A review of the development of nitric oxide as a topical treatment for cervical intraepithelial neoplasia caused by high-risk human papillomavirus infection
Main Article Content
Abstract
Persistent human papillomavirus (HPV) infection, especially of the high-risk (HR) HPV-16 and HPV-18 types, is linked to anogenital and oropharyngeal cancer. In women, HR-HPV infections of the cervix lead to growth of precancerous cervical intraepithelial neoplasias (CIN) before onset of invasive cervical cancer. Low incidence of widespread, preventive HPV vaccination and the disadvantages of surgical CIN excision (e.g., recurrence rates, pain, and risk of complications in future pregnancies) highlight the need for novel treatments to target HPV infection. Nitric oxide (NO) is a small molecule gaseous species with potent antiviral activity. This review of the preclinical and clinical development of nitric oxide-based topical treatments by Novan, Inc and others supports that NO delivery to the site of infection has the therapeutic potential to manage HPV infection and CIN.
Article Details
How to Cite
RICCIO, Daniel A. et al.
A review of the development of nitric oxide as a topical treatment for cervical intraepithelial neoplasia caused by high-risk human papillomavirus infection.
Medical Research Archives, [S.l.], v. 8, n. 6, june 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2151>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v8i6.2151.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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5. Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology. 2013;445(1-2):232-43.
6. Bzhalava D, Eklund C, Dillner J. International standardization and classification of human papillomavirus types. Virology. 2015;476:341-4.
7. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40(2):80-5.
8. McClung NM, Gargano JW, Park IU, Whitney E, Abdullah N, Ehlers S, et al. Estimated Number of Cases of High-Grade Cervical Lesions Diagnosed Among Women - United States, 2008 and 2016. MMWR Morb Mortal Wkly Rep. 2019;68(15):337-43.
9. McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief. 2017(280):1-8.
10. Yim EK, Park JS. The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat. 2005;37(6):319-24.
11. Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst. 2015;107(6):djv086.
12. Schiffman M, Wentzensen N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(4):553-60.
13. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest. 2006;116(5):1167-73.
14. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol. 2006;208(2):152-64.
15. Gravitt PE, Winer RL. Natural History of HPV Infection across the Lifespan: Role of Viral Latency. Viruses. 2017;9(10).
16. Hoffman SR, Le T, Lockhart A, Sanusi A, Dal Santo L, Davis M, et al. Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review. Int J Cancer. 2017;141(1):8-23.
17. Centers for Disease Control and Prevention. HPV-Associated Cancer Statistics [website]. [updated August 2, 2019; cited 2020. Available from: https://www.cdc.gov/cancer/hpv/statistics/index.htm.
18. Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702.
19. Walker TY, Elam-Evans LD, Yankey D, Markowitz LE, Williams CL, Fredua B, et al. National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2018. MMWR Morb Mortal Wkly Rep. 2019;68(33):718-23.
20. Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health. 2016;4(7):e453-63.
21. Mutombo AB, Simoens C, Tozin R, Bogers J, Van Geertruyden JP, Jacquemyn Y. Efficacy of commercially available biological agents for the topical treatment of cervical intraepithelial neoplasia: a systematic review. Syst Rev. 2019;8(1):132.
22. Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 2011;12(5):441-50.
23. Zhang W, Zhang A, Sun W, Yue Y, Li H. Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia and human papilloma virus infection: A systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore). 2018;97(21):e10864.
24. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-37, 37a-37d.
25. Ignarro LJ. Chapter 1 - Introduction and Overview. In: Ignarro LJ, editor. Nitric Oxide. San Diego: Academic Press; 2000. p. 3-19.
26. Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med. 1998;25(4-5):434-56.
27. Fang FC. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest. 1997;99(12):2818-25.
28. Fang FC. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol. 2004;2(10):820-32.
29. Fang FC, Vazquez-Torres A. Reactive nitrogen species in host-bacterial interactions. Curr Opin Immunol. 2019;60:96-102.
30. Colasanti M, Persichini T, Venturini G, Ascenzi P. S-nitrosylation of viral proteins: molecular bases for antiviral effect of nitric oxide. IUBMB Life. 1999;48(1):25-31.
31. Akaike T, Maeda H. Nitric oxide and virus infection. Immunology. 2000;101(3):300-8.
32. Rahkola P, Vaisanen-Tommiska M, Tuomikoski P, Ylikorkala O, Mikkola TS. Cervical nitric oxide release and persistence of high-risk human papillomavirus in women. Int J Cancer. 2011;128(12):2933-7.
33. Yu L, Sun B, Liu X, He J, Lou H, Chen X, et al. Nitric oxide inhibits the transcription of E6 gene of human papillomavirus. Acta Virol. 2018;62(4):447-53.
