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Betamethasone-17-benzoate in the treatment of recurrent aphthous ulcers
Betamethasone- 17-benzoate in the treatment of recurrent aphthous ulcers Hubert W. Merchant, D.D.S., M.S.D., Louis P. Gangarosa, D.D.S., Ph.D., Armand B. Glassman, M.D., * and Robert E. Sobel, Ph.D., Augusta, Ga. DEPARTMENTS OF ORAL MEDICINE, DENTAL PHARMACOLOGY, AND PATHOLOGY, SCHOOL OF DENTISTRY AND SCHOOL OF MEDICINE, MEDICAL COLLEGE OF GEORGIA A double-blind study of the effectiveness of betamethasone- 17-benzoate in the treatment of recurrent aphthous ulcers (RAU) was conducted. The drug was found to be effective in reducing symptoms and shortening healing time but not in preventing recurrences. Evaluation of the medical histories and laboratory studies suggests that multiple factors may be involved in the etiology of RAU, as reported
by others.
S u c c e s s f u l topical treatment of recurrent aphthous ulcers (RAU) is difficult at best for reasons probably related in part to the constant flow of saliva and the mobility of the involved tissues displacing even the more adherent forms of medication. There also appears to be a strong placebo effect with any medication and such a wide variety of healing times between lesions in a single person and among persons that evaluation of a new treatment is difficult. The study reported here was conducted on a double-blind basis with use of the vehicle as a control. The active drug was betamethasone-17-benzoate 0.025 per cent dissolved in a gel base consisting of carboxy-vinyl polymer, disodium edetate, propylene glycol, diisopropanolamine, purified water, and alcohol 13.8 per cent
(w/w). Materials and Methods Patients entering the study were volunteers who were advised of the experimental nature of the study and to whom the details of the study plan were given so that informed consent was obtained and compliance with human assurance protocols was met. Volunteers were accepted if they had monthly or more frequent occurrences of RAU. Diagnosis was made on the basis of clinical appearance, history, cytologic studies or biopsy to rule This study was supported in part by a grant from Warner-Chilcott Company. *Department of Laboratory Medicine, Medical University of South Carolina, 80 Barre St., Charleston, S. C. 29401.
870
0030-4220/78/0645-0870500.60/0 ~ 1978 The C. V. Mosby Co.
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
871
Table I. Healing <--6Days Drug Placebo
23* 14
]
>6 Days 10 16
Xz = 3.4387, l-tail test. *Significancep < 0,05 in favor of drug. out similar-appearing viral or other lesions, and blood studies. On entering the study, each patient completed a health history questionnaire, and an oral and adnexal exarrfination was performed. Laboratory studies, which included a Coulter hemogram, leukocyte differential, serum iron, total iron-binding capacity, plasma copper and zinc, as well as the SMA 6 and SMA 10 chemistries, were done on each patient. Drug or placebo for treating the lesions was given to the patient on a double-blind basis in a random sequence provided by a statistician. Prior to treatment, which was usually begun in the first 24 hours and never later than 48 hours, a description of the lesions was noted and photographs were made for later evaluation. All patients were seen every 1 to 3 days, usually every second day, during the healing phase and were rephotographed at each visit. The size, location, and appearance of the lesions were recorded at each visit. Evaluation of the effectiveness of treatment was based on healing time to complete epithelization and symptomatic relief between individual treatments. Epithelial covering was determined visually. A tube of medication (active drug or placebo) and a supply of cotton-tipped applicators were given each patient. The method of application was demonstrated, and instructions to use the medication after each meal and at the hour of sleep were given. The lesion was gently wiped with the swab to remove the fibrinous exudate, and then a drop of medication only large enough to just cover the lesion was applied. This was allowed to " d r y " for 15 seconds before further contact with saliva was permitted. The patient was advised not to intentionally disturb the medication by licking or sucking the area. A total of sixty-three treatment series was completed, thirty-three for the drug under study and thirty for the placebo. Of these, seventeen were paired, i.e., drug and placebo were studied in the same individual. The code was not broken until all studies were completed. RESULTS The results showed a statistical advantage for the drug in all aspects of healing time, relief of pain, and in unsolicited comments. The advantage of the drug was perceived whether it was used first or last in the paired groups. Table I indicates the differences in healing, with 6 days as the dividing line. This time interval was arbitrarily selected prior to statistical analysis and breaking the code, on the basis of our experience that in a group of patients having this incidence of RAU most of the RAU lesions require more than 6 days to heal completely. Table II reflects the subjective response of the patient to symptomatic relief. Because of the design protocol of the study (several hours between treatments), some patients did not experience relief of pain for the total time interval between drug applications. Relief of pain was considered to be positive if it occurred for at least 30 minutes subsequent to application of the sample. Complete relief of pain usually occurred with both drug and placebo 1 to 2 days before complete epithelization. Table III was also
872
Oral Surg. June, 1978
Merchant et al.
