Miscellaneous Therapies for the treatment of
Table of Contents:
Cryotherapy also called as Cryosurgery - works by destroying tissue by freezing. Tissue injury results from intra-cellular and extracellular formation of ice, disruption of cell membranes, and circulatory changes in the skin caused by freezing and thawing. Critical factors influencing cellular necrosis are rate of freezing, temperature, duration of freezing, and rate of thawing.
Cryotherapy is the freezing of Anal / peri-anal / ano-genital warts using very low temperature. The low temperature is achieve by a cryo gun or liquid nitrogen. Various handheld devices or cryotherapy machines are used for the procedure. This treatment option can be repeated weekly, biweekly or every 3 weeks and is a relatively simple technique, requiring minimal training. However, it requires many clinic visits and a second or third cycle of freezing may be needed. Clearance rates of 46–96% have been reported although treatment can cause pain, necrosis and blistering. Post‐inflammatory hypo/hyperpigmentation after treatment with cryotherapy can occur, as the ultra-low temperature destroys the (melanocytes) melanin pigment producing cells.
In general, a rapid freeze of tissue to at least -20oC followed by a slow thaw will destroy the tissue of benign lesions. For malignant lesions, tissue needs to be frozen to -50oC to kill the cells1. Critical factors influencing cellular necrosis are rate of freezing, temperature, duration of freezing, and rate of thawing.
Technique - The freezing unit is applied to the skin lesion, freezing begins immediately and can be observed as a whitish discoloration of the skin that spreads peripherally from the point of contact and is known as the lateral spread of freeze. Extent of freezing is estimated by the lateral spread of freeze, which closely approximates depth of freeze. Depth of freeze can be increased by applying pressure on the skin with either a cryoprobe. If liquid nitrogen spray is used, depth of freeze can be increased by prolonging duration of freeze. Successful treatment depends on the lesion's being included in the lethal freeze zone. For this reason, the lateral spread of freeze should extend at least 2 mm beyond the margins of benign lesions and 5mm beyond the margins of malignant lesions. repeat freeze-thaw cycle, will increase tissue destruction. A slow thaw increases the degree of tissue destruction; frozen tissue should be allowed to thaw gradually at room temperature and should never be warmed artificially.
The cryosurgery can be of two types - direct cryogens using carbon dixode ice or liquid nitrogen or by cryotherapy machines using nitrous oxide or carbon dioxide as cryogens.
|Cryotherapy||-20 C temp freezes and destroys lesions||Applied directly to lesions; repeat for two or three cycles. No anaesthesia required||
Rapid resultsMinimal training
High recurrence ratePain, necrosis, hypopigmentation
The Cryogen and its temperature achieved
|Boiling Point||Applied to Skin|
|Liquid Nitrogen||N2||-196 oC||-196 oC
|Nitrous Oxide||NO2||-88.4 oC||-60 to -85 oC|
|Halocarbon 22||CHClF2||-40.8 oC
The contact time is 5 to 10 seconds for warts and condyloma acuminata for cryotherapy
Treatment and technique
The cryogens most commonly used are nitrous oxide, carbon dioxide, liquid nitrogen, liquid carbon dioxide (dry ice) etc.
Cryosurgical units - use cryogens like Nitrous oxide gas / carbon dioxide gas which are sprayed through a special apparatus to produce cooling.
Direct application cryogens - The cryogens like liquid nitrogen, liquid carbon dioxide (dry ice) are directly applied to the lesion to create extreme temperatures to destroy the tissue.
These units operate by the Joulc-Thomson effect. This method o f refrigeration results from the principle or the expansion of the gas through a small opening. Pressurized nitrous oxide advances down the narrow cryogun barrel. When it reaches the hollow cryoprobc tip, the gas rapidly expands, lowering it to a temperature below freezing. Although the cryo-probe tip visibly cools with unit activation, the tip must actually be considered a heat sink. As the tip removes heat from the tissue, the tissue gradually cools. The size, material, composition, and temperature of the probe’s tip determine its capacity' as a heat sink. Other factors, such as tissue moistness, extent of tissue contact, the duration of freeze, and pressure exerted on the probe, affect heat diffusion.
Cryotherapy works by using a cryogen to cool the targeted lesion to sub-zero temperatures causing direct tissue necrosis. The thawing process induces osmolarity changes which also results in tissue damage.
The ice field is then maintained for 5 to 30 seconds depending on the lesion and depth of freeze. The treatment is repeated in some cases once thawing has completed. This is known as a ‘double freeze-thaw’.
The extent of cryonecrosis is influenced by the speed at which tissue freezes and thaws. A rapid freeze and a slow thaw maximize results. A freeze-thaw-freeze treatment cycle is also more effective than a single freeze technique.
The "cough technique" has been recommended to avoid cryogun blockage during treatment. It involves a cyclic momentary thawing of the cryogun probe by systematically interrupting freezing, it is employed with use of carbon dioxide gas as cryogen. The limitations to using CO2 include blockage of the cryogun during the cryotherapy procedure, inherently warmer tip temperatures due to the physical properties of the gas, and indications of lower therapeutic effect due to insufficient depth of tissue destruction using a freeze-flush-freeze cycle ("cough technique"). Thus cough technique should be avoided and continous freeze /thaw cycle should be employed to achieve best results7.
Cryo - gun
Freezing with nitrous oxide is accomplished with a cryo-gun attached to a nitrous oxide tank. The gas circulates through the gun to a metal probe where rapid expansion of the gas reduces the temperature of the probe to approximately -65oC to -85oC. The probe is applied to the skin lesion through a water-soluble lubricant and held there for an appropriate time. Usually 5 to 10 seconds or even more depending upon the size and extent of the lesion. The gas flows continuously to the probe tip while the gun trigger is activated. Thawing begins as soon as the nitrous oxide stops flowing. Nitrous oxide freezing requires longer freeze times because of the higher temperatures and, as a result, there is less likelihood of excessive tissue destruction. It is easy to control freeze times accurately, and a variety of metal probes are available, which means cryoguns can be adapted for treating a variety of lesions. For example, they are often used for gynecologic cryosurgery.
