Aldara
[Topical imiquimod cream in the treatment of external anogenital warts: personal experience]

[Article in Italian]

Senatori R, Dionisi B, Lippa P, Inghirami P.

Ambulatorio MST- AIED, Roma, Italy.

AIM: The clinical effects of home-therapy with 5% imiquimod cream in the treatment of cutaneous anogenital warts are evaluated. METHODS: From March 2000 to January 2002, 57 women presenting clinical cutaneous external genital and perianal warts were selected in the base-population observed at our clinical of vulvar pathology and sexually trasmitted diseases, AIED Rome. The patients were divided into 2 groups: Group A, with new cutaneous viral lesions and Group B with recurrent anogenital warts pre-treated with CO2-laser therapy. A total of 36% (20) of all patients presented contemporaneous HPV lesions of cervix and/or vaginal wall. The follow-up was carried out at 4 weeks, 3 months and 6 months, evaluating the safety, clinical efficacy and tolerance of women. The Pearson chi squared test was used to evaluate trends significance. All lesions were photo-documented. RESULTS: Sixty-four per cent (64%) of the patients had complete clearance of anogenital warts within 16 weeks, for 3 times per week self-application of imiquimod, with clinical remission at short term (6/8 weeks) (chi squared=1.42; p<0.05); 12% had partial clearance (<50%) and 20% had a clearance of about 75%. The coexistent lesions of cervix and/or vaginal walls had a high remission (>50%) and required surgical additional therapy with CO2-laser; 28% of patients (16/57) experienced mild to moderate drug-related side effects. There was a significant increase in the severity of local skin reactions due to the increased time and number of applications. CONCLUSION: These data confirm that imiquimod cream at the dose regimen of 3 times per week, is effective and well tolerated in the treatment of cutaneous external warts and is associated to a reduction of coexistent mucous viral lesions due to enhancement of local immune response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14676745&dopt=Abstract imiquimod Aldara



Aldara
Topically applied imiquimod inhibits vascular tumor growth in vivo.

Sidbury R, Neuschler N, Neuschler E, Sun P, Wang XQ, Miller R, Tomai M, Puscasiu E, Gugneja S, Paller AS.

Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.

Vascular tumors occur in approximately 10% of all infants and may be associated with significant morbidity. Available therapies for vascular tumors, such as systemic corticosteroids, vincristine, and interferon-alpha, may cause toxicity, limiting their use to complicated cases. Using a mouse hemangioendothelioma model, we investigated the efficacy and mechanism of action of imiquimod, a topically applied inducer of cytokines. Application of imiquimod cream, whether initiated at the time of cell inoculation or when tumors became visible, significantly decreased tumor growth and increased animal survival in comparison with control mice. Imiquimod-treated tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1 with decreased activity of matrix metalloproteinase-9. The demonstration that local application of imiquimod inhibits vascular tumor enlargement in the mouse vascular tumor model suggests a novel, less toxic means of treating infantile hemangioendotheliomas and perhaps other cutaneous vascular tumors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14708627&dopt=Abstract imiquimod Aldara



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Mechanism of action of imiquimod 5% cream in the treatment of anogenital warts.

Tyring SK, Arany I I, Stanley MA, Stoler MH, Tomai MA, Miller RL, Owens ML, Smith MH.

University of Texas Medical Branch, Texas, Galveston, USA

Objective: The objective of this randomized, double-blind, placebo-controlled trial was to evaluate the mechanism of action of imiquimod cream in the treatment of anogenital warts, and to apply the findings to the results of previously conducted safety and efficacy trials.Methods: Imiquimod (16 patients) or placebo (3 patients) cream was applied 3 times a week for up to 16 weeks; cream remained on the skin overnight for 8 +/- 2 hours. Wart biopsies were taken at prestudy, week 6, and the end of treatment (just prior to clearance or at week 16) and analyzed using PCR for HPV/DNA and RT-PCR for mRNA to identify cytokines, cellular markers, markers of proliferation and differentiation, and viral gene products. Efficacy was assessed based on wart area regression as documented by wart area measurements and photographs.Results: All patients enrolled in the trial had HPV type 6/11. All imiquimod-treated patients experienced a >/=75% clearance in baseline/target wart area. Imiquimod treatment stimulated significant increases in mRNA for IFN-alpha, 2'5' AS and IFN-gamma. Increases in mRNA for CD4, CD8, and TNF-alpha were also observed, suggesting activation of a T-helper type-1 cell mediated response. During the trial one of the vehicle treated patients also experienced spontaneous wart clearance; comparisons of the cytokine levels for this patient were similar to those observed for the imiquimod treated patients.Conclusions: The results of this mechanism of action trial indicate that the stimulation of local cytokines and cellular infiltrates by imiquimod leads to a reduction of HPV types 6 and 11 viral load with subsequent wart regression and normalization of keratinocyte proliferation without evidence of scarring. In two previous randomized vehicle-controlled trials evaluating patients with anogenital warts, the majority of patients had HPV-DNA types 6 or 11 as assessed by in situ hybridization. These results provide additional insight into the mechanism of total clearance for these otherwise healthy patients. The Th1 response demonstrated in this trial also explains the lower total clearance rates demonstrated in HIV-positive and AIDS patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10838280&dopt=Abstract imiquimod Aldara



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Topical imiquimod immunotherapy in the management of lentigo maligna.

