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The effectiveness of 5-iodo-2′-deoxyuridine (IDU) on herpes simplex labialis
The effectivenessof 5iodo-2:deoxyuridine (IDU) on herpessimplex labialis P. Michael Gardner, Captain, DC, USA,* and Forest X. Tennant, Jr., Captain, MC, USA**
H
erpes simplex in the primary ocular form was observed by Kaufman and associates1 in 1962 to be effectively controlled with 5-iodo-2’-deoxyuridine (IDUt). This observation represented a major medical advance, not only because it reduced the scarring and blindness associated with herpetic keratitis, but because IDU appeared to be the first drug with viricidal properties. IDU has subsequently been used to treat herpes simplex labialis (HSL), but it is still not known whether it is effective in treating this lesion.*-? Some studies have found that IDU shortens the healing time and relieves the pain of HSL,2-4 while other reports have been dubious. w In order to determine whether IDU is truly beneficial in the treatment of HSL, the following study was conducted under rigidly controlled conditions. PATHOGENESIS
OF HERPES SIMPLEX
There are two stages of this disease, both of which are caused by the same virus. Primary herpes simplex is usually an asymptomatic infection, but sometimes it is a localized or systemic disease in susceptible children who are exposed to the virus from an outside source. Because of the primary infection, herpes antibodies are formed, and these are present in approximately 90 per cent of the adult population.* Recurrent HSL is a localized vesicular eruption caused by activation of the virus that lies latent in the lips of persons with circulating antibodies. The stimulus for reactivation of the virus is nonspecific and in*Ninety-second Medical Detachment (DC), Aschaffenburg, Germany, APO New 09162. Work completed in part during dental internship at Fort Benning, Georgia. **Ninth Medical Dispensary, Aschaffenburg, Germany, APO New York 09162. tGeneric and trade names of drugs: 1. 5iodo-2’deoxyuridine (idoxuridine)-Stoxil, Herplex, Dendrid. 2. Inert base--Orabase.
York
451
452
Gardner
and Tennant
OS., OX & O.P. September, 1969
eludes fever, respiratory infection, trauma, gastrointestinal disturbances, pregnancy, menses, and physical or emotional stress. dpproximately 50 to 75 per cent of the population are susceptible to recurrent HSL.” These lesions appear as superficial clear vesicles on an erythematous base located at the mucocutaneous junction of the lips and face. The vesicles ulcerate in 1 to 3 days and scab and heal without a scar within 2 to 14 days unless secondarily infected with bacteria. Herpetic vesicle fluid on the first day contains about 1 million virus particles per cubic millimeter, but virus particles are almost nondemonstrable in the herpetic lesion past the vesicular stage.3 REVIEW OF LITERATURE
Several forms of treatment, including antibiotics, antihistamines, gamma globulin, smallpox vaccinations, and corticosteroids, have proved to be of little or no value in treating HSL.8-1Z Hall-Smith and colleagues2 first used topical IDU to treat HSL and reported that in eighteen of nineteen patients herpetic lesions were resolved within 24 to 72 hours. Other studies have also found that IDU decreases resolution time as well as relieving symptoms.4, 5 Some investigators, however, have found that in patients treated with IDU lesions are resolved no faster than in patients treated with placebos.“, 6 Unfortunately, the criterion for resolution in some of the studies has been disappearance of symptoms rather than disappearance of the lesionsG, 7 Also, IDU therapy was sometimes not started until after the vesicular stage. Reasons that have been suggested for the failure of IDU have been inappropriate concentration, infrequent application, and use of an ineffective vehicle for the drug.“, I4 PHARMACOLOGY
OF IDU
IDU is an analogue of the nucleoside, thymidine, which is necessary for the synthesis of deoxyribonucleic acid (DNA). The herpes-infected cell utilizes IDU rather than thymidine, thus constructing faulty DNA that interferes with growth and reduplication of the herpes virus. I4 As with all antimetabolites, IDU may interfere with the metabolism of normal mammalian DNA as well as viral DNA. It has been thought to be toxic to epithelial cells of the lip and actually to retard healing of HSL in some patients.3 METHODS
AND PATIENT MATERIAL
The subjects of this study were twenty-nine patients with a history of recurrent HSL, who presented with HSIJ in the vesicular stage. They included twentyeight male members of the Armed Forces serving at Fort Benning, Georgia, and one female patient. Ages ranged from 17 to 50 years. Nineteen patients were treated with topical IDU in ointment form (2.5 mg. per gram) which was prepared by mixing half-and-half portions of IDU (5 mg. per gram) and an inert base. Ten patients in a control group were treated with the inert base only. No patient was selected for either group if the herpetic lesion had progressed beyond the vesicular stage. Each patient was instructed to apply the ointment at least every 2 hours while awake or more often if it was apparent that the medication had disappeared, as right after meals. All patients were followed to complete resolution of the lesions. For purposes of this study, the time required
Volume Number
Efectiveness
28 3
of IOU
on herpes simplex
labialis
453
Table I. Number of patients in IDU and control groups with complete resolution of herpetic lesions in each 3-day period Treatment Idoxurine Control
group
Data show no shortening
1 1 to S days ( 4 to 6 days 17 to 10 dayslover 6 ir 4 ; of resolution time in IDU-treated group.
