Treatment of Vaccinial Keratitis With Trifluorothymidine Robert A. \s=b\ The efficacy of trifluorothymidine was compared with idoxuridine on a blind basis by noting the effect of topical administration of the drugs on the severity

of vaccinial keratitis induced in rabbits. Trifluorothymidine was found to be substantially more effective, and was well tolerated. In addition, positive viral cultures after the treatment period were substantially reduced in the trifluorothymidine groups when compared with the idoxuridine or control groups.

(Arch Ophthalmol 94:1785-1786, 1976)

Hyndiuk, MD; Sam Seideman, MD;

herpes simplex keratitis in prelimi¬

nary studies in rabbits'· and humans." It has also been shown to have cere¬ '

bral antiviral activity against the vaccinia virus in mice.7 The purpose of this study was to investigate the effi¬ cacy of trifluorothymidine in the treatment of vaccinial keratitis in the rabbit and to compare it with the currently available idoxuridine. To our knowledge, no similar report has been

previously published.

MATERIALS AND METHODS rare, vaccinial keratitis occur as a serious complica¬ may tion of smallpox vaccination. The inci¬ dence of keratitis after vaccinial blepharitis varies with the immune status of the patient, being 30% to 50%' when the immune status is low, and approximately 10% when the patient has a high antibody titer.-' Although the frequency of the disease seems to be decreasing along with the less universal attitude toward small¬ pox vaccination, it still continues to be a feared complication of a prophy¬ lactic medical procedure. Various agents have been used for treatment; however, none has been entirely successful. Recently, vidara¬ bine·' has been shown to be efficacious and well tolerated in vaccinial kera¬ titis in rabbits. Trifluorothymidine, a

Although .

relatively

new

pyrimidine analogue,

has been shown to be more effective than idoxuridine in the treatment of Accepted

for publication May 21, 1976. From the Cornea-External Disease Unit, Department of Ophthalmology, Medical College of Wisconsin, Milwaukee (Drs Hyndiuk and Seideman); and the Department of Ophthalmology, University of Iowa, Iowa City (Dr Leib-

sohn).

Reprint requests to Cornea-External Disease Unit, Milwaukee County Medical Complex, 8700 W Wisconsin Ave, Milwaukee, WI 53226 (Dr Hyndiuk).

After being anesthetized with topically applied proparacaine, both eyes of 32 New Zealand albino rabbits weighing approxi¬ mately 2 kg were traumatized by making ten interlocking circles with a 5-mm trephine set to a depth of 0.05 mm. One drop (0.1 ml) of vaccinia virus CL strain HA/4 (10s TCID.-„,/ml suspension) was

instilled onto the traumatized corneas, with the lids closed and massaged after each instillation. This was repeated twice at approximately five-minute intervals. After 36 hours, 40 eyes determined to have active keratitis were randomly assigned into the following four treatment groups.

Group 1 (control group—ten eyes) re¬ ceived petrolatum ointment vehicle with no active agent. Group 2 (ten eyes) received commercial preparation of idoxuridine 0.5% ointment. Group 3 (ten eyes) received trifluorothy¬ midine 0.5% in petrolatum ointment vehi¬ cle. Group 4 (ten eyes) received trifluorothy¬ midine 5.0% in petrolatum ointment vehi¬ cle. The medications, in ointment form, were coded, stored at 4 C before and during treatment, and administered topically ev¬ ery four hours from 7 am to 11 pm for 6.5 days. By use of the "single-blind" tech¬ nique, the lesions were examined daily by slit lamp by a single observer. The ulcers stained with fluorescein were graded topographically according to the following scoring system:1 grade 0,

no

ulcération;

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Joel M.

