Imiquimod

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Imiquimod
Imiquimod.svg
Systematic (IUPAC) name
3-(2-methylpropyl)-3,5,8-triazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,7,10,12-hexaen-7-amine
Clinical data
Trade names Aldara
AHFS/Drugs.com monograph
MedlinePlus a698010
Licence data EMA:Link, US FDA:link
Pregnancy cat. B1 (AU) C (US)
Legal status POM (UK) -only (US)
Routes Topical
Pharmacokinetic data
Half-life 30 hours (topical dose), 2 hours (subcutaneous dose)
Identifiers
CAS number 99011-02-6 YesY
ATC code D06BB10
PubChem CID 57469
DrugBank DB00724
ChemSpider 51809 YesY
UNII P1QW714R7M YesY
KEGG D02500 YesY
ChEBI CHEBI:36704 YesY
ChEMBL CHEMBL1282 YesY
Synonyms 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
Chemical data
Formula C14H16N4 
Mol. mass 240.304 g/mol
 YesY (what is this?)  (verify)

Imiquimod (INN) is a prescription medication that acts as an immune response modifier. It is marketed by Meda AB, Graceway Pharmaceuticals, and iNova Pharmaceuticals under the trade names Aldara and Zyclara, and by Mochida as Beselna. It is also referred to as R-837. Due to the bankruptcy of Graceway in 2011, Medicis Pharmaceutical Corporation is the current owner of these products.

History[edit]

The original FDA approval was on February 27, 1997, FDA Application No. (NDA) 020723, by 3M. Imiquimod is approved for the uses described below under Uses. Adverse side effects have been reported, in some cases serious and systemic, resulting in the revision of warning labels.

Uses[edit]

Imiquimod is a patient-applied cream used to treat certain diseases of the skin, including skin cancers (basal cell carcinoma, Bowen's disease,[1] superficial squamous cell carcinoma, some superficial malignant melanomas, and actinic keratosis) as well as genital warts (condylomata acuminata). However, Imiquimod is generally secondary to surgery, because surgery has a better chance to effectively treat at least some forms of skin cancer.[2]

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.[3]

Imiquiomd has also been tested for treatment of vulvar intraepithelial neoplasia, common warts that have proven difficult to treat,[4] and vaginal intraepithelial neoplasia.[5]

Outstanding cosmetic result has resulted from the treatment of both large superficial basal cell carcinoma and squamous cell carcinoma in-situ, but the morbidity and discomfort of the treatment can be severe, and can very occasionally result in some degree of permanent[citation needed] mild scarring. Focal recurrence of tumor has been seen after imiquimod treatment, but appear to be amenable to surgical excision.

Imiquimod can also cause subclinical lesions to become visible and to be killed by the immune system. Photographs of actinic keratosis and superficial basal cell carcinomas before, during and after treatment show the unmasking of subclinical disease.[6] The more-concentrated (5%) Imiquimod cream needs to be applied on and off for 4 months, while the less concentrated (3.75%) Imiquimod cream needs to be applied on and off for a number of months to be determined by the doctor.[7]

Imiquimod is more likely to cure skin disease that is identified earlier.[citation needed]

Mechanism of action[edit]

It is known that imiquimod signals to the innate arm of the immune system through the toll-like receptor 7 (TLR7), commonly involved in pathogen recognition.[8][9] Cells activated by imiquimod via TLR-7 secrete cytokines (primarily interferon-α (INF-α), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)).[10] 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.[11] Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes.[11]

New research has shown that imiquimod has anti-proliferative effects in vitro that are independent of immune system activation or function. However, those effects do not apply to skin cancer cells.[citation needed]

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.[12]

Disadvantages[edit]

Imiquimod effect on forehead
interim effect from broad use on a forehead and temple that have many lesions; such effect typically disappears fully