The initial cost of these units is fairly high. The nitrous oxide tanks last a long time, however, and cryogen is not wasted as it might be with liquid nitrogen.
Treating warts with cryosurgery weekly clears them more rapidly than treating them every 2 or 3 weeks, but the overall cure rate depends on the total number of treatments rather than the interval.
Effects of Cryotherapy / cryosurgery on tissues
Celluar Injury - The cell injury that occurs after freezing is thought to result from a high solute concentration causing cell dehydration. Intracellular ice formation causing intra-cellular organelle and cell membrane disruption has also been implicated. It is known that slow thawing allows solute effects and maximum ice growth during recrystallization to take place. Because solute effects and ice growth are deleterious to cells, complete thawing before the start of another cycle is important in determining the success of cryosurgery for oncological conditions. However, rapid cooling followed by rapid thawing can also be beneficial. During rapid cooling, the ice crystals tend to be small, with high surface energies. The longer the time of thawing, the easier it is for the ice to recrystallize, especially for crystals with high surface energies. The larger ice crystals can be more destructive than the smaller ones, because of the size of the crystals or the forces generated during recrystallization. The hold time – the duration of time the tissue is in the frozen state – is also an important factor in determining the degree of cryoinjury. Another mechanism of direct cell injury is membrane destabilization during freezing and thawing
Immunological Injury - Another theory is that freezing may stimulate immunological injury. It is believed that the immune system becomes sensitized to the destroyed frozen tissue, and any tissue left behind is attacked by the host’s own immune system after cryosurgery. MECHANISMS OF IMMUNOLOGICAL INJURY - The first theory is the production of antitumour antibodies. When the tumour cells die, the antigens inside the cells are released onto the membrane and phagocytosed by antigen-presenting cells. B cells with antibodies specific for the antigen are stimulated and transformed into plasma cells. Antibody formation induces complement fixation, leading to neutrophil and macrophage chemotaxis. These cells release free radicals and enzymes, which kill tumour cells left behind. The second mechanism of immunological involvement is through the induction of cytotoxic T cells. Normally, intracellular antigens are transferred to the cell membrane and recognized by cytotoxic T cells, which release enzymes and kill the cells. It was proposed that cryosurgery may sensitize the cytotoxic T cells or change the antigen presentation. The third possible mechanism is that cryosurgery may stimulate the activity of natural killer cells 2.
Vascular Injury - It has been theorized that freezing involves vascular injury. The hypothesis is that freezing results in stasis of blood flow, particularly in the capillaries. The resulting ischemia leads to tissue necrosis.
Freeze time for various Skin Lesions
LIQUID NITROGEN (SECONDS)
NITROUS OXIDE (SECONDS)
(Non-plantar - body warts)
|10-20||Up to 60||Overall cure rate of 60% to 70%.|
|Warts (Plantar)||30-60||40 after paring||A single freeze-thaw cycle is sufficient for hand warts, but plantar warts do better with a double freeze-thaw cycle|
|Warts (Peri-ungual)||Up to 45||40-60|
|Up to 30||Up to 45||Care should be exercised where the dermis is thin, such as on the penile shaft, where shorter freeze times are appropriate to avoid damaging tissue underneath
|Molluscum contagiosum||10||20||1- or 2-mm margin of freeze|
|Keloids||30-60||30-60||Very successful for earlobe keloids with good cosmetic results. Watch for hypo-pigmentation and slight atrophy|
Recommendations for use of Cryo-Surgery and Treatment Results
Cryosurgery is the safest treatment for genital warts in pregnant women.
Overall cure rate of 60% to 70% for treatment of warts by cryo-surgery. Cryosurgery remains one of the commonly used treatements for external genital warts. It has better cure rates than either trichloroacetic acid or podophyllin, but is less effective than electrodesiccation.
Complications of cryosurgery
In general, cryosurgery is very safe, but some complications do occur. Cryosurgery is contra-indicated for patients with cryoglobulinemia, Raynaud's phenomenon, immunosuppression, myeloproliferative disorders such as multiple myeloma, cold intolerance, and various blood dyscrasias.
Severe reaction and tissue destruction following cryosurgery are more likely with lesions on thin skin or skin previously damaged by radiation or sun exposure, with skin lesions over bony prominences, and in patients with impaired vascular supply (such as elderly people).
A short period of moderately intense pain with the freeze and during thawing is followed almost immediately by redness and swelling that might last several hours. Blistering, which often occurs within a few hours of treatment, might be both hemorrhagic and alarmingly large. Blisters tend to dry within 72 hours, and a crust forms. The crust gradually separates over 7 to 14 days. There can be possibility of potential hair loss, hypopigmentation, and scarring. steroid ointment can greatly reduce pain and swelling.
1. Wetmore SJ. Cryosurgery for common skin lesions. Treatment in family physicians' offices. Can Fam Physician. 1999;45:964-974.
2. Yiu WK, Basco MT, Aruny JE, Cheng SW, Sumpio BE. Cryosurgery: A review. Int J Angiol. 2007 Spring;16(1):1-6. doi: 10.1055/s-0031-1278235.
3. Ferris DG, Ho JJ. Cryosurgical equipment: a critical review. J Fam Pract. 1992;35(2):185-193
4. Mahmoudi H, Ghodsi SZ, Tavakolpour S, Daneshpazhooh M. Cryotherapy plus oral zinc sulfate versus cryotherapy plus placebo to treat common warts: A double blind, randomized, placebo-controlled trial. Int J Womens Dermatol. 2017 Oct 20;4(2):87-90. doi: 10.1016/j.ijwd.2017.09.004. PMID: 29872682; PMCID: PMC5986231.
