Topical Immune-Modulating Agents

TOPICAL IMMUNE-MODULATING AGENTS

Tacrolimus

Tacrolimus is a macrolide lactone originally derived from Streptomyces tsukubaensis. Although structurally unrelated to cyclosporine, tacrolimus has a very similar mechanism of action; that is, it blocks the production of proinflammatory cytokines by T lymphocytes by in-hibiting calcineurin. Tacrolimus, however, appears to be 10 to 100 times as potent as an immunosuppressive. Oral tacrolimus (FK506) is used for prevention of organ rejection in recipients of renal and hepatic transplants. A topical formulation (Protopic) has recently been ap-proved for treatment of moderate to severe atopic der-matitis in children and adults who have not responded to other therapies. Levels of systemic absorption are low even when applied to a relatively large body surface area. Local irritant reactions (burning, stinging, ery-thema) are a common side effect, but these usually re-solve within the first few days of treatment. The major benefit of topical tacrolimus over topical corticosteroids is that tacrolimus does not cause atrophy, striae, or telangiectasia, even with chronic use.

Pimecrolimus

Pimecrolimus (SDZ ASM 981, Elidel) is another re-cently approved macrolide immunosuppressant that acts by inhibiting calcineurin and blocking the release of proinflammatory cytokines from T lymphocytes. The parent compound, ascomycin, was originally isolated from Streptomyces hygroscopicus var ascomyceticus. Like tacrolimus, pimecrolimus is approved for the topi-cal treatment of moderate to severe atopic dermatitis that is refractory to other therapies. Transient local irri-tation is a common side effect.

Imiquimod

Imiquimod (Aldara) is a topical immune response mod-ifier approved for the treatment of anogenital warts(condylomata acuminata). The exact mechanism of ac-tion is unknown; it has no direct antiviral activity in vitro. It is thought to work in vivo by inducing the pro-duction of tumor necrosis factor (TNF ), interferons (IFN) and , and other cytokines with antiviral activ-ity. It may also be useful for treatment of other types of warts, molluscum contagiosum, and certain forms of skin cancer. Local irritant reactions related to the fre-quency of application are common.

5-Fluorouracil

5-Fluorouracil (Efudex, Fluoroplex) is an antimetabo-lite used for the topical treatment of actinic keratoses. It is also useful for the treatment of superficial basal cell carcinomas when conventional surgical modalities are impractical. Local inflammatory reactions characterized by erythema, edema, crusting, burning, and pain are common (and, some would argue, desirable) but may be minimized by reduced frequency of application or use in combination with a topical corticosteroid.

Mechlorethamine

Mechlorethamine (Mustargen) is a cytotoxic alkylating agent. Topical application of freshly prepared aqueous solutions are used in patients with early stages of cuta-neous T-cell lymphoma. A major disadvantage to the use of this drug is the rapid induction of allergic contact dermatitis in some patients.