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Imiquimod

Clinical data
Trade names	Aldara, others
Other names	1-isobutyl-1H-imidazoquinolin-4-amine
AHFS/Drugs.com	Monograph
MedlinePlus	a698010
License data	EU EMA: by INN US DailyMed: Imiquimod
Pregnancy category	AU: B1
Routes of administration	Topical
ATC code	D06BB10 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: WARNINGRx-only EU: Rx-only
Pharmacokinetic data
Elimination half-life	30 hours (topical dose), 2 hours (subcutaneous dose)
Identifiers
IUPAC name 3-(2-Methylpropyl)-3,5,8-triazatricyclotrideca-1(9),2(6),4,7,10,12-hexaen-7-amine
CAS Number	99011-02-6
PubChem CID	57469
IUPHAR/BPS	5003
DrugBank	DB00724
ChemSpider	51809
UNII	P1QW714R7M
KEGG	D02500
ChEBI	CHEBI:36704
ChEMBL	ChEMBL1282
CompTox Dashboard (EPA)	DTXSID7041047
ECHA InfoCard	100.131.047
Chemical and physical data
Formula	C14H16N4
Molar mass	240.310 g·mol
3D model (JSmol)	Interactive image
SMILES n3c1ccccc1c2c(ncn2CC(C)C)c3N
InChI InChI=1S/C14H16N4/c1-9(2)7-18-8-16-12-13(18)10-5-3-4-6-11(10)17-14(12)15/h3-6,8-9H,7H2,1-2H3,(H2,15,17) Key:DOUYETYNHWVLEO-UHFFFAOYSA-N
(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.

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.

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, as well as actinic keratosis.

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

• external genital and perianal warts (condylomata acuminata) in adults;
• small superficial basal-cell carcinomas (sBCCs) in adults;
• 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.

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.

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.

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

Mechanism of action

Imiquimod yields profound antitumoral activity by acting on several immunological levels synergistically. Imiquimod stimulates the innate immune system by activating toll-like receptor 7 (TLR7), commonly involved in pathogen recognition. 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)). 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. Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes.

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.

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. 3M obtained the first FDA approval for it in 1997 as a treatment for external genital and perianal warts under the brand "Aldara". In 2004, 3M obtained FDA approval to market imiquimod as a treatment for superficial basal cell carcinoma.

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.

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.

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

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

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.

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. These disprove earlier anecdotal claims and smaller, less reliable studies.

Imiquimod has also been tested for treatment of vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, common warts (a 2012 Cochrane review found no randomized controlled trials), plantar warts, warts in people with suppressed immune systems, flat warts on face and neck, and warts under and around fingernails and toenails. 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.

References

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7. "FDA Approval for Imiquimod". U.S. Food And Drug Administration. 1 January 2011. Archived from the original on 6 April 2015. Retrieved 19 October 2012. Imiquimod should be used for treatment of only when surgery is medically less appropriate
8. "Imiquimod Cream". Guide To Cancer Drugs. American Cancer Society. Archived from the original on 7 February 2015. Retrieved 28 April 2014.
9. ^ European Medicines Agency. First published 14 September 2009, updated 25 March 2015. EMA Summary of Product Characteristics Archived 25 September 2017 at the Wayback Machine
10. ^ "Aldara EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
11. ^ "Zyclara EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
12. PDR Health PDR: Aldara
13. Schön MP, Schön M (December 2007). "Imiquimod: mode of action". The British Journal of Dermatology. 157 (Suppl 2): 8–13. doi:10.1111/j.1365-2133.2007.08265.x. PMID 18067624. S2CID 36643157.
14. Walter A, Schäfer M, Cecconi V, Matter C, Urosevic-Maiwald M, Belloni B, et al. (2013). "Aldara activates TLR7-independent immune defence". Nature Communications. 4: 1560. Bibcode:2013NatCo...4.1560W. doi:10.1038/ncomms2566. PMID 23463003.
15. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. (February 2002). "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway". Nature Immunology. 3 (2): 196–200. doi:10.1038/ni758. PMID 11812998. S2CID 1694900.
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18. Zagon IS, Donahue RN, Rogosnitzky M, McLaughlin PJ (August 2008). "Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function". Experimental Biology and Medicine. 233 (8): 968–979. doi:10.3181/0802-RM-58. PMID 18480416. S2CID 35164284.
19. 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
20. Centerwatch. Centerwatch:Aldara (imiquimod) Page accessed 14 June 2015
21. "NCI: FDA Approval for Imiquimod". National Cancer Institute. 3 July 2013. Archived from the original on 23 January 2018.
22. "Press release: 3M Reaches Agreements to Sell its Pharmaceuticals Business]". 3M. 9 November 2006. Archived from the original on 21 August 2019.
23. Johnson JA (29 November 2011). "Medicis buys Graceway Pharmaceuticals for $455M". The Phoenix Business Journal.
24. Clinical trial number NCT00735462 for "Phase 3 Study of Imiquimod Creams in the Treatment of External Genital Warts" at ClinicalTrials.gov
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26. Molluscum Contagiosum~treatment at eMedicine
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29. Arican O (August 2006). "Topical treatment of molluscum contagiosum with imiquimod 5% cream in Turkish children". Pediatrics International. 48 (4): 403–405. doi:10.1111/j.1442-200X.2006.02229.x. PMID 16911087. S2CID 2867793.
30. van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, et al. (April 2008). "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". The New England Journal of Medicine. 358 (14): 1465–1473. doi:10.1056/NEJMoa072685. PMID 18385498.
31. Buck HW, Guth KJ (October 2003). "Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream". Journal of Lower Genital Tract Disease. 7 (4): 290–293. doi:10.1097/00128360-200310000-00011. PMID 17051086. S2CID 44649376.
32. Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R (September 2012). "Topical treatments for cutaneous warts". The Cochrane Database of Systematic Reviews. 2012 (9): CD001781. doi:10.1002/14651858.CD001781.pub3. PMC 8101088. PMID 22972052.
33. ^ "Imiquimod for non-genital cutaneous warts". www.dpic.org.
34. Harwood CA, Perrett CM, Brown VL, Leigh IM, McGregor JM, Proby CM (January 2005). "Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals". The British Journal of Dermatology. 152 (1): 122–129. doi:10.1111/j.1365-2133.2005.06322.x. PMID 15656812. S2CID 42369353.
35. Ahn CS, Huang WW (October 2014). "Imiquimod in the treatment of cutaneous warts: an evidence-based review". American Journal of Clinical Dermatology. 15 (5): 387–399. doi:10.1007/s40257-014-0093-5. PMID 25186654. S2CID 26624740.

External links

• DermNet treatments/imiquimod

• Medicine

• Antiviral drugs
• Antineoplastic drugs
• Imidazoquinolines
• Isobutyl compounds