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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.1 Rio de Janeiro Jan./Feb. 2009
Mariane StefaniI; Giuliana BottinoII; Elisa FontenelleIII; David Rubem AzulayIV
in Dermatology, Brazilian Society of Dermatology, and Specialist in Pediatrics
- Porto Alegre (RS), Brazil
IISpecialist in Dermatology, Brazilian Society of Dermatology, and Specialist in General Clinical Practice - Rio de Janeiro (RJ), Brazil
IIIIn Charge of Pediatric Dermatology Outpatient Center, Instituto de Dermatologia Professor Rubem David Azulay, Santa Casa da Misericordia do RJ, Dermatologist, Hospital Municipal Jesus - Rio de Janeiro (RJ), Brazil
IVHead of the Dermatology Center Professor Rubem David Azulay, Santa Casa da Misericordia do Rio de Janeiro. Full Professor, Pontificia Universidade Catolica do Rio de Janeiro (PUC-RJ), and Assistant of Fundação Técnico-Educacional Souza Marques (FTESM) and Federal University of Rio de Janeiro (UFRJ) - Rio de Janeiro (RJ), Brazil
Warts are epithelial proliferations on the skin and mucous membrane caused by
various types of HPV. They can decrease spontaneously or increase in number
and size according to patient's immune status. Cimetidine and zinc sulphate
have important effects on the immune system and are used as immunomodulators
in the treatment of various diseases.
OBJECTIVE: To compare the efficacy of cimetidine and zinc sulphate in the treatment of multiple and recalcitrant warts.
METHODS: A random double-blind prospective study. Eighteen patients with multiple warts were divided into two groups: one took 35mg/Kg/day of cimetidine (maximum 1200 mg/day) and the other 10 mg/Kg/day of zinc sulphate (maximum 600 mg/day) for three months.
Results: Among the 18 patients who participated in the study, nine took cimetidine and nine zinc sulphate. Just one patient in the zinc sulphate group did not complete treatment due to nausea and vomiting. Five patients who were treated with zinc sulphate were cured and only one did not show modifications in lesions. Among the group who was treated with cimetidine, five did not show modifications in lesions and four showed decrease from baseline below 30%.
CONCLUSIONS: 10 mg/Kg/day zinc sulphate dose seems to be more effective than cimetidine for the treatment of children and adults with multiple and difficult-to-handle warts. However, the small number of patients did not enable any definitive conclusion.
Keywords: Cimetidine; Papillomarividae; Zinc sulphate; Warts; Wrts/therapy
Warts are skin and mucosa epithelial proliferations caused by different types of human papillomavirus (HPV). It may take place at any age and it is more common in children and adolescents. The lesion is self-inoculated and the incubation time is variable, ranging from few weeks to more than one year 1.
They may progress spontaneously or increase in number and size according to the immune status of the patient. Cell immunity is very important and warts are particularly exuberant in patients with Hodgkin's disease, AIDS and also in patients taking immunosuppressant agents. Fifty-five percent of the immunosuppressed patients submitted to renal transplantation have warts, especially vulgaris and plantar, up to five years after the transplantation, whose percentage goes up to 70% after it. Humoral immunity seems to be less important, because patients with multiple myeloma are not particularly prone to have them 1. Warts may be divided into vulgaris (the most common ones), filiform, plantar - as a mosaic type, periungual, flat, genital and oral 1, 3, 4, 5.
There are different treatment approaches for warts such as electrocoagulation, liquid nitrogen, hot nitric acid, flexible colloid, and many others. In some cases owing to large number of warts and pain, some of these treatment options are no feasible .1, 3, 4, 5.
Treatment with oral zinc sulphate is well established for the treatment of enteropathic acrodermatitis. In other conditions, zinc deficiency has been acknowledged and can have different determining causes, such as alcohol abuse, gastrointestinal affections, pancreatic failure, cirrhosis, poor absorption syndrome, burns, neoplasm, infections, renal diseases and parenteral nutrition. Some studies report therapeutic efficacy of zinc sulphate on alopecia areata, uremic pruritus, cutaneous leishmaniasis, perifolliculitis capitis abscendens et sufodiens4,6, and inflammatory acne 7. Another study showed efficacy of zinc sulphate in treating recalcitrant warts. Zinc deficiency determines thymic hypoplasia with repercussion on T cell maturation, resulting in immune deficiency that favor associated infections 4, 6.
