Joints; Motor Activity; NF-kappa B; Organophosphorus Compounds; Rats; Rats, Inbred Lew; Sulindac; Synovial Membrane