Int J Pharm Pharm Sci, Vol 16, Issue 10, 1-4Review Article

BERDAZIMER SODIUM IS THE PROMISING DRUG FOR THE TREATMENT OF MOLLUSCUM CONTAGIOSUM

VIKRANT DANDEKAR1*, AMRIT KARMARKAR2

1Bharati Vidyapeeth's College of Pharmacy, C. B. D. Belapur, Navi-Mumbai, India, 2Cipla Ltd, Mumbai, India
*Corresponding author: Vikrant Dandekar; *Email: vikrantdandekar@gmail.com

Received: 23 Apr 2024, Revised and Accepted: 15 Aug 2024

ABSTRAC

Molluscum Contagiosum (MC) is an infectious dermatosis disease caused by Molluscum Contagiosum Virus (MCV). MC is treated with mechanical, chemical, immunomodulatory, and antiviral drugs. Predominantly, immunodeficiency HIV-positive patients expressing resistance to MC lesions effectively responded to available drug molecules; therefore, there is a need to develop an effective drug molecule for the treatment of MC infection. Berdazimer topical gel, 10.3% has been developed by Novan Inc. (Ligand Pharmaceuticals) under the brand name Zelsuvmi® for treating MC infection in adult and pediatric patients. Berdazimer topical gel, 10.3% is a Nitric Oxide (NO) releasing topical gel comprising novel NO-based technology platform NITRICI™, which stores gaseous NO species on large polymers.

Keywords: Molluscum contagiosum, Berdazimer, Berdazimer sodium topical gel, Zelsuvmi, NITRICI™

© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijpps.2024v16i10.51902 Journal homepage: https://innovareacademics.in/journals/index.php/ijpps

INTRODUCTION

Bateman has first time described and assigned the name of Molluscum Contagiosum (MC), a cutaneous and mucosal eruption which is mainly caused due to a Molluscipox virus in the early nineteen century [1]. Henderson and Paterson mentioned the intracytoplasmic inclusion bodies also known today as molluscum or Henderson Paterson bodies [2]. In the early twentieth century, Juliusberg, Wile, and Kingery were able to extract filterable virus from lesions and show transmissibility [3, 4]. Goodpasture later described the similarities of molluscum and vaccinia [5]. The virus infection cases are reported in humans and animals globally [6-9].

Search Criteria: The review article was critically searched from specialized databases like Google scholar, Elsevier, Pubmed and Mendeley. This paper utilizes existing literature on the subject published after 2014 to create a comprehensive representation of pharmaceutical research. Keywords used to search relevant literature are “Molluscum Contagiosum”, “MC infection”, “Berdazimer sodium”, “Berdazimer sodium topical gel”, “Zelsuvmi”, “NITRICI™” and “Nitric oxide (NO)-releasing agent” Other selections include articles from Springer, information from Internet sources, and online published articles from Medscape, Statpearls.

MC is a viral infection that commonly occurs in the mucous membranes and skin of children. MC infection cases have increased by up to 20% worldwide, with the trend raising in the United States [10–14]. Children with 2 to 11 y ages having immune system suppression are most commonly infected with MC [15, 16]. Patients suffering from Human Immunodeficiency Virus (H. I. V.) infection and leukemia may be more likely to develop extensive disease [17–19].

MC is manifested by skin infection caused by the largest cutaneous viruses, commonly known as poxvirus [20]. Globally, it has been detected that infecting humans, other primates, and the kangaroo [21-23]. The virus has been efficiently multiplying in the human foreskin [24].

There are four major types of Molluscum Contagiosum Virus (MCV) virus, mainly MCV-1, MCV-1a, MCV-2 and MCV-3, with the latter being extremely rare [24–27]. MCV-1 virus is more common than MCV-2 virus. MCV-1 is mainly responsible for MC infection in pediatric patients and MCV-2 found to infect adult patients and is more prevalent in sexually transmitted cases [28]. Molluscum Contagious infection occurs mostly among children and also affects sexually active adults [29]. MC has received special attention in the past two decades because of its prevalence as an opportunistic infection in HIV patients. MC infection, therefore, consider as first indication of HIV infection [30]. Multiple skin colors are the diagnostic indication of MC infection. Lesions can develop on all over body areas, including palmar and plantar skin. The distribution of lesions is quite irregular, and they are often grouped in clusters or distributed linearly because of self-inoculation by microtrauma or scratching. The diagnosis of MC is commonly performed by dermoscopy and in vivo confocal microscopy techniques [31]. Dermatoscope clearly shows a central pore or umbilication, polylobular white-to-yellow amorphous structures, and peripheral crown vessels as an indication of MC infection [32-33]. Reflectance Confocal Microscopy (RCM) is emerging advanced diagnostic tool for diagnosis of Molluscum Contagiosum. Reflectance Confocal Microscopy technique, commonly known as RCM involves round, well-circumscribed lesions with central round-to-cystic areas filled with bright refractile material [34, 35].

