Imiquimod
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| 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  |
| ATC code | D06BB10 |
| PubChem | CID 57469 |
| DrugBank | APRD01030 |
| ChemSpider | 51809 |
| UNII | P1QW714R7M |
| KEGG | D02500 |
| ChEBI | CHEBI:36704 |
| ChEMBL | CHEMBL1282 |
| Synonyms | 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
| Chemical data | |
| Formula | C14H16N4 |
| Mol. mass | 240.304 g/mol |
| SMILES | eMolecules & PubChem |
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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.
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[edit] History
The original FDA approval was on February 27, 1997, FDA Application No. (NDA) 020723, by 3M. Imiquimod is approved to treat actinic keratosis, superficial basal cell carcinoma, and external genital warts. Adverse side effects have been reported, in some cases serious and systemic, resulting in the revision of warning labels.
[edit] Uses
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). It has also been tested for treatment of molluscum contagiosum, vulvar intraepithelial neoplasia, common warts that have proven difficult to treat,[2] and vaginal intraepithelial neoplasia.[3] 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. 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. This unmasking effect is felt to be of clinical benefit as lesions that may have otherwise have been missed are being treated. Photographs of actinic keratosis and basal cell carcinomas before, during and after treatment show the unmasking of subclinical disease.[4]
[edit] Mechanism of action
The exact mechanism of action in which imiquimod and its analogs activate the immune system is not yet known. Nevertheless, it is known that imiquimod activates immune cells through the toll-like receptor 7 (TLR7), commonly involved in pathogen recognition.[5] 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)).[6] 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.[7] Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes.[7]
New research has shown that imiquimod has anti-proliferative effects in vitro that are independent of immune system activation or function. Imiquimod exerts its effect by increasing levels of the opioid growth factor receptor (OGFr). Blocking OGFr function with siRNA technology resulted in loss of any antiproliferative effect of imiquimod.[8]
[edit] Disadvantages
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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 keratosis cannot tolerate the resulting reaction either.[9] Fortunately, after completion of the therapy, the skin often heals with barely any scarring.[citation needed]
Recurrence of skin cancer has been noted 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. Recurrence can be treated surgically by local excision. 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.[10]
Other side effects include headaches, back pain, muscle aches, tiredness, flu-like symptoms, swollen lymph nodes, diarrhea, and fungal infections.[11]
[edit] Synthesis
Imiquimod can be prepared from 4-chloro-3-nitroquinoline.[12]
[edit] See also
[edit] References
- ^ 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.
- ^ 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. http://content.nejm.org/cgi/content/full/358/14/1465.
- ^ 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.
- ^ Photographs before, during, and after imiquimod therapy for actinic keratosis and basal cell carcinoma
- ^ Hemmi, H., et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol.. 2002 3(2):196-200. PMID 11812998.
- ^ Sauder, D.N., Imiquimod: modes of action. British Journal of Dermatology. 2003 149(Suppl. 66):5-8. PMID 14616337
- ^ a b Miller, R.L., et al. Imiquimod applied topically: a novel immune response modifier and a new class of drug. Int J Immunopharmacol. 1999 Jan;21(1):1-14. PMID 10411278
- ^ 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.
- ^ 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. http://www.redorbit.com/news/technology/388549/texan_blames_aldara_for_ailments_he_settled_lawsuit_but_continues/. Retrieved 13 April 2011.
- ^ Advances in the use of topical imiquimod to treat dermatologic disorders
- ^ Aldara website, What are the possible side effects of Aldara Cream?
- ^ Gertser, J. F.; 1985, EP 0145340
[edit] External links
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