Aldara
Cytokine induction in hairless mouse and rat skin after topical application of the immune response modifiers imiquimod and S-28463.

Imbertson LM, Beaurline JM, Couture AM, Gibson SJ, Smith RM, Miller RL, Reiter MJ, Wagner TL, Tomai MA.

3M Pharmaceuticals, Department of Pharmacology, St. Paul, Minnesota 55144, USA.

ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rats to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical administration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumor necrosis factor in the skin. The concentrations of interferon and tumor necrosis factor were higher at the site of drug application than in skin from the contralateral flank or skin from untreated animals. Interferon-alpha mRNA levels were also elevated in the skin of mice after topical application of either imiquimod or S-28463. In vitro, both imiquimod and S-28463 induced increases in interferon and tumor necrosis factor in cultures of cells isolated from hairless mouse skin. Imiquimod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor necrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin after topical application, which may play a major role in its activity in genital wart patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9579537&dopt=Abstract imiquimod Aldara



Aldara
Immune response modification: imiquimod.

Tyring S.

University of Texas Medical Branch, Galveston 77555, USA.

Imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and has a molecular formula of C14H16N4. It was discovered by researchers at 3M Pharmaceuticals (St Paul, MN, USA) and is the newest in a class of drugs known as immune response modifiers. Imiquimod 5% cream has been formulated for the treatment of external genital and perianal warts (condylomata acuminata) in male and female patients. Each gram of 5% cream contains 50 mg of imiquimod. In preclinical studies, imiquimod induced the production of cytokines, the principal one for antiviral activity being interferon-alpha. Imiquimod does not induce direct antiviral activity, nor does it cause direct, non-specific cytolytic destruction. Preclinical studies suggest that its antiviral action results from in vivo cytokine-induced activation of the immune system. A double-blind, placebo-controlled study designed to evaluate this hypothesis has been previously presented. The results of the study showed that wart regression after treatment with imiquimod is strongly correlated with a decrease in virally infected cells and with increases in the expression of a spectrum of cytokines. This supports the hypothesis that stimulation of local cytokines by imiquimod leads to a reduction of human papillomavirus load and wart regression, without evidence of scarring.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9842095&dopt=Abstract imiquimod Aldara



Aldara
Imiquimod in clinical practice.

Edwards L.

Carolinas Medical Center, Charlotte, North Carolina, USA.

Applied topically, imiquimod induces the production of interferon-alpha plus other cytokines. Because intralesional interferon is effective in the treatment of condylomata acuminata (genital warts), topical imiquimod has also been investigated as a potential therapy for this condition. The dosing regimen found to best balance efficacy, side-effects and practicality is 5% imiquimod cream applied overnight by the patient three times weekly until warts clear, for up to 16 weeks. The largest double-blind trial to examine this protocol involved 311 patients with external anogenital warts who were randomized to use imiquimod 5% cream, imiquimod 1% cream or vehicle cream. Evaluation of all patients given medication at any time showed that 50% of those who received 5% imiquimod experienced clearing of all baseline warts, as compared to 21% of those who used 1% imiquimod and 11% of those treated with vehicle. Overall, 5% imiquimod treatment was significantly more effective than vehicle (P < 0.0001). Excluding patients who discontinued medication for reasons unrelated to therapy (such as moving out of town or poor compliance), 56% of those who received 5% imiquimod experienced complete clearing of baseline warts. Clearing also occurred in 27% of those who received imiquimod 1%. Recurrence of baseline warts occurred in 13% of patients whose warts cleared with 5% imiquimod. When applied overnight at home three times each week, topical imiquimod 5% cream is an effective therapy with acceptable side-effects. The recurrence rate is low and further studies to specifically compare recurrence rates are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9842096&dopt=Abstract imiquimod Aldara



Aldara
Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod.

Wagner TL, Ahonen CL, Couture AM, Gibson SJ, Miller RL, Smith RM, Reiter MJ, Vasilakos JP, Tomai MA.

Department of Pharmacology, 3M Pharmaceuticals, 3M Center, St. Paul, Minnesota, 55144, USA.

