Imiquimod Cream Research Articles

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

Periocular Melanoma In Situ Treated With Imiquimod.

To evaluate the efficacy of topical 5% imiquimod cream in the treatment of periocular melanoma in situ (lentigo maligna). Retrospective case series. There were 12 patients in this series, and the mean patient age was 77 years. The anatomical locations were the lower eyelid (n=5), upper and lower eyelid (n=4), lower eyelid including the eyelid margin (n=1), brow (n=1), and the medial canthus (n=1). Topical 5% imiquimod cream was used as a primary treatment (n=6) or as an adjunctive therapy following local excision (n=2), cryotherapy (n=2), or excisional biopsy with cryotherapy (n=2). Twelve patients with periocular melanoma in situ were treated with topical 5% imiquimod cream daily for a mean treatment period of 3.9 months. The clinical features of the patients and the responses to treatment were evaluated in a retrospective case series. Histologic clearance of atypical melanocytes. Eleven patients achieved complete histologic clearance of atypical melanocytes on post-treatment biopsy. One patient could not tolerate local irritation from imiquimod and stopped in the first month of therapy with residual disease. The median follow-up time was 1.5 years. Side effects included redness (n=12), discomfort (n=6), swelling (n=4), ectropion (n=1), and conjunctival chemosis (n=1). The patients experienced no systemic side effects from the treatment. Topical 5% imiquimod cream is an effective option as primary or adjunct therapy in the treatment of periocular melanoma in situ.

Therapeutic Vaccination against A Modified Minimal Survivin Epitope Induces Functional CD4 T Cells That Recognize Survivin‐Expressing Cells

During the last decade, cancer vaccination has received a great deal of attention; however, documentation of the clinical effect remains limited. The introduction of immune checkpoint inhibitors as a novel therapeutic modality 1–4 could by combination increase the ability of a peptide vaccination to induce clinical responses. Survivin is an anti-apoptotic protein, first discovered in 1997. 5 It is overexpressed in a wide array of cancers, including malignant melanoma (MM), 5,6 and expression is correlated with disease progression and a poor prognosis in e.g. colon cancer and neuroblastoma. 7,8 Survivin is an excellent target for cancer vaccines due to its universal expression in cancer; in addition, down-regulation will impair the tumor cell's ability to proliferate and expand. This article is protected by copyright. All rights reserved.

Extramammary Paget disease of the perianal region: the potential role of imiquimod in achieving disease control

Extramammary Paget disease (EMPD) is a rare perineal neoplasia associated with a high rate of local recurrence. Surgical excision is the standard treatment; however, this has high rates of post-operative morbidity in combination with potentially mutilating results. Previous literature has demonstrated good response with imiquimod 5% cream in patients with vulval EMPD, yet its effectiveness in primary perianal disease is unknown.We describe the case of a 40-year-old woman presenting with EMPD of the perianal region, providing detailed histological and pictoral evidence of its response to topical imiquimod 5% cream over a 16-week period, which initially resulted in remission prior to metastatic lymph node recurrence. This case demonstrates the potential for topical imiquimod cream to avoid major surgery and its associated complications in patients presenting with EMPD of the perianal region. We discuss the current evidence for treating this rare condition with medical therapy, how this case adds to current literature and possible future directions.

Distinctive downmodulation of plasmacytoid dendritic cell functions by vitamin D3 analogue calcipotriol