for complete disappearance resolution time.
10 days1 :
Total 19 10
of all vesicles, ulcers, and scabs was considered the
RESULTS
In the IDU-treated group the shortest resolution time was one day and the longest was 12 days (Table I). The mean number of days necessary for complete resolution was 5.5, and the average was 5.7. In the control group the shortest resolution time was 2 days and the longest was 15 days. For this group the mean was 6.5 days, and the average as 7.0 days. No difference in the subjective amelioration of symptoms was observed in either group. Retardation of wound-healing was not apparent in the group treated with IDU. DISCUSSION
The results of this study show that IDU does not significantly shorten the resolution time or relieve the symptoms of HSL. Just why IDU is successful in treating acute herpetic keratitis and not HSL is uncertain. It has been suggested that inappropriate concentration, infrequent application, or the use of a nonabsorbable vehicle accounts for IDU’s poor results.3T I3 These variables were minimized in this study by an adequate concentration of IDU, frequent applications, and an absorbable vehicle. Some innate property of the recurrent virus or the rapid emergence of drug-resistant mutant viruses appears a more likely explanation for IDU’s therapeutic ineffectiveness. IDU has been shown to be of proven benefit only in treating primary herpetic keratitis, and it is much less effective in treating recurrent herpetic keratitis.15 All our patients had recurrent rather than primary HSL. Our data and the fact that IDU has a minimal effect on recurrent herpetic keratitis indicate that some property of the recurrent herpes virus renders it at least partially resistant to IDU therapy. Wound healing did not appear to be retarded in our patients treated with IDU, as suggested by other studies. 3p5 IDU is probably capable of prolonging resolution if used in high concentrations, since it may interfere with DNA synthesis in normal cells. If IDU is used to treat HSL, the use of low concentrations is recommended to prevent possible deleterious effects. Also, it is probably useless to apply IDU after the vesicular stage, because the herpes virus is essentially nondemonstrable in the lesion after 2 days.3 SUMMARY
IDU does not shorten the natural course of recurrent HSL. It appears that recurrent herpes virus infections of the lip, as well as the eye, are at least partially resistant to IDU therapy.
