Imiquimod applied topically: a novel immune response modifier and new class of drug.
Imiquimod (S-26308, R-837) (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4 amine), an immune response modifier, demonstrates potent antiviral and antitumor activity in animal models (see structure in Fig. 1). The drug exhibits no direct antiviral or antiproliferative activity when tested in a number of cell culture systems. Imiquimod's activity was discovered while screening for anti-herpes virus activity. One of the first analogs in the series, S-25059 was tested in the early 1980's and due to slight toxicity, caused slightly reduced herpes cytopathology in Vero cell cultures. Follow-up testing in herpes infected guinea pigs showed complete protection toward lesion development. Activity of these drugs results primarily from interferon alpha (IFN-alpha) induction and other cytokine induction. At least part of the cytokine induction is mediated through NF-kappaB activation. These cytokines stimulate several other aspects of the innate immune response. In addition, imiquimod stimulates acquired immunity, in particular the cellular arm which is important for control of viral infections and various tumors. This effect is mediated by drug induced IFN-alpha and Interleukin-12 (IL-12) and IFN-gamma induced by these cytokines. Imiquimod is expected to be effective where exogenous IFN-alpha has shown utility and where enhancement of cell-mediated immunity is needed. The following is a brief review of the preclinical pharmacology of imiquimod and the clinical results of genital wart trials. The mechanism of action of topically applied imiquimod will likely lead to benefits in several other chronic virus infections and tumors of the skin. Two other reviews on imiquimod that focus mainly on the clinical results have been published (Beutner & Geisse, 1997; Slade, Owens, Tomai & Miller, 1998).
3M Pharmaceuticals, St. Paul, Minnesota, USA.
R L
RL
Miller
J F
JF
Gerster
M L
ML
Owens
H B
HB
Slade
M A
MA
Tomai
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000287:Administration, Topical; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000077271:Imiquimod
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000998:Antiviral Agents; D000077271:Imiquimod