Topical HPMPC inhibits adenovirus type 5 in the New Zealand rabbit ocular replication model.
OBJECTIVE
To evaluate the antiviral inhibitory activity of HPMPC against ocular adenoviral serotypes in vitro and to determine the therapeutic efficacy and ocular toxicity of treatment with topical HPMPC on established adenovirus type 5 (AD5) McEwen infection in the New Zealand (NZ) rabbit ocular replication model.


METHODS
The 50% inhibitory dose (ID50) of HPMPC was determined for various clinical isolates of AD5 and AD8 by plaque assay in A549 cells. In vivo inhibitory effects were measured by serial ocular titers and duration of viral shedding in the AD5-NZ rabbit ocular model. Local ocular toxicity was evaluated by external and slit lamp examination for blepharitis, conjunctivitis, keratitis, and iritis.


RESULTS
The mean ID50 for seven isolates of AD8 was 0.47 (range, 0.02 microgram/ml to 0.82 microgram/ml), and the mean ID50 for seven isolates of AD5 was 1.03 (range, 0.15 microgram/ml to 2.80 micrograms/ml). In a series of in vivo experiments, topical administration of HPMPC for as long as 10 days (total dose, > 2.8 mg) significantly reduced both AD5 ocular titers and the number of days of viral shedding compared to that for vehicle-treated control eyes. Local ocular toxicity was not clinically significant at a total dose of < 10 mg administered for as long as 10 days.


CONCLUSIONS
HPMPC, a broad-spectrum, long-acting nucleoside monophosphate analog, is a promising candidate for the treatment of epidemic keratoconjunctivitis infections. Further studies to ensure safety and efficacy in humans are warranted.
Gordon
Y J
YJ
Charles T. Campbell Laboratory, Eye and Ear Institute of Pittsburgh, Pennsylvania 15213.
Romanowski
E G
EG
Araullo-Cruz
T
T
D000257:Adenoviridae Infections / Q000517:prevention & control*; D000260:Adenoviruses, Human / Q000145:classification / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D015828:Eye Infections, Viral / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007637:Keratoconjunctivitis / Q000517:prevention & control* / Q000821:virology; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D014779:Virus Replication / Q000187:drug effects*; D017201:Virus Shedding
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir