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.     

咪喹莫特乳膏的制备与治疗尖锐湿疣的临床应用

目的：研制治疗尖锐湿疣的新型外用免疫调节药咪喹莫特乳膏，并观察其临床疗效。方法：苯甲醇、异硬脂酸、十八醇等加热融化为油相，甘油、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等加热融化为水相，将油相加入水相制成乳膏基质，把咪喹莫特细粉加入乳膏基质制备咪喹莫特乳膏。采用紫外分光光度法测定其含量，并观察咪喹莫特乳膏治疗125例尖锐湿疣患者的疗效。结果：该制剂制备简单，质量可控，临床治疗尖锐湿疣患者，治疗8周总有效率97.6%。 结论：咪喹莫特乳膏是治疗尖锐湿疣的有效药物，可作为第一线药物应用于临床。     

Treatment of locally metastatic melanoma: a novel approach

We report a case of an 83-year-old female with locally metastatic melanoma treated with imiquimod and tazarotene. The patient originally presented to our dermatology clinic with local metastases of malignant melanoma after having undergone multiple surgical procedures and adjuvant radiation therapy for disease recurrence. At this juncture, she refused further surgical management but was interested in topical therapy. A 4-week course of topical imiquimod therapy was initiated. As no clinical response was noted at the end of the treatment period, tazarotene cream was introduced. The patient experienced complete clinical clearance of the treated area after a 6-week course of combination imiquimod and tazarotene therapy. The rationale for using both medications will be discussed.     

Treatment of Zoon's balanitis with imiquimod 5% cream

We report a case of a 43-year-old uncircumcised Caucasian, diabetic man with a 4-year history of Zoon's balanitis unresponsive to topical steroids, in whom control of the disease was achieved with topical imiquimod. A histopathological examination of a biopsy specimen was performed before and after treatment with imiquimod 5% cream applied 3 times a week. A moderate to marked increased local skin reaction occurred several times throughout the treatment period, necessitating multiple rest periods of several days' duration. Clinical but not histological resolution was obtained after 4 months of treatment, with no relapses at an 18-month follow-up. This positive treatment outcome indicates that imiquimod may have a role in the management of Zoon's balanitis. However, the dose and duration of therapy required to achieve complete clinical response still needs to be established. Also, the question of whether normalization of histology can be achieved with topical imiquimod has yet to be answered.     

Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod

Clinical use of the imidazoquinoline immunomodulator imiquimod for the topical treatment of dysplastic and neoplastic lesions has increased markedly in recent years. However, despite guidance from the manufacturer of the proprietary imiquimod cream, there seems to be little consensus between clinicians as to the topically applied dose. Given that patients often apply the cream themselves at home, further dosing variability is expected and, consequently, accurate comparison of the results of different published studies is difficult. This paper describes, for the first time, the formulation and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod as well as a new HPLC method for sensitive fluorescence determination of imiquimod released from such systems. Patches containing imiquimod loadings of 4.75, 9.50 and 12.50 mg cm(-2) all released significantly more drug across a model membrane than the proprietary cream over a period of 6h. Inclusion of imiquimod in patches did not adversely affect their physicochemical properties. Of major importance, patches contained defined drug loadings per unit area; therefore, their use could reduce inter-clinician variability. This would make critical comparison of clinical studies and determination of an appropriate imiquimod dose for successful treatment much simpler. Since bioadhesive formulations are capable of adhering to body tissues in moist environments, the use of a bioadhesive patch system may allow extension of the clinical uses of imiquimod to the treatment of neoplastic conditions of the oral cavity and cervix, as well as the vulva.     

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.     

咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣疗效对照观察

目的对比观察咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣的疗效。方法将98例患者分为咪喹莫特乳膏组与鬼臼毒素酊组,咪喹莫特乳膏组肌注重组人干扰素a-2b,口服盐酸伐昔洛韦片,病灶局部涂抹咪喹莫特乳膏;鬼臼毒素酊组：肌注重组人干扰素a－2b,口服盐酸伐昔洛韦片,病灶局部涂抹鬼臼毒素酊。结果咪喹莫特乳膏组痊愈53例,复发5例,有效率为91．2％,鬼臼毒素酊组痊愈30例,复发10例,有效率为75．0％,两组比较差异有显著性（P〈0．05）。结论咪喹莫特乳膏较鬼臼毒素酊治疗尖锐湿疣疗效更理想,复发率低。     

咪喹莫特在尖锐湿疣治疗中的应用

咪喹莫特是一种局部应用的免疫调节剂 ,可刺激皮肤粘膜产生干扰素、肿瘤坏死因子和白介素 1,6,8,提高细胞免疫应答 ,产生抗病毒效果。5 %咪喹莫特霜治疗尖锐湿疣 ,疣体完全清除率为37%～ 5 0 % ,不良反应为局部轻、中度的瘙痒、红斑、烧灼感、触痛、溃疡、糜烂、疼痛等 ,具有较好临床应用价值。     