Table II. Symptomatic relief
I Drug Placebo
Yes
No
29* 18
4 12
X ~ = 6.4462, l-tail test. *p < 0.01 in favor of drug.
Table IIh Patient response (unsolicited) Favoring drug Favoring placebo
10 3
related to the patients' subjective comments which were made without any solicitation on our part. These were thought to be valid because all patients were chronic sufferers of RAU and had tried many remedies, as illustrated by Fig. 1, which shows the drugs used by one of the patients over a period of several years. Evaluation of the blood chemistries and other laboratory procedures revealed variations in iron, iron binding, and iron saturation, as well as hemoglobin, hematocrit, and mean corpuscular volume in some subjects. Table IV shows the normal values for our laboratory and those instances in which two or more study subjects, of fifty-two examined, were found outside of the normal range on initial examination. In the health questionnaire responses of fifty-sevenwho were considered to be suitable subjects for this study, there were thirty positive responses relating to a history of allergy, and an additional eight of a positive history of sinus trouble. Following this in frequency were sixteen " Y e s " answers to the questions about familial diabetes, and one instance of diagnosed diabetes which was controlled by diet. Most of the patients reported easy bruising, but this is true of most of our clinic patients. In this group which consisted of forty-two females, five reported endocrine dysfunction, eight had menstrual difficulties, and four anemia. Six patients reported arthritis or other joint disease, five had a history of cardiovascular disease, and five reported a history of other ulcers, either gastric or duodenal. Three patients had a previous history of hepatitis, and three (all males) had a history of carcinoma, two of the prostate and one a basal-cell nevus syndrome.
DISCUSSION One would expect that a topical antiinflammatory corticosteroid drug such as betamethasone- 17-benzoate would provide some benefit in the treatment of RAU if prolonged contact with the inflamed area were maintained. That some of the benefit was due to the protectant action of the vehicle might be assumed, also, from the results obtained with the placebo. This created some difficulty in assessing the results just as Zegarelli and associates I noted in the report on evaluation of triamcinalone acetonide with a different oral adhesive vehicle, consisting of gelatin, pectin, and sodium carboxymethyl cellulose in a polyethylene and liquid petrolatum gel base. The vehicle used in our study, when applied to skin, dries to an invisible coat. We assumed that the same mechanism was operant in the mouth, although perhaps to a lesser extent, and that this accounted for the symptomat-
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
873
Fig. 1. Typical medications used by patients.
Table IV
Numberof subjects with low values
I
9
Hemoglobin (Gin)
5
Hematocrit (%)
4
MCV (/z3)
5 2
MCH (/x/zg) MCHC (%) Neutrophils (segmented) Lymphocytes Eosinophils LDH SGOT Serum iron TIBC Iron saturation Copper Zinc
4
2 1 9 l0 9
Normal(in our laboratory) M : 14-18 F: 12-16 M :42-52 F:37-47 M : 80-94 F:81-99 M and F:27-31 M and F:32-36 54-62% 25-33% 1-3% 92-204 mU/ml. 26-58 mU/ml. 50-150 p.g/dl. 250-350/.tg/dl. 20-55% 70-150/xg/dl. (? 70-150tzg/dl.)*
Numberof subjects with high values
27 11 3 2 2 2 14
* Normal plasma zinc levels are not firmly established. ic relief reported here with the placebo since we did attempt to apply it to a " d r i e d " surface and allowed a 15-second " d r y i n g " time after application. A topical drug administered in the oral cavity must be considered to be swallowed in part or in total also. Thus, the effect may be both local and systemic. We did not attempt any analysis of plasma cortisol or urinary 17-hydroxy steroids. There were no overt indications of clinical changes, and the levels administered were calculated to be a maximum daily level of 0.38 Gm. or 0.095 rag. of active drug in the treatment of three lesions four times per day. Actual weighing of tubes of medication after treatment indicated an average of 1.02 Gm. or 0.255 mg. of active drug used per patient per treatmemt series.
