Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions

Topical imiquimod 5% cream (Aldara) is an immune response modulator that is indicated for the treatment of external anogenital warts, superficial basal cell carcinoma and actinic keratoses. The cream is applied two to five times per week for varying periods, depending on the indication. Topical imiquimod cream has also been evaluated in the treatment of several other skin conditions.Immunomodulatory therapy with topical imiquimod 5% is an effective option for the approved indications. The drug appears to be relatively well tolerated, with the option of breaks from treatment as required for local skin reactions (which are common). Systemic reactions have been reported. Treatment of human papillomavirus- and UV-associated skin lesions with topical imiquimod offers a noninvasive, tissue-sparing alternative to ablative treatment options. However, well designed trials of the sustained, long-term efficacy and tolerability of topical imiquimod versus those of common treatment approaches including surgery and other topical alternatives are required before the place of the drug in the management of these lesions can be finalised. Nonetheless, while other treatments for anogenital warts, superficial basal cell carcinoma or actinic keratoses are available, the advantages of self treatment linked with the demonstrated efficacy of topical imiquimod offer an attractive alternative for many patients.     

Short incubation PDT versus 5-FU in treating actinic keratoses

The efficacy of photodynamic therapy (PDT) using broad area treatment with 5-aminolevulinic acid (ALA) has not been compared to topical 5-fluorouracil (5-FU) in the treatment of actinic keratoses (AK). The purpose of this study was to compare the efficacy and tolerability of PDT using short incubation time, broad area treatment with ALA plus activation with either blue light or laser light to topical 5-FU in the treatment of AK of the face and scalp. Thirty-six subjects with AK of either the face or scalp were randomized to receive either application of ALA for 1 hour followed by activation with blue light or pulsed dye laser or topical 5-FU. Efficacy was evaluated by grading AK lesions and photoaging signs. Tolerability was assessed by scoring crusting/erosions, erythema and stinging/burning. Treatment with PDT using ALA plus blue light was as effective as topical 5-FU in clearing AK. PDT using ALA plus laser light was the least effective treatment. All treatments made improvements in the signs of photoaging. Both PDT treatments were better tolerated than 5-FU. In conclusion, broad area PDT treatment with ALA plus activation with blue light appears to be as effective as 5-FU in the treatment of AK. ALA plus laser light is somewhat less effective than the above therapies. Efficacy could likely be improved with further study of laser parameters and incubation times.     

Diclofenac sodium 3% gel in the treatment of actinic keratoses postcryosurgery

BACKGROUND: Actinic keratoses are increasingly common skin lesions that are evaluated and treated by dermatologists on a daily basis. It is estimated that more than 90% of actinic keratoses in the US are treated by destructive therapies, such as cryosurgery. The purpose of this study was to evaluate the efficacy of sequential therapy of cryosurgery followed by diclofenac sodium 3% gel. METHODS: This prospective, double-arm, multicenter, open-label, phase 4 study was performed at 82 community dermatology centers in the US. A total of 714 subjects who had a clinical diagnosis of actinic keratosis with between 5 and 15 lesions contained in a target area such as the forehead, scalp, and hands were enrolled in the study. These subjects were randomized into 2 arms of the study: cryosurgery alone and cryosurgery followed by diclofenac sodium 3% gel for a period of 90 days. Lesion counts were assessed at baseline, and 45, 75, 105, and 135 days after cryosurgery. RESULTS: Of the 521 patients enrolled in the study who successfully completed all of the visits concluding on day 135, 277 were in the cryosurgery alone arm and 244 were in the cryosurgery followed by diclofenac sodium 3% gel arm. At the conclusion of the study, 46% of the subjects in the cryosurgery followed by the use of diclofenac sodium 3% gel arm achieved 100% cumulative (target plus new lesions) lesion clearance compared to 21% in the cryosurgery alone arm (P < .0001). One hundred percent target lesion clearance was achieved in 64% of the subjects in the active arm compared to 32% in the cryosurgery alone arm (P < .0001). CONCLUSIONS: With the increased prevalence of actinic keratoses, it is important to consider and evaluate emerging therapeutic options. The sequential treatment with cryosurgery followed by diclofenac sodium 3% gel for 90 days is well tolerated and can provide a therapeutic modality that may provide patients with actinic keratoses a more successful outcome than monotherapy with cryosurgery by effectively treating clinical and subclinical lesions.     