MC is intercepted by avoiding direct skin-to-skin contact with an infected patient. Early identification of risk in pregnant women shall avoid abrasion at later stage of delivery, certainly minimize the chances of transmission of MC infection [36, 37].

Currently, there are no treatment procedures for MC, approved by FDA. However, there are many different treatment practices have been reported in the literature, efficacy data is largely dependent on small case series and uncontrolled studies. It is found that significant differences in efficacy between the various treatment modalities are not accurately demonstrated by randomized controlled clinical trials [38]. The decision on whether treatment is necessary shall be based on the needs of the MC-infected patient, the recalcitrance of their infection, and the likelihood of treatments to leave pigmentary alteration or scarring [39, 40]. It is found in many cases that complicated treatment procedures are not required to resolve but natural way of resolution can be awaited. Resolution takes place without complications in normal patients, but immunocompetent patients often take a prolonged period of months to years. When lesions are symptomatic or associated eczema is infuriating, treatment may be prudent. The selection of treatment will be based on various factors, such as the age of the patient and the number and position of the lesions [41, 42].

The treatment for MC includes watchful waiting, procedure‐based treatments such as Cryotherapy, Curettage, Needle prick, Pulsed dye laser therapy, chemical agents such as cantharidin, Potassium hydroxide, Benzoyl peroxide, Trichloroacetic acid, Glycolic acid, Salicylic acid; immune modulator includes Imiquimod, Interferon‐alpha, Cimetidine, Antiviral agent like Cidofovir. MC treatments can cause unwanted adverse effects or side effects. Treatment procedures are usually advised for psychological reasons due to refractory lesions. In addition, multiple MC lesions can heal with scar tissue. It is advisable that all treatment procedures should be discussed with patients and their family members [43, 44]. Before performing treatment procedures, a thorough skin examination should be performed to diagnose the infected area and identify all lesions. Curettage is a simple and relatively inexpensive procedure, with the added advantage that the tissue removed can be kept for histopathological analysis in case of diagnostic doubt [45]. EMLA cream, a eutectic mixture of local aesthetics (2.5% lidocaine and 2.5% prilocaine), is very commonly used in children to mitigate the pain caused by the procedure, although its application on MC lesions can cause local, self-resolving purpuric reactions [46, 47]. The umbilicated nucleus of the lesion can be manually removed using the hands or any one of a variety of instruments, including a scalpel, lancet, insulin needle, slide, or forceps. The resulting scarring is similar to that caused by curettage [48]. The umbilicated nucleus of the lesion can be manually removed using the hands or any one of a variety of instruments, including a scalpel, lancet, insulin needle, slide, or forceps. The resulting scarring is similar to that caused by curettage. This technique is of particular interest as it is simple and fast and can be learned by patients, family members, and caregivers and therefore performed at Home [49]. Cryotherapy is an efficient treatment for MC. A cotton‐tipped swab dipped in liquid nitrogen is applied on each lesion for 6–10 sec during the procedure. It is preferred to use for multiple trunk MC lesions. However, it is not preferred to use on face MC lesions because it may cause hypo‐hyperpigmentation and scar formation. The application should be continued until umbilical formation [50]. Pulsed dye lasers have shown to be promising treatments in case reports and small, uncontrolled studies. It is preferred in child patients, recalcitrant cases, and immunocompromised patients. A novel 585 nm collagen remodeling pulsed dye laser stimulates the release of various growth factors via cell-mediated reaction with T‐lymphocytes that promotes collagen remodeling and tightening [51]. Trichloroacetic acid causes tissue destruction by immediate chemical coagulation and superficial necrosis. It is used at concentrations of 20% and 35% and repeatedly applied on the centre of the lesion until a white, frost-like covering forms [52, 53]. Salicylic acid is a keratolytic agent sold at concentrations of 10% to 30%. It can be used in young children, diabetic patients, and those with multiple lesions. Clinical studies on salicylic acid for MC treatment are limited. The combination of 50% salicylic acid paste and 10% PVP‐iodine solution is an effective treatment that may accelerate the healing process and is a less expensive and less painful procedure [54]. Topical cantharidin is usually applied every two to four weeks until all lesions are resolved. It should not apply on the face, genital, or perianal areas. Because it may cause transient burning, pain, erythema, and pruritus [55]. Potassium hydroxide (KOH) is an alkali that penetrates and destroys the skin by dissolving keratin. It is used in aqueous solution at concentrations of 5% to 20%, and applied to MC lesions once or twice per day [56, 57]. Orally administered cimetidine as H2 histamine receptors antagonist. It exerts immunomodulatory effects by stimulating delayed hypersensitivity. In a clinical study of 13 children of less than 10 y of age who were treated with 40 mg/kg of oral cimetidine once per day for 2 mo, complete lesion resolution was observed in 9 of 13 patients [58]. Podophyllotoxin is an effective antimitotic agent in podofilox 0.5% as a solution or gel forms. The safety and efficacy study of podophyllotoxin is unclear in young children. Studies on the use of podophyllotoxin in MC infection are few and limited [59]. İnterferon may be used in MC treatment for immunocompromised patients and refractory lesions [60]. Large and numerous MC lesion can be observed in patients with HIV infection, and the treatments of MC are mostly unsatisfactory in those patients. Cidofovir is a nucleoside analogue antiviral agent that has wide spectrum anti‐DNA virus activity, including herpes viruses, papovaviruses, pox viruses, and adenoviruses. It blocks viral DNA synthesis via interacting with viral DNA polymerase [61, 62].

