Efficacy and safety of a 0.05 % nanoencapsulated imiquimod hydrogel for the treatment of actinic cheilitis: Drug release analysis and clinical study.

Actinic cheilitis (AC) is a lip disorder, with no standard treatment. Imiquimod (IMIQ) is an immunomodulator that treat precancerous lesions; however, its commercial form causes severe adverse effects. This study aimed to assess IMQ release from a chitosan hydrogel containing 0.05 % nanoencapsulated (NANO) imiquimod (IMIQ-0.05 %-NANO) and its efficacy in AC treatment. The hydrogels were prepared by incorporating chitosan into polymeric nanocapsules (NCimiq) loaded with IMQ, produced using the interfacial deposition of preformed polymer method. IMQ release was evaluated using automated Franz Cells. A triple-blind randomized controlled trial (49 subjects) compared the efficacy of: IMIQ-0.05 %-NANO, 5 % free imiquimod (IMIQ-5 %), 0.05 % free imiquimod (IMIQ-0.05 %), and placebo hydrogel. The IMIQ-NANO-0.05 % and IMIQ-5 % groups exhibited significantly higher rates of clinical improvement (p < 0.05); however, the IMIQ-5 % group experienced more adverse effects (92.3 % of subjects) compared to other groups (p < 0.05). In conclusion, in the studied sample, IMIQ-NANO-0.05 % was a safe and effective option to treat AC.

Acquired epidermodysplasia verruciformis syndrome in HIV-infected patients: a systematic review.

Congenital epidermodysplasia verruciformis (CEV) is a Genodermatosis linked to different inheritance patterns and mutations of the EVER1/TMC6 and EVER2/TMC8 genes. There is an acquired form (AEV) associated with immunodeficiency states, including human immunodeficiency virus (HIV) infection; however, the literature about AEV is limited and imprecise, so a systematic review was performed. A search of the main databases from 1975 to 2021 identified 126 studies, of which 80 met the inclusion criteria. The diagnosis of AEV is complex due to atypical manifestations and locations, it requires a mean follow-up of 7 years, and the lesions do not change with ART therapy, CD4 count, or viral load. Histopathological findings are variable depending on the location of the lesions. HPV 5 remains the serotype most frequently associated with AEV and CEV, although HPV 20 is more frequent than HPV 8 in AEV. Most treatments have low efficacy, the most described are glycolic acid 15%, 5-fluorouracil 5%, imiquimod 5%, and topical retinoids all of them in monotherapy or combined with cryotherapy. Other alternatives include topical cidofovir and systemic retinoids with variable results. The oncologic prognosis is still inconclusive; however, the development of squamous cell carcinoma and melanoma are frankly lower concerning CEV. This review opens new opportunities for future research. Additionally, we provide clear and useful key points for the practice of dermatologists and all professionals treating HIV patients around the world.

Acné queloideo de la nuca: excelente respuesta al tratamiento con imiquimod 5% / Keloid acne of the nape: excellent response to treatment with imiquimod 5%

El acné queloideo de la nuca (AKN) o foliculitis esclerosante es un proceso inflamatorio crónico del folículo piloso en la región de la nuca. Su incidencia es baja y su etiología desconocida. Afecta con mayor frecuencia a hombres de mediana edad y de raza negra. A lo largo del tiempo se han utilizado diferentes modalidades terapéuticas con resultados variables. Presentamos el caso de un paciente con AKN que mostró una excelente respuesta al uso diario de imiquimod 5% tópico durante ocho semanas

Keloid acne of the neck (AKN) or sclerosing folliculitis of the nape of the neck is a chronic inflammatory process of the nape region. Its incidence is low and its etiology is unknown. It mainly affects brown-black males in middle age. Different treatment modalities have been used with different responses. We present the case of a patient with AKN who presented an excellent response to the daily use of topical imiquimod 5% for eight weeks

Design of Chitosan Nanocapsules with Compritol 888 ATO® for Imiquimod Transdermal Administration. Evaluation of Their Skin Absorption by Raman Microscopy.