Successful treatment of porokeratosis with topical imiquimod in 2 immunosuppressed cases

Porokeratosis is a group of cutaneous disorders of keratinization characterized by a predisposition to malignant transformation. The condition, which may be associated with immune suppression, is usually resistant to therapy and has a high frequency of recurrence. Imiquimod, a potent topical immune response modifier with antiviral, antitumor, and immunoregulatory properties, is currently approved for the treatment of external anogenital warts and actinic keratosis. However, there have been also several reports demonstrating its efficacy in a variety of premalignant and malignant conditions. We report on 2 cases with immunosuppression-associated porokeratosis successfully treated with 5% topical imiquimod application.     

Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp

It is timely to compare the efficacy and tolerability of 2 actinic keratosis (AK) therapies--5% 5-fluorouracil (5-FU) cream and imiquimod cream. Thirty-six patients with 4 or more AKs were randomly assigned to receive 5% 5-FU cream twice daily for 2 to 4 weeks or 5% imiquimod cream twice weekly for 16 weeks. Five percent 5-FU was more effective than imiquimod in exposing what were presumed to be subclinical AKs, reducing the final AK count (total AK count declined during the 24-week study by 94% vs. 66%, P < .05), achieving complete clearance (incidence of 84% vs. 24% by week 24, P < .01), and achieving clearance rapidly. Tolerability was similar except for erythema, which was initially significantly higher with 5-FU than imiquimod but resolved rapidly and was significantly lower than imiquimod by week 16. Five percent 5-FU remains the gold standard field therapy for AKs.     

Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp

Actinic keratoses (AKs) are a common precancerous condition and are said to account for 14% of visits to dermatologists in the US each year. Along with cryotherapy, topical treatments are a mainstay of therapy for these lesions. One of the potential benefits of topical therapy is less pain and irritation as compared to cryotherapy. Additionally, topical therapies have a perceived benefit of treating subclinical lesions along with clinically evident keratoses. We conducted a bilateral comparison study of the efficacy and tolerability of diclofenac 3% gel used for 90 days and 5% fluorouracil cream used for 28 days in thirty patients with AK of the face and scalp. The diclofenac gel and 5-fluorouracil cream each demonstrated substantial efficacy in the number of lesions cleared and the proportion of patients with significant lesion clearing. In most patients, diclofenac induced only mild signs of inflammation compared to 5-fluoruracil, despite a longer treatment period. A greater number of patients expressed significant satisfaction with diclofenac gel compared to the 5-fluorouracil cream.     

Topical photodynamic therapy for dermatologic disorders: results and complications

BACKGROUND: Topical photodynamic therapy (PDT) involves the use of a photosensitizing topical medication that is activated by a light source in the presence of oxygen leading to cellular destruction and subsequent photorejuvenation. In 1999, the US FDA approved PDT for the treatment of nonhyperkeratotic actinic keratoses (AKs) on the face and scalp. OBSERVATIONS: The study population comprised 85 patients treated with short-contact, topical aminolevulinic acid (ALA)-PDT for a total of 247 treatments. Ninety percent of patients with a variety of dermatologic disorders had significant improvement or total clearance. Ninety-eight percent of patients had no complications. Only 2 patients in our series had a significant complication. CONCLUSIONS: Short-contact, topical ALA-PDT is a safe and effective treatment for a variety of dermatologic disorders including photoaging and AKs.     