Cidofovir is deoxycytidine monophosphate nucleotide analogue. It inhibits viral DNA polymerase, therefore blocking the synthesis of viral DNA. Cidofovir is generally administered intravenously at 5 mg/kg per week for 2 w followed by 5 mg/kg once every two weeks or administered topically at 1%-3% cream or gel, applied daily [63].

The treatment of MC in immunocompromised patients like HIV-infected patients remains a major challenge. HIV-infected patients are treated with various treatment procedures such as Incision, curettage, cryotherapy with liquid nitrogen, electrodesiccation, and CO2 laser [64, 65]. Topical tretinoin cream may control the spread of MC but frequently causes severe, treatment-limiting irritation. None of the locally destructive modalities is consistently effective in patients with HIV infection. The presence of MC virus in the epidermis adjacent to MC lesions in immunocompromised patients with AIDS may explain the recurrence of the disease after the lesions are removed [66]. Treatment options for MC lesions are listed in table 1.

Table 1: Treatment options for MC and the corresponding degree of evidence

Topical treatment, outpatient Topical treatment,
home		 Immunotherapy Destructive treatment, outpatient Homeopathic/Natural References
Silver nitrate Imiquimod cream 5% Cimetidine Cryotherapy Australian essential oil (Backhousiacitriodora) [66]
Trichloroacetic acid Benzoyl peroxide Cidofovir Curettage Tea tree oil [64]
Podofilin Hydrogen peroxide Interferon-α Manual extrusion [66]
Cantharidin Potassium hydroxide Candidin Carbon dioxidelaser [65, 66]
Salicylic acid Pulsed dyelaser [64-66]

Fig. 1: Structure of berdazimer sodium

Currently, there is no effective systemic treatment for MC infection available worldwide. A recent report described the use of systemic interferon as an unsuccessful attempt. There was a significant need to develop effective drug for the treatment of MC infection. In January 2024, USFDA approved berdazimer topical gel, 10.3% under the brand name Zelsuvmi™. Novan Inc. (a Ligand Pharmaceuticals company) has developed Zelsuvmi™for the topical treatment of MC in adults and paediatric patients. Berdazimer sodium is a white to off-white powder with the chemical name poly[{[3-(methylamino)propyl]silasesquioxane}-co-{[3-(1-methyl-2-nitroso2-oxidohydrazin-1-yl)propyl] silasesquioxane}-co-silicate (1:3:6 x)], partially hydrolyzed (Si: OH ~ 10: 5), and the following structural and empirical formulas showed in fig. 1.

Berdazimer sodium is a polymeric drug substance comprising a polysiloxane backbone (Si-O-Si bonds) with covalently bound N-diazeniumdiolate NO donors throughout. Exposure to a proton donor like water, promotes NO release from the polymeric drug substance via decomposition of the N-diazeniumdiolates [67].

Novan Inc. has discovered a NO-based technology platform (NITRICIL™), which stores gaseous NO species on large polymers, in the development of berdazimer topical gel, 10.3%. Zelsuvmi®consists of berdazimer sodium gel, a new molecular entity (NME), and a proton-donating hydrogel. Mixing the two gels prior to the topical application to MC lesions releases NO, a pharmacologically active agent. NITRICIL™ technology allow to control the level of NO storage, the rate of release, and the molecule size for targeted delivery. The result is stabilized, druggable NO that is optimized for a specific indication. NITRICIL™provides the stable storage of large quantities of NO onto the polymeric drug substance scaffold and bypass the challenges associated with conventional low molecular weight NO donors. SB206 gel combines berdazimer sodium, a NO-releasing macromolecule, with a buffered hydrogel for topical administration. SB206 gel releases NO, which has bactericidal and virucidal activity, presumably through direct damage to various biomolecules by oxidation and nitration reactions. NO is a short-lived, lipophilic gas, that is endogenously produced and important for defending against infection. Inducible Nitric Oxide synthase (INOS) is the main enzyme for the synthesis of NO. In general, endogenous NO is considered protective against viruses, being produced by immune effector cells and critical to the innate immune response. NO may possess direct antiviral effects, covering impairment of viral enzymes through nitrosylation, destruction of viral DNA through oxidative and nitrosative stress, and repression of viral transcription factors. NO is also important to the modulation of vascular physiology, including vasodilation, leading to improved oxygenation. However, NO can have different physiological effects depending on the tissue and concentration, with high concentrations leading to apoptosis and cell cycle arrest. NO is also one of the key components in the formation of the tumor microenvironment caused by chronic infection and plays a role in cancer initiation and progression. The cytotoxic effect of exogenously administered NO has been investigated in a various literature report, using a number of delivery systems. In a study of gaseous NO to manage wound infection, no cytotoxic effects were observed at levels of up to 200 ppm (6.7 mmol, potentially much lower than the concentration of NO released from berdazimer sodium in the clinic to human dermal fibroblasts, keratinocytes and endothelial cells. In a study using NO-releasing nanoparticles, human lung fibroblasts were treated for 24 h and only minimal cytotoxicity was observed. NO-releasing patches have been tested for wound healing, and were shown to safely deliver up to 400 ppm (13 mmol) NO. Earlier studies tested NO-releasing cream containing ingredients nitrate and ascorbic acid effect on the skin of volunteers, and showed that the NO was pro-inflammatory and toxic to DNA, leading to the accumulation of p53 and subsequent apoptosis. A study using NO-loaded Zeolite ointment showed impairment of 3T3 fibroblast viability in a 24-hour cell culture assay, and that the cytotoxicity resulted from the NO release rather than the ointment itself. However, this cytotoxic effect was not recapitulated in the context of wound healing in obese rats [68].