BackgroundIn relation to Th17 cell actions, interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs) are involved in the pathogenesis of psoriasis. Vitamin D3 analogues are widely used in the treatment of psoriasis, however, their actions on pDCs are not well understood. ObjectiveTo investigate the effects of Vitamin D3 analogue calcipotriol (CAL) on pDCs, focusing on the cytokine production and chemotactic activity. MethodsWe compared in mice the effects of CAL, cyclosporine A (CyA), and triamcinolone acetonide (TA) on the cytokine production by pDCs (IFN-α), conventional DCs (TNF-α), and γd T cells (IL-17A). pDCs isolated from mouse spleen cells were stimulated with CpG-ODN in the presence or absence of each drug for 48h. Purified splenic conventional DCs (cDCs) and lymph node γδ T cells were stimulated with CpG-ODN or with anti-CD3/CD28 antibody, respectively. IFN-α, TNF-α and IL-17A in the 48-h culture supernatants were quantified by ELISA. We also studied the ability of CAL to inhibit the chemotaxis of freshly isolated pDCs toward chemerin and VEGF-A, representative chemoattractants of pDCs, by a real-time monitoring method, EZ-Taxiscan. To assess the effect of CAL on pDC accumulation in vivo, we painted CAL ointment to the mouse skin inflamed by topical application of imiquimod cream (IMQ) for 4 consecutive days. In the skin samples, we enumerated 440c+ pDCs by immunohistochemistry and evaluated the mRNA expression of cytokines by real-time PCR. ResultsCAL significantly inhibited CpG-enhanced pDC IFN-α production at a comparable level to T cell IL-17A production, whereas its effect on cDC TNF-α production was minimal. Accordingly, CAL suppressed the CpG-augmented expression of TLR9 and MyD88. On the contrary, CyA strongly suppressed the production of TNF-α and IL-17A, but not IFN-α. TA inhibited the production of all the cytokines tested. The effect of CAL on the chemotactic activity of pDCs was also evaluated, demonstrating a significant downmodulation by exposure to the reagent. CAL depressed chemerin receptor CMKLR1 expression in pDCs. The in vivo mouse study showed that simultaneous application of CAL to the imiquimod-applied skin reduce both the recruitment of pDCs and the expression of IFN-α2 in the skin. ConclusionsOur findings suggest that CAL uniquely downmodulates the cytokine production and chemotactic activity of pDCs. The CAL suppression of the in vivo pDC accumulation to the skin suggests that these actions are therapeutically relevant.

Treatment of oral dysplasia with 5% imiquimod cream: short communication

We report what we think is the first treatment of oral dysplasia with 5% imiquimod cream. A 60-year-old man presented with varying degrees of dysplasia on the soft palate. A cover plate was fabricated and the patient was prescribed 5% imiquimod cream, a topical imunomodulator, for six weeks. The lesion improved and histological examination of an incisional biopsy found no features of dysplasia. This case highlights the efficacy of imiquimod cream in the treatment of dysplasia, and the need for development of a preparation suitable for the oral mucosa.

A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget's disease

ObjectiveThe objective of this prospective pilot study was to assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease of the vulva. MethodsPatients with biopsy-proven recurrent extramammary Paget's disease presenting to the gynecology outpatient services at two participating institutions were recruited for conservative treatment with 5% imiquimod cream from 2007 to 2011. The topical cream was to be applied 3 times per week for 12weeks. Punch biopsy and photography were performed at baseline and at the 12-week time point. ResultsEight patients from two institutions were enrolled. Complete clinical and histologic response was achieved in 6 (75%) patients by the 12-week follow-up appointment. Of the two remaining patients, one had a complete clinical response but no significant histologic response; the other patient was removed from the study protocol secondary to intolerable local irritation. Two patients continue to have no evidence of disease after a median follow-up of 35months. Five are alive with disease. No patients progressed to invasive cancer while receiving therapy. ConclusionTopical 5% imiquimod cream is a safe and feasible option for women suffering from recurrent extramammary Paget's disease of the vulva, and should be considered as a viable alternative to surgical management. Given the rare nature of this disease, additional multi-institutional prospective studies should be conducted to explore the efficacy of this treatment regime.

Imiquimod treatment for Equus caballus papillomavirus infection in equine aural plaques.

Aural plaques are a dermatopathy associated with Equus caballus papillomavirus (EcPV). This disease affects horses of all ages, genders and breeds, and causes sensitivity of the ears. The aim of this study was to evaluate the clinical efficacy of 5% imiquimod cream for the treatment of aural plaques and to compare the PCR detection of EcPV 3, 4, 5 and 6 before and after treatment. Eight horses diagnosed with aural plaques (14 ears) were used. Three mares with unilateral aural plaques were used as untreated controls. Imiquimod cream was applied every 48 h until complete resolution of the aural plaques was observed. Animals were evaluated clinically for 180 days after the end of treatment. PCR for detecting EcPV 3, 4, 5 and 6 was performed using aural plaque biopsies collected before and at 90 days after the end of treatment. Clinical resolution was observed in 93% of the treated ears. Imiquimod treatment promoted the clearance of EcPV in 71.4% of the treated ears. Clinical remission of the aural plaques and changes in EcPV DNA positivity between the first and second biopsies were not observed in the control group. In 75% of horses, sedation was required in order to carry out pretreatment cleaning. The results of this study support the hypothesis that 5% imiquimod cream may be used as an effective treatment for aural plaques in horses.

