- Email: [email protected]
Phenytoin in the treatment of Buruli ulcer
TRANSACTIONS
Phenytoin ulcer
OFTHE
ROYAL
SOCIETY
in the treatment
OFTROPICAL
MEDICINE
of Buruli
De0. Adjeil*, M. R. W. Evans2~3 and A. Asiedu2 partments of ‘Microbiology and 2Medicine, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana; 3Division of Infectious Diseases, St George’s Hospital Medical School, Cranmer Terrace, London, UK Keywords: Buruli ulcer, Mycobacterium ulcerans, phenytoin Phenytoin (diphenylhydantoin), a hydantoin derivative, has been used in the treatment of a wide range of medical conditions including epilepsy, muscle disorders and other related types of pain. There is evidence that phenytoin has a beneficial role in wound repair (SMITH et al., 1988). Its ability to reduce pain and promote healing suggests that it may be useful in treating chronic cutaneous ulcers, including trophic ulcers of lepromatous origin, venous stasis decubitus and diabetic ulcers (MADAGHEGH et al., 1988). Buruli ulcer, caused by Mycobacterium ulcerans, is an infection of the dermis. It begins as a subcutaneous nodule which later develops into an ulcer with undermined edges and on healing often leaves extensive scars and
Figure. Buruli ulcer on the with phenytoin (B).
thigh
(1998) 92,108-109
ing to her, the ulcer started as a nodule and she had been using various antibiotics and traditional medicine over the past 7 years with no improvement. A swab taken from the undermined edges was examined using the Ziehl-Neelsen staining technique and microscopy revealed acid-fast bacilli. The ulcer site was cleaned daily with normal saline. Dry phenytoin powder was sprinkled into the ulcer which was dressed with sterile gauze. After 2 months of therapy, the ulcerative lesion had been replaced by granulation tissue with a smooth surface and its size was reduced. After a further 8 weeks of treatment, the ulcer had completely healed. Case 2 An 8 years old boy presented with an ulcer on his left arm. Two months before the development of the ulcer his parents had noticed a nodule on the arm. The ulcer measured 3.0x2.5 cm and had been present for 5 months. A swab was taken and Ziehl-Neelsen staining revealed acid-fast bacilli. Treatment was started with daily cleaning of the ulcer with normal saline. Dry phenytoin powder was applied topically and the ulcer was dressed with sterile gauze. After 6 weeks’ treatment, there was marked improvement with the formation of granulation tissue and decrease in the size of the ulcer. The ulcer healed after 9 weeks’ treatment. Case 3 A 10 years old schoolgirl was seen with a well defined, tender ulcerated area, 5.0x2.5 cm, on the medial aspect of the left thigh near the genitalia (Figure, A). According
ot Case no. 3, a 10 years old schoolgirl, on admission (A) and after 6 weeks of topical treatment
joint contractures. Chemotherapy so far has been disappointing (STANFORD et al., 1975). Treatment is usually surgical. In this paper we present 3 cases of Buruli ulcer which were successfully treated by the topical application of phenytoin powder. All 3 subjects were seen at Tontokrom Health Centre in the Amansie West District, Ashanti Region, Ghana. Case 1 A 17 years old female presented with a chronic ulcerated lesion on the left arm, 4.0x2.0 cm in size. Accord*Author for correspondence.
AND HYGIENE
to her mother, the lesion had been present for 3 weeks. Ziehl-Neelsen staining of a swab taken from the ulcer revealed acid-fast bacilli. After 2 weeks of phenytoin treatment there was formation of granulation tissue and reduction in size of the ulcer. After 4 more weeks of treatment, the ulcer was completely healed (Figure, B) . Discussion Buruli ulcer, the third commonest mycobacterial infection affecting humans, has become a very serious problem in various parts of Ghana, particularly in rural areas. There is an urgent need to find appropriate control measures and/or effective treatment. The mechanism by which phenytoin aids wound healing is uncertain, but its use has been shown in vivo
PHENYTOIN
FOR BURULI
109
ULCER
to result in decreased inflammatory response, increased fibroblast proliferation, increased collagen content, and increased new blood vessel formation (MONDIOLAGONZALEZ & ESPEJO-ELASCENCIA, 1983). In vitro studies have demonstrated increased tensile wound strength, stimulation of fibroblast activity, and inhibition of both collagenase activity and release of lysosomal and cytoplasmic enzymes (SHAFER, 1965; BAUER et al., 1980; LERNER & HANSTROM, 1980). Alteration in wound pH and improvement in local circulation may be the mechanisms responsible for reduction of bacterial contamination of wounds (MODAGHEGH et al., 1988). In the cases reported here, phenytoin was shown to be an effective, inexpensive and easily applicable drug in the treatment of Buruli ulcer. Healing occurred without the scarring and contractures which are normally associated with resolution of Buruli ulcer. However, further research is required before the true efficacy of the drug is known and before phenytoin can be recommended for the routine treatment of Buruli ulcer. This should include a placebo-controlled trial and studies to establish the optimal dose and the degree of systemic absorption, and to investigate the occurrence of side effects and the possibility of subsequent recurrence. The response of these 3 Buruli ulcers of varying duration to the application of topical phenytoin and the absence of any recurrence (to date) is encouraging. Acknowledgements We gratefully acknowledge the help given by Mr J. Adomako, Communicable Disease Control Officer, Amansie West District. We thank also the Regional Medical Officer, Dr G.