Berdazimer sodium is a NO-releasing agent. The mechanism of action Berdazimer sodium is not very well known so far. The pharmacodynamics of Berdazimer sodium are not known very well. Plasma hydrolyzed MAP3 (hMAP3), a structural marker for berdazimer, and nitrate levels were evaluated in n=34 subjects 2 to 12 y of age with Molluscum contagiosum.

Subjects applied Berdazimer sodium once a daily for two weeks to a total treatment area of 484 cm2 (mean lesion count=34), applying a mean dose of approximately 3 ml/d mean plasma nitrate levels were similar on days 1 and 15 and remained relatively flat during the PK sampling period (baseline through 1-, 3-, and 6 h post-application). There were no apparent differences in methemoglobin levels throughout the study signs of carcinogenicity, Mutagenesis, and Impairment of Fertility were detected in pre-clinical studies [69-73].

Clinical trial Data from two adequate and well-controlled trials NI-MC302 and NI-MC304 (trials-302 and-304) provided substantial evidence of the effectiveness of berdazimer gel, 10.3% for the topical treatment of MC in the target population. Both trials assessed as their primary efficacy endpoint the proportion of subjects with complete clearance of all treatable MC lesions at Week 12, and as a key secondary efficacy endpoint the complete clearance rate of all treatable MC lesions at Week 8. The primary efficacy endpoint results from Study NI-MC304 were statistically significant (p<0.0001; treatment difference of 12.8%, 95% CI (7.1%, 18.6%)), consistent across subgroups and sensitivity analyses, and supported by the findings on the key secondary endpoint at Week 8. Thus, efficacy has been demonstrated in Study NI-MC304. In Study NI-MC302, although the results for the primary endpoint analysis at Week 12 just missed the significance threshold (p=0.0510), the point estimates and treatment effect estimate were similar to those observed in Study NI-MC304 (treatment difference of 9.2%, 95% CI (-0.04%, 18.4%)) and the secondary endpoint (complete clearance at Week 8) was supportive of the Week 12 result. The prespecified method of handling missing data in Study NI-MC302 was conservative, and many sensitivity analyses that used reasonable alternative methods of handling missing data had nominally significant findings. In addition, exploratory endpoints that evaluated change or percent change in lesion counts, rather than a dichotomized response endpoint, support an efficacy finding for Study NI-MC302. The complete evaluation of the efficacy results, including primary endpoint results, sensitivity and supplementary analyses, and secondary and exploratory endpoint results, were persuasive and confirm that efficacy had been demonstrated in Study NI-MC302. Thus, Studies NI-MC304 and NI-MC302 are adequate and well-controlled trials that demonstrate substantial evidence of effectiveness.

The substantial evidence of effectiveness was demonstrated through two adequate and well-controlled trials (Studies NI-MC302 and-304). The primary efficacy endpoint results from Study NI-MC304 were statistically significant (p<0.0001; treatment difference of 12.8%, 95% CI [7.1%, 18.6%]), consistent across subgroups and sensitivity analyses, and supported by the findings on the key secondary endpoint at Week 8. Thus, efficacy has been demonstrated in Study NI-MC304.

In Study NI-MC302, although the results for the primary endpoint analysis at Week 12 just missed the significance threshold (p=0.0510), the point estimates and treatment effect estimate were similar to those observed in Study NI-MC304 (treatment difference of 9.2%, 95% CI [-0.04%, 18.4%]) and the secondary endpoint (complete clearance at Week 8) was supportive of the Week 12 result. The prespecified method of handling missing data in Study NI-MC302 was conservative, and many sensitivity analyses that used reasonable alternative methods of handling missing data had nominally significant findings. In addition, exploratory endpoints that evaluated change or percent change in lesion counts, rather than a dichotomized response endpoint, support an efficacy finding for Study NI-MC302. The complete evaluation of the efficacy results, including primary endpoint results, sensitivity and supplementary analyses, and secondary and exploratory endpoint results, were persuasive and confirmed that efficacy had been demonstrated in the study NI-MC302 [74-79].

