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Published on: July 23, 2016
An in vitro study of ophthalmic antiviral agent toxicity on rabbit corneal epithelium
P S Imperia1, H M Lazarus, E C Dunkel
1Division of Ophthalmology, University Hospitals of Cleveland, Ohio 44106.
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.
Insights
This study evaluated antiviral agents idoxuridine (IDU), trifluridine (TFT), ethyldeoxyuridine (EDU), and (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU) for corneal epithelial toxicity and antiviral activity. BVDU showed no toxicity, while IDU, TFT, and EDU exhibited dose-dependent toxicity, with TFT and IDU being most toxic.
Area of Science:
- Ophthalmology
- Virology
- Toxicology
Background:
- Corneal epithelial toxicity and antiviral activity of agents like IDU, TFT, EDU, and BVDU are critical for treating ocular viral infections.
- Existing in vivo data on these antiviral agents' toxicity is available, but in vitro validation is needed.
Purpose of the Study:
- To evaluate the in vitro corneal epithelial cytotoxicity and antiviral activity of idoxuridine (IDU), trifluridine (TFT), ethyldeoxyuridine (EDU), and (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU).
- To compare the toxicity and efficacy of these antiviral agents in a corneal epithelial cell culture model.
- To assess the potential clinical toxicity of EDU and validate the in vitro model for future toxicologic studies of antiviral agents.
Main Methods:
- Established confluent rabbit corneal epithelial cell cultures.
- Exposed cultures to varying concentrations and durations of IDU, TFT, EDU, and BVDU.
- Measured [3H]thymidine incorporation to assess cytotoxicity and plaque-forming unit (PFU) inhibition for antiviral activity against HSV type 1.
Main Results:
- Significant dose-dependent toxicity was observed for IDU, TFT, and EDU at clinical concentrations; BVDU showed no toxicity.
- TFT and IDU were the most cytotoxic, followed by EDU.
- All tested agents (IDU, TFT, BVDU) demonstrated significant antiviral activity, with efficacy order TFT > BVDU > IDU.
- In vitro toxicity results correlated with previous in vivo findings for IDU, TFT, and BVDU.
Conclusions:
- BVDU presents a favorable safety profile with no observed corneal epithelial toxicity in vitro.
- EDU may possess potential clinical toxicity, warranting further investigation.
- The established in vitro model is suitable for evaluating the toxicologic profile of new antiviral agents for ocular applications.