Three-Year Follow-Up Results of Photodynamic Therapy vs. Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, Randomized Controlled Trial

A randomized controlled trial including 601 patients previously showed that the effectiveness of imiquimod and fluorouracil cream were not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) in patients with superficial basal cell carcinoma after 1 year of follow-up. We now present the 3-year follow-up results. The probability of tumor-free survival at 3 years post-treatment was 58.0% for MAL-PDT (95% confidence interval [CI]= 47.8-66.9), 79.7% for imiquimod (95% CI= 71.6-85.7), and 68.2% for fluorouracil (95% CI= 58.1-76.3). The hazard ratio for treatment failure comparing imiquimod with MAL-PDT was 0.50 (95% CI= 0.33-0.76, P= 0.001). Comparison of fluorouracil with MAL-PDT and fluorouracil with imiquimod showed hazard ratios of 0.73 (95% CI= 0.51-1.05, P= 0.092) and 0.68 (95% CI= 0.44-1.06, P= 0.091), respectively. Subgroup analysis showed a higher probability of treatment success for imiquimod versus MAL-PDT in all subgroups with the exception of elderly patients with superficial basal cell carcinoma on the lower extremities. In this subgroup, the risk difference in tumor-free survival was 57.6% in favor of MAL-PDT. In conclusion, according to results at 3 years post-treatment, imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of superficial basal cell carcinoma.

Imiquimod Increases Cutaneous VEGF Expression in Imiquimod-induced Psoriatic Mouse Model.

Psoriasis is a chronic skin disease of unknown aetiology but increasing evidence suggests that cutaneous angiogenesis plays an important role. Vascular endothelial growth factor (VEGF) is one of the pro-angiogenic cytokines which is related to the pathogenesis of psoriasis. Our study evaluated the influence of imiquimod (IMQ) on VEGF in IMQ-induced mouse model. Balb/c female mice (n=16) 8-12 weeks of age were randomly divided into an experimental group (5% IMQ cream) and the control group (Vaseline cream). Serum levels of circulating VEGF-A were quantified by enzyme-linked immunosorbent assay. VEGF protein expression in tested skin was measured by western blotting and immunohistochemical staining. The tested skin in the experimental group expressed higher levels of VEGF protein than in the control group (p=0.012); immunohistochemical staining revealed that the cells over-expressing VEGF localized predominantly in the epidermis and vascular endothelium. Circulating VEGF-A levels showed no significant difference between the experimental and control groups (p=0.445). The IMQ-induced mouse psoriatic model showed an upregulation of VEGF in the skin lesions mimicking human psoriasis but the circulating VEGF-A levels showed no difference. This model may be useful to investigate the role of angiogenesis in psoriasis.

Talpi lokalizációjú Kaposi-sarcoma sikeres kezelése imikvimod krémmel

Talpi lokalizációjú Kaposi-sarcoma sikeres kezelése imikvimod krémmel

Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.

Efficacy of Imiquimod Cream Administered Intraperitoneally for Ovarian Metastases in Colorectal Cancer

In this case report, we sought to determine the efficacy of intraperitoneal Imiquimod cream for the treatment of persistent ovarian metastases in colorectal cancer after Avastin-based chemotherapy failure. Topical Imiquimod cream is an immune response modifier. It could trigger skin Langerhan cells (naive dendritic cells) as the priming responsive cell type and initiate a strong Th1-switched anti-tumor cellular immune response. This is a 50-year-old woman with rectal cancer with liver, lung, left adrenal gland and ovarian metastasis, and pelvic carcinomatosis. CEA level decreased after the initial optimal debulking surgery and 12 cycles of chemotherapy. However, CEA level persistently elevated, and CT scan showed progressed carcinomatosis, malignant ascites and diffused metastasis. After intraperitoneal immunomodulatory therapy (IMT) administration with intraperitoneal Interleukin-2 mix Thymoxin on Day 1, and intraperitoneal Imiquimod cream (5% 250 mg in normal saline 2 ml) on Day 2, the amount of drainage ascites gradually decreased, and CEA level dramatically decreased after IMT.