Leibsohn, MD

grade 1, ulcération affecting one fourth of the cornea; grade 2, ulcération affecting one half of the cornea; grade 3, ulcération affecting three fourths of the cornea; grade 4, ulcération affecting the entire When the area affected was between two grades, a score of 0.5 was added to the lower grade. Viral cultures were taken 10 to 12 hours after the conclusion of the treatment period. These cultures were taken by swab¬ bing moistened cotton-tipped applicators over the cornea, and inoculating the material directly into primary human amnion monolayer tubes containing 1.0 ml of Basal Medium Eagle with Hanks balanced salt solution, 10% fetal calf serum, L-glutamine, and a penicillin-streptomycin-mycostatin mixture. cornea.

RESULTS The Figure shows a comparison of the scores after completion of the period of treatment. Following are posttreatment scores, which represent the mean of the scores within each treatment group, plus or minus stan¬ dard deviation (SD) at the 0.95 confi¬ dence interval as determined by the Student t test. Control animals (ten eyes)—mean,

2.60; SD,

±

0.8.

Idoxuridine, 0.5% (ten eyes)—mean, 1.40; SD, ± 0.4. Trifluorothymidine, 0.5% (ten eyes)-mean, 0.30; SD, ± 0.2. Trifluorothymidine, 5.0% (ten eyes)-mean, 0.00; SD, ± 0.0.

Idoxuridine had some effect on vaccinial ulcers, the difference be¬ tween the control group and the idox¬ uridine group being significant (P < .05). Trifluorothymidine in either concentration was clearly much more effective than idoxuridine in clearing the vaccinial lesions. Differences be¬ tween the trifluorothymidine groups and the control group were significant even at < .01. Viral cultures, at the

other clinical units across the country to confirm clinical efficacy and safety. It may be a potentially valuable addi¬ tion to the ophthalmologist's antiviral

armamentarium.

This study was supported in part by grant X016 from the College of Medicine, University of Iowa, by grants EY-00310 and 5T01 EY-00045-08 from the National Institutes of Health, and by a grant from Research to Prevent Blindness, Inc.

Key Words.—Keratitis; vaccinial kerati¬ tis; idoxuridine; trifluorothymidine; antivi¬ rale; vaccinia. Comparison of clinical scores and 5.0%) treatment groups.

in control, idoxuridine

end of the treatment period, were positive in all eyes in the control group, six eyes in the idoxuridinetreated group, and one eye in the 0.5%

trifluorothymidine-treated

group. None of the eyes treated with 5.0% trifluorothymidine had positive viral cultures. Fine, discrete punctate corneal epithelial opacities were seen on the last day of treatment in two of ten eyes in group 4 treated with 5% trifluorothymidine. These changes cleared within three days of drug cessation. Since viral lesions had cleared in nine of ten eyes in this group by the fourth treatment day, this may represent a mild reversible keratitis due to the higher concentra¬ tion of trifluorothymidine. No similar changes were seen in the other three groups.

COMMENT Various agents have been used in the past in the treatment of vaccinial keratitis, including vaccine immune globulin,"" interferon,'" and idoxuri¬ dine." ""' ' Vaccine immune globulin is useful in the presence of vaccinial blepharitis or orbital cellulitis, but may actually make the stromal kera¬ titis worse once it is established." Interferon is not easily available, and idoxuridine has low potency and a low therapeutic index.'" Synthesis of a

pyrimidine analog, trifluorothy¬ midine, was reported in 1964 by Heidelberger et al,14 and was shown to be efficacious against herpes simplex keratitis in rabbits.' ' In addition, the drug was shown to be effective new

(IDU),

and

trifluorothymidine (0.5%

against vaccinia virus

in

mouse

brain

tissue,7 and was better than saline in a

group of rabbits with induced vaccin¬ ial keratitis.4 Trifluorothymidine is incorporated into DNA, as is idoxurid¬ ine, and in addition, it inhibits the enzyme thymidylate synthetase,4 which is necessary for DNA synthesis. Idoxuridine had a therapeutic effect in this study, but was clearly less effective than trifluorothymidine. In

