title: An in vitro study of ophthalmic antiviral agent toxicity on rabbit corneal epithelium.
abstract: Using an in vitro system we measured the corneal epithelial cytotoxicity and the antiviral activity of the antiviral agents idoxuridine (IDU), trifluridine (TFT), ethyldeoxyuridine (EDU), and (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU). Confluent rabbit corneal epithelial cell cultures were established, and the antiviral agents were added for 5, 30, or 60 min at a range of concentrations including that used clinically (IDU 0.1%, TFT 1.0%, BVDU 0.1%, EDU 2.0%). Twelve hour [3H]thymidine incorporation then was measured and expressed as % inhibition of control cultures. In separate experiments confluent corneal epithelial cell monolayers were inoculated with 10(4) plaque forming units (PFU) of HSV type 1 (McKrae strain) for 1 h, and IDU 0.1%, TFT 1.0%, and BVDU 0.1% were added to the culture for determination of PFU inhibition. Significant dose-, but not time-dependent, toxicity was observed at the clinical concentrations of IDU, TFT, and EDU. Toxicity was absent for BVDU. TFT and IDU were the most toxic, and EDU was of intermediate toxicity. IDU, TFT, and BVDU showed significant antiviral activity in this corneal epithelial cell culture system (TFT greater than BVDU greater than IDU). The results of this in vitro study paralleled the findings of previous in vivo corneal epithelial toxicity studies of IDU, TFT, and BVDU. Our data, however, suggest that EDU has a potential for clinical toxicity and further studies are recommended. Our model may be useful in the future toxicologic study of new antiviral agents.
authors.affiliation: Division of Ophthalmology, University Hospitals of Cleveland, Ohio 44106.
authors.forename: P S
authors.initials: PS
authors.lastname: Imperia
authors.forename: H M
authors.initials: HM
authors.lastname: Lazarus
authors.forename: E C
authors.initials: EC
authors.lastname: Dunkel
authors.forename: D
authors.initials: D
authors.lastname: Pavan-Langston
authors.forename: P A
authors.initials: PA
authors.lastname: Geary
authors.forename: J H
authors.initials: JH
authors.lastname: Lass
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D007065:Idoxuridine / Q000633:toxicity; D066298:In Vitro Techniques; D011817:Rabbits; D013936:Thymidine / Q000378:metabolism; D014271:Trifluridine / Q000633:toxicity
chemical_list: D000998:Antiviral Agents; C022811:edoxudin; C020235:brivudine; D001973:Bromodeoxyuridine; D007065:Idoxuridine; D014271:Trifluridine; D013936:Thymidine; D003857:Deoxyuridine