Imiquimod: new indication. Basal cell carcinoma: inferior to other treatments

(1) Basal cell carcinoma is a common malignancy that is rarely life-threatening. The aim of treatment is to remove the tumour and prevent local recurrences. Surgical excision is the standard treatment, with a mean relapse rate of about 5% at 5 years. The main alternative is radiotherapy. (2) The Indications section of the Summary of Product Characteristics (SPC) for imiquimod cream in Europe now includes "topical treatment of small superficial basal cell carcinomas in adults". (3) Imiquimod cream was primarily evaluated in 2 double-blind randomised controlled trials versus excipient, in a total of 724 patients. In these trials, small basal cell tumours (maximum 2 cm in diameter) disappeared in three-quarters of patients after imiquimod application 5 or 7 days a week for six weeks. (4) A non comparative trial involving 143 patients showed a relapse rate of 21% at 2 years. Indirect comparisons show that this is a much higher relapse rate than after other well-assessed treatments for basal cell cancer. (5) During clinical trials, nearly one-third of patients who used imiquimod 5 times a week complained of pruritus, a burning sensation, or local pain. Nearly one-half of patients experienced these problems with daily use. (6) Imiquimod cream is relatively inconvenient to use: it has to be applied in the evening; residual cream must be removed the following morning; and baths, showers and direct sunlight must be avoided during treatment.     

Topical treatment of partial thickness burns by silver sulfadiazine plus hyaluronic acid compared to silver sulfadiazine alone: a double-blind, clinical study

Since its introduction into clinical practice in 1967 by Charles Fox Jr., silver sulfadiazine has been the gold standard for topical burn therapy. The addition to it of hyaluronic acid, which forms a substantial part of the human tissue intercellular matrix, is aimed at overcoming one of its very few disadvantages, i.e. prolongation of the wound re-epithelialization process. Since both hyaluronic acid and silver sulfadiazine have been used in therapy for decades and their efficacy is well documented, a topical treatment combining these two agents was formulated. The aim of the study was to investigate the efficacy and tolerability of a cream containing a hyaluronic acid/silver sulfadiazine fixed combination, compared with silver sulfadiazine cream alone, for the treatment of superficial and deep second-degree burns in a prospective, double-blind, controlled clinical study. The findings of the study confirmed that the association of the two compounds in a new topical treatment significantly reduced the healing time and significantly accelerated the reduction of local edema occurring shortly after injury. Furthermore, this new hyaluronic acid and silver sulfadiazine formulation has proven to have favorable antibacterial, anti-edematous and local analgesic effects, together with a clear stimulatory activity on the re-epithelialization process. This product may, therefore, significantly enrich the assortment of topical medications available for the treatment of burns and skin defects of other origin.     

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.     

Safety studies of topical imiquimod 5% cream on normal skin exposed to ultraviolet radiation

BACKGROUND: Imiquimod 5% topical cream is an immune response modifier that induces interferon alpha and interleukin-12, and exhibits antiviral and tumor-inhibiting properties. It is currently available for treatment of genital and perianal warts. Three randomized, open-label or assessor-blinded, placebo-controlled studies were carried out to assess its safety on normal white skin exposed to ultraviolet radiation (UVR). METHODS: Healthy white volunteer adult subjects between the ages of 18 and 60 years with skin types I, II or III (Fitzpatrick Scale, US Federal Register 43:38260, 1978) were invited to participate. Imiquimod 5% cream (each dose approximately 0.1-0.2 ml) was compared with placebo cream. Two preliminary studies assessed the potential photosensitizing properties of the drug, and the third study added measurement of sunburn cell counts (SBC) and deoxyribonucleic acid (DNA) pyrimidine dimer (PD) formation. The three studies were: a 6-week standard photocontact allergenicity bioassay; a 4-day standard phototoxicity bioassay; and a 4-week photodamage study using biopsy sample analyses to determine SBC or PD frequency. RESULTS: Imiquimod had no detectable potential for inducing either photocontact allergy (n=115) or phototoxicity (n=20). The final study further assessing photodamage potential of imiquimod included 44 subjects. There were no significant differences between imiquimod vs. the control (no drug+UVB) for SBC counts (mean 0.88 vs. 0.93), or PD frequency (mean 60.86 vs. 70.03). CONCLUSIONS: Results from the two preliminary safety studies suggest that imiquimod 5% cream does not possess a detectable photosensitizing potential in humans. Furthermore, topical imiquimod did not enhance UVR-induced damage to epidermal cells or DNA.     

