Aldara
Imiquimod in basal cell carcinoma: how does it work?

Dummer R, Urosevic M, Kempf W, Hoek K, Hafner J, Burg G.

Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland. reinhard.drummer usz.ch

Imiquimod is a topical immune response modifier that binds to Toll-like receptor-7 and -8, inducing interferon-alpha. We treated superficial basal cell carcinomas (BCC) with imiquimod 5% cream daily for 5-8 days. The BCC lesions were biopsied before treatment and following imiquimod treatment, when the lesion showed the signs of erosion. We applied histology, immunohistochemistry and gene array technology (Affymetrix) to gain further insight into the mode of action of imiquimod. Our findings demonstrate that imiquimod-induced BCC regression is associated with a strong activity of the innate immune response, mediated by cells of macrophage-monocyte origin and is associated with the induction of apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14616353&dopt=Abstract imiquimod Aldara



Aldara
Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle.

Berman B, Sullivan T, De Araujo T, Nadji M.

University of Miami School of Medicine, 1600 NW 10th Avenue Room 2023, Miami, FL 33136, USA. bberman med.miami.edu

Treatment with imiquimod 5% cream, capable of inducing interferon (IFN)-alpha, effectively cures basal cell carcinoma (BCC), both clinically and histologically. IFN-alpha induces expression of CD95-receptor (FasR) on BCC cells, which normally fail to express Fas receptor (FasR). Expression of the FasR is postulated to lead to apoptosis via CD95 receptor-CD95 ligand (FasL) interaction. Absence of this receptor may be responsible for the longevity of the cells of BCCs by preventing them undergoing 'suicidal' apoptosis, as well as apoptosis induced by neighbouring BCC cells and/or by infiltrating T-lymphocytes. We examined the expression of FasR on BCC after very short-term exposure to imiquimod 5% cream or vehicle. In a double-blind study, 10 patients with BCC applied either imiquimod (n = 5) or vehicle (n = 5) five times per week for up to 2 weeks. At the end of treatment, the treated area was excised and examined for the presence or absence of FasR by immunoperoxidase staining of rat antihuman FasR with haematoxylin and eosin counterstaining. Histologically, BCC cells were present in all (5/5) of the vehicle-treated BCCs and in 4/5 of the imiquimod-treated BCCs. BCC cells expressed FasR in 3/4 imiquimod-treated BCCs but in none (0/5) of the vehicle-treated tumours. T-lymphocytes apposed to BCC cells were evident in all three imiquimod-treated BCCs expressing FasR and in none of the FasR-negative, vehicle-treated BCCs. Imiquimod-induced FasR-mediated apoptosis may contribute to the effectiveness of imiquimod 5% cream for the treatment of BCC.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14616354&dopt=Abstract imiquimod Aldara



Aldara
Topical application of imiquimod 5% cream to keloids alters expression genes associated with apoptosis.

Jacob SE, Berman B, Nassiri M, Vincek V.

Department of Dermatology and Cutaneous Surgery, University of Miami, 1600 NW 10th Ave, Room 2023 A, Miami, FL 33138, USA.

Keloids are benign mesenchymal tumours, usually present at and extending beyond the margins of sites of previous injury. It is reported that keloids display aberrant expression of apoptotic genes: TGFB1 is activated, whereas caspase 8 and 3 are not, thus indicating a block upstream in the apoptosis cascade in keloids. Interferon-alpha 2b normalizes the excessive synthesis of collagen, glycosaminoglycans and collagenase by keloidal fibroblasts, reduces recurrences following keloid excision, and enhances the expression of native p53 and apoptosis. Imiquimod, a rapid and potent inducer of interferons locally at the site of application to the skin, reduces recurrences following keloid excision and alters gene expression of markers of apoptosis in basal cell carcinoma cells. We investigated the effects with respect to the expression of apoptotic genes in keloidal tissue compared with nontreated controls of imiquimod 5% cream applied topically to keloids. Total RNA was extracted from excised keloidal tissue, cDNA probes synthesized and then hybridized to gene-specific cDNA fragments spotted on membranes. The expression levels of 96 genes involved in apoptosis, relative to cyclophilin expression, were compared in the imiquimod-treated and untreated groups. The mean ratio of expression, relative to cyclophilin of caspase 3 and DFFA were significantly enhanced. Caspase 3 was significantly downregulated and DFFA was significantly upregulated in the group of imiquimod-treated keloids (P < 0.05) compared with the untreated group of keloids. Although imiquimod is capable of altering the expression of these markers of apoptosis in keloids, their role, if any, in the therapeutic response of keloids to imiquimod requires further investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14616355&dopt=Abstract imiquimod Aldara



Aldara
Imiquimod does not affect shedding of viable chlamydiae in a murine model of Chlamydia trachomatis genital tract infection.

Ramsey KH, Shaba N, Cohoon KP, Ault KA.

