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Evaluation of 5-iodo-2′ deoxyuridine (IDU) in herpes simplex
Section
of the
Federal dental services
Evaluation of 5-iodo-2’ deoxyuridine (IDU) in herpes simplex Martin
P. Anderson, Major, DC, USA*
USITED
STATES
ARMY
HOSPITAL,
FORT
CAMPBELL,
KY.
C
linical evaluation of an agent’s effectiveness in the treatment of a disease is, of necessity, a matter of prejudiced impression. Some investigators have the ability to be more objective than others. Clinical investigation often has a disadvantage in that there are no clear-cut controls. The acceptance of an agent in the treatment of a disease, then, depends upon large numbers of clinicians obtaining essentially a desirable response. REVIEW
OF DISEASE
AND
THERAPY
Herpes simplex lesious are a benign, dermatologic manifestation of the herpes simplex virus. The reaction is prominent in all age groups, with equal distribution between the sexes.l Clinically, there appeares to be a strong predilection toward the Caucasian or fair-skinned races. Communicability of the disease was established through the work of Scott, Steigman, and Conney.2 In half the casesstudied, contact was reported. The course of the disease begins with an altered sensation in the affected area. This has been described as an itching or a mild neuralgia. Fever, pain, and regional lymphadenopathy may precede the appearance of the vesicles. Some patients state that the neuralgia decreases after vesicle formation. The lymphadenopathy usually continues throughout the course of the disease. Microscopically, the vesicle is characterized by separation of the epidermis as a result of the accumulation of fluid. After the rupture of the covering, an ulcer is produced. If the lesion appeares on the surface of a mucous membrane, there is an inflammatory red halo about the periphery of the ulcer. In a variable “Chief,
398
Hospital
Dental
Service,
United
States
Army
Hospital,
Fort
Ckdmpbell,
lip.
Volume Number
IDU
19 3
irl herpes sineple~
399
length of time 7 to 14 days) the area heals and epithelization occurs. On a dry surface, the eraterlike lesion produces fibrin and the area heals by scab formation. The disease can produce isolated Tesicles on the lips, face, and mucous membranes. It can be generalized throughout the mouth and, therefore, may be regarded as a gingivostomatitis. Often herpes xoster will affect the terminal endings of one of the branches of the trigeminal nerve, producing typical vesicles. These case3 can be separated from herpes simplex on the basis of severity and duration. In addition, herpes zoster frequently follows the distribution of the nerve. This neurotrophic virus is only distantly related to the simplex virus. A lasting immunity often results from herpes zostcr, whereas herpes simplex is usually recurrent.3 Some regard any oral lesion that produces a necrotic ulcer as being herpetic in origin. Griffin’9 work assures us that herpes simplex does occur on mucous membrane. No cause has been discovered for the aphthous ulcer, but fut.ure research might disclose a viral origin. At the present time, most investigators choose to separate these conditions. Since the advent of Kenalog in Orabase, which is widely used for the aphthous ulecr, the differentiation of these conditions becomes increasingly more important. The manufacturers of Kenalog state that it is contraindicated in herpetic lesions. As for treatment, clinicians have employed a wide variety of agents. As a rational to mild cauterization, agents that were astringent in nature have been used. Wet soaks of aluminum acetate, wet dressings of tannic acid with iodine and glycerine, boric acid, and camphor ice have been used. Others depend largely on warm sodium bicarbonate to restore normal pH and to give relief from the symptoms. Large doses of Aureomycin have been tried with varying success.Everett? believed strongly that this agent was of value in reducing the course of the disease. Kutapressin found favor a few pears ago among certain clinicians.6 This agent is a selective capillary-constricting derivate of liver in a sterile solution, and it is administered intramuscularly. Ultraviolet radiation has been recommended despite the warnings of Bierman and Krusen,7-9 who list herpes simplex as one of the contraindications to ultraviolet therapy. One of the oldest and presently controversial treatments is the int,radcrmal injection of smallpox vaccine as described by Arnold.l” Kerr” substantiates the success of this treatment. Zegarelli, Silvers, and KutschcP report that antihistamines have no effect, while others report that antihistaminic drugs bring improvement in the course of the disease.High therapeutic dosesof vitamin B complex and vitamin C have been suggested by Burket.13 Finally, there are those who advocate that care be taken to avoid producing damage as .a result of intensive drug therapy. INVESTIGATION
OF A NEW
THERAPEUTIC
AGENT
To the ophthalmologist, herpes simplex presents a far more dangerous picture. Severe damage t.o the eye has resulted from hrrpctic involvement. Once
O.S.,
O.&l. Mnrcll
& 0.1’. 1 1 Yti5 .