8th International
Congress
Amofah, for his assistance and advice. The Dreyfus Health Foundation (New York) provided the phenytoin and financial assistanceand the Wellcome Trust supported M. R. W. E.; we are very grateful to them. We also appreciate the technical assistance of Mr R. Lartey and Mr T. Gyampong, and we thank Mr Agyenim-Boateng for typing the manuscript. References Bauer, E. A., Cooper,T. W. &Tucker, D. R. (1980). Phenytoin therapy of recessive dystrophic epidermolysis bullosa; clinical trial and proposed mechanism of action on collagenase. New EnglandJournal of Medicine, 303,776-78 1. Lerner, U. & Hanstrom, L. (1980). Influence of diphenylhydantoin on lysosomal enzyme release during bone resorption in vitro. Acta PharmacologicaetToxicologica,47, 144-150. Modaghegh, S., Ghoraian, M. A., Moshkgou, M. & Reziazadeh, A. (1988). The effect of phenytoin on healing of war and non-war intractable wounds. Medical Journal of the Islamic Republic of Iran, 2, 81-86. Mondiola-Gonzalez, J. F. & Espejo-Plascencia, I. (1983). Sodium diphenylhydantoin in burns, effects on pain and healing. ZnvestigacionMedica International, 10,449-45 1. Shafer, W. H. (1965). Response of radiated human gingival fibroblast-like cells to dilantin sodium in tissue culture. 3ournal of Dental Research, 44, 671-677. Smith, B. H., Bogoch, S. & Dreyfus, J. (1988). The Broad Range of Clinical Useof Phenytoin. New York: Dreyfus Medical Foundation, pp. 89-120. Stanford, J. L., Revill, W. D. L., Gunthorpe, W. J. & Grange, J. M. (1975). The production and preliminary investigation of burulin, a new skin test for Mycobacterizm ulceram infection. Journal of Hygiene, 74,7-l 6. Received 15July 1997; revised 21 August 1997; accepted for publication 21 August 1997
on Infectious
Diseases
Boston, Massachusetts, USA 15-18 May 1998
Abstracts must be submitted not later than 15 January 1998. Further details can be obtained from the International Society for Infectious Diseases, 18 1 Longwood Avenue, Boston, MA 02 115, USA; phone + 1 6 17 277 0551 (800 799 8998 in USA only), fax +l 617 731 1541, e-mail [email protected]
Trypanosomiasis
and Leishmaniasis
Symposium
Arcachon, France 18-21 April 1998
This symposium is organized by the British Society for Parasitology and the University of Bordeaux. Further information can be obtained from Dr Jean-Jacques Toulme, INSERM U386, IFR Pathologies Infectieuses, Universitevictor Segalen Bordeaux 2, 146 rue Leo Saignat, F-33076 Bordeaux, France; fax +33 5 57571015, email [email protected] or Dr Simon Croft, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WClE 7HT, UK; fax +44 (0) 171 636 8739, e-mail [email protected]
VII&h
European
EMOP 2000 Multicolloquium
of Parasitology
Poznari, Poland 1 O-l 4 September 2000
The Multicolloquium will be organized by Z. Pawlowski and K. Boczon. Further information can be obtained from: Prof. Krystyna Boczon, VIIIth European Multicolloquium of Parasitology, Department of Biology and Medical Parasitology, Karol Marcinkowski University of Medical Sciences, Fredry 10, 60-701 Poznari, Poland; phone +48 61 85211 61, fax +48 61 85271 92.
