Imiquimod

The imidazoquinoline, imiquimod, is a low molecular weight, synthetic immune response modifier that is used for the treatment of external genital and perianal warts. It is formulated in a 5% vanishing cream as Aldara. This self-applied therapy has shown good efficacy and safety in the treatment of external genital and perianal warts caused by human papillomavirus (HPV) infection. The antiviral mechanism of action of this compound is unlike any other approved antiviral therapy in that it induces the production of antiviral cytokines and cytokines that enhance cellular immunity believed to be necessary for the control or elimination of HPV infection. Imiquimod does not exert its antiviral effects directly on virus-infected cells. Treatment with imiquimod results in resolution of wart tissue and reduction of viral burden. Post-marketing trials using imiquimod demonstrated that patients who experience complete clearance of either new or recalcitrant warts tend to remain clear for longer periods as compared to other treatment modalities. Preclinical data demonstrate in vitro and in vivo that imiquimod directly induces antiviral and immunomodulating cytokines from monocytes, macrophages and dendritic cells. These immunomodulating cytokines have been shown to potentiate Th1 immunity. Self-application, good tolerability, a unique mechanism of action and a relatively high sustained clearance rate combine to make imiquimod a cost-effective first-line therapy for external genital warts and an appropriate second-line therapy when other treatments are unsuccessful. In small-scale studies requiring replication, imiquimod has also been shown to be effective in the treatment of non-HVP-related skin infections and some dermal neoplasias.     

Pharmacokinetics of daily self-application of imiquimod 3.75% cream in adult patients with external anogenital warts

Imiquimod 3.75% cream is a new formulation intended for daily self-application. The objective of this study was to characterize serum imiquimod pharmacokinetics under maximal use conditions. Adults with ≥8 warts or total wart area ≥100 mm2 applied up to 1 packet of imiquimod 3.75% cream (250 mg cream, 9.375 mg imiquimod) once daily for 3 weeks. Blood was obtained prior to doses 1, 7, 14, and 21 and at selected time points after doses 1 and 21. Eighteen patients (13 men and 5 women) with a median wart count of 16 and total wart area of 60 mm2 were enrolled. Day 21 mean (SD) serum C(max) was 0.49 (0.37) ng/mL, AUC???? 6.80 (3.59) ng·h/mL, and t(1/2) 24.1 (12.4) hours. Steady state was achieved by day 7 with ~2-fold increase in C(max) and AUC after multiple dosing. Overall, C(max) was higher and t(max) shorter in women, with comparable AUC????. Imiquimod metabolites were sporadically quantifiable. No patients discontinued for adverse events; 1 interrupted dosing for an application site ulcer. Treatment-related adverse events occurred in 16.7% of the patients. In conclusion, serum imiquimod concentrations were low after daily self-application to external anogenital warts of up to 1 packet of imiquimod 3.75% cream for 21 days.     

Molecular analysis of the effect of topical imiquimod treatment of HPV 2/27/57-induced common warts

Imiquimod is effective in the treatment of genital warts and clinical studies suggest activity against common warts as well. We have analyzed the effect of topical imiquimod on gene expression and virus load in human papilloma virus (HPV) 2/27/57-induced common warts. mRNA was extracted from keratinocyte culture, from normal skin, from three untreated common warts and from three common warts treated topically with 5% imiquimod cream twice daily. Differential gene expression was demonstrated by RT-PCR and by cDNA microarray hybridization. We further analyzed viral DNA content in scales from three superficially pared imiquimod-treated warts by real-time PCR. Comparison of normal skin with wart tissue revealed that HPV 2/27/57 infection led to an induction of IL-6, IL-10 and interferon-gamma inducible protein (IP10) and to an up-regulation of TGF-beta. We could further detect expression of PCTAIRE-3, WNT2B, frizzled-3, notch-2, notch-4 and BRCA2 in normal skin and common warts. Analysis of imiquimod-treated warts demonstrated that imiquimod enhanced IL-6 expression and induced IL-8, GM-CSF, MRP-8 and MRP-14. It could also be shown that imiquimod led to an infiltration of wart tissue with macrophages and to a strong decrease of viral copy number in warts within 3 months of treatment. Our data thus provide molecular proof of principle for imiquimod treatment of cutaneous common warts.     

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 5% cream (Aldara)