addition,

trifluorothymidine

was

much more effective than idoxuridine in reducing positive virus cultures. Trifluorothymidine has some inher¬ ent advantages over idoxuridine. It is relatively nontoxic in rabbits' and humans." It is more potent than idox¬ uridine, and is ten times more watersoluble," with better corneal penetra¬ tion possible.' In addition, it is active in idoxuridine-resistant herpes sim¬ plex keratitis.4 Although direct simul¬ taneous comparative studies have not been done comparing trifluorothymi¬ dine with vidarabine, trifluorothymi¬ dine appears to have as good or possibly greater activity against the vaccinia virus, and better solubility. Both drugs seem relatively nontoxic. Recent reports indicate that vidara¬ bine will soon be commercially avail¬ able. Usefulness of trifluorothymidine has been limited in the United States because of unavailability primarily due to the high cost of producing it through a fermentation process. New methods of reducing cost of produc¬ tion, however, have recently permit¬ ted the institution of further clinical testing of this drug in our unit and '

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Name and Trademarks of Drug

Nonproprietary

Idoxuridine-Dewdrid, Herplex, Stoxil. References 1. Jones BR, Khalof M, Al Mussaini MV: Therapeutic considerations in ocular vaccinia. Trans Ophthalmol Soc UK 83:613-631, 1964. 2. Bonnet P, Bonamour G: Vaccine oculaire professionnelle. Bull Soc Ophthalmol Fr 425-427, 1955. 3. Hyndiuk RA, Okumoto MA, Damiano RE, et al: Treatment of vaccinial keratitis with vidarabine. Arch Ophthalmol 94:1363-1364, 1976. 4. Kaufman HE, Heidelberger C: Therapeutic antiviral action of 5-trifluoromethyl-2-deoxyuridine, herpes simplex keratitis. Science 145:585\x=req-\ 586, 1964. 5. Hyndiuk RA, Kaufman HE: Newer compounds in therapy of herpes simplex keratitis. Arch Ophthalmol 78:600-605, 1967. 6. Wellings PC, Awdry PN, Bors FH, et al: Clinical evaluation of trifluorothymidine in the treatment of herpes simplex corneal ulcers. Am J Ophthalmol 73:932-942, 1972. 7. Allen LB, Sidwell RW: Target organ treatment of neurotropic virus diseases: Efficacy as a chemotherapeutic tool and comparison of activity of adenine arabinoside, cytosine arabinoside, idoxuridine, and trifluorothymidine. Antimicrob Agents Chemother 2:229-233, 1972. 8. Ellis PP, Winograd LA: Ocular vaccinia: A specific treatment. Arch Ophthalmol 68:600-609, 1962. 9. Fulginiti VA, Winograd LA, Jackson M, et al: Therapy of experimental vaccinial keratitis. Arch Ophthalmol 74:539-544, 1965. 10. Jones BR, Galbraith JEK: Vaccinial keratitis treated with interferon. Lancet 1:875-879, 1962. 11. Jack MK, Sorenson RW: Vaccinial keratitis treated with IDU. Arch Ophthalmol 69:730-732, 1963. 12. Kaufman HE, Nesburn AB, Maloney ED: Cure of vaccinia infection by 5-iodo-2 deoxyuridine. Virology 18:567-569, 1962. 13. Lepri G, Parducci F: Iodo-deoxyuridine in experimental vaccinial keratitis. Ann Ottal 88:443-447, 1962. 14. Heidelberger C, Parsons DG, Remy DC: Synthesis of 5-trifluoromethyluracil and 5\x=req-\ trifluoromethyl-2 deoxyuridine. J Med Chem 7:1\x=req-\ 5, 1964. 15. Sugar J, Varnell E, Centifanto Y, et al: Trifluorothymidine treatment of herpetic iritis in rabbits and ocular penetration. Invest Ophthalmol 12:532-534, 1973.

Treatment of Vaccinial keratitis with trifluorothymidine.

Treatment of Vaccinial Keratitis With Trifluorothymidine Robert A. \s=b\ The efficacy of trifluorothymidine was compared with idoxuridine on a blind b...
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