5. Goel R, Anderson K, Slaton J, et al. Adjuvant approaches to enhance cryosurgery. J Biomech Eng. 2009;131(7):074003. doi:10.1115/1.3156804
6. Cooper SM, Dawber RP. The history of cryosurgery. J R Soc Med. 2001 Apr;94(4):196-201.
7. Seamans Y, Loesel C, Jeronimo J, Sellors J, Castle PE. Effect of cough technique and cryogen gas on temperatures achieved during simulated cryotherapy. BMC Womens Health. 2007 Oct 1;7:16. doi: 10.1186/1472-6874-7-16. PMID: 17908317; PMCID: PMC2048944
Thuja (Homeopathic remedy)
Salicyclic acid family of chemicals known as beta hydroxy acids (formula is C7H6O3 or HOC6H4COOH), Salicylic acid is a monohydroxybenzoic acid that is benzoic acid with a hydroxy group at the ortho position. It is obtained from the bark of the white willow and wintergreen leaves. It has a role as an antiinfective agent, an antifungal agent, a keratolytic drug.
When applied to the skin, salicylic acid works to break bonds inside the skin’s pores that are holding dead skin cells to living ones also called as a “keratolytic” medication because it has exfoliating properties.(Keratolytic Agents are those agents that soften, separate, and cause desquamation of the cornified epithelium or horny layer of skin). Salicylic acid softens and destroys the stratum corneum by increasing endogenous hydration (water concentration), probably because of decreased pH, which causes the cornified epithelium (horny layer) of the skin to swell, soften, and then desquamate.
Salicylic acid works to remove warts by exfoliating the skin cells until the wart is gone. The acid may also trigger an immune response to build healthy skin cells in the area. With continued daily application, the salicylic acid solution will often remove the wart. Salicylic acid is a first-line treatment for home use or self application for non-genital warts but not recommended for the genital warts as the skin of genitals is very sensitive and salicylic acid is highly irritant to the genital skin. In case the salicylic acid does not work for more than 2 weeks application then it is best to try some other alternative treatment. Salicylic acid will remove one layer of wart at a time and has slow action. concentration of 15 % or higher is used for warts. While salicylic acid for warts is a generally mild treatment, it can cause some side effects like skin irritation, discolored skin, and discomfort at the site of the wart. It is also not recommended on face application as it can cause hypo or hyper pigmentation of facial skin.
Care has to be taken while using salicylic acid application for warts as full thickness burns have been reported with its use3,7. Usually salicylic acid is used alone as Over the Counter Drug (OTC) being self applied or used in combination of cryotherapy6. The efficacy of the salicylic acid is equal to cryotherapy4,5.
1. Bruggink SC, Gussekloo J, Berger MY, Zaaijer K, Assendelft WJ, de Waal MW, Bavinck JN, Koes BW, Eekhof JA. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010 Oct 19;182(15):1624-30. doi: 10.1503/cmaj.092194. Epub 2010 Sep 13.
2.Stamuli E, Cockayne S, Hewitt C, Hicks K, Jayakody S, Kang'ombe AR, Turner G, Thomas K, Curran M, Hashmi F, McIntosh C, McLarnon N, Torgerson DJ, Watt I; EVerT team. Cost-effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts: economic evaluation alongside a randomised controlled trial (EVerT trial). J Foot Ankle Res. 2012 Feb 27;5:4.
3. Sjökvist O, Smolle C, Jensson D, Huss F. A full-thickness chemical burn to the hand using formic acid-based anti-wart treatment: a case report and literature review. Scars Burn Heal. 2020 Feb 5;6:2059513119897888.
4.Cockayne S, Hewitt C, Hicks K, Jayakody S, Kang'ombe AR, Stamuli E, Turner G, Thomas K, Curran M, Denby G, Hashmi F, McIntosh C, McLarnon N, Torgerson D, Watt I; EVerT Team. Cryotherapy versus salicylic acid for the treatment of plantar warts (verrucae): a randomised controlled trial. BMJ. 2011 Jun 7;342:d3271. doi: 10.1136/bmj.d3271. PMID: 21652750; PMCID: PMC3109952.
5. Redzic N, Benoy I, Vanden Broeck D, Bogers JP. Efficacy of AV2-Salicylic acid combination therapy for cutaneous warts: Study protocol for a single-center randomized controlled trial. Contemp Clin Trials Commun. 2020 Jan 21;17:100534.
6. Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, Bachmann MO, Howe AH, Rodgers S, Avery AJ, Harvey I, Williams HC. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model. Health Technol Assess. 2006 Aug;10(25):iii, ix-87.
7. Tavakkolizadeh A, Povlsen B. A serious complication of topical wart treatment on the hand. J R Soc Med. 2004 Apr;97(4):180.
Intra-lesional Vitamin D3 injections
Immunotherapy is emerging as a new modality of treatment which acts on enhancing cell-mediated immunity against human papillomavirus for clearance of both treated and distant warts. Various antigens have been tried including measles, mumps, rubella (MMR); tuberculin purified protein derivative (PPD); Mycobacterium w vaccine and Candida antigen.
Injection of the Vitamin D3 at the base of the warts is a new treatment option which causes immunomodulation. It has been observed that there is receptor activation of human macrophages which upregulated the expression of Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide.
The exact mechanism of action of Vitamin D in the clearance of warts is not known. Experimental evidence suggests that it has immunomodulatory effects by inhibiting the expression of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF)-α and TNF-γ mediated through VDR-dependent pathway.
The dose of Vitamin D3 injection is - 0.2 ml (15 mg/ml) injection is given to the base of warts. The injections can be repeated 2 weeks apart for a maximum of 4 sessions or until complete clearance, whichever was earlier.