established in the organ, it resists treat,ment. Kaufman’4 has had success with an ant,imetabolite, 5iodo-2’ dcoxyuridinc (Il)I:) . This agent, working in a blootlICSS fidd (the cornea), presumably blocks the rnct,abolic pathwa,vs ot’ virus reproduction. The continual prcscncc of the dru g Eipg?lWIltl~ SUp~~lYWW l)NA biosynthesis. Herpes simplex is a I)N,:X \-irlls, drpcndin, cr on clcosy~ihonnvkic acid for reproduction. UKA is comp(Wiveiy used by t.he virus. lnfwttd cells show a ninefold increase in I)SA during the acute stage as opposed to t IIC normal or uninfected stage. The rationale of WC, thcrcfore, is to inhibit, DNA uptake by the virus. Because of the competitive nature of the drug, the agent has been prescribed at one hour intervals. The Fact that 11)IT must bc refrigrratcd and operates in a narrow pII range presents problems with refcrencc to its use. At thr present time, however, this sgcnt offers the only real hope in s(xlect.ivc inhibit ion of the virus during the st,age of ;Ictivc virus proliferation. ITall-Smith, Corrigan, and Gilkcs,” using the ophthalmic preparation, 0.1 per cent Idoxuridine, reported su(*(aess in thirteen consecutive ca.sesof herpes simplex of the skin. The present stud-, using thr same gcncral outline and treatrnent plan, was undertaken to cx\-aluato furthrr the effectivcncss of this agen6. EXPERIMENTAL
INVESTIGATION
The group tested consisted of twenty-fi\c adults of mixed sex and rape. Only those cases in which yesiclc formation had occurred were treated. Cases that. were more than 1. day past vesicle appearance were not incorporated in the study. In this way, it was possible to diagnose the lesion clinically and, in addition, be assured of early trcatmcnt. In t,wenty-three patients this was not the first episodo of herpes simplex. This subjective history indicates that the stud\7 was directed toward secondary herpes simplex. The clear, odorless liquid was applied to the hcrpetic lesions t,welv-c times during a waking day. On each occasion the agent was in contact for a 30 minute period. In 42 per cent of the patients in the control group, the diseasehad a course of less than 1 week; in 46 per cent of the pat,ients under treatment with IDTJ t.hc clinical course was less than I week. The termination of the disease was not considered t,o be the absolute disappearance of the lesion hut, rather, thcb disappearance of discomfort, associated with it. In addition, the lack OS setondary infection and the obvious trend toward resolution marked the end of the clinical course. These findings, when rompared to t,he findin.gs in our control group, indicate that, there was a 1 per cent change. In a small series this was not, considered to bc statistically significant. The agent was not greatly effective in reducing t,he course of the disease. In contrast to its successin the field of ophthalmology, it. is t.hought that the rich blood supply of the skin causes IDU to be incffectirt~. Possibly other investigators might discover a. greater benefit, from this agent. It remains to he seen whether ointment forms providing longer periods of contact will be effective. Certainly, a wider testing should be undertaken.
Volume Numlrer
19 3
REFERENCES 1. Bernier, 2.
3. 4. 5. 6. 7. 8. 9. 10. Il. 12. 13. 14. 15. 16. 17.
