Effect of the combination of cantharidin-podophyllin-salicylic acid and nitric acid in the first session for the treatment of plantar warts.

Effect of the combination of cantharidin-podophyllin-salicylic acid and nitric acid in the first session for the treatment of plantar warts. | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 19 May 2025 V1 Latest version Share on Effect of the combination of cantharidin-podophyllin-salicylic acid and nitric acid in the first session for the treatment of plantar warts. Authors : M. Medina-Alcántara , J. Aguilera 0000-0002-1911-111X [email protected] , AM. Jiménez-Cebrián , A. Castillo-Domínguez , and M. V. de Gálvez Authors Info & Affiliations https://doi.org/10.22541/au.174767250.04177136/v1 488 views 192 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Plantar warts are a skin problem of great importance due to their prevalence and their negative effects on the patient’s quality of life. Of all the treatments used, the combination cantharidin-podophyllin-salicylic acid (CPS) has shown greater efficacy than the others, although its combination with nitric acid has not been studied. The objective was to analyze the efficacy and safety of the combination of CPS with nitric acid in the first session with respect to the individualized components for the treatment of plantar warts. We analyzed the number of visits and treatment sessions, side effects and evaluated the influence of sex, age range, comparing the combination of SCP and nitric acid in the first session versus the two treatments separately in 196 patients. There were no differences in sex, with a higher incidence in children under 15 years of age. The type of wart was single (86.6%) with a mean size of 6.13 ± 2.91 mm and metatarsal location in 49%. The first visit CPS-nitric acid combination resulted in a mean number of visits of 3.7±2.8, a mean of 2.5±2.9 applications and 45±23 days for lesion resolution, shorter time compared with individualized treatments. A complete resolution was observed in 96.4% of patients treated. The majority side effect was pain (65.5%) with low level on VAS scale (49.7%). In conclusion, the CPS-nitric acid combination was a very high effective treatment for plantar warts with a very fast and high rate for lesions resolution. Effect of the combination of cantharidin-podophyllin-salicylic acid and nitric acid in the first session for the treatment of plantar warts. M. Medina-Alcántara 1 , J. Aguilera 2* , AM. Jiménez-Cebrián 1 , A. Castillo-Domínguez 1 y M. V. de Gálvez 2 1 Department of Nursing and Podiatry, Faculty of Health Sciences, University of Malaga, Malaga, Spain . 2 Dermatological Photobiology Laboratory. Center for Medical and Health Research, Department of Medicine and Dermatology, Faculty of Medicine, University of Malaga, Malaga, Spain. *Corresponding author: email: [email protected] (J. Aguilera). Dermatological Photobiology Laboratory. Center for Medical and Health Research, Department of Medicine and Dermatology, Faculty of Medicine, University of Málaga, Málaga, Spain. Short title: Plantar warts treatment with cantharidin-podophyllin-salicylic acid combination Data availability statement : The data that support the findings of this study are available from the corresponding author upon reasonable request. Funding statement This work is part of the research of the Institute of Biomedicine of Malaga (IBIMA) and the research group of the Junta de Andalucía CTS-162. Conflict of interest disclosure The authors declare that they have no conflict of interest related to this work. Ethics approval statement: The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and good clinical practice with the approval of the reference Ethics Committee (CEUMA: 18-2024-H). Patient consent statement: Authors confirm that a informed consent has been signed by patients Plantar warts are a skin problem of great importance due to their prevalence and their negative effects on the patient’s quality of life. Of all the treatments used, the combination cantharidin-podophyllin-salicylic acid (CPS) has shown greater efficacy than the others, although its combination with nitric acid has not been studied. The objective was to analyze the efficacy and safety of the combination of CPS with nitric acid in the first session with respect to the individualized components for the treatment of plantar warts. We analyzed the number of visits and treatment sessions, side effects and evaluated the influence of sex, age range, comparing the combination of SCP and nitric acid in the first session versus the two treatments separately in 196 patients. There were no differences in sex, with a higher incidence in children under 15 years of age. The type of wart was single (86.6%) with a mean size of 6.13 ± 2.91 mm and metatarsal location in 49%. The first visit CPS-nitric acid combination resulted in a mean number of visits of 3.7±2.8, a mean of 2.5±2.9 applications and 45±23 days for lesion resolution, shorter time compared with individualized treatments. A complete resolution was observed in 96.4% of patients treated. The majority side effect was pain (65.5%) with low level on VAS scale (49.7%). In conclusion, the CPS-nitric acid combination was a very high effective treatment for plantar warts with a very fast and high rate for lesions