Chemistry:Imiquimod

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Short description: Chemical compound
Imiquimod
Imiquimod.svg
Clinical data
Trade namesAldara, others[1]
Other names1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
AHFS/Drugs.comMonograph
MedlinePlusa698010
License data
Pregnancy
category
Routes of
administration		Topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life30 hours (topical dose), 2 hours (subcutaneous dose)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC14H16N4
Molar mass240.310 g·mol−1
3D model (JSmol)
  (verify)

Imiquimod, sold under the brand name Aldara among others, is a medication that acts as an immune response modifier that is used to treat genital warts, superficial basal cell carcinoma, and actinic keratosis.[3]

Scientists at 3M's pharmaceuticals division discovered the drug and 3M obtained the first FDA approval in 1997. As of 2015, imiquimod is generic and is available worldwide under many brands. In 2021, it was the 290th most commonly prescribed medication in the United States, with more than 600,000 prescriptions.[4][5]

Medical uses

Imiquimod is a patient-applied cream prescribed to treat genital warts, Bowens disease (squamous cell carcinoma in situ), and, secondary to surgery, for basal cell carcinoma,[6][7] as well as actinic keratosis.[8]

Imiquimod 5% cream is indicated for the topical treatment of:

  • external genital and perianal warts (condylomata acuminata) in adults;[9]
  • small superficial basal-cell carcinomas (sBCCs) in adults;[9]
  • clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratoses (AKs) on the face or scalp in immunocompetent adults when size or number of lesions limit the efficacy and / or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate.[9]

Imiquimod 3.75% cream is indicated for the topical treatment of clinically typical, non-hyperkeratotic, non-hypertrophic, visible or palpable actinic keratosis of the full face or balding scalp in immunocompetent adults when other topical treatment options are contraindicated or less appropriate.[10]

Side effects

Side effects include local inflammatory reactions, such as blisters, a burning sensation, skin redness, dry skin, itching, skin breakdown, skin crusting or scabbing, skin drainage, skin flaking or scaling, skin ulceration, sores, swelling, as well as systemic reactions, such as fever, "flu-like" symptoms, headache, and tiredness.[8][11]

People who have had an organ transplant and are taking immune-suppressing drugs should not use imiquimod.[8]

Mechanism of action

Imiquimod yields profound antitumoral activity by acting on several immunological levels synergistically.[12] Imiquimod stimulates the innate immune system by activating toll-like receptor 7 (TLR7), commonly involved in pathogen recognition.[13][14] Cells activated by imiquimod via TLR-7 secrete cytokines (primarily interferon-α (IFN-α), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)).[15] There is evidence that imiquimod, when applied to skin, can lead to the activation of Langerhans cells, which subsequently migrate to local lymph nodes to activate the adaptive immune system.[16] Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes.[16]

Imiquimod exerts its effect by increasing levels of the opioid growth factor receptor (OGFr). In experiments, blocking OGFr function with siRNA technology resulted in loss of any antiproliferative effect of imiquimod.[17]

History

Scientists at 3M's pharmaceutical division discovered imiquimod as part of a program to discover inhibitors of herpes simplex virus replication based on a known adenine derivative.[18]:369–372 3M obtained the first FDA approval for it in 1997 as a treatment for external genital and perianal warts under the brand "Aldara".[19] In 2004, 3M obtained FDA approval to market imiquimod as a treatment for superficial basal cell carcinoma.[20]

In 2006, 3M sold its pharmaceutical business in the Americas to Graceway Pharmaceuticals, its European pharmaceutical business to Meda AB, and its pharmaceutical business in other territories to two private equity firms.[21]

Graceway declared bankruptcy in 2011, after the expiration of the patents on imiquimod, and its assets, including the rights to imiquimod branding and approvals in the Americas, were purchased by Medicis Pharmaceutical.[22]

Imiquimod 5% was approved for medical use in the European Union in September 1998.[9] Imiquimod 3.75% was approved for medical use in the European Union in August 2012.[10]

As of 2015, imiquimod is generic and is available worldwide under many brands.[1]

Research

One randomized double-blind Phase III clinical study found clearance of genital warts (an FDA-approved indication) improved from 9% with placebo to 24.9% with 3.75% imiquimod cream applied for up to eight weeks.[23]

Imiquimod has been tested for treatment of molluscum contagiosum. Two large randomized controlled trials, however, found no evidence of effectiveness of imiquimod in treating children with molluscum contagiosum, and concerning adverse effects were also noted.[24] These disprove earlier anecdotal claims and smaller, less reliable studies.[25][26][27][28]

Imiquimod has also been tested for treatment of vulvar intraepithelial neoplasia,[29] vaginal intraepithelial neoplasia,[30] common warts (a 2012 Cochrane review found no randomized controlled trials),[31] plantar warts,[32] warts in people with suppressed immune systems,[33] flat warts on face and neck,[32] and warts under and around fingernails and toenails.[32] As of 2014, insufficient evidence exists to recommend treatment of warts (other than genital warts) with imiquimod, due to the small size of and lack of controls in existing studies.[34][32]