J. L.: The Management of Oral Disease, ed. 2, St. Louis, 1959, The C. V. Mosby Company, pp. 298-304. Scott, T. J., Steigman, A. J., and Conney, J. H.: Acute Infectious Gingivostomatitis, J. A. M. A. 117: 999, 1944. Dennis, F. L,: Herpes Zoster Oticus ; a Case With Hwolvement of the Fifth, Seventh, Eighth, and Ninth Cranial Serves With Complete Vestibular Examination, Laryngoscopc 35: 665, 1925. Griffin, J. W.: Fluorescent Antibody Study of Herpes Simplex Virus Lesions and Recurrent Aphthae, ORAL SURG., ORAL MED. & ORAL PATH. 16: 945, 1963. Everett, F. G.: Aureomycin in the Therapy of Herpes Simplex Labialis and Recurrent Oral Aphthae J. Am. Dent. A. 40: 555? 1950. Wolf, Stewart University Hospital, Unrversity Oklahoma: Personal Communica.tion, 1954. Steele, Mada: Ultraviolet Radiation in Herpes Simplex, Phys. Ther. Rev. 41: 779, 1961. Bierman, W. and Licht, S.: Physical Medicine in Grneral Practice, ed. 3, New York, 1952, Paul B. Hoeber? Inc., pp. 271-272. Krusen, F. H.: Physmal Medicine, Philadelphia, 1951, W. B. Saunders Company. Arnold. H. L.. Jr.: Hermetic Stomatitis Treated bv Intradermal SmalluoxL Vaccine. Proc. Staff Meet. Clin., Honolulu 10: 85, 1944. Kerr, D. A.: Stomatitis and Gingivitis in the Adolescent and Preadolescent, J. Am. Dent. A. 44: 27, 1952. Zegarelli, E. V., Silvers, H. F., and Kutsehrr, A. H.: Antihistaminic Agents in the Treatment of Recurrent Aphthous Stomatitis, ORAL SURG., ORAL MED. 8; ORAL PATH. 6: 302, 1953. Burket, L. W.: Oral Medicine, Philadelphia, 1946, J. B. Lippineott Company. Kaufman, H. E., Nesburn, A. B., and Maloney, E. D.: Arch. Ophth. 67: 583, 1962. Kaufman, H. E., Martola, E., and Dohlman, C.: Arch. Ophth. 68: 235, 1962. Kaufman, H. E., and Maloney, E. 0.: Arch. Ophth. 68: 396, 1962. Hall-Smith, S. P., Corrigan, M. J., and Gilkes, M. J.: Treatment of Herpes Simplex Wit.1~ 5Iodo-2’ deoxyuridine, Brit. M. J. 5318: 1515-1516, 1962.
of the
Federal dental services
Evaluation of 5-iodo-2’ deoxyuridine (IDU) in herpes simplex Martin
P. Anderson, Major, DC, USA*
USITED
STATES
ARMY
HOSPITAL,
FORT
CAMPBELL,
KY.
C
linical evaluation of an agent’s effectiveness in the treatment of a disease is, of necessity, a matter of prejudiced impression. Some investigators have the ability to be more objective than others. Clinical investigation often has a disadvantage in that there are no clear-cut controls. The acceptance of an agent in the treatment of a disease, then, depends upon large numbers of clinicians obtaining essentially a desirable response. REVIEW
OF DISEASE
AND
THERAPY
Herpes simplex lesious are a benign, dermatologic manifestation of the herpes simplex virus. The reaction is prominent in all age groups, with equal distribution between the sexes.l Clinically, there appeares to be a strong predilection toward the Caucasian or fair-skinned races. Communicability of the disease was established through the work of Scott, Steigman, and Conney.2 In half the casesstudied, contact was reported. The course of the disease begins with an altered sensation in the affected area. This has been described as an itching or a mild neuralgia. Fever, pain, and regional lymphadenopathy may precede the appearance of the vesicles. Some patients state that the neuralgia decreases after vesicle formation. The lymphadenopathy usually continues throughout the course of the disease. Microscopically, the vesicle is characterized by separation of the epidermis as a result of the accumulation of fluid. After the rupture of the covering, an ulcer is produced. If the lesion appeares on the surface of a mucous membrane, there is an inflammatory red halo about the periphery of the ulcer. In a variable “Chief,
398
Hospital
Dental
Service,
United
States
Army
Hospital,
Fort
Ckdmpbell,
lip.