Prognostic markers in lentigo maligna patients treated with imiquimod cream: A long-term follow-up study

More data are needed to define factors that predict long-term success after imiquimod therapy for lentigo maligna (LM). We sought to determine the demographic, clinical, and histologic prognostic markers of relapse-free survival in patients with LM who were treated with imiquimod. This was a single-arm, open-label, nonrandomized, prospective study. Eighty-nine patients with histologically confirmed LM and a median follow-up time of 4.8years after imiquimod treatment were included in our study. Sixteen patients (18%) relapsed. Statistically significant indicators of an increased risk of local recurrence included: the total number of melanocytes, the number of basal and suprabasal melanocytes and the number of pagetoid spreading melanocytes. Our study was a single-center, nonrandomized study. An assessment of different melanocyte fractions in the diagnostic baseline biopsy specimen may help to predict the response of LM to imiquimod therapy.

P10.21 A study on the use of imiquimod for the treatment of genital molluscum contagiosum and genital warts in female patients

Introduction The clinical effect of imiquimod stems from cytokine-induced activation of the immune system. A randomised study was conducted to study the efficacy and safety of daily applications of 5% imiquimod cream in female patients with external genital warts and MC. Methods Patients were randomised to receive daily applications of 5% imiquimod cream for a maximum of 16 weeks. Before bedtime patients rubbed the study cream into clean, dry, lesional skin until it disappeared and washed the area with soap and water 8 ± 2 h after application. To investigate wart and MC recurrence, patients who had complete clearance of their baseline lesions at any time during the treatment period stopped treatment and entered a 12-week treatment free follow-up period. Patients were evaluated weekly for the first 4 weeks and every 2 weeks thereafter for the remainder of the 16-week treatment period as well as during the 12-week follow-up period. Results The clearance rate of lesions was 75% in genital MC patients and 50% in patients with genital warts. Erythema was the commonest adverse reaction seen 24% patients with the use of 5% imiquimod. Other side effects were excoriation seen in 16% patients, erosions in 10% patients, excoriation in 6% patients and pain was seen in 4% patients. Conclusions Nonspecific inflammation and dermatitis can occur during use of imiquimod for genital warts and molluscum.Fortunately, after completion of the therapy, the skin often heals with barely any scarring. Disclosure of interest Nil.

Cytokine-enhanced maturation and migration to the lymph nodes of a human dying melanoma cell-loaded dendritic cell vaccine.

Dendritic cells (DCs) are professional APCs used for the development of cancer vaccines because of their ability to activate adaptive immune responses. Previously, we designed the DC/Apo-Nec vaccine using human DCs loaded with dying melanoma cells that primed Ag-specific cytotoxic T cells. Here, we evaluate the effect of a standard pro-inflammatory cytokine cocktail (CC) and adjuvants on DC/Apo-Nec maturation and migration. CC addition to the vaccine coculture allowed efficient Ag uptake while attaining strong vaccine maturation with an immunostimulatory profile. The use of CC not only increased CCR7 expression and the vaccine chemokine responsiveness but also upregulated matrix metalloproteinase-9 secretion, which regulated its invasive migration in vitro. Neither IL-6 nor prostaglandin E2 had a negative effect on vaccine preparation. In fact, all CC components were necessary for complete vaccine maturation. Subcutaneously injected DC/Apo-Nec vaccine migrated rapidly to draining LNs in nude mice, accumulating regionally after 48 h. The migrating cells of the CC-matured vaccine augmented in proportion and range of distribution, an effect that increased further with the topical administration of imiquimod cream. The migrating proportion of human DCs was detected in draining LNs for at least 9 days after injection. The addition of CC during DC/Apo-Nec preparation enhanced vaccine performance by improving maturation and response to LN signals and by conferring a motile and invasive vaccine phenotype both in vitro and in vivo. More importantly, the vaccine could be combined with different adjuvants. Therefore, this DC-based vaccine design shows great potential value for clinical translation.