874
Merchant et al.
Oral Surg. June, 1978
Studies by Skipworth 2 have shown adrenal suppression to be directly proportional to the amount of body area covered when betamethasone benzoate was applied to 10 to 90 per cent of the body surface in patients with diseased skin. Spontaneous return to normal adrenal function occurred within 5 days after cessation of treatment in those studies. The amount of oral mucous membrane involved in even the most severe episodes which we observed would be much less than 10 per cent of body surface. From a practical point of view, this suggests that more frequent use of the drug would be well within the limits of safety. (We are now prescribing use on an as-needed basis but not to exceed eight applications per day.) As in other studies by Lehner a' 4 and Zegarelli and associates, 1 patients noted a greater effectiveness of the drug, but not the placebo, in aborting the prodromal phase or very early lesions. This was discovered serendipitously by some of our patients and was not part of the study and not entered into the data. It would be tempting to ascribe an association between the allergies and the occurrence of oral ulcers but this cannot be done on the basis of a health questionnaire. The same could be said of any of the other findings which were positive on the health questionnaire. However, in the instances of changes in laboratory findings the numbers of patients having probable deficiencies of vitamin B 12 or iron suggest that this is a positive association with some oral ulcers as reported by Wray and colleagues) There was no noticeable diminution of effect of the drag under study in reducing inflammation and promoting healing in the patients of these categories who were accepted in the study. It should be noted that the study of the drug and placebo did not include all of the patients examined. Some subjects who were considered to be unsuitable for a research study were excluded, and others discontinued because of the time required or other personal reasons, so that patients on whom initial laboratory data are available exceed the number of patients treated. Two of the several reasons given by patients for discontinuing were that no relief was obtained from the medication, and relief was so effective that they decided not to return until all the medication was used! CONCLUSION
Betamethasone- 17-benzoate in a solubilized gel base has been shown to be effective in the symptomatic relief of recurrent aphthous ulcers (RAU) and to reduce healing time when compared to a placebo consisting of the gel alone. Untoward effects of the drag were not seen. Although histologic study, clinical appearance, course, and history would support a diagnosis of recurrent oral aphthae or recurrent aphthous ulcers in all of the cases presented in this study, the laboratory findings tend to bear out the conclusions of Wray and associates ~ that defects in iron or other essential nutrient metabolism are, in some instances, associated. In our previously reported use of zinc sulfate as a preventive of oral ulcers in patients with plasma zinc levels below 110/zg/dl., we suggested that recurrent aphthous stomatitis may well be a single expression of multiple contributing factors. ~ REFERENCES
I. Zegarelli,E. V., Kutscher, A. H., Silvers, H. F., Beube, F. E., Stern, I. B., Berman, C. L., and Herlands, R. E.: Triamcinolone Acetonide in the Treatment of Acute and Chronic Lesions of the Oral Mucous Membranes, ORALSURe. 13: 170-175, 1960. 2. Skipworth, G.: Study of the PhysiologicalEffect of 0.025% Beben Gel (BetamethasoneBenzoateW597539) When Applied to Diseased Skin Areas As Measured by Parametersof Adrenal CorticalFunction (Study VII Protocol), Report No. CR-BG-VII,January, 1972. Research Report 932-0495, Data on file at Warner Lambert Research Institute.
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
875
3. Lehner, T.: Characterization of Mucosal Antibodies in Recurrent Aphthous Ulceration and Behget's Syndrome, Arch. Oral Biol. 14: 843-853, 1969. 4. Lehner, T.: Steroids and Oral Disease, Br. J. Dermatol. 94: Supp. 12, 59, 1976. 5. Wray, D., Ferguson, M. M., Mason, D. R., Hutcheon, A. W., and Dagg, J. H.: Recurrent Aphthae: Treatment With Vitamin B 12, Folic Acid, and Iron, Br. Med. J. 36: 490-493, 1975. 6. Merchant, H. W., Gangarosa, L. P., Glassman, A. B., and Sobel, R. E.: Zinc Sulfate Supplementation for Treatment of Recurring Oral Ulcers, South. Med. J. 70: 559-561, 1977.
