Imiquimod

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Imiquimod
Imiquimod.svg
Clinical data
Trade names Aldara, others [1]
Other names1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
AHFS/Drugs.com Monograph
MedlinePlus a698010
License data
Pregnancy
category
Routes of
administration 		Topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 30 hours (topical dose), 2 hours (subcutaneous dose)
Identifiers
  • 3-(2-Methylpropyl)-3,5,8-triazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,7,10,12-hexaen-7-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.131.047 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H16N4
Molar mass 240.310 g·mol−1
3D model (JSmol)
  • n3c1ccccc1c2c(ncn2CC(C)C)c3N
  • 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) Yes check.svgY
  • Key:DOUYETYNHWVLEO-UHFFFAOYSA-N Yes check.svgY
   (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. [4]

Contents

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. [5] [6]

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, [7] [8] as well as actinic keratosis. [9]

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

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. [11]

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. [9] [12]

People who have had an organ transplant and are taking immune-suppressing drugs should not use imiquimod. [9]

Mechanism of action

Imiquimod yields profound antitumoral activity by acting on several immunological levels synergistically. [13] Imiquimod stimulates the innate immune system by activating toll-like receptor 7 (TLR7), commonly involved in pathogen recognition. [14] [15] 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)). [16] 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. [17] Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes. [17]

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. [18]

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. [19] : 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". [20] In 2004, 3M obtained FDA approval to market imiquimod as a treatment for superficial basal cell carcinoma. [21]

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. [22]

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. [23]

Imiquimod 5% was approved for medical use in the European Union in September 1998. [10] Imiquimod 3.75% was approved for medical use in the European Union in August 2012. [11]

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. [24]

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. [25] These disprove earlier anecdotal claims and smaller, less reliable studies. [26] [27] [28] [29]

Imiquimod has also been tested for treatment of vulvar intraepithelial neoplasia, [30] vaginal intraepithelial neoplasia, [31] common warts (a 2012 Cochrane review found no randomized controlled trials), [32] plantar warts, [33] warts in people with suppressed immune systems, [34] flat warts on face and neck, [33] and warts under and around fingernails and toenails. [33] 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. [35] [33]

Related Research Articles

<span class="mw-page-title-main">Wart</span> Small, rough growth resembling a cauliflower or a solid blister

Warts are non-cancerous viral growths usually occurring on the hands and feet but can also affect other locations, such as the genitals or face. One or many warts may appear. They are distinguished from cancerous tumors as they are caused by a viral infection, such as a human papillomavirus, rather than a cancerous growth.

<span class="mw-page-title-main">Cantharidin</span> Chemical compound

Cantharidin is an odorless, colorless fatty substance of the terpenoid class, which is secreted by many species of blister beetles. It is a burn agent or a poison in large doses, but preparations containing it were historically used as aphrodisiacs. In its natural form, cantharidin is secreted by the male blister beetle, and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators.

<span class="mw-page-title-main">Genital wart</span> Sexually transmitted infection caused by certain types of human papillomaviruses

Genital warts are a sexually transmitted infection caused by certain types of human papillomavirus (HPV). They may be flat or project out from the surface of the skin, and their color may vary; brownish, white, pale yellow, pinkish-red, or gray. There may be a few individual warts or several, either in a cluster or merged together to look cauliflower-shaped. They can be itchy and feel burning. Usually they cause few symptoms, but can occasionally be painful. Typically they appear one to eight months following exposure. Warts are the most easily recognized symptom of genital HPV infection.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Plantar wart</span> Medical condition

A plantar wart, or verruca vulgaris, is a wart occurring on the bottom of the foot or toes. Its color is typically similar to that of the skin. Small black dots often occur on the surface. One or more may occur in an area. They may result in pain with pressure such that walking is difficult.

<span class="mw-page-title-main">Molluscum contagiosum</span> Viral infection of the skin

Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the skin may be affected, with abdomen, legs, arms, neck, genital area, and face being the most common. Onset of the lesions is around seven weeks after infection. They usually go away within a year without scarring.

<span class="mw-page-title-main">Basal-cell carcinoma</span> Most common type of skin cancer

Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma or rodent ulcer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raised area with ulceration. Basal-cell cancer grows slowly and can damage the tissue around it, but it is unlikely to spread to distant areas or result in death.

<span class="mw-page-title-main">Pimecrolimus</span> Chemical compound

Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis under the trade name Elidel.

<span class="mw-page-title-main">Adapalene</span> Third-generation topical retinoid

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions. Studies have found adapalene is as effective as other retinoids, while causing less irritation. It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation. It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide. Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent. The Swiss company Galderma sells adapalene under the brand-name product Differin.

<span class="mw-page-title-main">Clobetasol propionate</span> Clobetasol Propionate Cream usp 0.05

Clobetasol propionate is a corticosteroid used to treat skin conditions such as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis. It is applied to the skin as a cream, ointment, or shampoo. Use should be short term and only if other weaker corticosteroids are not effective. Use is not recommended in rosacea or perioral dermatitis.

<span class="mw-page-title-main">Actinic keratosis</span> Skin disorder

Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin. Actinic keratosis is a disorder of epidermal keratinocytes that is induced by ultraviolet (UV) light exposure. These growths are more common in fair-skinned people and those who are frequently in the sun. They are believed to form when skin gets damaged by UV radiation from the sun or indoor tanning beds, usually over the course of decades. Given their pre-cancerous nature, if left untreated, they may turn into a type of skin cancer called squamous cell carcinoma. Untreated lesions have up to a 20% risk of progression to squamous cell carcinoma, so treatment by a dermatologist is recommended.