resolution. Keywords: Nitric acid, Salicylic acid, Cantharidin, Podophyllin, Nitric acid, Salicylic acid, Cantharidin, Podophyllin, Topical treatment, Plantar warts Introducción Plantar warts are a skin problem of great importance worldwide due to their widespread prevalence ranging from 3% to 20% [1-3]; with an annual incidence of 14% [2]. They are skin lesions in the form of hyperkeratotic papules on the plantar aspect of the foot caused by the human papillomavirus (HPV) that infects keratinocytes [3,4]. Of the total set of 150 types of HPV, the most prevalent in cutaneous plantar warts are HPV 27, 57, 2 and 1 either in isolation or in combination. The most common combinations are 2-4 and 1-275. Two forms of plantar warts can be found: the single or solitary ones and the mosaic-forming ones. In the case of single forms, there are an endophytic and deep growth conditioned by the pressures to which the lesion is subjected, preferably located in support areas, which is accompanied by intense pain when the foot is supported. On the other hand, mosaic plantar warts tend to grow more in extension than in depth, generally remaining asymptomatic [5].There is numerous risk factors associated with this skin pathology: age and sex (girls at an early age and adult men), race (Caucasian), geographical and seasonal factors (winter), social behavior and socioeconomic. Personal hygiene measures, sports activities, and the relationship with plantar skin integrity influence the incidence rates of plantar warts [6-9]. Finally, incidence rates are higher in immunocompromised patients [3,9]. The diagnosis of plantar warts is basically clinical by direct observation or dermoscopy, supported in some cases by pathological anatomy in biopsies of the lesion [3,4,9]. Yellowish, pink or grayish-brown hyperkeratotic papules are observed, well delimited with loss of dermatoglyphs, presence of small black dots within the lesion and that usually give a twinge of pain in the support areas of the foot. There are numerous treatment methods such as surgical (electro scalpel, curettage, resection) [2] . Physical therapies consist of electrotherapy, ultrasound, radiofrequency, microwaves, infrared, lasers, cryotherapy, and photodynamic therapy [9-12]. However, the use of chemical substances is the first line of treatment, with keratolytic, antimitotic, antivirals, and immunotherapy being the most commonly used, with cure rates ranging from 45 to 83% [13-15]. As a potential first-choice topical treatment, the combination of cantharidin-podophyllin-salicylic acid (CPS) has shown high cure rates with intervals between 81-100% [16-17]. The CPS combination works as a topical keratolytic and vesicant inducing acantholysis and intraepidermal blisters within 24-48 h of application, resulting in exfoliation of virus-containing tissue. Recently, the use of nitric acid alone or combined with zinc is another topical form such as keratolytic that shows significant potential as a treatment for plantar warts, also with high cure rates seeking the least number of sessions and treatment time [18,19]. However, the use of the combination of cantharidin-podophyllin-salicylic acid (CPS) together with nitric acid as an initial treatment in plantar warts has not been studied, which could establish a combination of treatment with a high cure rate with a rapid response rate to reduce the number of sessions and treatment time as much as possible. The aim of this study was to analyze the efficacy and safety of the combination of CPS with nitric acid in the first treatment session with respect to the individualized components for the treatment of both single and mosaic plantar warts and to evaluate both the number of sessions, treatment time to resolution, the percentage of patients with full resolution and the possible side effects based on pain intensity. Material and methods A retrospective cross-sectional study in which data from a total of 196 patients who presented with plantar warts who were treated in a podiatry clinic between 2001 and 2021 were reviewed. All patients signed an informed consent prior to their treatment and were informed for the anonymized use of their clinical data for scientific purposes. The inclusion condition of the study was that patients had at least one plantar wart diagnosed after evaluation of the clinical and morphological aspects and without the presence of other podiatric or clinical lesions. Data was obtained and collected by reviewing medical records. The parameters included were the patient’s demographic characteristics, sex, age, type of plantar wart (single or mosaic), number of lesions, size, location, and the data were divided and compared by 3 types of treatment consisting of nitric acid (60%), the topical formula CPS (1% cantharidin, 5% podophyllin, and 30% elastic collodion), and the combination of nitric acid and CPS. When the CPS+ nitric acid treatment was combined, it was performed only in the first treatment session. In the case of no remission of lesions after one session, only nitric acid was continued in the following sessions. This choice was mainly due to the fact that, in our experience, the combined treatment was more aggressive. A set of clinical variables were analyzed to relate them to the incidence of lesions such as sex, age ranges, location, type and number