The idea of intra-lesional vitamin D3 arose after it was observed that patients with viral warts had deficiency of Vitamin D in serum3-6. And there may be deficiency of folate, vitamin B12 and ferritin in patients with viral warts3.Though this claim that patients with viral warts are deficient in vitamin D levels has been contested7. The intra-lesional effect of Vitamin D3 is not that effective as compared to intra-lesional injection of BCG (Purified protein Derivative - which is used for Montoux test in T.B)8.
1. Kavya M, Shashikumar BM, Harish MR, Shweta BP. Safety and Efficacy of Intralesional Vitamin D3 in Cutaneous Warts: An Open Uncontrolled Trial. J Cutan Aesthet Surg. 2017 Apr-Jun;10(2):90-94.
2. Rind T, Oiso N, Kawada A. Successful Treatment of Anogenital Wart with a Topical Vitamin D(3) Derivative in an Infant. Case Rep Dermatol. 2010 Apr 20;2(1):46-49.
3. Tamer F, Yuksel ME, Karabag Y. Pre-treatment vitamin B12, folate, ferritin, and vitamin D serum levels in patients with warts: a retrospective study. Croat Med J. 2020 Feb 29;61(1):28-32.
4.El Mongy, Naglaa N.a; Hilal, Rana F.a; Badr, Amul M.b; Alraawi, Samah A.a Serum vitamin D level in patients with viral warts, Journal of the Egyptian Women's Dermatologic Society: September 2018 - Volume 15 - Issue 3 - p 133-138.
5. Luciano Moscarelli, Filomena Annunziata, Anduela Mjeshtri, Nunzia Paudice, Aris Tsalouchos, Maria Zanazzi, Elisabetta Bertoni, "Successful Treatment of Refractory Wart with a Topical Activated Vitamin D in a Renal Transplant Recipient", Case Reports in Transplantation, vol. 2011, Article ID 368623, 3 pages, 2011.
6. Jinhee Shim, Adriana Pérez, Elaine Symanski, Alan G. Nyitray, Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States, The Journal of Infectious Diseases, Volume 213, Issue 12, 15 June 2016, Pages 1886–1892.
7. Goodarzi, A., Farshidzadeh, M., Roohaninasab, M., Atefi, N., Behrangi, E. Assessment of serum vitamin D level in patients with cutaneous warts: a case-control study. Iranian Journal of Dermatology, 2020; 23(2): 64-71. doi: 10.22034/ijd.2020.110927.
8. Mohamed, E., El Taieb, M., Abd El- sabour, G. Intralesional Vitamin D3 versus Purified Protein Derivatives in The Treatment of Multiple Cutaneous Warts: Comparative Study. The Egyptian Journal of Hospital Medicine, 2019; 76(2): 3589-3594. doi: 10.12816/ejhm.2019.39165
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Topical retinoic acid
There are some reports of use of topical application of retinoic acid (Vitamin A) for the warts. But the treatment is prolong 6 to 10 weeks or even lasting for 6 months for resolution of warts1,2. It is difficult to recommend the topical use of retinoic acid for treatment of warts with the current evidence available in literature. Topical application of retinoic acid be at the most kept as unproven effect on viral warts unless sufficient data is available on its efficacy, duration of treatment and strength to be applied or to be taken orally2,3.
1. de Bersaques J. Vitamin A acid in the topic treament of plantar warts. Dermatologica. 1975;150(6):369-71. doi: 10.1159/000251460. PMID: 1201813.
2. Gaston A, Garry RF. Topical vitamin A treatment of recalcitrant common warts. Virol J. 2012 Jan 17;9:21. doi: 10.1186/1743-422X-9-21. PMID: 22251397; PMCID: PMC3274422.
3. Barchitta M, Maugeri A, La Mastra C, Rosa MC, Favara G, Lio RMS, Agodi A. Dietary Antioxidant Intake and Human Papillomavirus Infection: Evidence from a Cross-Sectional Study in Italy. Nutrients. 2020 May 12;12(5):1384.
Apple cider vinegar
The use of vinegar to fight infections and other acute conditions dates back to Hippocrates (460-377 BC; the father of modern medicine), who recommended a vinegar preparation for cleaning ulcerations and for the treatment of sores1. Recent scientific investigations clearly demonstrate the antimicrobial properties of vinegar, but mainly in the context of food preparation, vinegar is not longer recommended for the treatment of wounds.
In the popular media, vinegar is commonly recommended for treating nail fungus, head lice, and warts, yet scientific support for these treatment strategies is lacking. Scattered reports suggest that the successive topical application of highly concentrated acetic acid solutions (up to 99%) alleviated warts, presumably due to the mechanical destruction of wart tissue.
In popular media vinegar is explained as acid which can kill some types of bacteria and viruses on contact just like salicylic acid and the irritation produced may lead to immune response against viruses. These are all conjectures and no proof is available that vinegar does help in control of warts. In general, apple cider vinegar is most commonly used for this purpose, but it has led to burns of skin rather then treat warts. Anyway vinegar is not recommended for genital warts as it causes lot of irritation to the sensitive skin of ano-genital region nor does it have any effect on warts in that region when used in dilute quantities.
Apple cider vinegar should not be applied to open wounds or directly to the face and neck. Also, it is not recommended to use apple cider vinegar on genital warts. There are lot of cases of deep and dangerous burns by vinegar when used by lay persons following the popular media2-7.
Intra-lesional MMR vaccine (measles, mumps and Rubella)
Intralesional Immunotherapy with Measles Mumps Rubella Vaccine for the Treatment of Anogenital Warts. MMR vaccine which is known to stimulate cellular immunity is injected to the base of the warts (0.5 ml per session) under the single largest wart and it is repeated after every 3 weeks to maximum of 3 injections1-8. Very few trials have been published to recommend the wide spread use of intra-lesional MMR vaccine. The complications of MMR vaccine like joint pains, fever, local pain at site of injections do remain even with intra-lesional use of vaccine.