Phenytoin ulcer
OFTHE
ROYAL
SOCIETY
in the treatment
OFTROPICAL
MEDICINE
of Buruli
De0. Adjeil*, M. R. W. Evans2~3 and A. Asiedu2 partments of ‘Microbiology and 2Medicine, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana; 3Division of Infectious Diseases, St George’s Hospital Medical School, Cranmer Terrace, London, UK Keywords: Buruli ulcer, Mycobacterium ulcerans, phenytoin Phenytoin (diphenylhydantoin), a hydantoin derivative, has been used in the treatment of a wide range of medical conditions including epilepsy, muscle disorders and other related types of pain. There is evidence that phenytoin has a beneficial role in wound repair (SMITH et al., 1988). Its ability to reduce pain and promote healing suggests that it may be useful in treating chronic cutaneous ulcers, including trophic ulcers of lepromatous origin, venous stasis decubitus and diabetic ulcers (MADAGHEGH et al., 1988). Buruli ulcer, caused by Mycobacterium ulcerans, is an infection of the dermis. It begins as a subcutaneous nodule which later develops into an ulcer with undermined edges and on healing often leaves extensive scars and
Figure. Buruli ulcer on the with phenytoin (B).
thigh
(1998) 92,108-109
ing to her, the ulcer started as a nodule and she had been using various antibiotics and traditional medicine over the past 7 years with no improvement. A swab taken from the undermined edges was examined using the Ziehl-Neelsen staining technique and microscopy revealed acid-fast bacilli. The ulcer site was cleaned daily with normal saline. Dry phenytoin powder was sprinkled into the ulcer which was dressed with sterile gauze. After 2 months of therapy, the ulcerative lesion had been replaced by granulation tissue with a smooth surface and its size was reduced. After a further 8 weeks of treatment, the ulcer had completely healed. Case 2 An 8 years old boy presented with an ulcer on his left arm. Two months before the development of the ulcer his parents had noticed a nodule on the arm. The ulcer measured 3.0x2.5 cm and had been present for 5 months. A swab was taken and Ziehl-Neelsen staining revealed acid-fast bacilli. Treatment was started with daily cleaning of the ulcer with normal saline. Dry phenytoin powder was applied topically and the ulcer was dressed with sterile gauze. After 6 weeks’ treatment, there was marked improvement with the formation of granulation tissue and decrease in the size of the ulcer. The ulcer healed after 9 weeks’ treatment. Case 3 A 10 years old schoolgirl was seen with a well defined, tender ulcerated area, 5.0x2.5 cm, on the medial aspect of the left thigh near the genitalia (Figure, A). According
ot Case no. 3, a 10 years old schoolgirl, on admission (A) and after 6 weeks of topical treatment
joint contractures. Chemotherapy so far has been disappointing (STANFORD et al., 1975). Treatment is usually surgical. In this paper we present 3 cases of Buruli ulcer which were successfully treated by the topical application of phenytoin powder. All 3 subjects were seen at Tontokrom Health Centre in the Amansie West District, Ashanti Region, Ghana. Case 1 A 17 years old female presented with a chronic ulcerated lesion on the left arm, 4.0x2.0 cm in size. Accord*Author for correspondence.
AND HYGIENE
to her mother, the lesion had been present for 3 weeks. Ziehl-Neelsen staining of a swab taken from the ulcer revealed acid-fast bacilli. After 2 weeks of phenytoin treatment there was formation of granulation tissue and reduction in size of the ulcer. After 4 more weeks of treatment, the ulcer was completely healed (Figure, B) . Discussion Buruli ulcer, the third commonest mycobacterial infection affecting humans, has become a very serious problem in various parts of Ghana, particularly in rural areas. There is an urgent need to find appropriate control measures and/or effective treatment. The mechanism by which phenytoin aids wound healing is uncertain, but its use has been shown in vivo
PHENYTOIN
FOR BURULI
109
ULCER
to result in decreased inflammatory response, increased fibroblast proliferation, increased collagen content, and increased new blood vessel formation (MONDIOLAGONZALEZ & ESPEJO-ELASCENCIA, 1983). In vitro studies have demonstrated increased tensile wound strength, stimulation of fibroblast activity, and inhibition of both collagenase activity and release of lysosomal and cytoplasmic enzymes (SHAFER, 1965; BAUER et al., 1980; LERNER & HANSTROM, 1980). Alteration in wound pH and improvement in local circulation may be the mechanisms responsible for reduction of bacterial contamination of wounds (MODAGHEGH et al., 1988). In the cases reported here, phenytoin was shown to be an effective, inexpensive and easily applicable drug in the treatment of Buruli ulcer. Healing occurred without the scarring and contractures which are normally associated with resolution of Buruli ulcer. However, further research is required before the true efficacy of the drug is known and before phenytoin can be recommended for the routine treatment of Buruli ulcer. This should include a placebo-controlled trial and studies to establish the optimal dose and the degree of systemic absorption, and to investigate the occurrence of side effects and the possibility of subsequent recurrence. The response of these 3 Buruli ulcers of varying duration to the application of topical phenytoin and the absence of any recurrence (to date) is encouraging. Acknowledgements We gratefully acknowledge the help given by Mr J. Adomako, Communicable Disease Control Officer, Amansie West District. We thank also the Regional Medical Officer, Dr G.