Volume Number
IDU
19 3
irl herpes sineple~
399
length of time 7 to 14 days) the area heals and epithelization occurs. On a dry surface, the eraterlike lesion produces fibrin and the area heals by scab formation. The disease can produce isolated Tesicles on the lips, face, and mucous membranes. It can be generalized throughout the mouth and, therefore, may be regarded as a gingivostomatitis. Often herpes xoster will affect the terminal endings of one of the branches of the trigeminal nerve, producing typical vesicles. These case3 can be separated from herpes simplex on the basis of severity and duration. In addition, herpes zoster frequently follows the distribution of the nerve. This neurotrophic virus is only distantly related to the simplex virus. A lasting immunity often results from herpes zostcr, whereas herpes simplex is usually recurrent.3 Some regard any oral lesion that produces a necrotic ulcer as being herpetic in origin. Griffin’9 work assures us that herpes simplex does occur on mucous membrane. No cause has been discovered for the aphthous ulcer, but fut.ure research might disclose a viral origin. At the present time, most investigators choose to separate these conditions. Since the advent of Kenalog in Orabase, which is widely used for the aphthous ulecr, the differentiation of these conditions becomes increasingly more important. The manufacturers of Kenalog state that it is contraindicated in herpetic lesions. As for treatment, clinicians have employed a wide variety of agents. As a rational to mild cauterization, agents that were astringent in nature have been used. Wet soaks of aluminum acetate, wet dressings of tannic acid with iodine and glycerine, boric acid, and camphor ice have been used. Others depend largely on warm sodium bicarbonate to restore normal pH and to give relief from the symptoms. Large doses of Aureomycin have been tried with varying success.Everett? believed strongly that this agent was of value in reducing the course of the disease. Kutapressin found favor a few pears ago among certain clinicians.6 This agent is a selective capillary-constricting derivate of liver in a sterile solution, and it is administered intramuscularly. Ultraviolet radiation has been recommended despite the warnings of Bierman and Krusen,7-9 who list herpes simplex as one of the contraindications to ultraviolet therapy. One of the oldest and presently controversial treatments is the int,radcrmal injection of smallpox vaccine as described by Arnold.l” Kerr” substantiates the success of this treatment. Zegarelli, Silvers, and KutschcP report that antihistamines have no effect, while others report that antihistaminic drugs bring improvement in the course of the disease.High therapeutic dosesof vitamin B complex and vitamin C have been suggested by Burket.13 Finally, there are those who advocate that care be taken to avoid producing damage as .a result of intensive drug therapy. INVESTIGATION
OF A NEW
THERAPEUTIC
AGENT
To the ophthalmologist, herpes simplex presents a far more dangerous picture. Severe damage t.o the eye has resulted from hrrpctic involvement. Once
O.S.,
O.&l. Mnrcll
& 0.1’. 1 1 Yti5 .
established in the organ, it resists treat,ment. Kaufman’4 has had success with an ant,imetabolite, 5iodo-2’ dcoxyuridinc (Il)I:) . This agent, working in a blootlICSS fidd (the cornea), presumably blocks the rnct,abolic pathwa,vs ot’ virus reproduction. The continual prcscncc of the dru g Eipg?lWIltl~ SUp~~lYWW l)NA biosynthesis. Herpes simplex is a I)N,:X \-irlls, drpcndin, cr on clcosy~ihonnvkic acid for reproduction. UKA is comp(Wiveiy used by t.he virus. lnfwttd cells show a ninefold increase in I)SA during the acute stage as opposed to t IIC normal or uninfected stage. The rationale of WC, thcrcfore, is to inhibit, DNA uptake by the virus. Because of the competitive nature of the drug, the agent has been prescribed at one hour intervals. The Fact that 11)IT must bc refrigrratcd and operates in a narrow pII range presents problems with refcrencc to its use. At thr present time, however, this sgcnt offers the only real hope in s(xlect.ivc inhibit ion of the virus during the st,age of ;Ictivc virus proliferation. ITall-Smith, Corrigan, and Gilkcs,” using the ophthalmic preparation, 0.1 per cent Idoxuridine, reported su(*(aess in thirteen consecutive ca.sesof herpes simplex of the skin. The present stud-, using thr same gcncral outline and treatrnent plan, was undertaken to cx\-aluato furthrr the effectivcncss of this agen6. EXPERIMENTAL