The treatment of actinic keratoses with a combination of 5-fluorouracil and imiquimod creams

BACKGROUND: 5-fluorouracil (5-FU) and imiquimod creams are accepted topical therapies for actinic keratosis (AK). Both are associated with a prolonged course of treatment with an inflammatory response that may preclude the treatment process. OBJECTIVES: To describe the treatment regimen and the extent of side effects in the use of the combined application of 5-FU and imiquimod creams in patients presenting with AKs and to demonstrate the convenience and ease of the methodology of this regimen. METHODS: The patients applied 5-FU and imiquimod creams to their lesions daily for one week each month over the course of 3 months. The patients were seen after the completion of each one-week course to evaluate their progress and side effects. RESULTS: There were 64 patients in the study, 48 of whom completed the study and demonstrated a clearing of their AKs by the end of the third course of treatment. All of the patients developed an inflammatory response at the sites of their AKs as well as at subclinical sites with no apparent AKs. Nearly all of these inflammatory reactions were confined to localized sites without involvement of the surrounding skin. CONCLUSIONS: Therapy with the combined application of 5-FU and imiquimod creams is a relatively rapid and convenient form of therapy as compared to the separate use of each medication.     

Peripheral neuropathy exacerbation associated with topical 5-fluorouracil

Peripheral neuropathy secondary to 5-flourouracil and capecitabine (Xeloda) has been reported. We report the first case of exacerbation of peripheral neuropathy related to topical 5-flourouracil (Efudex). A 70-year-old Caucasian male with a history of actinic keratosis for 15 years was treated intermittently with topical application of 5-flourouracil. He also developed sensory peripheral neuropathy around the same time, but extensive work-up disclosed no clear etiology. In early 2005, he developed an exacerbation of his peripheral neuropathy following a 21-day course of topical 5-flourouracil for actinic keratosis, especially pain and parasthesias. Dihydropyrimidine dehydrogenase activity was evaluated in the peripheral mononuclear cells both by radioassay and by [2-C] uracil breath test. Dihydropyrimidine dehydrogenase activity was within the normal range by both methods. Stopping topical 5-flourouracil resolved the symptoms to baseline. Instead of topical 5-flourouracil, topical imiquimod was used which did not exacerbate his neuropathy. He was not re-challenged with topical 5-flourouracil. Topical 5-flourouracil has been known to cause mainly dermatological adverse effects, but systemic effects because of absorption are possible, especially in dihydropyrimidine dehydrogenase-deficient patients. As our patient had no other cause responsible for his neuropathy, the onset of symptoms coincided historically with topical application of 5-flourouracil and the 5-flourouracil usage preceded an exacerbation of sensory symptoms, we conclude that this drug was responsible for his polyneuropathy.     

The antiviral activity of Toll-like receptor 7 and 7/8 agonists

Imiquimod 5% cream is approved for the topical treatment of external anogenital warts caused by human papillomavirus (HPV) and for the skin cancer conditions superficial basal cell carcinoma and actinic keratosis. This drug is the first approved topically active Toll-like receptor (TLR) 7 agonist. Imiquimod activates innate immune cells to produce interferon-a and other cytokines. The induced cytokine cascade, in combination with effects in enhancing antigen presentation, also promotes an antigen-specific T helper type 1 cell-mediated immune response. This immune-based mechanism provides activity against a number of viruses and other intracellular pathogens. Imiquimod was effective topically in clinical studies for HPV but caused mixed results for Molluscum contagiosum, and herpes simplex virus (HSV). Activity against several other viruses were reported in case reports or patient series involving "off-label" usage of imiquimod, while others were evaluated only in preclinical models. Resiquimod, a more potent investigational analogue of imiquimod with mixed TLR7/8 agonist activity, was evaluated in clinical studies topically for the treatment of HSV and systemically for hepatitis C virus also with mixed success. This review focuses on the mechanism of action and antiviral usage reported for the TLR7 agonist imiquimod, the TLR7/8 agonist resiquimod and related imidazoquinoline analogues.     

