Imiquimod
Encyclopedia
Imiquimod is a prescription medication that acts as an immune response modifier. It is marketed by Meda AB
Meda AB
MEDA AB is a Swedish pharmaceutical company that concentrates on "marketing and market-adapted product development". Through their purchase of Medpointe, they own the pharmaceutical products of Carter-Wallace, now marketed under the name Wallace Pharmaceuticals....

, 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.

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.

Uses

Imiquimod is a patient-applied cream used to treat certain diseases of the skin, including skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...

s (basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...

, Bowen's disease
Bowen's disease
Bowen's disease is a neoplastic skin disease, it can be considered as an early stage or intraepidermal form of squamous cell carcinoma. It was named after Mark Bowen...

, superficial squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...

, some superficial malignant melanomas, and actinic keratosis
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...

) as well as genital warts (condylomata acuminata). It has also been tested for treatment of molluscum contagiosum
Molluscum contagiosum
Molluscum contagiosum is a viral infection of the skin or occasionally of the mucous membranes. It is caused by a DNA poxvirus called the molluscum contagiosum virus . MCV has no animal reservoir, infecting only humans. There are four types of MCV, MCV-1 to -4; MCV-1 is the most prevalent and...

, vulvar intraepithelial neoplasia
Vulvar intraepithelial neoplasia
The term Vulvar intraepithelial neoplasia refers to particular changes that can occur in the skin that covers the vulva. VIN is not cancer, and in some women it disappears without treatment...

, common warts that have proven difficult to treat, and vaginal intraepithelial neoplasia
Vaginal intraepithelial neoplasia
Vaginal intraepithelial neoplasia is a condition that describes premalignant histological findings in the vagina characterized by dysplastic changes.The disorder is rare and generally has no symptoms...

. Outstanding cosmetic result has resulted from the treatment of both large superficial basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...

 and squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...

 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.

Mechanism of action

The exact mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...

 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
TLR 7
Toll-like receptor 7, also known as TLR7, is protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.- Function :...

 (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.

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
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...

 technology resulted in loss of any antiproliferative effect of imiquimod.

Disadvantages

Nonspecific inflammation and dermatitis can occur during use of imiquimod for genital warts and molluscum. This often occurs where the skin is traumatized from scratching, or between skin folds. Blisters, bloody dry eschar
Eschar
An eschar is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, necrotizing spider bite wounds, and exposure to cutaneous anthrax....

, pain and discomfort often follows the use of imiquimod for skin cancers and precancerous growths. During the treatment of large superficial basal cell carcinoma or squamous cell cancer in situ, areas of black dried crust often form. Many individuals with extensive actinic keratosis cannot tolerate the resulting reaction either. Fortunately, after completion of the therapy, the skin often heals with barely any scarring.

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.

Other side effects include headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

s, back pain, muscle aches, tiredness, flu-like symptoms, swollen lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...

s, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, and fungal infections.

Chemistry

Imiquimod can be prepared from 4-chloro-3-nitroquinoline.

External links

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