Reprint requests to: Dr. Hubert W. Merchant Department of Oral Medicine School of Dentistry Medical College of Georgia Augusta, Ga. 30901
COPYRIGHT INFORMATION The appearance of a code at the bottom of the first page of an original article in this journal indicates the copyright owner's consent that copies of the article may be made for per~nal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, N. Y. 12301,518-3744430, for copying beyond that permitted by Sections 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.
by others.
S u c c e s s f u l topical treatment of recurrent aphthous ulcers (RAU) is difficult at best for reasons probably related in part to the constant flow of saliva and the mobility of the involved tissues displacing even the more adherent forms of medication. There also appears to be a strong placebo effect with any medication and such a wide variety of healing times between lesions in a single person and among persons that evaluation of a new treatment is difficult. The study reported here was conducted on a double-blind basis with use of the vehicle as a control. The active drug was betamethasone-17-benzoate 0.025 per cent dissolved in a gel base consisting of carboxy-vinyl polymer, disodium edetate, propylene glycol, diisopropanolamine, purified water, and alcohol 13.8 per cent
(w/w). Materials and Methods Patients entering the study were volunteers who were advised of the experimental nature of the study and to whom the details of the study plan were given so that informed consent was obtained and compliance with human assurance protocols was met. Volunteers were accepted if they had monthly or more frequent occurrences of RAU. Diagnosis was made on the basis of clinical appearance, history, cytologic studies or biopsy to rule This study was supported in part by a grant from Warner-Chilcott Company. *Department of Laboratory Medicine, Medical University of South Carolina, 80 Barre St., Charleston, S. C. 29401.
870
0030-4220/78/0645-0870500.60/0 ~ 1978 The C. V. Mosby Co.
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
871
Table I. Healing <--6Days Drug Placebo
23* 14
]
>6 Days 10 16
Xz = 3.4387, l-tail test. *Significancep < 0,05 in favor of drug. out similar-appearing viral or other lesions, and blood studies. On entering the study, each patient completed a health history questionnaire, and an oral and adnexal exarrfination was performed. Laboratory studies, which included a Coulter hemogram, leukocyte differential, serum iron, total iron-binding capacity, plasma copper and zinc, as well as the SMA 6 and SMA 10 chemistries, were done on each patient. Drug or placebo for treating the lesions was given to the patient on a double-blind basis in a random sequence provided by a statistician. Prior to treatment, which was usually begun in the first 24 hours and never later than 48 hours, a description of the lesions was noted and photographs were made for later evaluation. All patients were seen every 1 to 3 days, usually every second day, during the healing phase and were rephotographed at each visit. The size, location, and appearance of the lesions were recorded at each visit. Evaluation of the effectiveness of treatment was based on healing time to complete epithelization and symptomatic relief between individual treatments. Epithelial covering was determined visually. A tube of medication (active drug or placebo) and a supply of cotton-tipped applicators were given each patient. The method of application was demonstrated, and instructions to use the medication after each meal and at the hour of sleep were given. The lesion was gently wiped with the swab to remove the fibrinous exudate, and then a drop of medication only large enough to just cover the lesion was applied. This was allowed to " d r y " for 15 seconds before further contact with saliva was permitted. The patient was advised not to intentionally disturb the medication by licking or sucking the area. A total of sixty-three treatment series was completed, thirty-three for the drug under study and thirty for the placebo. Of these, seventeen were paired, i.e., drug and placebo were studied in the same individual. The code was not broken until all studies were completed. RESULTS The results showed a statistical advantage for the drug in all aspects of healing time, relief of pain, and in unsolicited comments. The advantage of the drug was perceived whether it was used first or last in the paired groups. Table I indicates the differences in healing, with 6 days as the dividing line. This time interval was arbitrarily selected prior to statistical analysis and breaking the code, on the basis of our experience that in a group of patients having this incidence of RAU most of the RAU lesions require more than 6 days to heal completely. Table II reflects the subjective response of the patient to symptomatic relief. Because of the design protocol of the study (several hours between treatments), some patients did not experience relief of pain for the total time interval between drug applications. Relief of pain was considered to be positive if it occurred for at least 30 minutes subsequent to application of the sample. Complete relief of pain usually occurred with both drug and placebo 1 to 2 days before complete epithelization. Table III was also
872
Oral Surg. June, 1978
Merchant et al.