8th International
Congress
Amofah, for his assistance and advice. The Dreyfus Health Foundation (New York) provided the phenytoin and financial assistanceand the Wellcome Trust supported M. R. W. E.; we are very grateful to them. We also appreciate the technical assistance of Mr R. Lartey and Mr T. Gyampong, and we thank Mr Agyenim-Boateng for typing the manuscript. References Bauer, E. A., Cooper,T. W. &Tucker, D. R. (1980). Phenytoin therapy of recessive dystrophic epidermolysis bullosa; clinical trial and proposed mechanism of action on collagenase. New EnglandJournal of Medicine, 303,776-78 1. Lerner, U. & Hanstrom, L. (1980). Influence of diphenylhydantoin on lysosomal enzyme release during bone resorption in vitro. Acta PharmacologicaetToxicologica,47, 144-150. Modaghegh, S., Ghoraian, M. A., Moshkgou, M. & Reziazadeh, A. (1988). The effect of phenytoin on healing of war and non-war intractable wounds. Medical Journal of the Islamic Republic of Iran, 2, 81-86. Mondiola-Gonzalez, J. F. & Espejo-Plascencia, I. (1983). Sodium diphenylhydantoin in burns, effects on pain and healing. ZnvestigacionMedica International, 10,449-45 1. Shafer, W. H. (1965). Response of radiated human gingival fibroblast-like cells to dilantin sodium in tissue culture. 3ournal of Dental Research, 44, 671-677. Smith, B. H., Bogoch, S. & Dreyfus, J. (1988). The Broad Range of Clinical Useof Phenytoin. New York: Dreyfus Medical Foundation, pp. 89-120. Stanford, J. L., Revill, W. D. L., Gunthorpe, W. J. & Grange, J. M. (1975). The production and preliminary investigation of burulin, a new skin test for Mycobacterizm ulceram infection. Journal of Hygiene, 74,7-l 6. Received 15July 1997; revised 21 August 1997; accepted for publication 21 August 1997
on Infectious
Diseases
Boston, Massachusetts, USA 15-18 May 1998
Abstracts must be submitted not later than 15 January 1998. Further details can be obtained from the International Society for Infectious Diseases, 18 1 Longwood Avenue, Boston, MA 02 115, USA; phone + 1 6 17 277 0551 (800 799 8998 in USA only), fax +l 617 731 1541, e-mail [email protected]
Trypanosomiasis
and Leishmaniasis
Symposium
Arcachon, France 18-21 April 1998
This symposium is organized by the British Society for Parasitology and the University of Bordeaux. Further information can be obtained from Dr Jean-Jacques Toulme, INSERM U386, IFR Pathologies Infectieuses, Universitevictor Segalen Bordeaux 2, 146 rue Leo Saignat, F-33076 Bordeaux, France; fax +33 5 57571015, email [email protected] or Dr Simon Croft, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WClE 7HT, UK; fax +44 (0) 171 636 8739, e-mail [email protected]
VII&h
European
EMOP 2000 Multicolloquium
of Parasitology
Poznari, Poland 1 O-l 4 September 2000
The Multicolloquium will be organized by Z. Pawlowski and K. Boczon. Further information can be obtained from: Prof. Krystyna Boczon, VIIIth European Multicolloquium of Parasitology, Department of Biology and Medical Parasitology, Karol Marcinkowski University of Medical Sciences, Fredry 10, 60-701 Poznari, Poland; phone +48 61 85211 61, fax +48 61 85271 92.