1. Sharma S, Agarwal S. Intralesional Immunotherapy with Measles Mumps Rubella Vaccine for the Treatment of Anogenital Warts: An Open-label Study. J Clin Aesthet Dermatol. 2020 Aug;13(8):40-44. Epub 2020 Aug 1. PMID: 33178381; PMCID: PMC7595364.
2. Zamanian A, Mobasher P, Jazi GA. Efficacy of intralesional injection of mumps-measles-rubella vaccine in patients with wart. Adv Biomed Res. 2014 Mar 31;3:107. doi: 10.4103/2277-9175.129701. PMID: 24804181; PMCID: PMC4009748.
3. Chauhan PS, Mahajan VK, Mehta KS, Rawat R, Sharma V. The Efficacy and Safety of Intralesional Immunotherapy with Measles, Mumps, Rubella Virus Vaccine for the Treatment of Common Warts in Adults. Indian Dermatol Online J. 2019 Jan-Feb;10(1):19-26. doi: 10.4103/idoj.IDOJ_142_18. PMID: 30775294; PMCID: PMC6362737.
4. Rezai MS, Ghasempouri H, Asqary Marzidareh O, Yazdani Cherati J, Rahmatpour Rokni G. Intralesional Injection of the Measles-Mumps-Rubella Vaccine into Resistant Palmoplantar Warts: A Randomized Controlled Trial. Iran J Med Sci. 2019 Jan;44(1):10-17. PMID: 30666071; PMCID: PMC6330524.
5. Awal G, Kaur S. Therapeutic Outcome of Intralesional Immunotherapy in Cutaneous Warts Using the Mumps, Measles, and Rubella Vaccine: A Randomized, Placebo-controlled Trial. J Clin Aesthet Dermatol. 2018 May;11(5):15-20. Epub 2018 May 1. PMID: 29785233; PMCID: PMC5955628.
6. Sinha S, Relhan V, Garg VK. Immunomodulators in warts: Unexplored or ineffective? Indian J Dermatol. 2015 Mar-Apr;60(2):118-29. doi: 10.4103/0019-5154.152502. PMID: 25814698; PMCID: PMC4372902.
7.Shaheen MA, Salem SA, Fouad DA, El-Fatah AA. Intralesional tuberculin (PPD) versus measles, mumps, rubella (MMR) vaccine in treatment of multiple warts: a comparative clinical and immunological study. Dermatol Ther. 2015 Jul-Aug;28(4):194-200. doi: 10.1111/dth.12230. Epub 2015 Apr 6. PMID: 25847793.
8. Gupta P, Tegta GR, Verma GK, Gupta A, Gupta M, Sharma S. A Study to Evaluate the Role of Intradermal and Intralesional Measles, Mumps, Rubella (MMR) Vaccine in Treatment of Common Warts. Indian Dermatol Online J. 2020 Jul 13;11(4):559-565. doi: 10.4103/idoj.IDOJ_144_19. PMID: 32832442; PMCID: PMC7413434.
Intra-lesional / Topical Bleomycin injections
1. Lee JY, Kim CW, Kim SS. Preliminary study of intralesional bleomycin injection for the treatment of genital warts. Ann Dermatol. 2015 Apr;27(2):239-41. doi: 10.5021/ad.2015.27.2.239. Epub 2015 Mar 24. PMID: 25834378; PMCID: PMC4377428.
2. Al-Naggar MR, Al-Adl AS, Rabie AR, Abdelkhalk MR, Elsaie ML. Intralesional bleomycin injection vs microneedling-assisted topical bleomycin spraying in treatment of plantar warts. J Cosmet Dermatol. 2019 Feb;18(1):124-128. doi: 10.1111/jocd.12537. Epub 2018 Apr 23. PMID: 29687566.
3. Soni P, Khandelwal K, Aara N, Ghiya BC, Mehta RD, Bumb RA. Efficacy of Intralesional Bleomycin in Palmo-plantar and Periungual Warts. J Cutan Aesthet Surg. 2011 Sep;4(3):188-91. doi: 10.4103/0974-2077.91250. PMID: 22279384; PMCID: PMC3263129.
4.Pasquali P, Freites-Martinez A, Gonzalez S, Spugnini EP, Baldi A. Successful treatment of plantar warts with intralesional bleomycin and electroporation: pilot prospective study. Dermatol Pract Concept. 2017 Jul 31;7(3):21-26. doi: 10.5826/dpc.0703a04. PMID: 29085716; PMCID: PMC5661162.
5. Rausch LJ. Dermatology-important advances in clinical medicine: immunotherapy and bleomycin in the treatment of recalcitrant warts. West J Med. 1983 Jun;138(6):863-4. PMID: 18749384; PMCID: PMC1010841.
Multiple puncture technique
1. Mclaughlin JS, Fischer TJ, Merrell GA. Treatment of Cutaneous Warts With Multiple Puncture Technique. Hand (N Y). 2019 Sep;14(5):689-690. doi: 10.1177/1558944718771389. Epub 2018 May 15. PMID: 29761740; PMCID: PMC6759976.
2. De Vita V, Goldust M. Efficacy and Safety of Microneedling for the Treatment of Cutaneous Warts. Hand (N Y). 2019 Sep;14(5):705-706. doi: 10.1177/1558944718810895. Epub 2018 Nov 8. PMID: 30406683; PMCID: PMC6759969.
3. Kolte SR Jr, Sardesai VR. Comparison of Intralesional Measles, Mumps, Rubella Vaccine and Needling in the Treatment of Recurrent Warts. J Cutan Aesthet Surg. 2020 Jul-Sep;13(3):217-221. doi: 10.4103/JCAS.JCAS_164_19. PMID: 33208998; PMCID: PMC7646425.
