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Effects of Eye Drops Containing Hyaluronic Acid-Nimesulide Conjugates in a Benzalkonium Chloride-Induced Experimental Dry Eye Rabbit Model.

ABSTRACT: Dry eye syndrome (DES) is a common ocular disease worldwide. Currently, anti-inflammatory agents and immunosuppressive drugs, such as cyclosporine A, have been widely used to treat this chronic condition. However, the multifactorial etiology of DES, poor tolerance, low bioavailability, and prolonged treatment to response time have limited their usage. In this study, nimesulide, a cyclooxygenase (COX)-2 selective inhibitor, was conjugated with hyaluronic acid (HA), and the HA-nimesulide conjugates were expected to increase the solubility and biocompatibility for alleviating the DES in the benzalkonium chloride (BAC)-induced goblet cell-loss dry eye model. The therapeutic efficacy of HA-nimesulide was assessed using fluorescein staining, goblet cell density by conjunctival impression cytology, and histology and immunohistochemistry of corneal tissues. Compared to commercial artificial tears and Restasis^®, the HA-nimesulide conjugates could promote goblet cell recovery and enhance the regeneration of the corneal epithelium. Importantly, immunofluorescent staining studies demonstrated that the HA-nimesulide conjugates could decrease the number of infiltrating CD11b-positive cells after two weeks of topical application. In the anti-inflammatory test, the HA-nimesulide conjugates could inhibit the production of pro-inflammatory cytokines and prostaglandin E₂ (PGE2) in the lipopolysaccharide (LPS)-stimulated Raw 264.7 cell model. In conclusion, we demonstrated that HA-nimesulide conjugates had anti-inflammatory activity, and promoted goblet cell recovery and corneal epithelium regeneration when used as topical eye drops; accordingly, the HA-nimesulide conjugates could potentially be effective for the treatment of DES.

SUBMITTER: Chen TY

PROVIDER: S-EPMC8469214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Dry eye may be caused or exacerbated by deficient lipid secretion. Recently, lipid-containing artificial tears have been developed to alleviate this deficiency. Our study compared the efficacy, safety, and acceptability of lipid-containing eye drops with that of aqueous eye drops. METHODS:A non-inferiority, randomized, parallel-group, investigator-masked multicenter trial was conducted. Subjects with signs and symptoms of dry eye were randomized to use one of two lipid-containing artificial tears, or one of two aqueous artificial tears. Subjects instilled assigned drops in each eye at least twice daily for 30 days. The primary efficacy analysis tested non-inferiority of a preservative-free lipid tear formulation (LT UD) to a preservative-free aqueous tear formulation (AqT UD) for change in Ocular Surface Disease Index (OSDI) score from baseline at day 30. Secondary measures included OSDI at day 7, tear break-up time (TBUT), corneal and conjunctival staining, Schirmer's test, acceptability and usage questionnaires, and safety assessments. RESULTS:A total of 315 subjects were randomized and included in the analyses. Subjects reported instilling a median of three doses of study eye drops per day in all groups. At days 7 and 30, all groups showed statistically significant improvements from baseline in OSDI (P<0.001) and TBUT (P?0.005). LT UD was non-inferior to AqT UD for mean change from baseline in OSDI score at day 30. No consistent or clinically relevant differences for the other efficacy variables were observed. Acceptability was generally similar across the groups and there was a low incidence of adverse events. CONCLUSION:In this heterogeneous population of dry eye subjects, there were no clinically significant differences in safety, effectiveness, and acceptability between lipid-containing artificial tears and aqueous eye drops. The results suggest that lipid-containing artificial tears can be used to counteract lipid deficiency that is common in dry eye, without compromising overall acceptability.

Project description:Dry eye disease (DED) is a chronic ocular surface disorder often characterized by decreased tear production and rapid tear evaporation that affect tear film stability and homeostasis. The common symptoms of DED include ocular discomfort, visual disturbances, dryness, and itching. Artificial tears are the mainstay of DED management and supplement one or more layers of the tear film. Artificial tear drops are available as a combination of viscosity-enhancing agents (demulcents/lubricants), humectants, and buffers either with or without preservatives. Artificial tears, as a combination of components (polymers/demulcents/viscosity-enhancing agents), can provide synergistic action compared with a single component for the management of multifactorial signs and symptoms of DED. This review describes the formulation components, physicochemical properties, mechanism of action, and summary of preclinical and clinical evidence on the hydroxypropyl guar-hyaluronic acid (HPG-HA) dual-polymer lubricant eye drops (SYSTANE™ HYDRATION). The dual-polymer eye drops consist of dual demulcents (propylene glycol and polyethylene glycol 400) and the polymers hydroxypropyl guar (HPG) and hyaluronic acid (HA). When instilled on the ocular surface, HPG forms a cross-linked gel matrix with borate ions that prolongs the retention of demulcents, thus providing long-lasting lubrication and ocular surface protection. Additionally, HA stabilizes the tear film, increases corneal wettability, and reduces friction during blinks due to its hygroscopic and viscoelastic properties. Preclinical evidence demonstrates that HPG HA dual-polymer lubricant eye drops provide protection against desiccation by cell hydration and surface retention, cell barrier protection, prolonged lubrication, and promotion of corneal re-epithelialization. Clinical scientific evidence demonstrates that HPG HA dual-polymer lubricant eye drops are safe and effective in the management of DED. Specifically, they reduce the signs and symptoms of DED, reduce dry eye symptoms post-cataract surgery, and improve tear film quality in healthy eyes.

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Effects of Eye Drops Containing Hyaluronic Acid-Nimesulide Conjugates in a Benzalkonium Chloride-Induced Experimental Dry Eye Rabbit Model.

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