PURPOSE: Design imiquimod-loaded chitosan nanocapsules for transdermal delivery and evaluate the depth of imiquimod transdermal absorption as well as the kinetics of this absorption using Raman Microscopy, an innovative strategy to evaluate transdermal absorption. This nanovehicle included Compritol 888ATO®, a novel excipient for formulating nanosystems whose administration through the skin has not been studied until now. METHODS: Nanocapsules were made by solvent displacement method and their physicochemical properties was measured by DLS and laser-Doppler. For transdermal experiments, newborn pig skin was used. The Raman spectra were obtained using a laser excitation source at 532 nm and a 20/50X oil immersion objective. RESULTS: The designed nanocapsules, presented nanometric size (180 nm), a polydispersity index <0.2 and a zeta potential +17. The controlled release effect of Compritol was observed, with the finding that half of the drug was released at 24 h in comparison with control (p < 0.05). It was verified through Raman microscopy that imiquimod transdermal penetration is dynamic, the nanocapsules take around 50 min to penetrate the stratum corneum and 24 h after transdermal administration, the drug was in the inner layers of the skin. CONCLUSIONS: This study demonstrated the utility of Raman Microscopy to evaluate the drugs transdermal penetration of in the different layers of the skin. Graphical Abstract New imiquimod nanocapsules: evaluation of their skin absorption by Raman Microscopy and effect of the compritol 888ATO® in the imiquimod release profile.

Case Report: Treatment of Chromoblastomycosis with Combinations including Acitretin: A Report of Two Cases.

Chromoblastomycosis is a cutaneous fungal infection caused by dematiaceous fungi that belong to the order Chaetothyriales and family Herpotrichiellaceae. This infection is prevalent in tropical and subtropical areas and has been designated as a neglected tropical disease according to the WHO. Chromoblastomycosis infection is difficult to treat, and there are limited therapeutic options, making urgent the characterization of new medicines or approaches to treat such infection. In the present case report, two patients with extensive chromoblastomycosis lesions were treated with the combination of itraconazole, acitretin, and imiquimod. In the fourth month of treatment, both patients showed improvement of verrucous plates, suggesting that acitretin combined with drugs already used in chromoblastomycosis therapy can decrease the time of treatment, improving patient's quality of life.

New pectin-based hydrogel containing imiquimod-loaded polymeric nanocapsules for melanoma treatment.

We developed a pectin-based hydrogel containing nanocapsules as a new strategy for melanoma treatment. Our first objective was to evaluate the nanoencapsulation effect of imiquimod on melanoma. Imiquimod-loaded polymeric nanocapsules (NCimiq) showed significant time-dependent decrease in cell viability after treatment at 3 µmol L-1 (79% viable cells in 24 h and 55% in 72 h), which was not observed in cells treated with the solution of the drug (IMIQ) (99% viable cells in 24 h and 91% in 72 h). The second objective was to develop the hydrogel containing the drug-loaded nanocapsules (PEC-NCimiq). In vitro release study showed that 63% of imiquimod was released from the pectin-based hydrogel containing the drug (PEC-imiq) after 2 h, while 60% of the drug was released from PEC-NCimiq after 8 h. In the permeation study, 2.5 µg of imiquimod permeated the skin within 8 h after the initial contact of PEC-NCimiq, whereas only 2.1 µg of drug permeated after 12 h of contact when PEC-imiq was assayed. Pectin-based hydrogels enabled the drug penetration in all skin layers, especially the dermis (PEC-NCimiq = 6.8 µg and PEC-imiq = 4.3 µg). In the adhesion study, PEC-NCimiq showed the highest adhesiveness (42% removed from the skin) in comparison to PEC-imiq (71% removed from the skin). In conclusion, the nanoencapsulation provided a higher cytotoxic effect of imiquimod in SK-MEL-28, and the incorporation of the drug-loaded nanocapsules in pectin-based hydrogel showed higher adhesiveness and deeper penetration of the drug into the skin. Graphical abstract.

Successful treatment of chromoblastomycosis caused by Fonsecaea pedrosoi using imiquimod.