Bowen's disease of the penis treated with topical imiquimod 5% cream

Bowen's disease of the penis is relatively uncommon, but the prevalence has increased in recent years. Risk factors for penile squamous cell cancer include smoking, infection with human papilloma virus (HPV), immunosuppression, and a history of conditions such as balanitis, phimosis, and lichen sclerosis et atrophicus. Bowen's disease of the penis is often managed by local excision of the lesion. Less invasive methods are now employed more frequently and include laser ablation, electrodessication and curettage, cryosurgery, application of5-fluorouracil, and topical imiquimod 5% cream. This case report describes the successful treatment of Bowen's disease of the penis with topical imiquimod 5% cream in a 42-year-old African American male with human immunodeficiency virus (HIV) disease.     

咪喹莫特对尖锐湿疣激光术后复发的预防作用

目的评价外用5%咪喹莫特乳膏在CO2激光治疗尖锐湿疣后的临床疗效、减少复发性及药物安全性。方法采用随机法将118例患者分成激光治疗组和联合治疗组。激光治疗组(61例)为单一CO2激光治疗,联合治疗组(57例)以CO2激光联合5%咪喹莫特乳膏,每周3次外搽,疗程8周。治疗后连续随访3个月。结果联合治疗组复发率为17.5%;激光治疗组复发率为49.2%,两组差异具有统计学意义(P<0.01)。联合治疗组于治疗后随访1、2、3个月其复发率分别为12.3%、3.5%、1.8%;激光治疗组的复发率分别为26.2%、14.8%、8.2%,联合治疗组各随访阶段的复发率均低于激光治疗组,差异具有统计学意义(P<0.01)。外搽5%咪喹莫特乳膏后局部出现的不良反应有红斑、水肿、糜烂、瘙痒、灼热和疼痛,发生率为74%(42/57),无系统性不良反应发生。结论CO2激光治疗尖锐湿疣后外用5%咪喹莫特乳膏临床疗效显著,病变复发率低,无系统性不良反应,具有较好的安全性。     

咪喹莫特乳膏对家兔皮肤的刺激性研究

目的 考察咪喹莫特乳膏对家兔皮肤的刺激性作用。方法 分别进行单次和多次给药对家兔皮肤的刺激性实验。单次给药实验时，取家兔8只，随机平均分成实验组1和实验组2，均对称脱去脊柱两侧毛，将每只家兔脱毛皮肤自上而下平均分为4块，脊柱两侧共8块，下部4块制作破损皮肤模型。所有家兔脊柱左侧均给予赋形剂1 g，实验组1脊柱右侧给予1%咪喹莫特乳膏1 g，实验组2脊柱右侧给予5%咪喹莫特乳膏1 g。涂药后用医用手术巾包扎8 h，观察并记录除去咪喹莫特乳膏及赋形剂后1，24，48，72 h给药部位皮肤的红斑、水肿、焦痂等刺激反应情况。多次给药实验时，分组、给药方法、剂量及包扎时间均同单次给药实验，每日给药1次，连续7 d。每次给药后8 h，用温水洗去药物及赋形剂。结果 1%和5%咪喹莫特乳膏在家兔完整及破损皮肤单次给药时未见皮肤刺激性反应；1%咪喹莫特乳膏在家兔完整皮肤多次给药未见明显刺激反应，破损皮肤多次给药有轻度刺激反应；5%咪喹莫特乳膏在家兔完整皮肤多次给药有轻度刺激反应，破损皮肤多次给药有中度刺激反应。但停药后刺激反应消失，皮肤恢复正常。未见赋形剂对家兔皮肤的明显刺激作用。结论咪喹莫特乳膏单次给药对家兔完整和破损皮肤无刺激性，多次给药对家兔破损和完整皮肤的刺激反应小。预期咪喹莫特乳膏临床可用。     

Topical imiquimod: a review of its use in genital warts.

