International Journal of Immunopharmacology
Review Article Imiquimod applied topically: a novel immune response modifier and new class of drug
Section snippets
Effects on innate immunity
When incubated with mouse spleen cells in vitro, imiquimod at 0.2 μg/ml induces the synthesis and release of IFN, IL-6, tumor necrosis factor-α (TNF-α) and probably other cytokines (Reiter et al., 1994). Imiquimod also causes non-specific B-cell proliferation which may be mediated directly by the drug and not through cytokine induction (Tomai et al., 1994).
The mouse macrophage cell line, RAW 264.7, produces TNF in response to 3 μg/ml of imiquimod. Saturable specific binding of closely related
Effects on acquired immunity
Although imiquimod does not stimulate T cells to divide or directly induce T cell cytokines such as IL-2, IL-4 or IL-5, imiquimod is capable of indirectly stimulating production of the T helper type 1 (Th1) cytokine, IFN-γ, in mouse splenic and bone marrow cultures as well as human PBMC cultures. Production of IFN-γ in response to imiquimod is inhibited by antibodies to IL-12 and IFN-α, demonstrating the importance of these monocyte/macrophage cytokines (Tomai et al., 1998). The mechanism of
Clinical mechanism of action study
The data generated in animal models suggest that imiquimods antiviral and antitumor effects are largely mediated through the induction of cytokines that drive the innate and cell-mediated immune response. A study was carried out in humans to further explore the drugs mechanism of action (Tyring et al., 1998). The objective of this study was to evaluate the mechanism of action of imiquimod 5% cream when applied topically to genital warts in human patients by: (1) investigating local and systemic
Summary of clinical efficacy trials
Imiquimod cream was applied topically and tested for efficacy in patients with external genital and/or perianal warts (condylomata acuminata). Genital warts, the most common viral sexually transmitted disease, was chosen as the first clinical target because injectable IFN-α had demonstrated some benefit and the current therapies do not meet the patients or physicians needs. Patient dissatisfaction with current therapeutic options is significant due to pain, tissue destruction, high recurrence
Oral delivery
Some clinical testing of imiquimod was also carried out by the oral route. A single dose study in normal volunteers indicated that measurable serum IFN levels were obtained in four of six subjects after 200 mg and in six of six subjects after 300 mg. Peak levels of IFN were seen at 12 h after dosing and levels returned to baseline by 24 h. Activity of 2,5-AS was elevated for 96 h after the 300 mg dose and this activity correlated with antiviral activity in the subject PBMCs. The drug was well
New class of drug
The preclinical and mechanism of action study in patients indicate that topically applied imiquimod results in the induction of several cytokines at the treatment site. Cytokines such as IFN and others inhibit virus production and inhibit tumor cell growth. The drug also enhances aspects of the cell mediated immune (CMI) response and may result in long term protection from the initial virus or tumor. Application of the drug to warts by wart patients, in the privacy of their own home produced a
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