INVESTIGATION
The group tested consisted of twenty-fi\c adults of mixed sex and rape. Only those cases in which yesiclc formation had occurred were treated. Cases that. were more than 1. day past vesicle appearance were not incorporated in the study. In this way, it was possible to diagnose the lesion clinically and, in addition, be assured of early trcatmcnt. In t,wenty-three patients this was not the first episodo of herpes simplex. This subjective history indicates that the stud\7 was directed toward secondary herpes simplex. The clear, odorless liquid was applied to the hcrpetic lesions t,welv-c times during a waking day. On each occasion the agent was in contact for a 30 minute period. In 42 per cent of the patients in the control group, the diseasehad a course of less than 1 week; in 46 per cent of the pat,ients under treatment with IDTJ t.hc clinical course was less than I week. The termination of the disease was not considered t,o be the absolute disappearance of the lesion hut, rather, thcb disappearance of discomfort, associated with it. In addition, the lack OS setondary infection and the obvious trend toward resolution marked the end of the clinical course. These findings, when rompared to t,he findin.gs in our control group, indicate that, there was a 1 per cent change. In a small series this was not, considered to bc statistically significant. The agent was not greatly effective in reducing t,he course of the disease. In contrast to its successin the field of ophthalmology, it. is t.hought that the rich blood supply of the skin causes IDU to be incffectirt~. Possibly other investigators might discover a. greater benefit, from this agent. It remains to he seen whether ointment forms providing longer periods of contact will be effective. Certainly, a wider testing should be undertaken.
Volume Numlrer
19 3
REFERENCES 1. Bernier, 2.
3. 4. 5. 6. 7. 8. 9. 10. Il. 12. 13. 14. 15. 16. 17.
J. L.: The Management of Oral Disease, ed. 2, St. Louis, 1959, The C. V. Mosby Company, pp. 298-304. Scott, T. J., Steigman, A. J., and Conney, J. H.: Acute Infectious Gingivostomatitis, J. A. M. A. 117: 999, 1944. Dennis, F. L,: Herpes Zoster Oticus ; a Case With Hwolvement of the Fifth, Seventh, Eighth, and Ninth Cranial Serves With Complete Vestibular Examination, Laryngoscopc 35: 665, 1925. Griffin, J. W.: Fluorescent Antibody Study of Herpes Simplex Virus Lesions and Recurrent Aphthae, ORAL SURG., ORAL MED. & ORAL PATH. 16: 945, 1963. Everett, F. G.: Aureomycin in the Therapy of Herpes Simplex Labialis and Recurrent Oral Aphthae J. Am. Dent. A. 40: 555? 1950. Wolf, Stewart University Hospital, Unrversity Oklahoma: Personal Communica.tion, 1954. Steele, Mada: Ultraviolet Radiation in Herpes Simplex, Phys. Ther. Rev. 41: 779, 1961. Bierman, W. and Licht, S.: Physical Medicine in Grneral Practice, ed. 3, New York, 1952, Paul B. Hoeber? Inc., pp. 271-272. Krusen, F. H.: Physmal Medicine, Philadelphia, 1951, W. B. Saunders Company. Arnold. H. L.. Jr.: Hermetic Stomatitis Treated bv Intradermal SmalluoxL Vaccine. Proc. Staff Meet. Clin., Honolulu 10: 85, 1944. Kerr, D. A.: Stomatitis and Gingivitis in the Adolescent and Preadolescent, J. Am. Dent. A. 44: 27, 1952. Zegarelli, E. V., Silvers, H. F., and Kutsehrr, A. H.: Antihistaminic Agents in the Treatment of Recurrent Aphthous Stomatitis, ORAL SURG., ORAL MED. 8; ORAL PATH. 6: 302, 1953. Burket, L. W.: Oral Medicine, Philadelphia, 1946, J. B. Lippineott Company. Kaufman, H. E., Nesburn, A. B., and Maloney, E. D.: Arch. Ophth. 67: 583, 1962. Kaufman, H. E., Martola, E., and Dohlman, C.: Arch. Ophth. 68: 235, 1962. Kaufman, H. E., and Maloney, E. 0.: Arch. Ophth. 68: 396, 1962. Hall-Smith, S. P., Corrigan, M. J., and Gilkes, M. J.: Treatment of Herpes Simplex Wit.1~ 5Iodo-2’ deoxyuridine, Brit. M. J. 5318: 1515-1516, 1962.