Treatment of basal cell carcinoma with sequential photodynamic therapy and imiquimod cream may improve long-term patient outcomes

Treatment of basal cell carcinoma with sequential photodynamic therapy and imiquimod cream may improve long-term patient outcomes

Patient Perception of Imiquimod Treatment for Actinic Keratosis and Superficial Basal Cell Carcinoma in 202 Patients

Objective: To document the impact on patient-reported outcomes and health-related quality of life (HRQoL) of treatment with imiquimod cream in patients with actinic keratosis (AK) and superficial basal cell carcinoma (sBCC). Methods: This open-label, multicenter study included AK and sBCC patients eligible for treatment with imiquimod 5% cream. HRQoL was measured by the Skindex-17 and the Skin Cancer Index (SCI) and treatment satisfaction by the Treatment Satisfaction Questionnaire for Medication. Results: 118 AK patients and 84 patients with sBCC were included. Low baseline HRQoL impairment was found on both questionnaires, which remained low after treatment, except for a small dip at the end of the application period. Conclusion: Imiquimod 5% cream treatment has no clinically relevant HRQoL impact in AK and sBCC patients according to the Skindex-17 and SCI. The effect of imiquimod treatment on HRQoL may be limited or these questionnaires do not fully capture relevant issues, such as fear of recurrence.

Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type

Surgical resection of lentigo maligna (LM) is complicated by noncontiguous, subclinical extension and actinic melanocytic hyperplasia in sun-damaged skin of older individuals. We sought to determine the long-term effectiveness of imiquimod as primary or adjuvant therapy for LM. Patients were retrospectively identified from January 1, 2003, to December 31, 2013, with LM, early/evolving LM, and LM melanoma who had used topical imiquimod 5% cream for either primary therapy after diagnostic biopsy, or adjuvant therapy after narrow-margin surgical resection or complete clinical but not histologic resection of LM. Follow-up occurred through December 31, 2014. In all, 63 cases were identified in 61 patients, mean (SD) age 71.1 (12.4) years; 58 were analyzed for local recurrence. Imiquimod was used as primary therapy in 22 of 63 (34.9%) and adjuvant therapy in 41 of 63 (65.1%) for mean duration of 11.7 (range 2-60) weeks. Fifty cases (86.2%) demonstrated clinical clearance at mean (SD) follow-up of 42.1 (27.4) months: 72.7% primary and 94.4% adjuvant at 39.7 (23.9) and 43.1 (28.9) months, respectively. Retrospective cohort study and lack of standardized imiquimod application are limitations. Imiquimod cream appears to be a viable option for primary or adjuvant treatment of LM in older patients who are poor surgical candidates.

Clinical efficacy, safety and tolerance of the Kerawort (imiquimod) cream used for treatment of anogenital warts

Goal of the study. To assess the efficacy and safety of Kerawort (Imiquimod, 5% cream for topical administration) vs. placebo used for treatment of anogenital warts. Methods and materials. The single-blind comparative placebo-controlled study involved 90 patients (44 female and 46 male) with anogenital warts. The patients were randomized into two groups: the main group (n = 45) receiving treatment with Kerawort (Imiquimod, 5% cream) and the control group (n = 45) receiving placebo. The diagnosis was confirmed by the identification of human papillomavirus by the polymerase chain reaction method. The patients received treatment three times a week until clinical signs disappeared but for not more than 16 weeks. Results. In 95.6% of patients from the main group and 8.9% of patients from the control group, anogenital warts disappeared completely or the quantity/area of pathological eruptions reduced at least by 70% as compared to the baseline. No relapses occurred during the treatment and follow-up period (28 days after the completion of treatment) in patients from the main group. An increase in the size and/or area of anogenital warts and/or development of new eruptions on the skin and mucous membrane of the genitals were recorded in 11.1% of patients from the control group. No serious adverse events were revealed during the study. Conclusion. Higher efficacy (р &lt; 0.0000001) and comparable safety of Kerawort (Imiquimod, 5% cream for topical administration) used for treatment of anogenital warts vs. placebo were reliably established.