CONCLUSION

MC is skin disease caused by a virus characterized by distinctive raised, skin-toned-to-pink-colored lesions called Mollusca that can cause pain, inflammation, itching, and bacterial infection. Berdazimer topical gel, 10.3% has received USFDA approval under brand name Zelsuvmi™for the treatment of molluscum infections. Berdazimer sodium is the first novel drug for the treatment of MC in adult patients and pediatric patients one year of age and older. ZelsuvmiTM has developed by Novan Inc. (Ligand Pharmaceuticals) as a NO-releasing agent. Berdazimer sodium is shown to have antiviral effects, mechanism of action is not known. NO-based technology platform (NITRICIL™) has been developed by Novan Inc. NITRICIL™ stores gaseous NO species on large polymers in the development of berdazimer topical gel, 10.3%.

ACKNOWLEDGEMENT

Authors are thankful to pharmaceutical chemistry department of Bharati Vidyapeeth’s college of pharmacy, Navi-Mumbai for their valuable help and support.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

VD was actively involved in conceptualizing and designing the review, literature search, data acquisition, manuscript preparation, editing, and review. AK supported in the review work design, manuscript preparation, and review of the manuscript.

CONFLICT OF INTERESTS

The authors declare no conflict of interest, financial or otherwise.

REFERENCESReferences

  1. Bateman F. Molluscum contagiosum. In: Shelley WB Crissey JT, Editors. Classics in dermatology. Springfield IL: Charles C thomas; 1953. p. 20.

  2. Brown ST, Nalley JF, Kraus SJ. Molluscum contagiosum. Sex Transm Dis. 1981 Jul-Sep;8(3):227-34. doi: 10.1097/00007435-198107000-00012, PMID 7027479.

  3. Juliusberg M. Zur kenntnis des virus des molluscum contagiosum des menschen. Dtsch Med Wochenschr. 1905;31(40):1598-9. doi: 10.1055/s-0029-1188377.

  4. Wile, Kingery J. Cutan Dis; 1917. p. 431.

  5. Bretz S. Molluscum contagiosum. Emedicine Journal. 2001 Apr;2(4):25.

  6. Pusey WA. Moluscum contagiosum. In: The principals and practice of dermatology. 4th ed. Appleton; 1924. p. 989-90.

  7. Douglas JD, Tanner KN, Prine JR, Van Riper DC, Derwelis SK. Molluscum contagiosum in chimpanzees. J Am Vet Med Assoc. 1967 Oct;151(7):901-4. doi: 10.1136/vr.100721, PMID 6070316.

  8. Dangall BG, Witson GR. MC in a red kangaroo. Australas J Dermatol. 1974 Dec;15:115-20. doi: 10.1111/j.1440-0960.1974.

  9. Van Rensburg IB, Collett MG, Ronen N, Gerdes T. Molluscum contagiosum in a horse. J S Afr Vet Assoc. 1991 Jun;62(2):72-4. doi: 10.4102/jsava.v62i2.1596, PMID 1941892.

  10. Janniger CK, Schwartz RA. Molluscum contagiosum in children. Cutis. 1993 Oct;52(4):194-6. PMID 8261802.

  11. Oren B, Wende SO. An outbreak of molluscum contagiosum in a kibbutz. Infection. 1991 May;19(3):159-61. doi: 10.1007/BF01643239, PMID 1889869.

  12. Vander Straten M, Tyring SK. Mucocutaneous manifestations of viral diseases in children. Clin Dermatol. 2002 Jan-Feb;20(1):67-73. doi: 10.1016/S0738081X(01)00233-4, PMID 11849896.

  13. Sturt RJ, Muller HK, Francis GD. MC in villages of the West Septik District of New Guinea. Med J Aust. 1971 Oct;2(15):751-4. doi: 10.5694/j.1326-5377.1971.

  14. Becker TM, Blount JH, Douglas J, Judson FN. Trends in molluscum contagiosum in the United States 1966-1983. Sex Transm Dis. 1986 Apr-Jun;13(2):88-92. doi: 10.1097/00007435-198604000-00007, PMID 3715678.

  15. Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000 Sep;43(3):503-7. doi: 10.1067/mjd.2000.106370, PMID 10954663.

  16. Epstein WL. Molluscum contagiosum. Semin Dermatol. 1992 Sep;11(3):184-9. PMID 1390033.

  17. Cotton DW, Cooper C, Barrett DF, Leppard BJ. Severe atypical molluscum contagiosum infection in an immunocompromised host. Br J Dermatol. 1987;116(6):871-6. doi: 10.1111/j.1365-2133.1987.tb04908.x, PMID 3620349.

  18. Wiederkehr M, Schwartz RA. Giant proliferative molluscum contagiosum. Acta Derm Venerol (Ljubljana). 2002;11:101-4.

  19. Dangall BG, Wison GR. MC in a red kangaroo. Australas J Dermatol. 1974 Dec;15(15):115-20. doi: 10.1111/j.1440-0960.1974.