Topical Garlic extract
1. Rouf R, Uddin SJ, Sarker DK, Islam MT, Ali ES, Shilpi JA, Nahar L, Tiralongo E, Sarker SD. Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data. Trends Food Sci Technol. 2020 Oct;104:219-234. doi: 10.1016/j.tifs.2020.08.006. Epub 2020 Aug 19. PMID: 32836826; PMCID: PMC7434784.
Intra-lesional BCG/ PPD
1. Al-Yassen AQ, Al-Maliki SK, Al-Asadi JN. The Bacillus Calmette-Guérin (BCG) Vaccine: Is it a better choice for the treatment of viral warts? Sultan Qaboos Univ Med J. 2020 Aug;20(3):e330-e336. doi: 10.18295/squmj.2020.20.03.013. Epub 2020 Oct 5. PMID: 33110649; PMCID: PMC7574799.
2. Jaisinghani AK, Dey VK, Suresh MS, Saxena A. Bacillus Calmette-Guerin Immunotherapy for Recurrent Multiple Warts: An Open-Label Uncontrolled Study. Indian J Dermatol. 2019 Mar-Apr;64(2):164. doi: 10.4103/ijd.IJD_558_16. PMID: 30983619; PMCID: PMC6440180.
3. Rao AG, Haqqani R. Study of BCG Immunotherapy in the Management of Multiple, Extensive Non-Genital Cutaneous Common Warts. Indian Dermatol Online J. 2020 Sep 19;11(5):784-788. doi: 10.4103/idoj.IDOJ_461_19. PMID: 33235846; PMCID: PMC7678529.
1. Kim SY, Jung SK, Lee SG, Yi SM, Kim JH, Kim IH. New alternative combination therapy for recalcitrant common warts: the efficacy of imiquimod 5% cream and duct tape combination therapy. Ann Dermatol. 2013 May;25(2):261-3. doi: 10.5021/ad.2013.25.2.261. Epub 2013 May 10. PMID: 23717030; PMCID: PMC3662932.
2. Goldman RD. Duct tape for warts in children: Should nature take its course? Can Fam Physician. 2019 May;65(5):337-338. PMID: 31088871; PMCID: PMC6516695.
1. Mohamed EE, Tawfik KM, Mahmoud AM. The Clinical Effectiveness of Intralesional Injection of 2% Zinc Sulfate Solution in the Treatment of Common Warts. Scientifica (Cairo). 2016;2016:1082979. doi: 10.1155/2016/1082979. Epub 2016 Mar 31. PMID: 27123361; PMCID: PMC4830730.
Podophyllin / Podophyllotoxin
1. Nguyen AL, Quint KD, Bouwes Bavinck JN, Erceg A, de Kort WJA, Körver JEM. Real-life treatment of cutaneous warts with cantharidin podophyllin salicylic acid solution. Dermatol Ther. 2019 Nov;32(6):e13143. doi: 10.1111/dth.13143. Epub 2019 Nov 20. PMID: 31664756; PMCID: PMC6916542.
Auto-inocculation of warts
1. Choi JW, Cho S, Lee JH. Does immunotherapy of viral warts provide beneficial effects when it is combined with conventional therapy? Ann Dermatol. 2011 Aug;23(3):282-7. doi: 10.5021/ad.2011.23.3.282. Epub 2011 Aug 6. PMID: 21909196; PMCID: PMC3162255.
1. Caucanas M, Gillard P, Vanhooteghem O. Efficiency of photodynamic therapy in the treatment of diffuse facial viral warts in an immunosuppressed patient: towards a gold standard? Case Rep Dermatol. 2010 Dec 29;2(3):207-13. doi: 10.1159/000323215. PMID: 21537372; PMCID: PMC3085036.
Intra-lesional 5% KOH
Potassium hydroxide is a strong alkali that has been shown to be safe and effective for the treatment of genital warts and molluscum contagiosum.This is due to its ability to dissolve keratin and penetrate deeply the skin. Furthermore, treatment is generally well tolerated and does not entail systemic side effects. KOH 5% aqueous solution is to be applied daily using a toothpick with cotton wrap on the tip. The KOH (5%) is to be used daily, until mild inflammation is observed. The process is repeated for three months or until complete regression is observed. The result is a success rate of 65% with use of KOH (5%) and is comparable to cryo-therapy. The complications include pain, skin ulcerations, hypo-pigmentation and erosions. It is considered that erosion results from the digestive properties of KOH and are known side effects of use of KOH solution. Chances of Recurrence are also low with use of KOH.
1. Camargo CL, Belda Junior W, Fagundes LJ, Romiti R. A prospective, open, comparative study of 5% potassium hydroxide solution versus cryotherapy in the treatment of genital warts in men. An Bras Dermatol. 2014 Mar-Apr;89(2):236-40. doi: 10.1590/abd1806-4841.20141702. PMID: 24770498; PMCID: PMC4008052.
Intra-lesional Candida albicans antigen
Nitric zinc Complex
Nitric–zinc complex is a solution for topical application containing nitric acid, zinc, copper and organic acids, currently used to treat common warts. It has a caustic effect on the wart through mummification and protein denaturation or a coagulation action. The solution can be applied topically once, or up to four times, at 2‐week intervals until a complete clinical cure rate is observed. Clearance rates in one study ranged from 90 to 99%, and the product was well tolerated with no serious adverse events recorded. Initial data suggest promising result, however, additional studies are needed.
|Nitric–zinc complex topical solution||
Induces a caustic effect on the wart through mummification and protein denaturation/
|repeat at 2‐week intervals if needed||
still under research / study
|Easy Application||Recurrence rate is still under study / evaluation|
Sinecatechins consist of green tea polyphenols, which have anti‐inflammatory, anti‐proliferative, pro‐apoptotic and antiviral properties, although their exact mode of action is unknown. They are available for the treatment of warts as a 15% ointment or cream, which is self‐applied by the patient three times per day for a maximum of 16 weeks. In comparison, imiquimod 5% is applied three times weekly while application of imiquimod. Sinecatechin 15% ointment is a brown formulation, which could stain light‐coloured clothing and bedding, reducing patient adherence. Clinical studies of sinecatechins have shown similar clearance rates to that of imiquimod 5% therapy. Sinecatechins have resulted in complete clearance rates of 40–81%, No long‐term data are available for sinecatechins. The most commonly observed application site reactions are erythema, pruritus, irritation, pain and ulceration; these side‐effects may indicate the greater likelihood of a clinical response.