454
Gardner and Tennant
O.S., ox. & O.P. ~September, 1969
REFERENCES
1. Kaufman, H. E., Martola, E. C., and Dohlman, E. H.: Use of 5Iodo-2’-Deoxyuridine (IDU) in Treatment of Herpes Simplex Keratitis, Arch. Ophth. 68: 235-239, 1962. 2. Hall-Smith, 5. P., Corrigan, M. J., and Gilkes, M. J.: Treatment of Herpes Simplex With 5-Iodo-2’-Deoxyuridie, Brit. M. 5. 2: 15151516, 1962. in the Treatment of 3. Corbett, M. B., Sidell, C. M., and Zimmerman, M.: Idoxuridine Cutaneous Herpes Simplex, J.A.M.A. 196: 441-444, 1966. 4. Schofield, C. B. S.: The Treatment of Herpes Progenitalis With 5Iodo-2’-Deoxyuridine, Brit. J. Dermat. 76: 465-470, 1964. 5. Juel-Jensen, B. E., and MacCallum, F. 0.: Treatment of Herpes Simplex Lesions of the Face With Idoxuridine: A Double-Blind Controlled Trial, Brit. M. J. 2: 987-988, 1964. 6. Anderson, M. F.: Evaluation of 5Iodo-2’-Deoxyuridine (IDU) in Herpes Simplex, OFAL SURCT.,ORAL MED.& ORAL PATH. 19: 39%401,1965. 7. Jackson, N.: Treatment of Herpes Simplex of the Skin With 5-Iodo-2’-Deoxyuridine, J. Irish M. A. 52: X6-157, 1963. 8. Levin, H. L.: Bacteriostasis and Virology of Herpetic Lesions of the Face and Oral MUCOUS Membranes, ORAL SURG., ORAL MED. & ORAL PATH, 20: 726-742, 1965. 9. Zegarelli, E. V., Silvera, H. F., and Kutscher, A. H.: Systemic Aureomycin in the Treatment of Recurrent Aphthous Stomatitis, New York State D. J. 18: 137-140, 1952. 10. Smith, J. F.: The Clinical Use of Triameinolone Acetonide in the Treatment of Herpes ORAL SURG., ORAL MED. & ORAL PATH. 16: Simplex of the Oral Mucous Membranes, X0-153, 1963. 11. Barile, M. F., and Graykowski, E. A.: Primary Herpes, Recurrent Herpes, Recurrent Aphthae: A Review With Some New Observations, J. Dist. Columbia D. Sot. 88: 7-15, 1963. 12. Zegarelli, E. V., Silvers, H. F., and Kutscher, A. H.: Antihistaminic Agents in the Treatment of Recurrent Aphthous Stomatitis, ORAL SURG., ORAL MED. & ORAL PATH. 6: 302-304, 1953. 13. Shell, J.: Unique Factors Influencing the Topical Absorption of Icloxuridine, J. Pharm. SC. 54: 1392, 1965. 14. Roizman, B. G., Aurelian, L., and Roave, P. R,., Jr.: The Multiplication of Herpes Simplex Virus : 1. The Programming of Viral DNA Duplicat,ion in HEp-2 Cells, Virology 21: 482-498, 1963. 15. Wagner, R. R.: Herpes Simplex. In Beeson, P, B. and McDermott, W. (editors) : Text1967, W. B. Saunders Company, pp 117-119. book of Medicine, Philadelphia,
H
erpes simplex in the primary ocular form was observed by Kaufman and associates1 in 1962 to be effectively controlled with 5-iodo-2’-deoxyuridine (IDUt). This observation represented a major medical advance, not only because it reduced the scarring and blindness associated with herpetic keratitis, but because IDU appeared to be the first drug with viricidal properties. IDU has subsequently been used to treat herpes simplex labialis (HSL), but it is still not known whether it is effective in treating this lesion.*-? Some studies have found that IDU shortens the healing time and relieves the pain of HSL,2-4 while other reports have been dubious. w In order to determine whether IDU is truly beneficial in the treatment of HSL, the following study was conducted under rigidly controlled conditions. PATHOGENESIS
OF HERPES SIMPLEX
There are two stages of this disease, both of which are caused by the same virus. Primary herpes simplex is usually an asymptomatic infection, but sometimes it is a localized or systemic disease in susceptible children who are exposed to the virus from an outside source. Because of the primary infection, herpes antibodies are formed, and these are present in approximately 90 per cent of the adult population.* Recurrent HSL is a localized vesicular eruption caused by activation of the virus that lies latent in the lips of persons with circulating antibodies. The stimulus for reactivation of the virus is nonspecific and in*Ninety-second Medical Detachment (DC), Aschaffenburg, Germany, APO New 09162. Work completed in part during dental internship at Fort Benning, Georgia. **Ninth Medical Dispensary, Aschaffenburg, Germany, APO New York 09162. tGeneric and trade names of drugs: 1. 5iodo-2’deoxyuridine (idoxuridine)-Stoxil, Herplex, Dendrid. 2. Inert base--Orabase.