  20. Epstein WL. Molluscum contagiosum. Semin Dermatol. 1992 Sep;11(3):184-9. PMID 1390033.

  21. Sturt RJ, Muller HK, Francis GD. MC in villages of the West Septik District of New Guinea. Med J Aust. 1971 Oct;2(15):751-4. doi: 10.5694/j.1326-5377.1971.

  22. Dangall BG, Wison GR. MC in a red kangaroo. Australas J Dermatol. 1974 Dec;15:115-20. doi: 10.1111/j.1440-0960.1974.

  23. Douglas JD, Tanner KN, Prine JR, Van Riper DC, Derwelis SK. Molluscum contagiosum in chimpanzees. J Am Vet Med Assoc. 1967 Oct;151(7):901-4. PMID 6070316.

  24. Fife KH, Whitfeld M, Faust H, Goheen MP, Bryan J, Brown DR. Growth of molluscum contagiosum virus in a human foreskin xenograft model. Virology. 1996 Dec;226(1):95-101. doi: 10.1006/viro.1996.0631, PMID 8941326.

  25. Porter CD, Blake NW, Archard LC, Muhlemann MF, Rosedale N, Cream JJ. Molluscum contagiosumvirus types in genital and nongenital lesions. Br J Dermatol. 1989 Jan;120(1): 37-41. doi: 10.1111/j.1365-2133.1989.tb07763.x.

  26. Thompson CH. Immunoreactive proteins of molluscum contagiosum virus types 1, 1v, and 2. J Infect Dis. 1998;178(4):1230-1. doi: 10.1086/515706, PMID 9806070.

  27. Porter CD, Archard LC. Characterisation by restriction mapping of three subtypes of molluscum contagiosum virus. J Med Virol. 1992 Sep;38(1):1-6. doi: 10.1002/jmv.1890380102, PMID 1328506.

  28. Agromayor M, Ortiz P, Lopez Estebaranz JL, Gonzalez Nicolas J, Esteban M, Martin Gallardo A. Molecular epidemiology of molluscum contagiosum virus and analysis of the host serum antibody response in spanish HIV negative patients. J Med Virol. 2002 Feb;66(2):151-8. doi: 10.1002/jmv.2124, PMID 11782922.

  29. Cobbold RJ, Macdonald A. MC as a sexually transmitted disease. Practitioner. 1970 Mar;204:416-9.

  30. Schwartz JJ, Myskowski PL. Molluscum contagiosum in patients with human immunodeficiency virus infection a review of twenty-seven patients. J Am Acad Dermatol. 1992; Oct;27(4):583-8. doi: 10.1016/0190-9622(92)70226-6, PMID 1357010.

  31. Ianhez M, Cestari SD, Enokihara MY, Seize MB. Dermoscopic patterns of molluscum contagiosum: a study of 211 lesions confirmed by histopathology. An Bras Dermatol. 2011 Jan-Feb;86(1):74-9. doi: 10.1590/s036505962011000100009, PMID 21437525.

  32. Morales A, Puig S, Malvehy J, Zaballos P. Dermoscopy of molluscum contagiosum. Arch Dermatol. 2005 Dec;141(12):1644. doi: 10.1001/archderm.141.12.1644, PMID 16365277.

  33. Zaballos P, Ara M, Puig S, Malvehy J. Dermoscopy of molluscum contagiosum: a useful tool for clinical diagnosis in adulthood. J Eur Acad Dermatol Venereol. 2006;20(4):482-3. doi: 10.1111/j.1468-3083.2006.01480.x, PMID 16643165.

  34. Lacarrubba F, Verzi AE, Ardigo M, Micali G. Handheld reflectance confocal microscopy for the diagnosis of molluscum contagiosum: histopathology and dermoscopy correlation. Australas J Dermatol. 2017 Aug;58(3):e123-5. doi: 10.1111/ajd.12511, PMID 27282954.

  35. Scope A, Benvenuto Andrade C, Gill M, Ardigo M, Gonzalez S, Marghoob AA. Reflectance confocal microscopy of molluscum contagiosum. Arch Dermatol. 2008;144(1):134. doi: 10.1001/archderm.144.1.134, PMID 18209192.

  36. Choong KY, Roberts LJ. Molluscum contagiosum swimming and bathing: a clinical analysis. Australas J Dermatol. 1999;40(2):89-92. doi: 10.1046/j.1440-0960.1999.00327.x, PMID 10333619.

  37. Berbegal DeGracia L, Betlloch Mas I, DeLeon Marrero FJ, Martinez Miravete MT, Miralles Botella J. Neonatal molluscum contagiosum: five new cases and a literature review. Australas J Dermatol. 2015 May;56(2):e35-8. doi: 10.1111/ajd.12127, PMID 24344837.

  38. Forbat E, Al Niaimi F, Ali FR. Molluscum contagiosum: review and update on management. Pediatr Dermatol. 2017 Sep;34(5):504-15. doi: 10.1111/pde.13228, PMID 28884917.