Table II. Symptomatic relief
I Drug Placebo
Yes
No
29* 18
4 12
X ~ = 6.4462, l-tail test. *p < 0.01 in favor of drug.
Table IIh Patient response (unsolicited) Favoring drug Favoring placebo
10 3
related to the patients' subjective comments which were made without any solicitation on our part. These were thought to be valid because all patients were chronic sufferers of RAU and had tried many remedies, as illustrated by Fig. 1, which shows the drugs used by one of the patients over a period of several years. Evaluation of the blood chemistries and other laboratory procedures revealed variations in iron, iron binding, and iron saturation, as well as hemoglobin, hematocrit, and mean corpuscular volume in some subjects. Table IV shows the normal values for our laboratory and those instances in which two or more study subjects, of fifty-two examined, were found outside of the normal range on initial examination. In the health questionnaire responses of fifty-sevenwho were considered to be suitable subjects for this study, there were thirty positive responses relating to a history of allergy, and an additional eight of a positive history of sinus trouble. Following this in frequency were sixteen " Y e s " answers to the questions about familial diabetes, and one instance of diagnosed diabetes which was controlled by diet. Most of the patients reported easy bruising, but this is true of most of our clinic patients. In this group which consisted of forty-two females, five reported endocrine dysfunction, eight had menstrual difficulties, and four anemia. Six patients reported arthritis or other joint disease, five had a history of cardiovascular disease, and five reported a history of other ulcers, either gastric or duodenal. Three patients had a previous history of hepatitis, and three (all males) had a history of carcinoma, two of the prostate and one a basal-cell nevus syndrome.
DISCUSSION One would expect that a topical antiinflammatory corticosteroid drug such as betamethasone- 17-benzoate would provide some benefit in the treatment of RAU if prolonged contact with the inflamed area were maintained. That some of the benefit was due to the protectant action of the vehicle might be assumed, also, from the results obtained with the placebo. This created some difficulty in assessing the results just as Zegarelli and associates I noted in the report on evaluation of triamcinalone acetonide with a different oral adhesive vehicle, consisting of gelatin, pectin, and sodium carboxymethyl cellulose in a polyethylene and liquid petrolatum gel base. The vehicle used in our study, when applied to skin, dries to an invisible coat. We assumed that the same mechanism was operant in the mouth, although perhaps to a lesser extent, and that this accounted for the symptomat-
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
873
Fig. 1. Typical medications used by patients.
Table IV
Numberof subjects with low values
I
9
Hemoglobin (Gin)
5
Hematocrit (%)
4
MCV (/z3)
5 2
MCH (/x/zg) MCHC (%) Neutrophils (segmented) Lymphocytes Eosinophils LDH SGOT Serum iron TIBC Iron saturation Copper Zinc
4
2 1 9 l0 9
Normal(in our laboratory) M : 14-18 F: 12-16 M :42-52 F:37-47 M : 80-94 F:81-99 M and F:27-31 M and F:32-36 54-62% 25-33% 1-3% 92-204 mU/ml. 26-58 mU/ml. 50-150 p.g/dl. 250-350/.tg/dl. 20-55% 70-150/xg/dl. (? 70-150tzg/dl.)*
Numberof subjects with high values
27 11 3 2 2 2 14
* Normal plasma zinc levels are not firmly established. ic relief reported here with the placebo since we did attempt to apply it to a " d r i e d " surface and allowed a 15-second " d r y i n g " time after application. A topical drug administered in the oral cavity must be considered to be swallowed in part or in total also. Thus, the effect may be both local and systemic. We did not attempt any analysis of plasma cortisol or urinary 17-hydroxy steroids. There were no overt indications of clinical changes, and the levels administered were calculated to be a maximum daily level of 0.38 Gm. or 0.095 rag. of active drug in the treatment of three lesions four times per day. Actual weighing of tubes of medication after treatment indicated an average of 1.02 Gm. or 0.255 mg. of active drug used per patient per treatmemt series.
874
Merchant et al.