References

  1. ↑ 1.0 1.1 Drugs.com Drugs.com international listings for imiquimod Page accessed 14 June 2015
  2. ↑ "Imiquimod topical Use During Pregnancy". 29 May 2019. https://www.drugs.com/pregnancy/imiquimod-topical.html. 
  3. ↑ "Imiquimod Topical". National Library of Medicine. https://medlineplus.gov/druginfo/meds/a698010.html. 
  4. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  5. ↑ "Imiquimod - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Imiquimod. 
  6. ↑ "FDA Approval for Imiquimod". U.S. Food And Drug Administration. 1 January 2011. http://www.cancer.gov/cancertopics/druginfo/fda-imiquimod. "Imiquimod should be used for treatment of [superficial basal cell carcinoma] only when surgery is medically less appropriate" 
  7. ↑ "Imiquimod Cream". Guide To Cancer Drugs. American Cancer Society. http://www.cancer.org/treatment/treatmentsandsideeffects/guidetocancerdrugs/imiquimod-cream. 
  8. ↑ 8.0 8.1 8.2 European Medicines Agency. First published 14 September 2009, updated 25 March 2015. EMA Summary of Product Characteristics
  9. ↑ 9.0 9.1 9.2 9.3 "Aldara EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/aldara.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. ↑ 10.0 10.1 "Zyclara EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/zyclara.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ↑ PDR Health PDR: Aldara
  12. ↑ "Imiquimod: mode of action". The British Journal of Dermatology 157 (Suppl 2): 8–13. December 2007. doi:10.1111/j.1365-2133.2007.08265.x. PMID 18067624. 
  13. ↑ "Aldara activates TLR7-independent immune defence". Nature Communications 4: 1560. 2013. doi:10.1038/ncomms2566. PMID 23463003. Bibcode: 2013NatCo...4.1560W. 
  14. ↑ "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway". Nature Immunology 3 (2): 196–200. February 2002. doi:10.1038/ni758. PMID 11812998. 
  15. ↑ "Imiquimod: modes of action". The British Journal of Dermatology 149 (Suppl 66): 5–8. November 2003. doi:10.1046/j.0366-077x.2003.05628.x. PMID 14616337. 
  16. ↑ 16.0 16.1 "Imiquimod applied topically: a novel immune response modifier and new class of drug". International Journal of Immunopharmacology 21 (1): 1–14. January 1999. doi:10.1016/s0192-0561(98)00068-x. PMID 10411278. 
  17. ↑ "Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function". Experimental Biology and Medicine 233 (8): 968–979. August 2008. doi:10.3181/0802-RM-58. PMID 18480416. 
  18. ↑ Randall L. Halcomb. TLR-7 Agonists for the Treatment of Viral Hepatitis. Chapter 10 in Successful Strategies for the Discovery of Antiviral Drugs. Issue 32 of RSC drug discovery series. Eds Manoj C. Desai and Nicholas A. Meanwell. Royal Society of Chemistry, 2013. ISBN:9781849736572
  19. ↑ Centerwatch. Centerwatch:Aldara (imiquimod) Page accessed 14 June 2015
  20. ↑ "NCI: FDA Approval for Imiquimod". National Cancer Institute. 3 July 2013. http://www.cancer.gov/about-cancer/treatment/drugs/fda-imiquimod. 
  21. ↑ "Press release: 3M Reaches Agreements to Sell its Pharmaceuticals Business"]. 3M. 9 November 2006. https://news.3m.com/press-release/company/3m-reaches-agreements-sell-its-pharmaceuticals-business. 
  22. ↑ "Medicis buys Graceway Pharmaceuticals for $455M". The Phoenix Business Journal. 29 November 2011. https://www.bizjournals.com/phoenix/news/2011/11/29/medicis-buys-graceway-pharmaceuticals.html?page=all. 
  23. ↑ Clinical trial number NCT00735462 for "Phase 3 Study of Imiquimod Creams in the Treatment of External Genital Warts" at ClinicalTrials.gov
  24. ↑ "Aldara (imiquimod) cream for topical use. Prescribing information.". http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7fccca4e-fb8f-42b8-9555-8f78a5804ed3. 
  25. ↑ Molluscum Contagiosum~treatment at eMedicine
  26. ↑ "Effectiveness of imiquimod cream 5% for treating childhood molluscum contagiosum in a double-blind, randomized pilot trial". Cutis 74 (2): 134–8, 141–2. August 2004. PMID 15379366. 
  27. ↑ "Experience in treating molluscum contagiosum in children with imiquimod 5% cream". The British Journal of Dermatology 149 (Suppl 66): 25–29. November 2003. doi:10.1046/j.0366-077x.2003.05631.x. PMID 14616342. 
  28. ↑ "Topical treatment of molluscum contagiosum with imiquimod 5% cream in Turkish children". Pediatrics International 48 (4): 403–405. August 2006. doi:10.1111/j.1442-200X.2006.02229.x. PMID 16911087. 
  29. ↑ "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". The New England Journal of Medicine 358 (14): 1465–1473. April 2008. doi:10.1056/NEJMoa072685. PMID 18385498. 
  30. ↑ "Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream". Journal of Lower Genital Tract Disease 7 (4): 290–293. October 2003. doi:10.1097/00128360-200310000-00011. PMID 17051086. 
  31. ↑ "Topical treatments for cutaneous warts". The Cochrane Database of Systematic Reviews 2012 (9): CD001781. September 2012. doi:10.1002/14651858.CD001781.pub3. PMID 22972052. 
  32. ↑ 32.0 32.1 32.2 32.3 "Imiquimod for non-genital cutaneous warts". http://www.dpic.org/article/professional/imiquimod-non-genital-cutaneous-warts. 
  33. ↑ "Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals". The British Journal of Dermatology 152 (1): 122–129. January 2005. doi:10.1111/j.1365-2133.2005.06322.x. PMID 15656812. 
  34. ↑ "Imiquimod in the treatment of cutaneous warts: an evidence-based review". American Journal of Clinical Dermatology 15 (5): 387–399. October 2014. doi:10.1007/s40257-014-0093-5. PMID 25186654. 

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