Cimetidine is an H2 receptor antagonist and has immunomodulating effect, used in children to treat warts 8,9, 10. In adults, the use of cimetidine in the treatment of warts has shown conflicting results 1, 511, 12.
In view of that, it seems to be interesting to define the therapeutic efficacy of cimetidine and zinc sulphate in patients with recalcitrant and multiple warts.
MATERIAL AND METHODS
This is a randomized prospective double-blind study carried out between April and December 2006, at Instituto de Dermatologia Professor Rubem David Azulay, comprising management of patients with multiple and/or recalcitrant cutaneous warts. Eighteen patients were divided into two random groups according to the demand: one group was treated with cimetidine 35mg/Kg/day (maximum 1,200mg/day) and another group received zinc sulphate 10 mg/Kg/day (maximum 600mg/day) for three months.
Patients were selected according to the following criteria: presence of ten or more cutaneous or recalcitrant warts, that is, patients who had been submitted to two or more treatment approaches by destructive methods without resolution of clinical presentation, whose last treatment course had finished at least two months before the study started; absence of chronic diseases, commitment not to use other drugs during treatment, and signature of informed consent term to take part in the study.
The exclusion criteria were: presence of immunodeficiency, pregnancy, use of immunosuppressant drugs, and medication to inhibit activity of cytochrome P450.
The study was approved by the Ethics Committee, Hospital Santa Casa da Misericordia, Rio de Janeiro. Selected patients were referred to two physicians responsible for filling in the forms and performing monthly follow-up blindly to the medication they were taking. A third physician was responsible for prescribing the medication, randomly dividing the patients into two groups, nine patients in each. Patients did not know what they were taking either. Reviews were performed monthly, observing number of warts and side effects of the medication. Patients were treated for 3 months and were followed up monthly for two more months after the end of treatment. Drugs were supplied to patients for free, all dispensed by the same pharmacy.
Statistical analysis was made by non-parametric Mann-Whitney test for comparison of age range and duration of the disease between the two study groups; to compare the proportion of clinical response, we applied Fisher exact test. We used non-parametric test because age range and duration of the disease did not show Gauss distribution owing to data dispersion and/or lack of symmetric distribution. The criterion to determine significance level was 5%. The statistical analysis was processed by software SAS 6.04 (SAS Institute, Inc., Cary, North Carolina).
Out of 18 patients in the study, nine were treated with cimetidine and nine with zinc sulphate, eight men and one woman in each group. The number of warts varied from 11 to 120. Table 1 shows the statistical analysis of age range and duration of the disease according to medication. We observed statistically significant difference for age (p = 0.84) and duration of disease (p = 0.73) between the two studied groups.
Table 2 shows frequency and percentage of clinical response according to medication. We observed that there was significant difference in the proportion of clinical response between the two studied groups (p=0.024). The group treated with zinc sulphate had proportion of complete response significantly higher than the group treated with cimetidine, which in turn presented proportion of absence of response significantly higher than the group treated with zinc sulphate. The characteristics of the five patients who achieved complete resolution of the warts with zinc sulphate are shown in Chart 1. Figures 1 and 2 show patients one and two before starting the treatment and at the end of treatment.
Only one patient treated with zinc sulphate did not show modification of lesions, one had 36% improvement and the other 85.72% improvement.
Adverse effects reported by the patients treated with cimetidine included nausea, epigastralgia, diffuse pruritus and pain at the lesion sites, and four of them did not show any adverse effect. Patients treated with zinc sulphate reported that the most frequent symptom (in five patients) was nausea, followed by two reports of vomiting and one of diarrhea, and four patients did not show any symptom. Only one six-year-old patient abandoned treatment owing to nausea and vomiting. In both groups, adverse effects were attenuated by dividing the total dose into three daily doses and taking the medication together with the meals.