Pharmacoeconomic analysis of the treatment of multiple actinic keratoses

Actinic keratosis (AK) is common and lesions may progress to squamous cell carcinoma. The choice of therapy depends mainly on 2 factors: the efficacy of therapeutic options and the number of lesions present. Cryotherapy alone is suitable for treating a few lesions, whereas topical medications, photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA), or either in combination with cryotherapy are appropriate for treating multiple (>15) lesions. When combinations are necessary, the total cost to treat multiple AKs to 100% clearance becomes important. This report provides a simple pharmacoeconomic analysis of 4 FDA-cleared therapies (imiquimod, diclofenac, 5-fluorouacil [5-FU], and ALA PDT) for AK given in combination with cryotherapy. This analysis assumes standard costs of procedures and office visits (based on April 2007 reimbursement data) and 2 treatment courses (medications: imiquimod, diclofenac, 5-FU) or sessions (ALA PDT) of each modality followed by cryotherapy to 100% clearance. The total cost of each combination is $725.17 for ALA PDT, $845.07 for diclofenac, $942.13 for 5-FU, and $1,473.39 for imiquimod. When phase III trial efficacies of the 4 modalities are considered, the actual cost of using imiquimod or diclofenac increases because additional treatments may be required. Among these 4 FDA-cleared therapies for multiple AK lesions, ALA PDT is the least expensive treatment and imiquimod is the most expensive treatment under the stated assumptions.     

Innovative uses of imiquimod

Imiquimod (Aldara, 3M Pharmaceuticals) is a potent stimulator of the innate and adaptive arms of the immune system through induction, synthesis, and release of cytokines and chemokines. An extensive review of clinical trials, case reports, and letters published in peer-reviewed journals was performed regarding imiquimod use in skin disorders. A reference module was developed for physicians to consult as a guide. Studies have validated the benefit of imiquimod in treating external genital and perianal warts, superficial basal cell carcinomas, and actinic keratoses. This new topical therapeutic agent has shown to be of benefit in other various skin disorders through its broad immunomodulatory properties. Since many skin conditions are immunologically influenced, it is reasonable to expect several diseases to respond to imiquimod. Our research consolidates the therapeutic trials and reports on the innovative uses of imiquimod, thereby serving as a useful resource to benefit dermatologists treating patients with refractory or recalcitrant skin diseases.     

Evaluation of imiquimod for topical treatment of vaccinia virus cutaneous infections in immunosuppressed hairless mice

Imiquimod is an immune response modifier prescribed as a topical medication for a number of viral and neoplastic conditions. We evaluated the antiviral activity of imiquimod against vaccinia virus (WR strain) cutaneous infections in immunosuppressed (with cyclophosphamide) hairless mice when administered after virus exposure. Primary lesions progressed in severity, satellite lesions developed, and infection eventually killed the mice. Once daily topical treatment with 1% imiquimod cream for 3, 4, or 5 days were compared to twice daily topical treatment with 1% cidofovir cream for 7 days. Survival time of mice in all treated groups was significantly prolonged compared to placebo controls. The mean day of death for the placebo group, 3-day imiquimod, 4-day imiquimod, 5-day imiquimod, and cidofovir groups were 15.5, 20.0, 20.5, 19.5, and 20.5 days post-infection, respectively. All treatment groups showed significant reductions in primary lesion size and in the number of satellite lesions. The cidofovir and 4-day imiquimod treatments delayed the appearance of lung virus titers by 3 and 6 days, respectively, although cutaneous lesion and snout virus titers were not as affected by treatment. Benefits in survival and lesion reduction were observed when imiquimod treatment was delayed from 24, 48, and 72 h post-infection. However, increasing the treatment dose of imiquimod from 1% to 5% led to a significant decrease in antiviral efficacy. These results demonstrate the protective effects of topically administered imiquimod against a disseminated vaccinia virus infection in this mouse model.     

Severe cutaneous reaction to photodynamic therapy with blue light

Photodynamic therapy (PDT) has been considered a safe and efficacious treatment for actinic keratoses (AKs) of the scalp and face. The procedure involves exposing a patient to a blue light source 1-4 hours after application of photosensitizing aminolevulinic acid (ALA) at a dose of 10 J/cm2 for up to 1000 seconds.(1,2) We suggest that amount of exposure time and area of exposure should be stratified according to baseline photodamage.     