  39. Janniger CK, Schwartz RA. Molluscum contagiosum in children. Cutis. 1993 Oct;52(4):194-6. PMID 8261802.

  40. Thompson CH, Biggs IM, De Zwart Steffe RT. Detection of molluscum contagiosum virus DNA by in situ hybridization. Pathology. 1990 Oct;22(4):181-6. doi: 10.3109/00313029009086657, PMID 2090999.

  41. Tom W, Friedlander SF. Poxvirus infections. In: Fitzpatrick TB Freedberg IM Eison AZ, Wolff K, Austenk F, Goldsmith LA, Katz SI, editors. Fitzpatrick’s dermatology in general medicine. 6th ed. Vol. 34. New York: McGraw-Hill-Company; 2008. p. 1081.

  42. Sterling JC. Virus infections. In: Burns T, Breathnach S, Cox N, Griffith C, editors. Rook’s textbook of dermatology. 7th ed. Vol. 25. Oxford: Blackwell Publishing; 2004. p. 11-25. doi: 10.1002/9781444317633.ch33.

  43. Coloe J, Morrell DS. Cantharidin use among pediatric dermatologists in the treatment of molluscum contagiosum. Pediatr Dermatol. 2009 Jul-Aug;26(4):405-8. doi: 10.1111/j.1525-1470.2008.00860.x, PMID 19689514.

  44. Coloe J, Burkhart CN, Morrell DS. Molluscum contagiosum: whats new and true. Pediatr Ann. 2009 Jun;38(6):321-5. doi: 10.3928/00904481-20090513-01, PMID 19588675.

  45. Harel A, Kutz AM, Hadj Rabia S, Mashiah J. To treat molluscum contagiosum or not curettage: an effective well accepted treatment modality. Pediatr Dermatol. 2016 Nov;33(6):640-5. doi: 10.1111/pde.12968, PMID 27601304.

  46. Valentine CL, Diven D. Treatment modalities for molluscum contagiosum. Dermatol Ther. 2000 Dec;13(3):285-9. doi: 10.1046/j.1529-8019.2000.00030.x.

  47. Neri I, Savoia F, Guareschi E, Medri M, Patrizi A. Purpura after application of EMLA cream in two children. Pediatr Dermatol. 2005 Nov-Dec;22(6):566-8. doi: 10.1111/j.1525-1470.2005.00142.x, PMID 16354264.

  48. Cervigon I, Torres Iglesias LM, Palomo A. Purpura after application of a eutectic mixture of local anesthetic. Actas Dermosifiliogr. 2008 Jul-Aug;99(6):499-500. doi: 10.1016/S1578-2190(08)70304-4, PMID 18558068.

  49. Valentine CL, Diven D. Treatment modalities for molluscum contagiosum. Dermatol Ther. 2000;13(3):285-9. doi: 10.1046/j.1529-8019.2000.00030.x.

  50. Hughes CM, Damon IK, Reynolds MG. Understanding U.S. healthcare providers practices and experiences with molluscum contagiosum. PLOS ONE. 2013;8(10):e76948. doi: 10.1371/journal.pone.0076948, PMID 24155912.

  51. Griffith RD, Yazdani Abyaneh MA, Falto Aizpurua L, Nouri K. Pulsed dye laser therapy for molluscum contagiosum: a systematic review. J Drugs Dermatol. 2014 Nov;13(11):1349-52. PMID 25607701.

  52. Ting PT, Dytoc MT. Therapy of external anogenital warts and molluscum contagiosum: a literature review. Dermatol Ther. 2004 Feb;17(1):68-101. doi: 10.1111/j.1396-0296.2004.04009.x, PMID 14756893.

  53. Bard S, Shiman MI, Bellman B, Connelly EA. Treatment of facial molluscum contagiosum with trichloroacetic acid. Pediatr Dermatol. 2009;26(4):425-6. doi: 10.1111/j.1525-1470.2009.00945.x, PMID 19689517.

  54. Kose O, Ozmen I, Arca E. An open comparative study of 10% potassium hydroxide solution versus salicylic and lactic acid combination in the treatment of molluscum contagiosum in children. J Dermatolog Treat. 2013;24(4):300-4. doi: 10.3109/09546634.2011.649690, PMID 22214282.

  55. Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidintherapy in 300 patients. J Am Acad Dermatol. 2000 Sep;43(3):503-7. doi: 10.1067/mjd.2000.106370, PMID 10954663.

  56. Kose O, Ozmen I, Arca E. An open comparative study of 10% potassium hydroxide solution versus salicylic and lactic acid combination in the treatment of MC in children. J Dermatol Treat. 2012 Jan31;24(4)300-4. doi: 10.3109/09546634.2011.649690.

  57. Semkova K, Palamaras I, Robles W. Hydrogen peroxide 1% cream under occlusion for treatment of molluscum contagiosum in an 8 mo old infant: an effective and safe treatment option. Clin Exp Dermatol. 2014 Jun;39(4):560-1. doi: 10.1111/ced.12344, PMID 24825145.