Cytokines produced by antigen-presenting cells are known to affect the development and cytokine profile of T cells. The immune response modifiers imiquimod and R-848 were previously shown to stimulate human and mouse cultures to secrete interferon-alpha. Results from the present study demonstrate that R-848 and imiquimod are capable of inducing interleukin-12 and interferon-gamma in mouse and human cell cultures. Both CD4(+) and CD8(+) T lymphocytes were responsible for producing IFN-gamma following stimulation with R-848. Macrophages were required for induction of interferon-gamma by R-848 and the cytokines IFN-alpha and IL-12 mediated this response. R-848 and imiquimod were also found to inhibit IL-4 and IL-5 production in mouse and human culture systems. The inhibition of IL-5 in response to R-848 is seen in cultures containing CD4(+) lymphocytes and macrophages and is mediated in part by IFN-alpha. These data suggest that imiquimod and R-848 may have clinical utility in diseases where cell-mediated immune responses are important and in diseases associated with overexpression of IL-4 or IL-5 such as atopic disease. Copyright 1999 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9918682&dopt=Abstract imiquimod Aldara



Aldara
Cytokine induction and modifying the immune response to human papilloma virus with imiquimod.

Slade HB.

3M Pharmaceuticals, Building 270-3A-01, 3M Center, St Paul, Minnesota, USA. hbslade mmm.com

Imiquimod is the newest in a class of drugs known as immune response modifiers. In preclinical studies, imiquimod induced the production of cytokines - the principal cytokine for antiviral activity being interferon alpha. Imiquimod does not inhibit viruses directly, nor does it cause direct, non-specific cytolytic destruction [1]. Preclinical studies suggest that its antiviral action results from in vivo cytokine-induced activation of the immune system. This paper reviews a recent double blind, placebo-controlled study designed to evaluate this hypothesis. The results of this study showed that wart regression following treatment with imiquimod strongly correlated with a decrease in viral DNA and gene transcripts; a decrease in mRNA expression for proteins associated with cellular proliferation, and an increase in keratinocyte markers. These results support the hypothesis that stimulation of local cytokines by imiquimod leads to a reduction in human papilloma virus (HPV) load; to wart regression and to the normalisation of keratinocyte proliferation without evidence of scarring.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10387958&dopt=Abstract imiquimod Aldara



Aldara
Reduction of recurrent HSV disease using imiquimod alone or combined with a glycoprotein vaccine.

Harrison CJ, Miller RL, Bernstein DI.

Creighton University, Division of Pediatric Infectious Diseases, 2500 California Plaza, Criss II-Room 409, Omaha, NE 68178, USA. charriso creighton.edu

The aim of this study is to evaluate the effects of an immune modulator, imiquimod, given alone or in combination with an HSV vaccine on HSV immune responses and as immunotherapy of a genital recurrence model. After recovery from primary genital HSV infection, animals were randomized to placebo, 21 days of imiquimod plus a placebo vaccine, or 21 days of imiquimod plus an HSV-2 glycoprotein vaccine. Placebo or HSV vaccine was given in the footpad on days 16 and 37 after HSV-2 genital inoculation. Daily imiquimod or placebo was given subcutaneously in the shoulder on days 16 through 37. Genital recurrences were monitored and HSV specific NK activity, IL-2 response and ELISA antibody were assayed. For the entire 15 week observation period, imiquimod alone reduced recurrences 62.6%, while addition of HSV vaccine to imiquimod reduced recurrences 80.6% compared to placebo/placebo. The duration of significant recurrence reduction was more notable with the addition of vaccine. Imiquimod alone significantly reduced the weekly HSV recurrent disease in the first 10 weeks (53-94% reduction, mean 75.9%), as did imiquimod plus HSV-vaccine (71-98% reduction, mean 89.5%). In weeks 10-15, imiquimod alone reduced recurrences significantly only in week 10 (20-53% reduction, mean 33%), whereas the addition of vaccine extended the significant recurrence reduction to 14 weeks (44-71% reduction, mean 56.8%). The recurrence reduction is correlated to an increased HSV-induced in vitro IL-2 response and NK activity against HSV targets in treated groups. Both imiquimod and the imiquimod/vaccine combination significantly reduced genital HSV recurrences, but the combination extended the duration and extent of protection for recurrences compared to imiquimod alone. Enhanced HSV specific immune responses correlated to the protection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11166907&dopt=Abstract imiquimod Aldara