Chromoblastomycosis (CBM) is a fungal infection caused by fungi belonging to the order Chaetothyriales, and caused mainly by Fonsecaea pedrosoi. The classic treatment, based on itraconazole and/or terbinafine as well as physical approaches, is considered complex and ineffective due to the high rate of relapses. Thus, new strategies are needed to manage CBM; in this regard, the present work reports the evolution of lesions in patients successfully treated with imiquimod. Of note, classic treatment was not effective in healing the lesions of two of them, but single topical treatment with imiquimod healed the lesions.

Anti-HPV Nanoemulsified-Imiquimod: A New and Potent Formulation to Treat Cervical Cancer.

Cervical cancer is associated with the human papilloma virus (HPV) and nowadays is the fourth most frequent cancer among women. One of the treatments for this disease is based on the application of imiquimod. In this study, we postulated that the use of imiquimod in nanoemulsion results in a better antitumoral effect than the drug administered in its nonencapsulated form for the treatment of cervical cancer. Permeability studies using vaginal mucosa, as membrane, and in vitro studies involving cervical cancer cells (viability, clonogenic assay, and cell death analysis) were performed. We showed that low amount of encapsulated imiquimod permeated the vaginal mucosa. However, a higher percentage of cells died after the treatment with low amount (3.0 µmol L-1) of the formulation compared to the free drug. In addition, the innovative formulation presented a combinatory mechanism of cell death involving autophagy and apoptosis. Our results demonstrate that the imiquimod-loaded nanoemulsioncan be an alternative product for the treatment of cervical cancer validating the hypothesis.

Vegetative chronic genital herpes with satisfactory response to imiquimod.

Vegetative chronic genital herpes is an atypical presentation of herpes simplex 2 that it is usually seen in patients coinfected with human immunodeficiency virus. Clinically, it is characterized by extensive ulcers that evolve to chronification and hypertrophic pseudotumor forms. Antiviral drugs are recommended for the treatment, and acyclovir is the most used one. Foscarnet is the treatment of choice to resistant cases, although treatment failure has been reported. We report a male patient, previously diagnosed with human immunodeficiency virus who developed vegetative chronic genital herpes resistant to acyclovir and successfully treated with imiquimod.

Vegetative chronic genital herpes with satisfactory response to imiquimod

Abstract Vegetative chronic genital herpes is an atypical presentation of herpes simplex 2 that it is usually seen in patients coinfected with human immunodeficiency virus. Clinically, it is characterized by extensive ulcers that evolve to chronification and hypertrophic pseudotumor forms. Antiviral drugs are recommended for the treatment, and acyclovir is the most used one. Foscarnet is the treatment of choice to resistant cases, although treatment failure has been reported. We report a male patient, previously diagnosed with human immunodeficiency virus who developed vegetative chronic genital herpes resistant to acyclovir and successfully treated with imiquimod.

Novel imiquimod nanovesicles for topical vaccination.

Development of needle and pain free noninvasive immunization procedures is a top priority for public health agencies. In this work the topical adjuvant activity of the immunomodulator imiquimod (IMQ) carried by ultradeformable archaeosomes (UDA2) (nanovesicles containing sn-2,3 ether linked phytanyl saturated archaeolipids) was surveyed and compared with that of ultradeformable liposomes lacking archaeolipids (UDL2) and free IMQ, using the model antigen ovalbumin and a seasonal influenza vaccine in Balb/c mice. UDA2 (250 ± 94 nm, -26 ± 4 mV Z potential) induced higher IMQ accumulation in human skin and higher production of TNF-α and IL-6 by macrophages and keratinocytes than free IMQ and UDL2. Mixed with ovalbumin, UDA2 was more efficient at generating cellular response, as measured by an increase in serum IgG2a and INF-γ production by splenocytes, compared with free IMQ and UDL2. Moreover, mixed with a seasonal influenza vaccine UDA2 produced same IgG titers and IgG2a/IgG1 isotypes ratio (≈1) than the subcutaneously administered influenza vaccine. Topical UDA2 however, induced highest stimulation index and INF-γ levels by splenocytes. UDA2 might be a promising adjuvant for topical immunization, since it produced cell-biased systemic response with ≈ 13-fold lower IMQ dose than the delivered as the commercial IMQ cream, Aldara.