Severe reaction to 5% imiquimod cream with excellent clinical and cosmetic outcomes

Imiquimod, an immune response modifier approved for the treatment of external genital warts, actinic keratoses, and superficial basal cell carcinoma, can induce a severe local inflammatory response. This phenomenon can accompany inappropriately overzealous, as well as entirely conventional, drug utilization. Despite strikingly brisk reactions, the 9 patients reported herein ultimately experienced excellent cosmetic and clinical outcomes. We report this series to alert clinicians of the good prognosis for a satisfactory outcome even when faced with extreme imiquimod cream-induced inflammation.     

Prospective, case-based assessment of sequential therapy with topical Fluorouracil cream 0.5% and ALA-PDT for the treatment of actinic keratosis

The sequential use of topical therapies and short-incubation photodynamic therapy for actinic keratosis (AK) has not been extensively studied. The author reports on treatment with sequential 5-fluorouracil (5-FU) cream 0.5% and 5-aminolevulinic acid?photodynamic therapy (ALA-PDT) in three older men with photodamaged skin and a history of AK. These findings suggest that this combination therapy, when compared with short-contact (1 hour) ALA-PDT alone, is more effective, minimizes the recurrence of areas of field cancerization and improves the appearance of the skin. The use of 5-FU cream 0.5% before and after photodynamic therapy is effective in revealing the presence of both clinical and subclinical AK lesions.     

Imiquimod as an antiangiogenic agent

Imiquimod (imidazoquinoline 5%) is a topical immune response modifier agent that inhibits angiogenesis, the growth of new blood vessels. In addition to its stimulation of cell-mediated immunity, imiquimod's antiangiogenic activity contributes to its clinical efficacy by interfering with pathological neovascularization that promotes disease progression. The antiangiogenic mechanisms of imiquimod are due to its: 1) induction of cytokines that themselves inhibit angiogenesis (interferons, IL-10, IL-12); 2) local up-regulation of endogenous angiogenesis inhibitors (TIMP, TSP-1); 3) local down-regulation of pro-angiogenic factors (bFGF, MMP-9); and 4) promotion of endothelial cell apoptosis. This report discusses these mechanisms and the rationale for imiquimod's use as an antiangiogenic agent. Key principles of antiangiogenic therapy are presented to describe how imiquimod may be applied in a well-tolerated fashion to treat a broad range of angiogenesis-dependent dermatological conditions, including actinic keratosis (AK), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), lentigo maligna, hemangiomas, Kaposi's sarcoma, pyogenic granuloma, and external genital warts.     

Actinic keratosis and imiquimod: a review of novel carriers and patents

Introduction: Actinic keratosis is one of the most common disorder characterized by erythematic and generally attached scaly lesions which are present either alone or in clusters. World Health Organization defines actinic keratosis as a common intraepidermal neoplasm of sun-damaged skin, characterized by variable atypia of keratinocytes.

Area covered: At the beginning of the 20th century, a new immunomodulator molecule, imiquimod, appears in the market for the treatment of actinic keratosis but suffers from the pitfalls of the conventional approach of dosage form preparation including high dose, poor stability and more side effects. The present article attempts to compile the scatter information related to actinic keratosis and imiquimod at one place. The special emphasis will be made on the information available in various research articles and patents with respect to the efforts made for overcoming shortcomings associated with imiquimod by novel drug delivery or other approaches.

Expert opinion: The conventional drug delivery systems are unsuccessful to improve the actinic keratosis. The patient acceptance and compliance with these treatments are generally poor due to associated side effects, poor cosmetic outcomes and high costs. Therefore, several available and reported novel therapeutic approaches are being developed in order to provide better action.     

Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.     

Mechanisms of action of new treatment modalities for actinic keratosis

Actinic keratosis (AK) constitutes the initial lesion in a disease continuum that can progress to invasive squamous cell carcinoma (SCC). In this article, we describe the mechanisms of action, tolerability, and efficacy of the most frequently used chemopreventative, chemotherapeutic, destructive, and novel immunologic methods for the control and treatment of actinic keratoses.