Glycyrrhetinic acid glycoside, Glycyrrhizic acid, Glycyrrhizinic acid, 3-O-(2-O-β-D-Glucopyranuronosyl-α-D-glucopyranuronosyl)-18β-glycyrrhetinic acid. Glycyrrhizin is the major active constituent of licorice root and has been used in traditional medicine to alleviate bronchitis, gastritis, and jaundice. One of its main active ingredients is glycyrrhizinic acid, which is a substance found in the Glycyrrhiza glabra root, commonly known as “sweet root”, that was used way back in ancient Egypt and China to treat respiratory infections and as an antiinflammatory.
Modern-day research has demonstrated its anti-inflammatory activity, its antiulcerative and antiviral effect. It has been reported that glycyrrhizin possesses antiinflammatory and antioxidant activities and can stimulate endogenous production of interferons Through in vitro studies with human hepatoma cells, Crance et al. showed that glycyrrhizin inhibited penetration of hepatitis A virus likely by altering cell membrane fluidity. In addition, glycyrrhizin has been shown to decrease the release of AST via inhibiting the activation of phospholipase A2, as well as via prevention of changes in the hepatocyte membrane permeability. Also, glycyrrhizin was found to suppress hepatitis B surface antigen (HBsAg) production.
Glycyrrhizic acid is widely applied in foods as a natural sweetener. As a therapeutic agent, is has been used in a vast variety of formulations as it is reported to be anti-inflammatory, anti-ulcer, anti-allergic, antioxidant, anti-tumor, anti-diabetic and hepatoprotective. Due to this properties, its indications have been: treatment of premenstrual syndrome, treatment of viral infections, anti-lipidemic and antihyperglycemic. It is also known to be used as a remedy for peptic ulcer and other stomach diseases.
Glycyrrhizic acid can be found in the alpha and beta forms. The alpha form is predominant in the liver and duodenum and thus, it is thought that the anti-inflammatory liver effect of this drug are mainly due to the action of this isomer. Glycyrrhizic acid anti-inflammatory effect is generated via suppression of TNF alpha and caspase 3. The antiviral activity of glycyrrhizic acid includes the inhibition of viral replication and immune regulation. The antiviral activity of glycyrrhizic acid seems to be of a broad spectrum and be able to cover several different viral types such as vaccinia virus, herpes simplex virus, Newcastle disease virus and vesicular stomatitis virus. Using Glizigen together with Viusid was effective in treating the external anogenital warts. Glycyrrhizic acid 0.1% was only partially efficacious for anogenital warts among HIV-positive patients.
It is available in India in brand name of Glizigen spray - and it contains Propylene Glycol, Aqua, Polysorbate, Glycyrrhizic Acid as active agents.
Direction for use/Dosage:
- Genital Warts: 4-5 applications per day for 2-3 weeks depending on the results
- Genital Herpes: 3-4 applications daily for 5 days.
- Shingles: 3-4 applications per day for 7-10 days.
- Genital Wart, molluscum, genital herpes, and shingles
1. Domínguez Gómez J, Simón RD, Abreu Daniel A, Zelenkova H. Effectiveness of glycyrrhizinic Acid (glizigen) and an immunostimulant (viusid) to treat anogenital warts. ISRN Dermatol. 2012;2012:863692. doi: 10.5402/2012/863692. Epub 2012 Aug 14. PMID: 22957266; PMCID: PMC3431102.
2. Achdiat, Pati & Rowawi, Rasmia & Gunawan, Hendra & Suwarsa, Oki & Sutantoyo, Catherina Jessica & Pati, Aji & Achdiat,. (2021). Clinical dermatoscopical response of glycyrrhizinic acid 0.1% spray in treating external anogenital warts in HIV patients: a case series CASE REPORT. HIV and AIDS Review. 20. 65-69. 10.5114/hivar.2021.105050.
Inosine Pranobex (IP)
Inosine pranobex (Isoprinosine or Methisoprinol) is a combination of inosine, acetamidobenzoic acid, and dimethylaminoisopropanol used as an antiviral drug.
Inosine pranobex is also indicated for mucocutaneous infections due to herpes simplex virus (type 1 and type II) and for treatment of genital warts as adjunctive therapy to podophyllin or carbon dioxide laser. Works by slowing the growth and spread of the virus in the body. It also stimulates the immune system in the body, which helps to increase the body's ability to fight these infections. The administration of Inosine pranobex positively impact the host’s immune system, by enhanc-
ing T-cell lymphocyte proliferation and activity of natural killer cells, increasing levels of pro-inflammatory cytokines, and thereby restoring deficient responses in immunosuppressed patients. At the same time, it has been shown that it can affect viral RNA levels and hence inhibit growth of several viruses.
The efficacy of IP to conventional treatments (podophyllin, cryotherapy, electrocautery, CO 2 laser and surgery), a combined use of oral IP plus conventional non-surgical treatment of genital warts was found to produce more increased cure rates that conventional treatment alone. A properly functioning immune system impedes HPV progress and helps clear the pathogen from the body. IP has antiviral efficacy because it modulates both cellular and humoral immunities. To date, no antiviral drugs effectively kill or hinder the progress of cervical HPV. Hence, host immunity alone must fend off and clear genital HPV. However, the host immune response may be inadequate and require modulation. Suppressive modulations may be required when the host immune response is too strong. In contrast, immunostimulation is needed when host immunity is weak.
