Imiquimod.

In this issue of the Southern Medical Journal, Yuchi Chang and Stephen Tyring present an interesting review of the dermatologic product imiquimod (Aldara, 3M Pharmaceuticals) in their article "Current and Potential Uses of Imiquimod". Although approved by the United States Food and Drug Administration since 1997 as a topical treatment for genital and perianal warts, investigators have found this compound may offer an alternative treatment for a wide variety of medical conditions.

This unique product is an immune response modifier and stimulates the patient's own immune system to release various chemical immune modifiers including various cytokines such as interferon-[alpha] and interleukin-12. Interestingly, the effectiveness of imiquimod as an antiviral agent in the treatment of genital and perianal warts does not result from a direct in vitro or in vivo antiviral mechanism, but rather from its ability to stimulate peripheral monocytes and macrophages to release various cytokines, including those mentioned above. This results in a reduction of the accumulation of human papillomavirus as the host's own immune system induces a regression in viral protein production. Clinical trials are now demonstrating the beneficial effects that immune system modulation via imiquimod administration may have in treating other immune-related, dermatologic disorders. As Chang and Tyring state, imiquimod may offer effective therapy for actinic keratosis, molluscum contagiosum, genital herpes, and various carcinomas (basal cell and squamous cell). Because imiquimod is administered locally, systemic side effects are infrequent. Local reactions occur most frequently and include itching, burning, pain, and soreness. Although only a small amount of drug should reach systemic circulation (if used correctly), uncommon systemic side effects have included flu-like symptoms and fatigue.

Recognition of the role of the immune system in various disease states is the key to immunotherapy. Immune modification is not a new concept in medicine. Recent medical advances have allowed physicians to greatly affect immune response with various drugs and thus treat many immune-mediated diseases. Glucocorticoids have been effectively used for years to modulate immune response. Suppression of specific elements of the immune response (eg, cyclosporine) has enabled organ transplantation to become commonplace. Suppression of tumor necrosis factor with specific tumor necrosis factor-blocking agents [etanercept (Enbrel), infliximab (Remicade), and so forth] is routinely used to treat rheumatoid arthritis and ulcerative colitis.

Enhancing the immune response is also standard therapy for various disease states. Interferons are available as antiviral therapy for hepatitis C and are used in treating multiple sclerosis. Other biological response modifiers, such as aldesleukin (Proleukin), a commercially available human recombinant interleukin-2 product, have been used to treat certain cancers, including renal cell carcinoma and metastatic melanoma. Originally heralded as major breakthroughs in oncology treatment, the biological response modifiers have not routinely demonstrated clinical efficacy in difficult-to-treat tumors. Although immunotherapy is a component of the chemotherapy armamentarium, researchers are still learning how to effectively use immunotherapy as a cancer treatment.

The more specific the action the drug has on a specific immune system component, the better, as the response and potential hazards of the drug can be more easily anticipated. As researchers understand the precise effects imiquimod has on immune response, more information will be gained on which dermatologic conditions or oncologic conditions the drug would be most effective at treating. Conversely, as the immune response to various dermatologic (and oncologic) disease states is better understood, it will be much easier to predict the potential efficacy (and toxicity) of a drug such as imiquimod. Modifying the immune system in such a way to treat certain diseases can be tricky, to say the least. As physicians observe on a daily basis when attempting to calculate the correct warfarin dose for a desired therapeutic response, predicting the effect of a certain dose (of warfarin) can be an impossible task because all patients appear to respond quite differently. Similarly, immune modifiers may produce quite variable effects in patients making "standard doses" impossible to calculate. Thorough knowledge of the effect the immune system has on various disease states and the effect that different disease states has on the immune response will enhance the role that immunotherapy has in medical practice. Understanding the pharmacology of drugs such as imiquimod is another step to fully understanding the power of the human immune system.

James M. Wooten, PHARMD

From the Department of Medicine, Section of Clinical Pharmacology, University of Missouri-Kansas City School of Medicine, Kansas City, MO.

Reprint requests to James M. Wooten, PharmD, Section of Clinical Pharmacology, University of Missouri-Kansas City School of Medicine, Gold 4 Unit, 2411 Holmes Street, Kansas City, MO 64108-2792. Email: [e-mail]

Accepted March 23, 2005.