Powell AM, Russell-Jones R, Barlow RJ.

The Skin Tumour Unit, St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK. amipowell doctors.org.uk

Melanoma in situ of the lentigo maligna (LM) type is a precursor lesion of LM melanoma. It most commonly occurs in elderly individuals, on the head and neck. Although surgical excision is recommended, this may not be practical for large lesions at cosmetically sensitive sites. In addition, histological changes commonly extend beyond the clinical margins of the lesion. This study describes the use of imiquimod 5% cream as topical immunotherapy in the management of lentigo maligna. Twelve patients (average age 63 years, 10 female), of biopsy-proven facial LM were treated with topical imiquimod, three times a week for 6 weeks. In the absence of an inflammatory response, patients were asked to apply the treatment daily. Seven showed clearance of the LM clinically and histologically. A further three patients showed clearance histologically with persisting pigmentation due to dermal melanin and melanophages. Thus, 10 of 12 patients cleared with no relapse after a median follow-up of 6 months. Two patients failed to respond to imiquimod and their lesions were treated with surgical excision. Imiquimod was well tolerated, except in three patients who experienced an intense inflammatory response. Two of these also developed secondary infection. Imiquimod 5% cream appears to offer a potential noninvasive method for the treatment of lentigo maligna.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14723712&dopt=Abstract imiquimod Aldara



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Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.

Todd RW, Steele JC, Etherington I, Luesley DM.

Department of Gynaecologic Oncology, Birmingham Women's NHS Trust, Birmingham B15 2TG, UK. rick todd38.freeserve.co.uk

OBJECTIVES: To investigate CD8+ T cell reactivity to human papillomavirus (HPV) 16 antigens in patients with high-grade vulval intraepithelial neoplasia (VIN) before, during and after treatment with 5% imiquimod cream. METHODS: CD8-enriched responder cell populations were obtained from 10 patients with high-grade VIN using imiquimod cream as a treatment. Overlapping synthetic peptides covering the entire primary sequences of the HPV16 E6, E7 and E4 proteins were used to screen for CD8+ T cell responses using an ELISPOT assay of interferon (IFN)-gamma release. RESULTS: Reactivity to the proteins was detected in all patients on at least one occasion. With the exception of one patient, CD8+ T cell reactivity generally increased at some stage during treatment. The magnitude and specificities of responses changed over the treatment period. This was particularly noticeable in response to peptides derived from the E4 protein. CD8+ T cell reactivity to HPV16 E7 appeared to be dominant amongst women with high-grade VIN. The magnitude and specificity of response had no correlation with clinical response to imiquimod. CONCLUSIONS: HPV16 specific CD8+ T cell activity was detected in patients with high-grade VIN. Imiquimod use appeared to increase the magnitude of the response and broaden the specificity of response in some patients. Despite the presence of these CD8+ T cells, the disease state persisted; therefore, a role for HPV-specific cytotoxic T cells (CTLs) in VIN resolution remains unproven.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14751153&dopt=Abstract imiquimod Aldara



Aldara
C/EBPbeta activity and HPV-16 E6/E7 mRNA expression are not altered by imiquimod (ALDARA) in human cervical cancer cells in vitro.

Belcastro M, Miller MR, Flynn DC, Soisson AP.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, West Virginia University School of Medicine, Morgantown, WV 26506, USA. mbelcastro hsc.wvu.edu

OBJECTIVE: The purpose of this study was to determine the potential relationship between imiquimod and C/EBPbeta by investigating the extent to which imiquimod could alter C/EBPbeta binding activity to known sequences of the HPV-16 NCR, which could lead to the repression of HPV-16 E6/E7 oncogene expression, possibly impacting a major mechanism by which HPV causes cellular transformation. METHODS: The effect of imiquimod treatment on C/EBPbeta binding activity to its consensus sequence as well as to two specific regions of the HPV-16 NCR was determined by electromobility shift assay (EMSA) in CaSki cervical cancer cells. HPV-16 E6/E7 gene expression was evaluated by RNase protection assay (RPA) in CaSki and in W12-E cells treated with imiquimod. In addition, C/EBPbeta mRNA expression and protein production in response to imiquimod were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, respectively, in the cervical cancer cell lines, CaSki, HeLa, and C33A. RESULTS: C/EBPbeta binding activity, mRNA expression, and protein production remained unchanged with imiquimod treatment. Initially, HPV-16 E6/E7 expression appeared to be increased with imiquimod treatment in CaSki cells, but this effect was not reproducible. HPV-16 E6/E7 expression was not reproducibly altered with imiquimod treatment in W12-E cells. CONCLUSION: While these results indicate that imiquimod does not alter C/EBPbeta binding activity, nor does it appear to decrease HPV-16 E6/E7 oncogene expression in vitro, it remains possible that imiquimod may have utility in treating cervical dysplasia or cervical cancer via another mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14766263&dopt=Abstract imiquimod Aldara