Liposomes can both enhance or reduce drugs penetration through the skin.

The adequate formulation of topical vehicles to treat skin diseases is particularly complex. A desirable formulation should enhance the accumulation of the active drugs in the target tissue (the skin), while avoiding the penetration enhancement to be so large that the drugs reach the systemic circulation in toxic amounts. We have evaluated the transcutaneous penetration of three drugs chosen for their widely variable physicochemical properties: Amphotericin B, Imiquimod and Indole. We incorporated the drugs in fluid or ultra-flexible liposomes. Ultra-flexible liposomes produced enhancement of drug penetration into/through human skin in all cases in comparison with fluid liposomes without detergent, regardless of drug molecular weight. At the same time, our results indicate that liposomes can impede the transcutaneous penetration of molecules, in particular small ones.

Rare perianal extramammary Paget disease successfully treated using topical Imiquimod therapy.

BACKGROUND: Perianal Paget's disease (PPD) is a rare intraepithelial adenocarcinoma of the anal margin. Primary PPD likely represents intra-epithelial neoplasm from an apocrine source, whereas secondary disease may represent "pagetoid" spread from an anorectal malignancy. CASE PRESENTATION: Histologic CDX-2 and CK20 are hallmark markers for colorectal-derived Paget's cells. Interestingly, our primary PPD patient presented both positive and no internal malignancy was identified. In addition, a negative CK7 marker was observed in our case in contrast with previously reported. Surgical excision is the standard treatment; however, previous studies have demonstrated good response with Imiquimod 5% cream in patients with vulval extramammary Paget disease (EMPD). The efficiency of Imiquimod treatment for PPD has not been well described. Our PPD patient was successfully treated using Imiquimod 5% cream. CONCLUSIONS: This study describes a primary cutaneous PPD patient CDX-2+/CK20+/CK7- without invasion of the dermis and no associated colorectal carcinoma effectively treated using topical Imiquimod therapy, suggesting that Imiquimod might potentially be considered as a first-line treatment for PPD.

Intravesical Immunomodulatory Imiquimod Enhances Bacillus Calmette-Guérin Downregulation of Nonmuscle-invasive Bladder Cancer.

BACKGROUND: The Toll-like receptor (TLR)2/4 agonist bacillus Calmette-Guérin (BCG), although not failure proof, has been the most efficient immunomodulatory treatment of immunogenic nonmuscle-invasive bladder cancer (NMIBC) for > 40 years. We investigated the role of the immunomodulatory molecule TLR7 agonist imiquimod through the BCG key receptors TLR2/4 and the main downstream molecules of the mammalian target of rapamycin pathway in NMIBC treatment. MATERIALS AND METHODS: A total of 40 Fischer-344 rats, 7 weeks old, received 4 doses of 1.5 mg/kg N-methyl-N-nitrosourea intravesically on weeks 0, 2, 4, and 6 for cancer induction. At week 8, the rats were randomized into 4 groups (10 per group) and treated intravesically once a week for 6 weeks: control (0.2 mL of vehicle); BCG (2 × 106 colony-forming units Connaught strain in 0.2 mL); imiquimod (20 mg/kg in 0.2 mL), and associated treatment BCG plus imiquimod in 0.2 mL. The bladders were extracted and analyzed for histopathology, immunohistochemistry, cell proliferation (Ki-67), apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and immunoblotting for TLR2, TLR4, p-P70S6K, and p-4E-BP1 proteins. RESULTS: The histopathology results showed that BCG and imiquimod decreased bladder tumorigenesis compared with the control group, with a proliferation decrease (Ki-67) and an apoptosis increase (TUNEL). BCG upregulated TLR2/4, imiquimod upregulated TLR4, and both downregulated P70S6K1. CONCLUSION: Imiquimod is able to efficiently decrease bladder carcinogenesis through upregulation of TLR7/4 and downregulation of P70S6K1 protein, generating new perspectives to boost BCG effects in the future.