34. Sudhesh P, Tamilarasan K, Arumugam P, Berchmans S. Nitric oxide releasing photoresponsive nanohybrids as excellent therapeutic agent for cervical cancer cell lines. ACS Appl Mater Interfaces. 2013;5(17):8263-6.
35. Hrabie JA, Keefer LK. Chemistry of the nitric oxide-releasing diazeniumdiolate ("nitrosohydroxylamine") functional group and its oxygen-substituted derivatives. Chem Rev. 2002;102(4):1135-54.
36. Riccio DA, Schoenfisch MH. Nitric oxide release: part I. Macromolecular scaffolds. Chem Soc Rev. 2012;41(10):3731-41.
37. Shin JH, Schoenfisch MH. Inorganic/Organic Hybrid Silica Nanoparticles as a Nitric Oxide Delivery Scaffold. Chem Mater. 2008;20(1):239-49.
38. Baldwin H, Blanco D, McKeever C, Paz N, Vasquez YN, Quiring J, et al. Results of a Phase 2 Efficacy and Safety Study with SB204, an Investigational Topical Nitric Oxide-releasing Drug for the Treatment of Acne Vulgaris. J Clin Aesthet Dermatol. 2016;9(8):12-8.
39. Eichenfield LF, Gold LS, Nahm WK, Cook-Bolden FE, Pariser DM. Results of a Phase 2, Randomized,Vehicle-Controlled Study Evaluating the Efficacy,Tolerability, and Safety of Daily or Twice Daily SB204 for the Treatment of Acne Vulgaris. J Drugs Dermatol. 2016;15(12):1496-15027.
40. Stasko N, McHale K, Hollenbach SJ, Martin M, Doxey R. Nitric Oxide-Releasing Macromolecule Exhibits Broad-Spectrum Antifungal Activity and Utility as a Topical Treatment for Superficial Fungal Infections. Antimicrob Agents Chemother. 2018;62(7).
41. Hebert AA, Siegfried EC, Durham T, de Leon EN, Reams T, Messersmith E, et al. Efficacy and tolerability of an investigational nitric oxide-releasing topical gel in patients with molluscum contagiosum: A randomized clinical trial. J Am Acad Dermatol. 2020;82(4):887-94.
42. Banerjee NS, Moore DW, Wang HK, Broker TR, Chow LT. NVN1000, a novel nitric oxide-releasing compound, inhibits HPV-18 virus production by interfering with E6 and E7 oncoprotein functions. Antiviral Res. 2019;170:104559.
43. Banerjee NS, Wang H, Moore DW, McHale K, Chow LT, Broker TR. Antiviral Effects of Nitric Oxide-Releasing Drug Candidates in Suppressing Productive Infection of HPV-18 in an Organotypic Epithelial Raft Culture Model System. International Papillomavirus Conference; Feb 28 - Mar 4, 2017; Cape Town, South Africa.
44. Coggan K, Balogh K, Johnston B, Martin M, Zhang Y, Doxey R, et al. Antiviral Efficacy of Nitric Oxide-Releasing Drug Candidates In Vivo Utlilizing the Cotttontail Rabbit Papillomavirus Model. Interscience Conference on Antimicrobial Agents and Chemotherapy; 05 Sept 2014 - 09 Sept 2014; Washington, D.C.
45. McHale KA, Balogh K, Wang H, Hollenbach S, Christensen N, Chow L, et al. 536 In vitro and in vivo efficacy of nitric oxide-releasing antiviral therapeutic agents. Journal of Investigative Dermatology. 2016;136(5):S95.
46. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. Jama. 2007;297(8):813-9.
47. Rosen T, Nelson A, Ault K. Imiquimod cream 2.5% and 3.75% applied once daily to treat external genital warts in men. Cutis. 2015;96(4):277-82.
48. Kjaer SK, Tran TN, Sparen P, Tryggvadottir L, Munk C, Dasbach E, et al. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007;196(10):1447-54.
49. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102(5a):3-8.
50. Safi F, Bekdache O, Al-Salam S, Alashari M, Mazen T, El-Salhat H. Management of peri-anal giant condyloma acuminatum--a case report and literature review. Asian J Surg. 2013;36(1):43-52.
51. Aubin F, Pretet JL, Jacquard AC, Saunier M, Carcopino X, Jaroud F, et al. Human papillomavirus genotype distribution in external acuminata condylomata: a Large French National Study (EDiTH IV). Clin Infect Dis. 2008;47(5):610-5.
52. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH. Detection of multiple human papillomavirus types in Condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol. 1999;37(10):3316-22.
53. Greer CE, Wheeler CM, Ladner MB, Beutner K, Coyne MY, Liang H, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol. 1995;33(8):2058-63.