Warts are caused by two-spiral DNA viruses that belong to family papovaviridae and genus papillomavirus 3. The prevalence of warts in the general population is unknown, estimating an incidence of 3-20% in children at school age 1. The peak incidence occurs between the ages of 12 and 16 years, divided into 70% vulgaris, 24% plantar, 3.5% flat, 2% filiform, and 0.5% anogenital. In this study, age of patients ranged from 5 to 63 years. We did not match patients based on wart sites because most of them presented more than one type of wart and more than one affected body part. The more frequent types of HPV in flat warts are 3 and 10, in vulgaris, palmar and plantar warts HPV1, 2, 4 1, 3.
The transmission of HPV occurs through small solutions of continuity on the skin, explaining its location in trauma areas 1, 3, 5. Spontaneous cure of warts may occur, but it takes much time, in general years. In children, spontaneous regression of warts may reach 60% within two-year follow-up, but some may never be cured spontaneously and still present some new lesions during follow up 1, 3, 4, 5. The duration of lesions in patients in this study was four months to five years. A new study should be carried out focusing on age matching and adding a placebo-controlled group to try to observe the situation of spontaneous regression in children.
Many research studies in humans and animals have shown cell immune and humoral dysfunction at all levels of zinc deprivation, if for prolonged periods of time 13, 14. Marginal zinc deficiency in newborns and children had been shown as a cause in failure to thrive, based on different anthropometric parameters 15.
In cases of enteropathic acrodermatitis thymic atrophy is a consequence - as a result, thymocytes and immunocell functions, especially in large series of T cell functions, are deprived. Neutrophils, peripheral blood monocytes, tissue macrophages and mast cells are known for requiring excellent zinc concentrations to ensure appropriate operation 15. Marginal zinc deficiency may be silent in the pathogenesis of different systemic and skin diseases, abnormal lymphocytic function, enhanced susceptibility to infection, prolonged healing, and destruction of free radicals is impaired 15.
Al- Gurairi et al. used 10 mg/Kg/day of zinc sulphate (maximum 600 mg/day) to treat recalcitrant warts. Out of 40 patients who were treated with zinc sulphate, only 23 completed treatment and 20 were cured from lesions within 2 months. Related adverse effects were temporary pruritis, nausea, vomiting, and epigastric pain 6.
The present study showed cure in five (62.5%) out of eight patients who finished treatment. The most frequently reported side effects were nausea in five patients (41.66%), vomiting in 2 (16.66%), and diarrhea in one (8.33%). These effects may be reduced by dividing the total dose into three daily doses to be taken with the meals. This resource was used and we observed relief of symptoms, but one six-year-old patient did not tolerate the medication because of nausea and vomiting and abandoned treatment.
The 2.5 mg/Kg/day (maximum 150mg/day) dose of elemental zinc is safe. Pharmacological doses of 4 to 12 mg/Kg/day of elemental zinc may induce gastroenteritis, gastrointestinal bleeding, microcytosis, relative neutropenia and hypoceruloplasminemia. Prolonged use may induce copper deficiency and anemia, which responds when zinc is withdrawn 6.
Zinc may be administered as acetate, gluconate or sulphate, but the latter seems to be better tolerated. One 100 mg capsule of zinc sulphate has 22.5mg of elemental zinc. Animal protein and seafood are rich in zinc 16. The study of its bioavailability is important because there are some substances that modify its absorption. Phytates are present in most cereal grains and vegetables, being powerful zinc chelators 7, 15, 16. Other zinc chelators are tetracycline, penicillin, corticosteroids, high doses of iron and calcium, alcohol, tanino and oral contraceptives 7. Zinc supplementation reduces the absorption of quinolone, iron, penicillamine and tetracycline.
Normal plasma levels of zinc are 70 to 110 µg/dl. The activity of alkaline phosphatase in serum is one moderately sensitive indicator of zinc condition, even though it is a specific early marker of insufficiency. Its activity remains close to normal until there is excessive and prolonged deficiency.
Sample collection and laboratory techniques are important, because contamination with environmental zinc or in test tubes is a constant threat. The time between blood collection and separation of plasma and serum affects zinc concentration, leading to increase in plasma concentration by 6% within the first two hours if not separated. It is recommendable to use vacuum tubes without zinc and stainless still needles, avoid contact with rubber taps and hemolysis, separate cell plasma or serum within 45 minutes from collection and use anticoagulating agent without zinc. There is a daily rhythm in plasma zinc concentration, and morning fast is recommended for more exact values 15. We do not use the serum dosage of zinc owing to these peculiar characteristics that hinder the determination of accurate dosage of zinc and the high cost of the test, because the patients in the study came from low income level populations.