Oral Surg. June, 1978
Studies by Skipworth 2 have shown adrenal suppression to be directly proportional to the amount of body area covered when betamethasone benzoate was applied to 10 to 90 per cent of the body surface in patients with diseased skin. Spontaneous return to normal adrenal function occurred within 5 days after cessation of treatment in those studies. The amount of oral mucous membrane involved in even the most severe episodes which we observed would be much less than 10 per cent of body surface. From a practical point of view, this suggests that more frequent use of the drug would be well within the limits of safety. (We are now prescribing use on an as-needed basis but not to exceed eight applications per day.) As in other studies by Lehner a' 4 and Zegarelli and associates, 1 patients noted a greater effectiveness of the drug, but not the placebo, in aborting the prodromal phase or very early lesions. This was discovered serendipitously by some of our patients and was not part of the study and not entered into the data. It would be tempting to ascribe an association between the allergies and the occurrence of oral ulcers but this cannot be done on the basis of a health questionnaire. The same could be said of any of the other findings which were positive on the health questionnaire. However, in the instances of changes in laboratory findings the numbers of patients having probable deficiencies of vitamin B 12 or iron suggest that this is a positive association with some oral ulcers as reported by Wray and colleagues) There was no noticeable diminution of effect of the drag under study in reducing inflammation and promoting healing in the patients of these categories who were accepted in the study. It should be noted that the study of the drug and placebo did not include all of the patients examined. Some subjects who were considered to be unsuitable for a research study were excluded, and others discontinued because of the time required or other personal reasons, so that patients on whom initial laboratory data are available exceed the number of patients treated. Two of the several reasons given by patients for discontinuing were that no relief was obtained from the medication, and relief was so effective that they decided not to return until all the medication was used! CONCLUSION
Betamethasone- 17-benzoate in a solubilized gel base has been shown to be effective in the symptomatic relief of recurrent aphthous ulcers (RAU) and to reduce healing time when compared to a placebo consisting of the gel alone. Untoward effects of the drag were not seen. Although histologic study, clinical appearance, course, and history would support a diagnosis of recurrent oral aphthae or recurrent aphthous ulcers in all of the cases presented in this study, the laboratory findings tend to bear out the conclusions of Wray and associates ~ that defects in iron or other essential nutrient metabolism are, in some instances, associated. In our previously reported use of zinc sulfate as a preventive of oral ulcers in patients with plasma zinc levels below 110/zg/dl., we suggested that recurrent aphthous stomatitis may well be a single expression of multiple contributing factors. ~ REFERENCES
I. Zegarelli,E. V., Kutscher, A. H., Silvers, H. F., Beube, F. E., Stern, I. B., Berman, C. L., and Herlands, R. E.: Triamcinolone Acetonide in the Treatment of Acute and Chronic Lesions of the Oral Mucous Membranes, ORALSURe. 13: 170-175, 1960. 2. Skipworth, G.: Study of the PhysiologicalEffect of 0.025% Beben Gel (BetamethasoneBenzoateW597539) When Applied to Diseased Skin Areas As Measured by Parametersof Adrenal CorticalFunction (Study VII Protocol), Report No. CR-BG-VII,January, 1972. Research Report 932-0495, Data on file at Warner Lambert Research Institute.
Volume 45 Number 6
Treatment of recurrent aphthous ulcers
875
3. Lehner, T.: Characterization of Mucosal Antibodies in Recurrent Aphthous Ulceration and Behget's Syndrome, Arch. Oral Biol. 14: 843-853, 1969. 4. Lehner, T.: Steroids and Oral Disease, Br. J. Dermatol. 94: Supp. 12, 59, 1976. 5. Wray, D., Ferguson, M. M., Mason, D. R., Hutcheon, A. W., and Dagg, J. H.: Recurrent Aphthae: Treatment With Vitamin B 12, Folic Acid, and Iron, Br. Med. J. 36: 490-493, 1975. 6. Merchant, H. W., Gangarosa, L. P., Glassman, A. B., and Sobel, R. E.: Zinc Sulfate Supplementation for Treatment of Recurring Oral Ulcers, South. Med. J. 70: 559-561, 1977.
Reprint requests to: Dr. Hubert W. Merchant Department of Oral Medicine School of Dentistry Medical College of Georgia Augusta, Ga. 30901
COPYRIGHT INFORMATION The appearance of a code at the bottom of the first page of an original article in this journal indicates the copyright owner's consent that copies of the article may be made for per~nal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, N. Y. 12301,518-3744430, for copying beyond that permitted by Sections 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.