  58. Dohil M, Prendiville JS. Treatment of MC with oral cimetidine: clinical experience in 13 patients. Pediatr Dermatol. 1996 Jul-Aug;13(4):310-2. doi: 10.1111/j.1525-1470.1996.tb01247.x.

  59. Isaacs SN. Molluscum contagiosum. Available from: https://www.uptodate.com/contents/molluscum‐contagiosum?source=search_resultandsearch=molluscum%20contagiosumandselectedTitle=1~52#H8725830.

  60. Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps candida and trichophyton skin test antigens: a single blinded randomized and controlled trial. Arch Dermatol. 2005;141(5):589-94. doi: 10.1001/archderm.141.5.589, PMID 15897380.

  61. Erickson C, Driscoll M, Gaspari A. Efficacy of intravenous cidofovir in the treatment of giant molluscum contagiosum in a patient with human immunodeficiency virus. Arch Dermatol. 2011 Jun;147(6):652-4. doi: 10.1001/archdermatol.2011.20, PMID 21339417.

  62. Zabawski EJ Jr, Cockerell CJ. Topical cidofovir for molluscum contagiosum in children. Pediatr Dermatol. 1999 Sep-Oct;16(5):414-5. doi: 10.1046/j.1525-1470.1999.016005406.7.x, PMID 10627225.

  63. De Clercq E. Cidofovir in the therapy and short term prophylaxis of poxvirus infections. Trends Pharmacol Sci. 2002;Oct(10):456-8. doi: 10.1016/S0165-6147(02)02091-6, PMID 12368068.

  64. Schwartz JJ, Myskowski PL. Molluscum contagiosum in patients with human immunodeficiency virus infection a review of twenty-seven patients. J Am Acad Dermatol. 1992;27(4):583-8. doi: 10.1016/0190-9622(92)70226-6, PMID 1357010.

  65. Meadows KP, Tyring SK, Pavia AT, Rallis TM. Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus infected patients treated with cidofovir. Arch Dermatol. 1997;133(8):987-90. doi: 10.1001/archderm.1997.03890440061010, PMID 9267245.

  66. Buckley R, Smith K. Topical imiquimod therapy for chronic giant molluscum contagiosum in a patient with advanced human immunodeficiency virus 1 disease. Arch Dermatol. 1999 Oct;135(10):1167-9. doi: 10.1001/archderm.135.10.1167, PMID 10522662.

  67. Hrabie JA, Keefer LK. Chemistry of the nitric oxide releasing diazeniumdiolate (nitrosohydroxylamine) functional group and its oxygen substituted derivatives. Chem Rev. 2002 Apr;102(4):1135-54. doi: 10.1021/cr000028t, PMID 11942789.

  68. Novan Inc. Our science: Nitriciltm; 2024.

  69. LNHC Inc. ZELSUVMI™ (berdazimer topical gel, 10.3%): US prescribing information; 2024.

  70. Ligand Pharmaceuticals Inc. Ligand acquires assets of Novan, Inc. for $12.2 million; 2023.

  71. Ligand Pharmaceuticals Inc. Ligand acquires assets of Novan, Inc. for $12.2 million media release; 2023.

  72. Ligand Pharmaceuticals Inc. U.S. Food and Drug Administration approves ZELSUVMI™ as a first-in-class medication for the treatment of MC; 2024.

  73. Riccio DA, Schoenfisch MH. Nitric oxide release: part I. macromolecular scaffolds. Chem Soc Rev. 2012 May;41(10):3731-41. doi: 10.1039/c2cs15272j, PMID 22362355.

  74. Becker TM, Blount JH, Douglas J, Judson FN. Trends in molluscum contagiosum in the United States 1966-1983. Sex Transm Dis. 1986 Apr-Jun;13(2):88-92. doi: 10.1097/00007435-198604000-00007, PMID 3715678.

  75. Brain KR, Walters KA, James VJ, Dressler WE, Howes D, Kelling CK. Percutaneous penetration of dimethylnitrosamine through human skin in vitro: application from cosmetic vehicles. Food Chem Toxicol. 1995 Apr;33(4):315-22. doi: 10.1016/0278-6915(94)00146-f, PMID 7737604.

  76. Dohil MA, Lin P, Lee J, Lucky AW, Paller AS, Eichenfield LF. The epidemiology of molluscum contagiosum in children. J Am Acad Dermatol. 2006;54(1):47-54. doi: 10.1016/j.jaad.2005.08.035, PMID 16384754.

  77. Hebert AA, Bhatia N, Del Rosso JQ. Molluscum contagiosum: epidemiology considerations treatment options and therapeutic gaps. J Clin Aesthet Dermatol. 2023 Aug;16(8)Suppl 1:S4-S11. PMID 37636018.

  78. Isaacs SN, Hirsch M, Ofori A. Up to date: molluscum contagiosum wolters kluwer health; 2023.

  79. Konya J, Thompson CH. Molluscum contagiosum virus: antibody responses in persons with clinical lesions and seroepidemiology in a representative Australian population. J Infect Dis. 1999 Mar;179(3):701-4. doi: 10.1086/314620, PMID 9952381.