54. Garland SM, Steben M, Sings HL, James M, Lu S, Railkar R, et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis. 2009;199(6):805-14.
55. Tyring SK, Rosen T, Berman B, Stasko N, Durham T, Maeda-Chubachi T. A Phase 2 Controlled Study of SB206, a Topical Nitric Oxide-Releasing Drug for Extragenital Wart Treatment. J Drugs Dermatol. 2018;17(10):1100-5.
2. Small W, Jr., Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, et al. Cervical cancer: A global health crisis. Cancer. 2017;123(13):2404-12.
3. Galloway DA, Laimins LA. Human papillomaviruses: shared and distinct pathways for pathogenesis. Curr Opin Virol. 2015;14:87-92.
4. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.
5. Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology. 2013;445(1-2):232-43.
6. Bzhalava D, Eklund C, Dillner J. International standardization and classification of human papillomavirus types. Virology. 2015;476:341-4.
7. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related diseases and cancers. New Microbiol. 2017;40(2):80-5.
8. McClung NM, Gargano JW, Park IU, Whitney E, Abdullah N, Ehlers S, et al. Estimated Number of Cases of High-Grade Cervical Lesions Diagnosed Among Women - United States, 2008 and 2016. MMWR Morb Mortal Wkly Rep. 2019;68(15):337-43.
9. McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief. 2017(280):1-8.
10. Yim EK, Park JS. The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat. 2005;37(6):319-24.
11. Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst. 2015;107(6):djv086.
12. Schiffman M, Wentzensen N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(4):553-60.
13. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest. 2006;116(5):1167-73.
14. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol. 2006;208(2):152-64.
15. Gravitt PE, Winer RL. Natural History of HPV Infection across the Lifespan: Role of Viral Latency. Viruses. 2017;9(10).
16. Hoffman SR, Le T, Lockhart A, Sanusi A, Dal Santo L, Davis M, et al. Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review. Int J Cancer. 2017;141(1):8-23.
17. Centers for Disease Control and Prevention. HPV-Associated Cancer Statistics [website]. [updated August 2, 2019; cited 2020. Available from: https://www.cdc.gov/cancer/hpv/statistics/index.htm.
18. Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702.
19. Walker TY, Elam-Evans LD, Yankey D, Markowitz LE, Williams CL, Fredua B, et al. National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2018. MMWR Morb Mortal Wkly Rep. 2019;68(33):718-23.
20. Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health. 2016;4(7):e453-63.
21. Mutombo AB, Simoens C, Tozin R, Bogers J, Van Geertruyden JP, Jacquemyn Y. Efficacy of commercially available biological agents for the topical treatment of cervical intraepithelial neoplasia: a systematic review. Syst Rev. 2019;8(1):132.
22. Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 2011;12(5):441-50.
23. Zhang W, Zhang A, Sun W, Yue Y, Li H. Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia and human papilloma virus infection: A systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore). 2018;97(21):e10864.
24. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-37, 37a-37d.
25. Ignarro LJ. Chapter 1 - Introduction and Overview. In: Ignarro LJ, editor. Nitric Oxide. San Diego: Academic Press; 2000. p. 3-19.
26. Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med. 1998;25(4-5):434-56.
27. Fang FC. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest. 1997;99(12):2818-25.
28. Fang FC. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol. 2004;2(10):820-32.
29. Fang FC, Vazquez-Torres A. Reactive nitrogen species in host-bacterial interactions. Curr Opin Immunol. 2019;60:96-102.
30. Colasanti M, Persichini T, Venturini G, Ascenzi P. S-nitrosylation of viral proteins: molecular bases for antiviral effect of nitric oxide. IUBMB Life. 1999;48(1):25-31.
31. Akaike T, Maeda H. Nitric oxide and virus infection. Immunology. 2000;101(3):300-8.
32. Rahkola P, Vaisanen-Tommiska M, Tuomikoski P, Ylikorkala O, Mikkola TS. Cervical nitric oxide release and persistence of high-risk human papillomavirus in women. Int J Cancer. 2011;128(12):2933-7.
33. Yu L, Sun B, Liu X, He J, Lou H, Chen X, et al. Nitric oxide inhibits the transcription of E6 gene of human papillomavirus. Acta Virol. 2018;62(4):447-53.
34. Sudhesh P, Tamilarasan K, Arumugam P, Berchmans S. Nitric oxide releasing photoresponsive nanohybrids as excellent therapeutic agent for cervical cancer cell lines. ACS Appl Mater Interfaces. 2013;5(17):8263-6.
35. Hrabie JA, Keefer LK. Chemistry of the nitric oxide-releasing diazeniumdiolate ("nitrosohydroxylamine") functional group and its oxygen-substituted derivatives. Chem Rev. 2002;102(4):1135-54.