of lesions, as well as initial treatment, number of visits to the clinic, number of treatment sessions, the presence of adverse events and the level of pain estimated by the visual analogue scale (VAS). The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and good clinical practice with the approval of the reference Ethics Committee (CEUMA: 18-2024-H). A descriptive analysis of the continuous variables was performed, representing means ± standard deviation. Comparative analysis by pairs (e.g. sex) the Student’s t-test or ANOVA was used when there were more than 2 strata followed by Bonferroni’s test to distinguish by pairs. For discrete variables (in %) Chi2 analysis was used for contingency tables. The statistical significance level was established at p<0.05 using the IBM-SPSS statistical application, version 20.0. Results The clinical results of the population studied are shown in Table 1. Of the total of 196 patients who attended the podiatry clinic with plantar warts, 101 were female (51.6%) compared to 95 male (48.4%) and mean age was 23.7 ±15.9 years (Table 1). 43.3% of the patients treated were less than 15 years old, followed by patients in the 15-30 age range (28.7%). Single type treated warts appeared in 86.6% of cases (n=170) while mosaic warts were treated in 26 patients (13.4%). Most patients came to the clinic with one lesion (30.6%) and with two lesions in 33.8% and 35.7% with 3 or more lesions. The mean size of the lesions was 6.13 ± 2.91 mm ranging from 2-12 mm. The location of the lesions did not suffer significant differences between the left and right feet, with the metatarsal being the location where 49% of the lesions were found, followed by the heel (24.8%), the toes (22.9%) and the area of lesser location that corresponded to the midfoot (3.8%). The initial treatment of choice for 196 patients included in the study was the association of nitric acid with the CPS compound formula (n=133; 67.9% of patients) followed by nitric acid alone (n=33, 16.8%) and cantharidin formula alone (n=30, 15.3%). In case of patients needing a second or more treatment sessions, all patients were treated with nitric acid alone. The mean number of visits made by patients was 3.74±2.8 with a mean of 2.56±2.9 applications, with a period of 45±23 days used for the resolution of the lesions. 31.2 % (n=61) of the patients received 1 treatment session, and 34.4 % received 2 treatments sessions, reaching complete resolution in most patients after these 2 treatment sessions. Most patients underwent 3 or more revision visits, obtaining a total resolution in 92.4% of patients (Table 1). Figure 1 shows the number of treatments performed according to the type of initial treatment. Of the three types of initial treatments, the CPS+nitric acid combination was the treatment with the fewest treatment sessions until total resolution, with more than 70% of patients resolved in 2 visits, followed by CPS treatment, which mostly required more than 2 sessions. The use of nitric acid as monotherapy was the least effective where most patients needed more than 5 applications for total resolution. The number of total visits for each patient was also lower in patients who received the CPS+ nitric acid combination, with 80% of patients attending 4 or fewer follow-up visits (Figure 2) mostly attending 3 to 6 times, while those treated with nitric acid attended mostly follow-up visits more than 5 times. The sex of the patients showed significant differences by age intervals. The mean age of the group of female patients was 22.32±13.56 while for the male patients it was 26.1±16.54. Although the female sex showed a lower mean, no significant differences were observed in the t-Student test. (p=0.08). In the case of sex segmentation by age (Fig. 3), significant differences were observed in Chi2 in contingency tables (p<0.05) where it was shown that the percentage of girls who attended the clinic between 0-15 years old was 49.4% while 36.8% was boys. The percentage of young people between 16-30 was slightly higher in men than in the 31-45 age range. The percentage of men was higher in the age ranges above 45 years. The presence of sweating on the foot correlated with the sex of the patients by age ranges, especially more clearly in young ages, where girls aged 0-15 years showed higher percentages of sweating (64%) compared to 34.3% of boys (Fig. 4). From the age of 16, the presence of sweat in men was slightly higher than in women with a much higher percentage from the age of 45. Pain associated with treatment was also significantly different depending on the sex of the patients (Figure 5). Pain associated with treatment was slightly higher in girls than in boys, where 85.4% showed mild pain and 70% in women. Moderate pain increased in women compared to men (21.8% vs. 14.6%). About 4% of both sexes suffered severe pain. No significant differences were found by sex in terms of the number of lesions, location, number of visits and outcome of treatments. Eva’s pain level was not significantly related to the type of treatment. Most patients showed a low level of pain (Fig. 6). 