Periocular basal cell carcinoma: cost of topical immunotherapy versus estimated cost of surgical treatment / Carcinoma basocelular periocular: custo da imunoterapia tópica versus custo estimado do tratamento cirúrgico

PURPOSE: The objective of this study was to compare the estimated cost of clinical and surgical treatment for basl cell carcinoma of the eyelid. METHODS: This was a pilot study of 12 patients with basal cell carcinoma receiving treatment with 5% imiquimod cream at the ocular plastic surgery center, medical school University of São Paulo (HC-FMUSP, Brazil). The cost of clinical treatment was estimated based on the time of treatment and amount of medication consumed by patients in the home setting. The cost of surgical treatment was estimated by ophthalmologists with experience in reconstructive plastic surgery based on analysis of images of the same patients. Surgeons responded to a questionnaire with four questions about surgical technique, surgical materials required, estimated duration of surgery and type of anesthesia. RESULTS: Immunotherapy lasted from 8 to 12 weeks.All patients reported each coldstored sachet with 5% imiquimod cream lasted 3 days.According to the institution, a box with 12 sachets costs BRL 480.00. Patients required 1.58-3.11 boxes for complete treatment, corresponding to a total cost of BRL 758.401,492.80. Based on image analysis, surgeons evaluated surgery would require 1-3 hours. The estimated cost of surgery room and staff was BRL 263.00, to which the cost of supplies was added. Thus, the total cost of surgical treatment was BRL 272.61-864.82. On the average, immunotherapy was 57,64% more costly than surgical treatment. CONCLUSIONS: Malignant eyelid tumors are a common finding in clinical ophthalmology. Surgery is still the treatment of choice at our institution, but immunotherapy with 5% imiquimod cream may be indicated for patients with multiple lesions or high surgical risk and for patients declining surgery for reasons of fear or esthetic concerns.The ability to estimate costs related to the treatment of malignant eyelid tumors is an important aid in the financial planning of health care institutions. Further studies should evaluate the possibility of institutions equating the cost of immunotherapy and surgical treatment by acquiring similar but less expensive medications.

OBJETIVO: O objetivo deste estudo foi comparar os custos do tratamento clínico e cirúrgico para carcinoma basocelular palpebral. MÉTODO: Neste estudo piloto, doze pacientes com carcinoma basocelular atendidos no departamento de Plástica Ocular do Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) foram tratados com imiquimode creme 5%. O Custo do tratamento clínico foi estimado baseado no tempo de tratamento e quantidade de medicação utilizada pelo paciente no domicilio. O custo do tratamento cirúrgico foi baseado na análise das imagens dos mesmos pacientes submetidos ao tratamento clínico, por Oftalmologistas experientes em cirurgia plástica reconstrutiva. Os profissionais responderam um questionário com quatro perguntas relacionadas à técnica cirúrgica, à quantidade de material gasto, ao tempo cirúrgico estimado e anestesia utilizada. RESULTADOS: O tempo de tratamento clínico variou entre 8 a 12 semanas.Todos os pacientes referem que um sachê dura 3 dias e armazenaram na geladeira. O valor informado pela instituição na compra do imiquimode creme 5% foi de 40,00 reais/sachê, portanto o custo da caixa medicação foi de R$ 480,00 a caixa.A média de caixas consumidas por tratamento variou de 1,58 a 3,11 caixas, portanto o custo do tratamento clínico variou de R$ 758,40 a R$1.492,80. Os cirurgiões avaliaram as imagens dos pacientes submetidos ao tratamento clínico e informaram que o tempo estimado de cirurgia para cada paciente seria de 1 a 3 horas se a opção fosse cirúrgica.Foi estimado um custo de centro cirúrgico, incluindo espaço físico e pessoal de R$ 263,00 ao qual foi acrescido o valor do material que seria utilizado.Assim, observou-se que o valor variou entre R$ 272,61 a R$ 864,82 para o tratamento cirúrgico. O tratamento clínico em média foi de 57,64% superior ao tratamento cirúrgico. CONCLUSÃO: As lesões palpebrais malignas são responsáveis por uma porção importante na prática clínica oftalmológica. A cirurgia continua ...