Cantua scientific publication: Dermatography with bleomycin

[pages 1 and 4. The reference no.'s have been omitted from the text]

Pharmacology and therapeutics

Dermatography with bleomycin as a new treatment tor verrucae vulgaris

Eddy M. van der Velden, RD, Otto E. IJsselmuiden, MD, PhD, Brigitte H.I.M. Drost, MD, RD, and Avraham M. Baruchin, MD, PhD

From the Department of Dermatovenerology, Academic Hospital Rotterdam-Dijkzigt, Rotterdam, the Netherlands; and the Department of Plastic and Reconstructive Surgery, The Barzilai Medical Centre, Ashkelon, Israel

Abstract
Background Common warts are caused by infection with human papilloma viruses (HPVs). Many, largely ineffective, treatment modalities have been tried in the past. The cytostatic drug bleomycin has been found to selectively affect squamous cell and reticulo-endofhelial tissue, but the method of its delivery directly into affected tissue such as warts has been of little efficacy. This study assessed the efficacy of a new mode of intralesional administration of bleomycin by dermatography.
Methods The warts of patients were treated with increasing concentrations of bleomycin using the van der Velden Derma-injector, a modified tattooing machine, under local or block anesthesia. The effects of the procedure were evaluated 1, 24, and 48 h later and the patients followed for up to 2 years.
Results Thirteen patients with warts on the hands and/or feet, resistant to conventional therapy, were entered into the study, and two patients dropped out. Of the 11 remaining patients, seven went into full remission that was maintained for at least 2 years. One patient showed moderate progress and in three patients little progress was noted and dermatography was stopped. The dosage of bleomycin varied between 0.1 and 1.0 mg/ml. Conclusions Dermatography proved to be an effective technique for intralesional administration of bleomycin in more than two-thirds of patients resistant to conventional therapy. Treatment tailures in this study could in part be explained by a detective immune system in the patients. Dermatography is a technique that can be learned by any skilful dermatologist or plastic surgeon.

Introduction
The therapy of common warts bas historically always been a challenging subject for investigation. Many methods and the application of various, sometimes exotic, substances have been described, all capable of the partial eradication of troublesome warts. The multitude of the described therapies probably either reflects the imperfection of these regimes or simply reflects the fact that warts can disappear without any form of treatment. Solutions were sought in psychological approaches or in the administration of drugs. The former approaches include magic, psychological treatment, or methods using suggestion. Drugs described for the treatment of warts include arsenic, mercury, nitric acid, ethyl chloride, carbondioxide, sodium bisulfite, calcium phosphate, fresh cow's milk, bismuth, magnesium sulfate, sulfarsphenamine, and nitricsalicylic acid. In addition, radium, X-ray, electrolysis, autohemotherapy, immunotherapy, and ultrasound therapy have been advocated.
The common wart caused by infection with HPVs is becoming more and more of a nuisance. In the past, warts on the hands or feet could easily be cured by treatment modalities such as liquid nitrogen, electrodesiccation, or curettage; however, at present, HPV species are largely resistant to current therapies. Furthermore, immunodeficiency due to immunosuppressive therapy or illness is increasing. Failure of the common therapies bas forced physicians to look for alternatives; a variety of methods, including various kinds of laser therapy and electrocoagulation, dephencyprone, vitamin A, glutaraldehyde, podophyllin, cryotherapy, topical 5-fluorouracil, radiotherapy, or interferon, covering with banana skin, intralesional administration of bleomycin by injection, and adhesive tape containing bleomycin, have been evaluated for the treatment of recalcitrant warts. We report the intralesional administration of bleomycin by […]

[page 4] ...dermatography with bleomycin, but after the cyclosporine/ prednisone therapy was stopped his warts disappeared spontaneously without any treatment. In three patients (No.'s I, 9, and I0) little progress was observed. Two of them (No.'s 9 and I0) discontinued treatment for medical reasons. The third patient (No. 1) received cyclosporine and a prednisone, and the bleomycin treatment was stopped because of myocardial infarction. After a follow-up of 2 years, the seven patients still showed full remission of all warts, treated and untreated alike. Figures 1-7 show the extensive wart formation on the feet of Patients 3 and 6, the finger of Patient 8, and the results after treatment. They are representative of the results in the whole group.

Discussion
Bleomycin represents a group of cytostatic drugs of great importance for epidermal tumours because of its selective influence on squamous-cell and reticulo-endothelial-cell tissues38,46. lts use bas been studied in the treatment of common warts, but because of the imperfect method of administration in these studies -intralesional injection with a Mantoux needle 36,38 -bleomycin was unequally distributed in the wart tissue. The technique was very painful and the depth of bleomycin deposition could not be controlled. The resulting unequal distribution may be the main reason for the failure of earlier farms of treatment with bleomycin.
In this study we present a new method, dermatography, derived from tattooing techniques, for introducing bleomy- cin into the skin. With dermatography the therapeutic agent is introduced into the epidermis, and in addition grooves are cut into the hyperplastic epidermis, facilitating the treatment of deeper tumour layers. The Derma-injector makes 10,000 punctures in the skin per minute and, therefore, the bleomycin solution reaches every epidermal cell down to a chosen depth. We believe that the resulting equal distribution of cytostatic drug throughout the tumour tissue is responsible for the success rare of bleomycin dermatography. Treatment failures in this study can partially be explained by a defective immune system of patients who use immunosuppressive drugs such as cyclosporine and prednisone. This was illustrated by the spontaneous remission of warts of Patient 11 after discontinuing cyclo- sporine therapy.
With our method, the effective close of bleomycin can be kept very low, 2 ml of 1 mg/ml solution of bleomycin per treatment, mainly because of its exact administration into the wart. The considerable side-effects of higher doses of bleomycin - such as Raynaud's phenomenon and necrosis due to haemorrhages - can thus be avoided. The results show that this very low close is so effective that the immune system is stimulated to form
enough antibodies to neutralize HPV through the entire body.
The relatively low pain level of dermatography, both during and after treatment, may be explained by the fast repetitive introduction of the needles into the skin, which causes far less pain than the slow introduction of one needle in other techniques.

Conclusions
Dermatography is a technique that may be learned by any skilful dermatologist or plastic surgeon. Provided that the right equipment is used, it may be a good solution for the treatment of warts that are unresponsive to any other therapy.

Acknowledgments
Dr H.B. van der WaIle provided scientific support and drs L.D. den DuIk provided editorial support and translation. E.M.A. Sopacuwa assisted in preparing the manuscript.

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