77.4% of patients treated with the combination of nitric acid and CPS showed a low pain level and only 19% of patients showed a moderate pain level and 3.6% severe pain, being not significantly different from the use of CPS alone, while with nitric acid the pain level was 9.1% severe pain. These patients used NSAIDs to control pain. The final treatment response was very high both in the CPS-nitric acid combination and using each of the treatments individually (Table 1). The CPS-nitric acid combination resulted in the final resolution of lesions in 96.4% of the treated patients, followed by nitric acid-based treatment in only 94.5%. Finally, treatment with the CP formula resulted in complete resolution in 87.5% of patients. In the face of such high efficacy values, the treatment success of the CPS-nitric acid combination lay in the fewest sessions and visits to achieve complete resolution. Discussion The topical treatment of plantar warts based on keratolytics is a simple procedure that can be applied on an outpatient basis, non-disabling and generalizable to a wide spectrum of patients. The use of CPS is one of the best treatment alternatives because of its high cure rate in a relatively quick time. Through physical therapies, cure rates are lower, cryotherapy (45.6% mean cure in 4.7 weeks) 19 , laser therapy (79% average cure in 36 weeks) [20], ultrasound (81% average cure) [21] or hyperthermia (53.57% average cure) [22]. Chemical alternatives such as bleomycin produced a 78-88.5% cure rate in 3 months [23,24], vitamin D 80% in 6 months [25,26], acyclovir with 38.8% in 8 weeks [27], or immunotherapy (mean cure 83.5% in 6 months) [28]. On the other hand, treatment with CPS showed cures in 72% of patients in 1 session and 100% in the second [29], while Ghonemy showed cure rates of 93.3% in 6 months [20]. The fundamental contribution introduced by our study has been the use of the combination of the combination of nitric acid at 60% and CPS compared with both substances separately in a total of 196 patients, with a total resolution in 96.4% of patients and shortening the average number of visits to 3.74±2.8, with a mean of 2.56±2.9 applications and a period of 45±23 days used for the resolution of the lesions, thus significantly improving the use of nitric acid and CPS applied alone, although their resolution efficiency was also very high (94 and 87% respectively). The side effects manifested in the associated treatment of topical treatment (nitric acid + CPS) are similar to those reported in other studies. Kasar et al. [30] described the most common side effects with CPS as pain (81.3%) and blisters (15%). Other rare effects (18.7%) were pruritus, mild infection, significant irritation, and bleeding [18,29]. In the present study, pain was the most frequent, although with a VAS level of low in 77.4% and moderate in 19%, so the combination of CPS with nitric acid is a safe and painless treatment, with better percentages of low pain in females than in males. The combination of CPS nitric acid was not significantly more painful than with the application of both therapies separately and the most common treatment for pain was the use of analgesics or NSAIDs. In conclusion, the study with the largest series of patients has been carried out where the association of nitric acid with CPS was used as treatment in the first session against plantar warts. This treatment resulted in an efficacy of over 90% of total cure in a short period of time and a similar safety profile as both therapeutic options separately. 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Dermatol Ther. 2015;29:269-273. https://doi.org/10.1111/dth.12356. 30-Kaçar N, Taşli L, Korkmaz S, Ergin Ş, Erdoǧan BŞ. Cantharidin-podophylotoxin-salicylic acid versus cryotherapy in the treatment of plantar warts: A randomized prospective study. J Eur Acad Dermatol Venereol. 2012;26:889-893. https://doi.org/10.1111/j.1468-3083.2011.04186.x. Figure Legends Figure 1. Distribution (%) of the number of treatments performed according to the type of initial treatment. Figure 2. Distribution (%) of the number of patient visits by type of treatment. Figure 3. Distribution (%) of the number of patients by age and sex ranges. Figure 4. Presence (%) of sweat in patients related to age range. Figure 5. Distribution (%) of the number of patients according to the level of pain of VAS was shown according to the sex of the patients. Figure 6. Distribution (%) of the number of patients according to VAS pain shown by different types of treatment. Supplementary Material File (table 1.docx) Download 18.29 KB Information & Authors Information Version history V1 Version 1 19 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords combination therapy disease control foot and mouth disease virus hand human papillomavirus infection pathogenesis skin virus classification Authors Affiliations M. Medina-Alcántara Universidad de Malaga View all articles by this author J. Aguilera 0000-0002-1911-111X [email protected] Universidad de Malaga Departamento de Medicina y Dermatologia View all articles by this author AM. Jiménez-Cebrián Universidad de Malaga View all articles by this author A. Castillo-Domínguez Universidad de Malaga View all articles by this author M. V. de Gálvez Universidad de Malaga Departamento de Medicina y Dermatologia View all articles by this author Metrics & Citations Metrics Article Usage 488 views 192 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation M. 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