Imiquimod is a topically active immunomodulatory agent that is formulated as a 5% cream for application by the patient. It is the first agent of its class, the immune response modifiers, to be used in the treatment of genital warts. In immunocompetent patients with genital warts, imiquimod stimulates the production of interferon-alpha and various other cytokines, and has indirect antiviral activity. In randomised, double-blind, vehicle-controlled clinical trials, complete clearance of warts occurred in 37 to 50% of immunocompetent patients with genital warts treated with imiquimod 5% cream 3 times a week for up to 16 weeks; partial clearance of warts (defined as a reduction in wart area of > or = 50%) was observed in 76% of recipients of imiquimod 5% cream. Rates of complete or partial clearance of warts were significantly higher in patients who applied imiquimod 5% cream 3 times a week than in recipients of imiquimod 1% or vehicle cream, each applied 3 times a week. A between-gender difference in clinical response to imiquimod 5% cream has been reported, with female patients experiencing higher rates of complete clearance of warts than males. Recurrence(s) of > or = 1 wart occurred in 13 to 19% of immunocompetent patients in whom complete clearance of warts had been achieved with imiquimod 5% cream. Imiquimod 5% cream also shows some clearance of warts in immunosuppressed HIV-infected patients with genital warts. Preliminary results of a vehicle-controlled study showed that the rate of partial clearance of warts (defined as a reduction in baseline wart area of >50%) [38%] was significantly higher with imiquimod 5% cream than with vehicle cream; however, the rate of complete clearance was not significantly higher than with vehicle cream. Imiquimod 5% cream is generally well tolerated by immunocompetent and HIV-infected patients. Local skin reactions (mainly mild or moderate), including erythema, itching and burning, are the most commonly reported adverse events, occurring in < or = 67% of patients applying imiquimod 5% cream 3 times a week. The incidence of adverse events is lower in patients applying the cream 3 times a week than with daily application. The incidence of systemic adverse events with imiquimod 5% cream (applied daily or 3 times a week) is similar to that of vehicle cream. The tolerability profile of imiquimod cream appears favourable compared with that of podophyllotoxin. CONCLUSION: Imiquimod 5% cream is a new therapeutic option for patients with genital warts. It produces clearance rates broadly similar to those of other treatment approaches and rates of wart recurrence compare favourably with those reported for established treatments. In contrast to most alternative treatment strategies. which are administered in the physician's office, imiquimod cream is a self-administered therapy for outpatient use.     

Regression of internal melanoma metastases following application of topical imiquimod to overlying skin

The prognosis for metastatic melanoma is grim, and treatment options are limited. Imiquimod is a topically applied immune modulator that has been used to treat superficial cutaneous melanoma, but has not been reported to treat metastatic melanoma. We report a patient whose liver and iliac fossa melanoma metastases regressed after topical application of imiquimod cream to overlying skin. This supports further investigation of the potential use of imiquimod for metastatic melanoma.     

5%咪喹莫特乳膏治疗尖锐湿疣的多中心随机双盲平行对照研究

目的 了解5％咪喹莫特乳膏治疗肛周和外生殖器尖锐湿疣的临床疗效和安全性。方法 采用随机、双盲、平行对照临床研究方法，共入选尖锐湿疣患者237例，随机分为治疗组119例，给予5％咪喹莫特乳膏适量；对照组118例，给予2．5％氟尿嘧啶乳膏适量；均为每周3次外搽。疗程8周；疣体完全消退者继续随访8周以观察复发率。结果 治疗组和对照组的痊愈率分别为66．4％，66．1％（P〉0．05）；有效率分别为85．7％，85．6％（P〉0．05）。治疗组痊愈后复发6例，复发率5．O％；对照组痊愈后复发27例，复发率22．9％（P〈0．05）。治疗组发生不良反应29例。发生率24.4％，时照组发生不良反应44例，发生率37．3％（P〈0.05）。治疗组不良反应主要为给药部位的红斑和糜烂，无系统不良反应。结论 5％咪喹莫特乳膏治疗尖锐湿疣疗效好，安全性好，使用方便。     

外用咪喹莫特对尖锐湿疣激光术后复发的预防作用

目的观察咪喹莫特乳膏局部外用预防尖锐湿疣激光术后复发的效果。方法将107例尖锐湿疣患者随机分成2组,治疗组在CO2激光术后局部外用咪喹莫特乳膏8 wk,对照组单纯用CO2激光治疗,随访6 mo,观察2组患者有无疣体复发。结果随访6 mo,治疗组的复发率为12.50%,对照组的复发率为45.10%(P<0.01)。结论咪喹莫特乳膏局部外用对尖锐湿疣激光术后复发具有预防作用。     

Pilot study using topical imiquimod 5% cream in the treatment of nodular basal cell carcinoma after initial treatment with curettage

BACKGROUND: Nodular basal cell carcinoma (nBCC) is the most common cutaneous malignancy and studies assessing the use of topical imiquimod 5% cream as a monotherapy in the treatment of nBCC have resulted in less than optimal clearance rates. OBJECTIVE: This pilot study was designed to evaluate the efficacy of imiquimod 5% cream on nodular basal cell carcinoma lesions after initial treatment with curettage. METHODS: After obtaining informed consent, 17 nBCCs on 15 patients were included in this institutional review board-approved, open-label study with initial treatment using curettage without electrodesiccation followed by once-daily application of imiquimod 5% cream 5 times per week for 6 weeks. The area was excised and examined histologically 6 weeks after cessation of imiquimod cream. RESULTS: All 17 lesions (100%) showed no histologic evidence of residual tumor on the post-treatment excision. Local site reactions necessitating a rest period from medication application were experienced by most patients (67%), but the majority of patients stated that they would choose this treatment modality over excision if they developed a subsequent tumor. CONCLUSION: Imiquimod 5% cream appears to be an effective treatment method for nodular basal cell carcinoma if combined with curettage prior to application.