Imiquimod is a novel synthetic molecule with potent immune-modifying activities. Formulated in a 5% vanishing cream as Aldara, this self-applied therapy has shown good efficacy and safety in the treatment of external genital and perianal warts caused by human papillomavirus (HPV) infection (Condyloma acuminata). The molecule does not demonstrate direct antiviral activity, but through induction of cytokines results in immune-based resolution of wart tissue and reduction of viral burden. Phase III trials of imiquimod have demonstrated that patients who experience complete clearance of either new or recalcitrant warts tend to remain clear, possibly related to Th1 immune recognition and memory. Self-application, good tolerability and a unique mechanism of action combine to make imiquimod a reasonable first-line therapy for genital warts. The effects of imiquimod on immune function suggest several potential uses. Preclinical studies of infection with herpes simplex virus (HSV), cutaneous leishmaniasis, Rift Valley Fever virus and vesiculostomatitis virus have shown reduced viral persistence, reduced recurrence (HSV) and diminished pathology (Leishmania donovani). In a murine tumour model using the FCB bladder cancer cell line, imiquimod behaves as a potent adjuvant leading to immune-based tumour cell eradication and immunity against subsequent FCB cell challenge. The ability of imiquimod to induce significant production of interferon alpha (IFN-alpha) by monocytes/macrophages suggests that diseases responsive to recombinant interferon therapy, such as basal cell carcinoma, may be reasonable clinical targets. The induction of tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and interleukin-12 (IL-12) leads to inhibition of IL-5, with animal models demonstrating immune deviation away from Th2 immune responses. The observation that several patients with hepatitis C infection and eosinophilia showed normalisation of elevated eosinophil counts in association with oral imiquimod therapy encourages further exploration of the immune modifying properties of this novel molecule. This review is focused on the use of imiquimod for the treatment of external genital and perianal warts.     

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.     

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.     

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.     

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.     

高频电刀联合膦甲酸钠和咪喹莫特乳膏治疗女性尖锐湿疣

目的观察高频电刀联合膦甲酸钠和咪喹莫特乳膏治疗女性尖锐湿疣的疗效。方法将130例女性尖锐湿疣患者分成3组,A组采用单纯高频电刀治疗;B组采用高频电刀治疗,患处涂咪喹莫特乳膏;C组在B组治疗方案的基础上给予膦甲酸钠。三组治疗结束后随访6个月,比较三组的复发率。结果 A组复发率为37.14%,B组为27.19%,C组为15.38%,3组比较均有显著性差异。结论高频电刀联合膦甲酸钠和咪喹莫特乳膏治疗女性尖锐湿疣复发率低,不良反应少。     

The imidazoquinolines and their place in the therapy of cutaneous disease

The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.     

The imidazoquinolines and their place in the therapy of cutaneous disease

The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.     

Polyhexamethylene biguanide for treatment of external genital warts: a prospective, double-blind, randomized study

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Polyhexamethylene biguanide is a new agent, that has been demonstrated to have potent in vivo antiviral effects in animal and in human models. The present prospective, double-blind, randomized, placebo (vehicle-controlled) trial evaluated the efficacy and safety of daily patient-applied polyhexamethylene biguanide for up to 16-weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with polyhexamethylene biguanide cream versus and 3 of 95 (4%) placebo patients; the differences between the groups treated with placebo and polyhexamethylene biguanide were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the polyhexamethylene biguanide cream group, 17% cream group, and 0% (0 of 3) in the placebo group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common in the polyhexamethylene biguanide cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied polyhexamethylene biguanide cream is effective for the treatment of external genital warts and has a favorable safety profile.     

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.     

Plantar wart treatment with combination imiquimod and salicylic acid pads

Treatment of plantar warts is often difficult and may be painful, often employing destructive treatment modalities. We report the successful treatment of a patient with a large plantar wart using Imiquimod 5% cream under occlusion with a 40% salicylic acid pad. This combination treatment modality likely allows successful delivery of Imiquimod through the thick skin on the plantar surface. Once penetrated, an anti-viral state is created by upregulating specific cytokines to eradicate the human papilloma virus (HPV).     

Plantar wart treatment with combination imiquimod and salicylic acid pads

Treatment of plantar warts is often difficult and may be painful, often employing destructive treatment modalities. We report the successful treatment of a patient with a large plantar wart using Imiquimod 5% cream under occlusion with a 40% salicylic acid pad. This combination treatment modality likely allows successful delivery of Imiquimod through the thick skin on the plantar surface. Once penetrated, an anti-viral state is created by upregulating specific cytokines to eradicate the human papilloma virus (HPV).     

5%咪喹莫特乳膏每日1次治疗尖锐湿疣68例

目的观察5%咪喹莫特乳膏每日一次治疗尖锐湿疣的疗效。方法尖锐湿疣患者98例,分为2组。试验组68例,每日患处直接外用足量5%咪喹莫特乳膏一次,共4 wk。对照组30例,隔日患处直接外用足量5%咪喹莫特乳膏一次,共8 wk。观察治疗前后疣体发生的部位、数目、形状、大小及用药后局部刺激和全身不良反应。结果试验组退出1例,治疗4 wk后有效率为69%(46/67),对照组治疗8 wk后有效率为73%(22/30),2组疗效无显著差异(P>0.05)。试验组疣体消退时间为(12.5±6.5)d,对照组为(40.5±12.2)d,试验组短于对照组,差异有显著意义(P<0.05)。试验组不良反应发生率为50%,对照组为40%,无显著差异(P>0.05)。结论 5%咪喹莫特乳膏每日一次治疗尖锐湿疣疗效与隔日一次相当,可缩短疗程。     

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。     

Topical imiquimod: mechanism of action and clinical applications

Imiquimod is a synthetic imidazoquinoline heterocyclic amine of 240.3 Da (C14H16N4). Imiquimod is a cytokine inducer and a modifier of the innate immune response, as well as acquired antiviral and antitumor immune responses. Imiquimod 5% cream has proven to be an effective treatment for external genital warts, superficial basal cell carcinoma, and actinic keratosis.