36. Riccio DA, Schoenfisch MH. Nitric oxide release: part I. Macromolecular scaffolds. Chem Soc Rev. 2012;41(10):3731-41.
37. Shin JH, Schoenfisch MH. Inorganic/Organic Hybrid Silica Nanoparticles as a Nitric Oxide Delivery Scaffold. Chem Mater. 2008;20(1):239-49.
38. Baldwin H, Blanco D, McKeever C, Paz N, Vasquez YN, Quiring J, et al. Results of a Phase 2 Efficacy and Safety Study with SB204, an Investigational Topical Nitric Oxide-releasing Drug for the Treatment of Acne Vulgaris. J Clin Aesthet Dermatol. 2016;9(8):12-8.
39. Eichenfield LF, Gold LS, Nahm WK, Cook-Bolden FE, Pariser DM. Results of a Phase 2, Randomized,Vehicle-Controlled Study Evaluating the Efficacy,Tolerability, and Safety of Daily or Twice Daily SB204 for the Treatment of Acne Vulgaris. J Drugs Dermatol. 2016;15(12):1496-15027.
40. Stasko N, McHale K, Hollenbach SJ, Martin M, Doxey R. Nitric Oxide-Releasing Macromolecule Exhibits Broad-Spectrum Antifungal Activity and Utility as a Topical Treatment for Superficial Fungal Infections. Antimicrob Agents Chemother. 2018;62(7).
41. Hebert AA, Siegfried EC, Durham T, de Leon EN, Reams T, Messersmith E, et al. Efficacy and tolerability of an investigational nitric oxide-releasing topical gel in patients with molluscum contagiosum: A randomized clinical trial. J Am Acad Dermatol. 2020;82(4):887-94.
42. Banerjee NS, Moore DW, Wang HK, Broker TR, Chow LT. NVN1000, a novel nitric oxide-releasing compound, inhibits HPV-18 virus production by interfering with E6 and E7 oncoprotein functions. Antiviral Res. 2019;170:104559.
43. Banerjee NS, Wang H, Moore DW, McHale K, Chow LT, Broker TR. Antiviral Effects of Nitric Oxide-Releasing Drug Candidates in Suppressing Productive Infection of HPV-18 in an Organotypic Epithelial Raft Culture Model System. International Papillomavirus Conference; Feb 28 - Mar 4, 2017; Cape Town, South Africa.
44. Coggan K, Balogh K, Johnston B, Martin M, Zhang Y, Doxey R, et al. Antiviral Efficacy of Nitric Oxide-Releasing Drug Candidates In Vivo Utlilizing the Cotttontail Rabbit Papillomavirus Model. Interscience Conference on Antimicrobial Agents and Chemotherapy; 05 Sept 2014 - 09 Sept 2014; Washington, D.C.
45. McHale KA, Balogh K, Wang H, Hollenbach S, Christensen N, Chow L, et al. 536 In vitro and in vivo efficacy of nitric oxide-releasing antiviral therapeutic agents. Journal of Investigative Dermatology. 2016;136(5):S95.
46. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. Jama. 2007;297(8):813-9.
47. Rosen T, Nelson A, Ault K. Imiquimod cream 2.5% and 3.75% applied once daily to treat external genital warts in men. Cutis. 2015;96(4):277-82.
48. Kjaer SK, Tran TN, Sparen P, Tryggvadottir L, Munk C, Dasbach E, et al. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007;196(10):1447-54.
49. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102(5a):3-8.
50. Safi F, Bekdache O, Al-Salam S, Alashari M, Mazen T, El-Salhat H. Management of peri-anal giant condyloma acuminatum--a case report and literature review. Asian J Surg. 2013;36(1):43-52.
51. Aubin F, Pretet JL, Jacquard AC, Saunier M, Carcopino X, Jaroud F, et al. Human papillomavirus genotype distribution in external acuminata condylomata: a Large French National Study (EDiTH IV). Clin Infect Dis. 2008;47(5):610-5.
52. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH. Detection of multiple human papillomavirus types in Condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol. 1999;37(10):3316-22.
53. Greer CE, Wheeler CM, Ladner MB, Beutner K, Coyne MY, Liang H, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol. 1995;33(8):2058-63.
54. Garland SM, Steben M, Sings HL, James M, Lu S, Railkar R, et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis. 2009;199(6):805-14.
55. Tyring SK, Rosen T, Berman B, Stasko N, Durham T, Maeda-Chubachi T. A Phase 2 Controlled Study of SB206, a Topical Nitric Oxide-Releasing Drug for Extragenital Wart Treatment. J Drugs Dermatol. 2018;17(10):1100-5.