Nonspecific inflammation and dermatitis can occur during use of imiquimod for genital warts and molluscum.[citation needed] This often occurs where the skin is traumatized from scratching or between skin folds. Blisters, bloody dry eschar, pain, and discomfort often follows the use of imiquimod for skin cancers and precancerous growths.[citation needed] During the treatment of large superficial basal cell carcinoma or squamous cell cancer in situ, areas of black dried crust often form.[citation needed] Many individuals with extensive actinic keratoses cannot tolerate the resulting reaction.[13][unreliable medical source?] Fortunately, despite frequent significant inflammation, the areas treated generally heal well with no scarring.[citation needed]

Recurrence of skin cancer can occur with imiquimod, but often appears to be localized. It is more common when there are deeply penetrating nests of tumor cells such as in nodular basal cell carcinoma.[medical citation needed] However, nodular basal cell carcinomas should generally not be treated with imiquimod.[citation needed] Recurrence of superficial basal cell carcinomas can be treated by repeat courses of imiquimod, surgically by simple local excision or by Mohs' micrographic surgery. The recurrence rate depends on the condition being treated and the frequency of topical imiquimod application. A 6-week study on 99 patients with superficial basal cell carcinomas found success rates of 100%, 88%, 73% and 70% for twice daily, once daily, 6 times weekly and 3 times weekly application, respectively.[14]

Other side effects include headaches, back pain, muscle aches, tiredness, flu-like symptoms, swollen lymph nodes, diarrhea, and fungal infections.[15]

Synthesis[edit]

Imiquimod can be prepared from 4-chloro-3-nitroquinoline.[16]

Imiquimod.png

See also[edit]

References[edit]

  1. ^ van Egmond S, Hoedemaker C, Sinclair R (2006). "Successful treatment of perianal Bowen's disease with imiquimod". Int J Dermatol 46 (3): 318–9. doi:10.1111/j.1365-4632.2007.03200.x. PMID 17343595. 
  2. ^ 'Imiquimod should be used for treatment of [superficial basal cell carcinoma] only when surgery is medically less appropriate ... .' USA Food And Drug Administration, 'FDA Approval for Imiquimod', [1], current at 2011-Jan-1, accessed 2012-Oct-19
  3. ^ Aldara (imiquimod) cream for topical use. Prescribing information. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7fccca4e-fb8f-42b8-9555-8f78a5804ed3
  4. ^ van Seters M, van Beurden M, ten Kate FJ, et al. (April 2008). "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". The New England Journal of Medicine 358 (14): 1465–73. doi:10.1056/NEJMoa072685. PMID 18385498. 
  5. ^ 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): 290–3. doi:10.1097/00128360-200310000-00011. PMID 17051086. 
  6. ^ Photographs before, during, and after imiquimod therapy for actinic keratosis and basal cell carcinoma
  7. ^ American Cancer Society, Guide To Cancer Drugs, [2] (accessed 2014-Apr-28)
  8. ^ http://www.ncbi.nlm.nih.gov/pubmed/23463003
  9. ^ Hemmi H. et al. (February 2002). "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol.. '". 2002' 3 (2): 196–200. doi:10.1038/ni758. PMID 11812998. 
  10. ^ Bilu D, Sauder DN (November 2003). "Imiquimod: modes of action". Br. J. Dermatol. 149 Suppl 66: 5–8. doi:10.1046/j.0366-077x.2003.05628.x. PMID 14616337. 
  11. ^ a b Miller R.L. et al. (January 1999). "Imiquimod applied topically: a novel immune response modifier and a new class of drug. Int J Immunopharmacol". 1999 Jan;' 21 (1): 1–14. doi:10.1016/s0192-0561(98)00068-x. PMID 10411278. 
  12. ^ 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". Exp. Biol. Med. (Maywood) 233 (8): 968–79. doi:10.3181/0802-RM-58. PMID 18480416. 
  13. ^ John Welbes, (13 Feb 2006). "Texan Blames Aldara for Ailments: He Settled Lawsuit but Continues Campaign Against 3M Skin Cream Though Web Site". Pioneer Press, St. Paul, Minn. Retrieved 13 April 2011. 
  14. ^ Advances in the use of topical imiquimod to treat dermatologic disorders
  15. ^ Aldara website, What are the possible side effects of Aldara Cream?
  16. ^ Gertser, J. F.; 1985, EP 0145340 

External links[edit]