Natural skin care uses topical creams and lotions made of ingredients available in nature. Much of the recent literature reviews plant-derived ingredients, which may include herbs, roots, flowers and essential oils, but natural substances in skin care products include animal-derived products such as beeswax, and minerals. These substances may be combined with various carrier agents, preservatives, surfactants, humectants and emulsifiers.

<i>Molluscum contagiosum virus</i> Species of virus

Molluscum contagiosum virus (MCV) is a species of DNA poxvirus that causes the human skin infection molluscum contagiosum. Molluscum contagiosum affects about 200,000 people a year, about 1% of all diagnosed skin diseases. Diagnosis is based on the size and shape of the skin lesions and can be confirmed with a biopsy, as the virus cannot be routinely cultured. Molluscum contagiosum virus is the only species in the genus Molluscipoxvirus. MCV is a member of the subfamily Chordopoxvirinae of family Poxviridae. Other commonly known viruses that reside in the subfamily Chordopoxvirinae are variola virus and monkeypox virus.

<span class="mw-page-title-main">Clobetasone</span> Chemical compound

Clobetasone (INN) is a corticosteroid used in dermatology, for treating such skin inflammation as seen in eczema, psoriasis and other forms of dermatitis, and ophthalmology. Topical clobetasone butyrate has shown minimal suppression of the hypothalamic–pituitary–adrenal axis.

<span class="mw-page-title-main">Actinic cheilitis</span> Medical condition

Actinic cheilitis is cheilitis caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip. It is a premalignant condition, as it can develop into squamous cell carcinoma.

<span class="mw-page-title-main">Bowenoid papulosis</span> Medical condition

Bowenoid papulosis is a cutaneous condition characterized by the presence of pigmented verrucous papules on the body of the penis. They are associated with human papillomavirus, the causative agent of genital warts. The lesions have a typical dysplastic histology and are generally considered benign, although a small percentage will develop malignant characteristics.

<span class="mw-page-title-main">Resiquimod</span> Chemical compound

Resiquimod (R-848) is a drug that acts as an immune response modifier, and has antiviral and antitumour activity. It is used as a topical gel in the treatment of skin lesions such as those caused by the herpes simplex virus and cutaneous T cell lymphoma, and as an adjuvant to increase the effectiveness of vaccines. In an animal disease model, systemic administration of resiquimod-loaded nanoparticles has been shown to improve response rates to cancer immunotherapy with a checkpoint inhibitor through stimulation of tumor-associated macrophages. It has several mechanisms of action, being both an agonist for toll-like receptor 7 and 8, and an upregulator of the opioid growth factor receptor. On 28 April 2016, orphan designation (EU/3/16/1653) was granted by the European Commission to Galderma R&D, France for resiquimod to be used in the treatment of cutaneous T-cell lymphoma.

<span class="mw-page-title-main">Ingenol mebutate</span> Chemical compound

Ingenol mebutate, sold under the brand name Picato, is a substance that is found in the sap of the plant Euphorbia peplus, commonly known as petty spurge, and is an inducer of cell death. This compound was isolated first from this plant in 2000. A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the topical treatment of actinic keratosis. Two different strengths of the gel have been approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively. In 2020 the drug was withdrawn from the market in the EU.

Laser-assisted drug delivery (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration.

<span class="mw-page-title-main">Berdazimer sodium</span> Medication

Berdazimer sodium, sold under the brand name Zelsuvmi, is a medication used for the treatment for molluscum contagiosum. Berdazimer sodium is a nitric oxide releasing agent. It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3- propyl)-1-triazene-2-oxide and tetraethyl silicate.

References

  1. 1 2 Drugs.com Drugs.com international listings for imiquimod Page accessed 14 June 2015
  2. ↑ "Imiquimod topical Use During Pregnancy". Drugs.com. 29 May 2019. Retrieved 14 July 2020.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. ↑ "Imiquimod Topical". MedlinePlus. National Library of Medicine . Retrieved 2 June 2021.
  5. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  6. ↑ "Imiquimod - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  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 [superficial basal cell carcinoma] 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. 1 2 3 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. 1 2 3 4 "Aldara EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. 1 2 "Zyclara EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 July 2020. Text was copied from this source which is © 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.
  16. ↑ Bilu D, Sauder DN (November 2003). "Imiquimod: modes of action". The British Journal of Dermatology. 149 (Suppl 66): 5–8. doi:10.1046/j.0366-077x.2003.05628.x. PMID   14616337. S2CID   41274637.
  17. 1 2 Miller RL, Gerster JF, Owens ML, Slade HB, Tomai MA (January 1999). "Imiquimod applied topically: a novel immune response modifier and new class of drug". International Journal of Immunopharmacology. 21 (1): 1–14. doi:10.1016/s0192-0561(98)00068-x. PMID   10411278.
  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
  25. ↑ "Aldara (imiquimod) cream for topical use. Prescribing information". Archived from the original on 2 November 2013.
  26. ↑ Molluscum Contagiosum~treatment at eMedicine
  27. ↑ Theos AU, Cummins R, Silverberg NB, Paller AS (August 2004). "Effectiveness of imiquimod cream 5% for treating childhood molluscum contagiosum in a double-blind, randomized pilot trial". Cutis. 74 (2): 134–8, 141–2. PMID   15379366.
  28. ↑ Bayerl C, Feller G, Goerdt S (November 2003). "Experience in treating molluscum contagiosum in children with imiquimod 5% cream". The British Journal of Dermatology. 149 (Suppl 66): 25–29. doi:10.1046/j.0366-077x.2003.05631.x. PMID   14616342. S2CID   23728783.
  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. 1 2 3 4 "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.
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