York
451
452
Gardner
and Tennant
OS., OX & O.P. September, 1969
eludes fever, respiratory infection, trauma, gastrointestinal disturbances, pregnancy, menses, and physical or emotional stress. dpproximately 50 to 75 per cent of the population are susceptible to recurrent HSL.” These lesions appear as superficial clear vesicles on an erythematous base located at the mucocutaneous junction of the lips and face. The vesicles ulcerate in 1 to 3 days and scab and heal without a scar within 2 to 14 days unless secondarily infected with bacteria. Herpetic vesicle fluid on the first day contains about 1 million virus particles per cubic millimeter, but virus particles are almost nondemonstrable in the herpetic lesion past the vesicular stage.3 REVIEW OF LITERATURE
Several forms of treatment, including antibiotics, antihistamines, gamma globulin, smallpox vaccinations, and corticosteroids, have proved to be of little or no value in treating HSL.8-1Z Hall-Smith and colleagues2 first used topical IDU to treat HSL and reported that in eighteen of nineteen patients herpetic lesions were resolved within 24 to 72 hours. Other studies have also found that IDU decreases resolution time as well as relieving symptoms.4, 5 Some investigators, however, have found that in patients treated with IDU lesions are resolved no faster than in patients treated with placebos.“, 6 Unfortunately, the criterion for resolution in some of the studies has been disappearance of symptoms rather than disappearance of the lesionsG, 7 Also, IDU therapy was sometimes not started until after the vesicular stage. Reasons that have been suggested for the failure of IDU have been inappropriate concentration, infrequent application, and use of an ineffective vehicle for the drug.“, I4 PHARMACOLOGY
OF IDU
IDU is an analogue of the nucleoside, thymidine, which is necessary for the synthesis of deoxyribonucleic acid (DNA). The herpes-infected cell utilizes IDU rather than thymidine, thus constructing faulty DNA that interferes with growth and reduplication of the herpes virus. I4 As with all antimetabolites, IDU may interfere with the metabolism of normal mammalian DNA as well as viral DNA. It has been thought to be toxic to epithelial cells of the lip and actually to retard healing of HSL in some patients.3 METHODS
AND PATIENT MATERIAL
The subjects of this study were twenty-nine patients with a history of recurrent HSL, who presented with HSIJ in the vesicular stage. They included twentyeight male members of the Armed Forces serving at Fort Benning, Georgia, and one female patient. Ages ranged from 17 to 50 years. Nineteen patients were treated with topical IDU in ointment form (2.5 mg. per gram) which was prepared by mixing half-and-half portions of IDU (5 mg. per gram) and an inert base. Ten patients in a control group were treated with the inert base only. No patient was selected for either group if the herpetic lesion had progressed beyond the vesicular stage. Each patient was instructed to apply the ointment at least every 2 hours while awake or more often if it was apparent that the medication had disappeared, as right after meals. All patients were followed to complete resolution of the lesions. For purposes of this study, the time required
Volume Number
Efectiveness
28 3
of IOU
on herpes simplex
labialis
453
Table I. Number of patients in IDU and control groups with complete resolution of herpetic lesions in each 3-day period Treatment Idoxurine Control
group
Data show no shortening
1 1 to S days ( 4 to 6 days 17 to 10 dayslover 6 ir 4 ; of resolution time in IDU-treated group.
for complete disappearance resolution time.
10 days1 :
Total 19 10
of all vesicles, ulcers, and scabs was considered the
RESULTS
In the IDU-treated group the shortest resolution time was one day and the longest was 12 days (Table I). The mean number of days necessary for complete resolution was 5.5, and the average was 5.7. In the control group the shortest resolution time was 2 days and the longest was 15 days. For this group the mean was 6.5 days, and the average as 7.0 days. No difference in the subjective amelioration of symptoms was observed in either group. Retardation of wound-healing was not apparent in the group treated with IDU. DISCUSSION
The results of this study show that IDU does not significantly shorten the resolution time or relieve the symptoms of HSL. Just why IDU is successful in treating acute herpetic keratitis and not HSL is uncertain. It has been suggested that inappropriate concentration, infrequent application, or the use of a nonabsorbable vehicle accounts for IDU’s poor results.3T I3 These variables were minimized in this study by an adequate concentration of IDU, frequent applications, and an absorbable vehicle. Some innate property of the recurrent virus or the rapid emergence of drug-resistant mutant viruses appears a more likely explanation for IDU’s therapeutic ineffectiveness. IDU has been shown to be of proven benefit only in treating primary herpetic keratitis, and it is much less effective in treating recurrent herpetic keratitis.15 All our patients had recurrent rather than primary HSL. Our data and the fact that IDU has a minimal effect on recurrent herpetic keratitis indicate that some property of the recurrent herpes virus renders it at least partially resistant to IDU therapy. Wound healing did not appear to be retarded in our patients treated with IDU, as suggested by other studies. 3p5 IDU is probably capable of prolonging resolution if used in high concentrations, since it may interfere with DNA synthesis in normal cells. If IDU is used to treat HSL, the use of low concentrations is recommended to prevent possible deleterious effects. Also, it is probably useless to apply IDU after the vesicular stage, because the herpes virus is essentially nondemonstrable in the lesion after 2 days.3 SUMMARY
IDU does not shorten the natural course of recurrent HSL. It appears that recurrent herpes virus infections of the lip, as well as the eye, are at least partially resistant to IDU therapy.