Inosine pranobex (IP), also known as inosine acedobendimepranol (INN) or methisoprinol, is an antiviral drug consisting of a 1:3 ratio of inosine and dimepranolacedoben. The latter is a salt of acetamidobenzoic acid and dimethylaminoisopropanol. Since 1971, IP has been licensed for the treatment of cell-mediated immunodeficiency associated with human papillomavirus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). HPV is an epitheliotropic virus that exclusively attacks epithelial cells and primarily spreads and acts locally in this type of tissue. In the cervix, HPV infects the keratinocytes in the basal layer of the cervical epithelium in the transformation zone of the cervix. Viral particles are assembled when differentiated keratinocytes die and the virus is released during desquamation into the ambient environment. Downregulated protein expression in the lower epithelial layers, high non-cytolytic genomic replication, and the absence of a viremic phase enable the virus to evade immune system recognition.
HPV-infected patients have a weakened immune response caused by the HPV infection. A direct effect of depressed CD8 T cell activity is delayed or poor genital wart clearing while adequate T cell immune responses regress HPV-induced lesions and clear local HPV infection. Inactive T cell immune responses are associated with long-term viral persistence and HPV induced cancers.
As HPV lacks a viremic phase, immune cells cannot easily enter into contact with it. HPV attacks basal epithelial layers of the skin as immunocompetent Langerhans cells occur only in the surface epithelial layers and avoid invoking the T cell immune response. HPV does not cytolyse the cervical epithelium. In this way, it attenuates inflammatory and immune signal responses and can persist incognito. Evasion of a local immune response is required for the development of HPV infection. Therefore, the therapeutic agents stimulating innate immunity may effectively prevent the onset of local HPV infections.
IP suppresses the synthesis and translational ability of lymphocyte mRNA and inhibits viral RNA synthesis by:
1) inosine-mediated inclusion of orotic acid in polyribosomes;
2) suppression of polyadenylic acid capture by viral mRNA; and
3) molecular reorganization and a nearly threefold increase in the density of intramembrane plasma particles (IMP).
The humoral immune response consists of activating B lymphocyte transformation into plasma cells and initiating antibody production. B lymphocyte transformation may be a response to IP action but also a consequence of the effects of IP on macrophages and T helper cells.
1. Sliva J, Pantzartzi CN, Votava M. Inosine Pranobex: A Key Player in the Game Against a Wide Range of Viral Infections and Non-Infectious Diseases. Adv Ther. 2019 Aug;36(8):1878-1905. doi: 10.1007/s12325-019-00995-6. Epub 2019 Jun 5. PMID: 31168764; PMCID: PMC6822865.
2. Kovachev SM. A Review on Inosine Pranobex Immunotherapy for Cervical HPV-Positive Patients. Infect Drug Resist. 2021 Jun 2;14:2039-2049. doi: 10.2147/IDR.S296709. PMID: 34103950; PMCID: PMC8180272.
Levamisole is levamisole is a nicotinic receptor agonist used to treat helminth infections and some skin infections. It has minimal to moderate effect in treatment of HPV infection or warts regression.
It is administered as levamisole 150 mg tablets on 2 consecutive days a week for 12 weeks. or 2.5 mg - 5 mg / kg / day for 3 consecutive days every 2 weeks for 4 to 5 months.
Mechanism of action
As an immunomodulator, it appears that Levamisole is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients The mechanism of action of levamisole as an antiparasitic agent appears to be tied to its agnositic activity towards the L-subtype nicotinic acetylcholine receptors in nematode muscles. This agonistic action reduces the capacity of the males to control their reproductive muscles and limits their ability to copulate. The mechanism of action of Levamisole as an anticancer drug in combination with fluorouracil is unknown. The effects of levamisole on the immune system are complex. The drug appears to restore depressed immune function rather than to stimulate response to above-normal levels. Levamisole can stimulate formation of antibodies to various antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis and chemotaxis, and increase neutrophil mobility, adherence, and chemotaxis.
Levamisole has ability to cause serious adverse effects, including agranulocytosis. Other side effects caused by levamisole,Diarrhea, Metallic taste, Nausea, Anxiety or nervousness, Dizziness, Headache, Mental depression, Nightmares, Pain in joints or muscles, Skin rash or itching, Trouble in sleeping, Unusual tiredness or sleepiness, Vomiting, Blurred vision, Confusion, Convulsions (seizures), Lip-smacking or puffing, Numbness, tingling, or pain in the face, hands, or feet, Paranoia (feelings of persecution), Puffing of cheeks, Rapid or worm-like movements of the tongue, Trembling or shaking, Trouble in walking, Uncontrolled movements of arms and legs
Though in combination with cimetidine it has shown promise in treatment of warts, monotherapy has not. Only one double-blind placebo-controlled trial by Amer et al. in 40 patients with warts treated with 5 mg/kg on 3 consecutive days fortnightly for 5 months showed 60% cure rate (vs 5% for placebo) but other randomized trials have not shown much efficacy
1. Gupta M. Levamisole: A multi-faceted drug in dermatology. Indian J Dermatol Venereol Leprol 2016;82:230-236
2. Schou M, Helin P. Levamisole in a double-blind study: no effect on warts. Acta Dermato-venereologica. 1977 ;57(5):449-454. PMID: 73313.
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4. Sinha S, Relhan V, Garg VK. Immunomodulators in warts: Unexplored or ineffective? Indian J Dermatol. 2015 Mar-Apr;60(2):118-29. doi: 10.4103/0019-5154.152502. PMID: 25814698; PMCID: PMC4372902.