Department of Microbiology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA. kramse midwestern.edu

OBJECTIVE: We postulated that either oral or vaginal administration of the immune response modifier imiquimod would decrease vaginal shedding of Chlamydia trachomatis, mouse pneumonitis strain (MoPn), in a murine model. METHODS: Female BALB/c mice were infected intravaginally with C. trachomatis (MoPn) and were administered imiquimod either orally (30 mg/kg) or vaginally (10 microl of 5% imiquimod cream) prior to infection and every second day after infection for a total of four doses. The course of infection was monitored by collecting cervical-vaginal swabs and isolation in HeLa 229 cell culture. To determine whether the drug affected T helper type 1 or T helper type 2 immune response polarization, immunoglobulin G (IgG) subclass antibody responses were assessed at day 56 after infection. RESULTS: There was no significant difference in the course of infection when imiquimod-treated mice were compared with sham-treated controls, regardless of whether the drug was administered orally or vaginally. IgG subclass antibody responses, and by extension, T helper type 1 to T helper type 2 immune response polarization, were also unaffected. CONCLUSIONS: Imiquimod has no efficacy in controlling C. trachomatis (MoPn) infection in the murine model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14627213&dopt=Abstract imiquimod Aldara



Aldara
Safety and efficacy of locally applied imiquimod cream 5% for the treatment of condylomata acuminata of the vulva.

Haidopoulos D, Diakomanolis E, Rodolakis A, Vlachos G, Elsheikh A, Michalas S.

1st Department of Obstetrics and Gynaecology, Colposcopy Unit, Alexandra Hospital, University of Athens, Vassilisis Sophias str 80, 115 28 Athens. Greece. dhaidopoulos hotmail.com

AIM: The aim of the present study was to assess the efficacy and safety of local application of imiquimod cream 5% for managing condylomata acuminata of the vulva in women referred to a tertiary University Hospital centre. METHOD: From a total of 283 patients referred over a 3-year period, 73(26%) were treated with imiquimod. RESULTS: Approximately 6% failed to continue therapy due to lack of therapeutic effect whereas 71% experienced total clearance of the lesions and 85% reduction of more than 50% in the size of the condylomata. Forty-three percent of the patients observed complete response in the first 6 weeks of therapy. There were no serious adverse events encountered with mild erythema being the commonest. From the patients who were followed-up for the next 12 weeks from the completion of treatment, 13% presented recurrent warts and were managed by a different mode of therapy. CONCLUSION: Imiquimod cream 5% seems to be an effective and safe method for treating condylomata acuminata of the vulva resulting possibly in lower recurrence rates than other current therapies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14648072&dopt=Abstract imiquimod Aldara



Aldara
Percutaneous penetration of Aldara cream, 5% during the topical treatment of genital and perianal warts.

Owens ML, Bridson WE, Smith SL, Myers JA, Fox TL, Wells TM.

3M Pharmaceuticals, Minnesota, St. Paul, USA

Objective: The objective of this single-center, open-label trial was to evaluate the percutaneous penetration of Aldara (imiquimod) cream, 5% when applied topically to patients with anogenital warts using a more frequent/aggressive dosing regimen.Methods: Ten otherwise healthy males and six otherwise healthy, nonpregnant, nonlactating females with histology results suggestive of, or diagnostic of, human papilloma virus/condyloma acuminata were enrolled. Females were required to be practicing an acceptable form of contraception control. Patients applied cream daily (8 +/- 2 hours) until complete wart clearance, or for a maximum of 16 weeks. Following the initial dose, at approximately week 4, and at the end-of-treatment, patients were confined for 42 hours in order to obtain a series of blood and urine samples. These samples were analyzed for levels of imiquimod and two metabolites, S-26704 and S-27700. Biological marker levels were not included as a part of this trial.Results: No quantifiable (>/=5 ng/mL) levels of imiquimod or the two metabolites were observed in any of the serum samples collected. Five patients had quantifiable (>/=10 ng/mL) imiquimod, S-26704, or both in urine. No quantifiable levels of S-27700 were observed. Complete clearance of warts occurred in 40% of male patients and 83% of female patients. Erythema was the most frequently observed local skin reaction and was moderate in intensity, although 6 of 16 patients reported a severe erythema reaction at some point in the study. Application site reactions (itching, burning and pain) were the most frequently reported adverse events.Conclusion: The lack of quantifiable levels of imiquimod or metabolites in serum, together with sporadically occurring quantifiable but low levels in urine, indicate that systemic exposure, after daily application of Aldara cream to genital/perianal skin, may occur but is minimal; however, pharmacological (immune marker) effects were not evaluated because cytokine measurements were not obtained. A future trial assessing cytokine levels after topical Aldara therapy with minimal systemic levels of imiquimod would help assess systemic drug and pharmacological effects and utility of this product in pregnant women.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10838279&dopt=Abstract imiquimod Aldara