In dermatology, cimetidine is an H2 receptor antagonist that has been used in treatment of urticaria, mastocytosis, different eosinophilic dermatoses, warts, external condyloma acuminatum, molluscum contagiosum 17 and verruciform epidermodysplasia 18.
The incidence of adverse reactions is low and normally minimum, below 3%. In this study, the most frequent adverse events from the use of cimetidine were nausea, epigastralgia, and diffuse pruritus in 18.18% of the patients, but they were attenuated by dividing the total dose and taking the pills with the meals. These agents are well tolerated in doses much higher than the required ones to promote substantial inhibition of secretion of gastric acid. Consequently, despite the short plasma half-lives, H2 receptor antagonists may be administered in relatively high amount one or two times a day to provide effective therapy 10.
Cimetidine has proved to be an immunomodulator probably blocking H2 receptors from suppression T cells, increasing cell immunity. Administration of cimetidine increases proliferation of lymphocytes, inhibits the function of suppressing T cells, and enhances the reactivity of skin tests. It has been successfully used to stimulate the immune system of patients with immunodeficiencies mediated by T cells, such as variable common immunodeficiency, mucocutaneous candidiasis 8, 17, 19, hyperimmunoglobulinemia E and chronic herpes zoster in immunocompromised patients 8.
High doses of cimetidine 30-40 mg/Kg/ day have been reported as effective in the treatment of recalcitrant warts in adults 12, and in children 8,19,20, but other studies have not observed better results with cimetidine compared to placebo 11,2122,23.
In the present study, the use of cimetidine for multiple warts did not cure any patient; three presented reduction in wart size, and three had reduction in number of lesions, but none below 30% compared to baseline - the results were not very significant, which does not justify its use. Mitsuishi et al. carried out a study with 55 patients aged 6 to 77 years with multiple warts who were treated with cimetidine for 4 months. Patients were divided into two groups, one received =20mg/Kg/day and the other received 30 to 40 mg/Kg/day; the authors measured levels of interleukin 2 (IL2), interleukin 8 (IL8) and gamma interferon (IFN-µ) of skin biopsies of the lesions before and during treatment. Complete remission or dramatic clinical improvement was observed in 34.5% and partial response was detected in 23.6% of the patients. Complete remission did not depend on number of warts. Levels of IL-2 and IFN-µ increased significantly and IL8 levels dropped in warts effectively treated; they also observed that higher doses of cimetidine were more effective in the treatment of multiple warts 24.
Orlow and Paller performed a study with 32 children with multiple warts treated with 25 to 40 mg/Kg/day dose of cimetidine for two months, and two thirds received also topical treatment with salicylic acid preparations. The results obtained were 81% of cure, but without good results with condyloma acuminatum 8. This was one of the best responses reported in the literature with the use of cimetidine to treat multiple warts, because other studies did not show such good results. Other authors have questioned the concomitant use of topical treatment 21. A randomized double blind study using cimetidine in a group of children with recalcitrant warts and the use of cimetidine with levamisole in another study showed complete cure of lesions in 31.5% and 65% of the patients, respectively. 25
In the present study, the five patients who had no response to treatment with cimetidine were offered zinc sulphate, and two returned for review of the case. One had cure within 30 days of use and the other had not had response within 2 months of treatment.
Zinc sulphate in doses of 10 mg/Kg/day seems to be more effective than cimetidine to treat children and adults with multiple recalcitrant warts. The small sample did not enable any definite conclusions. The use of cimetidine did not cure any of the patients, producing poor results and leading to reduction in size in some cases and disappearance of few lesions.
To Fernanda Chalabi and Compound Pharmacy Officilab that have offered for free the required medication for the performance of the present study.
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How to cite this article: Stefani M , Bottino G, Fontenelle E, Azulay DR. Comparação entre a eficácia da cimetidina e do sulfato de zinco no tratamento de verrugas múltiplas e recalcitrantes. An Bras Dermatol. 2009;84(1):23-29.