454
Gardner and Tennant
O.S., ox. & O.P. ~September, 1969
REFERENCES
1. Kaufman, H. E., Martola, E. C., and Dohlman, E. H.: Use of 5Iodo-2’-Deoxyuridine (IDU) in Treatment of Herpes Simplex Keratitis, Arch. Ophth. 68: 235-239, 1962. 2. Hall-Smith, 5. P., Corrigan, M. J., and Gilkes, M. J.: Treatment of Herpes Simplex With 5-Iodo-2’-Deoxyuridie, Brit. M. 5. 2: 15151516, 1962. in the Treatment of 3. Corbett, M. B., Sidell, C. M., and Zimmerman, M.: Idoxuridine Cutaneous Herpes Simplex, J.A.M.A. 196: 441-444, 1966. 4. Schofield, C. B. S.: The Treatment of Herpes Progenitalis With 5Iodo-2’-Deoxyuridine, Brit. J. Dermat. 76: 465-470, 1964. 5. Juel-Jensen, B. E., and MacCallum, F. 0.: Treatment of Herpes Simplex Lesions of the Face With Idoxuridine: A Double-Blind Controlled Trial, Brit. M. J. 2: 987-988, 1964. 6. Anderson, M. F.: Evaluation of 5Iodo-2’-Deoxyuridine (IDU) in Herpes Simplex, OFAL SURCT.,ORAL MED.& ORAL PATH. 19: 39%401,1965. 7. Jackson, N.: Treatment of Herpes Simplex of the Skin With 5-Iodo-2’-Deoxyuridine, J. Irish M. A. 52: X6-157, 1963. 8. Levin, H. L.: Bacteriostasis and Virology of Herpetic Lesions of the Face and Oral MUCOUS Membranes, ORAL SURG., ORAL MED. & ORAL PATH, 20: 726-742, 1965. 9. Zegarelli, E. V., Silvera, H. F., and Kutscher, A. H.: Systemic Aureomycin in the Treatment of Recurrent Aphthous Stomatitis, New York State D. J. 18: 137-140, 1952. 10. Smith, J. F.: The Clinical Use of Triameinolone Acetonide in the Treatment of Herpes ORAL SURG., ORAL MED. & ORAL PATH. 16: Simplex of the Oral Mucous Membranes, X0-153, 1963. 11. Barile, M. F., and Graykowski, E. A.: Primary Herpes, Recurrent Herpes, Recurrent Aphthae: A Review With Some New Observations, J. Dist. Columbia D. Sot. 88: 7-15, 1963. 12. Zegarelli, E. V., Silvers, H. F., and Kutscher, A. H.: Antihistaminic Agents in the Treatment of Recurrent Aphthous Stomatitis, ORAL SURG., ORAL MED. & ORAL PATH. 6: 302-304, 1953. 13. Shell, J.: Unique Factors Influencing the Topical Absorption of Icloxuridine, J. Pharm. SC. 54: 1392, 1965. 14. Roizman, B. G., Aurelian, L., and Roave, P. R,., Jr.: The Multiplication of Herpes Simplex Virus : 1. The Programming of Viral DNA Duplicat,ion in HEp-2 Cells, Virology 21: 482-498, 1963. 15. Wagner, R. R.: Herpes Simplex. In Beeson, P, B. and McDermott, W. (editors) : Text1967, W. B. Saunders Company, pp 117-119. book of Medicine, Philadelphia,