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• Ingenol mebutate

  Ingenol mebutate (PicatoTM, Leo Pharma), a macrocyclic diterpene ester, is the active constituent in the sap of Euphorbia peplus. Commonly known as radium weed, petty spurge, or milkweed, E. peplus has been used for centuries as a traditional remedy for cutaneous conditions including skin cancer.
  
  Owing to a substantially shorter course of treatment (2-3 days) and duration of local cutaneous reaction, ingenol mebutate offers an appealing alternative to other topical agents used for the treatment of actinic keratoses. ;

• Mechanism of action

  Ingenol mebutate has a dual mechanism of action. Ingenol mebutate first induces rapid and direct cell death within hours of application followed by an acute inflammatory response that eliminates residual tumor cells.
  In vitro and in vivo studies on B16 mouse melanoma cells exposed to ingenol mebutate revealed disruption of the cell membrane, loss of mitochondrial membrane potential, and mitochondrial swelling resulting in rapid primary necrosis. As a result of the rapid destruction of tumor cells, a treatment duration of 2–3 days is sufficient. Unlike other anti-cancer agents, ingenol mebutate does not trigger apoptosis, and thus the development of apoptosis resistance in tumor cells is unlikely to compromise its activity.
  Following the initial cell necrosis, an acute inflammatory response occurs. Ingenol mebutate activates protein kinase c resulting in the release of pro-inflammatory cyto-kines (IL-1B, IL-8, TNF-alpha), the production of tumor-specific antibodies, an enhanced endothelial adhesion molecule expression, and a substantial infiltration of neutro-phils which generate tumoricidal reactive oxygen intermediates. The end-result is eradication of residual tumor cells via neutrophil mediated antibody depen-dent cellular cytotoxicity (ADCC). The elimination of resid-ual tumor cells is thought to be essential in preventing relapse. Furthermore, the inflammatory response appears to confer a favorable cosmetic outcome via expedited healing and a rapid regeneration of the normal cutaneous architecture. ;

• Clinical Use

  Ingenol mebutate is the active ingredient in the sap from the Euphorbia peplus plant that has been used to treat a variety of skin lesions including warts, AKs, and NMSC. Recent clinical trials have demonstrated that two or three applica-tions of ingenol mebutate is effective in clearing AKs and BCCs. The efficacy of the treatment increased in a dose dependent manner with only mild dose dependent dermatological side effects, confirming that short term use of ingenol mebutate is safe when treating a variety of skin lesions.;

• Dosage and Administration

  Ingenol mebutate (chemical structure C25H34O6) has been formulated as a topical gel. Each gram contains 150 or 500 mcg of ingenol mebutate in a base of isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol, and purified water.
  For the indication of actinic keratoses. The 0.015 % gel is applied once daily for three consecutive days (face or scalp) while the 0.05 % gel is applied once daily for two consecu-tive days (trunk or extremities). ;

• side effects

  The most common side effects of ingenol mebutate were application-site reactions including erythema, scale, crust-ing, edema, vesiculation, erosions, ulceration, pruritus, pain, and irritation. Skin reactions typically occurred within 1 day of treatment initiation, peaking in intensity 1 week following application, and resolving within 2 weeks on the face/scalp and 4 weeks on the trunk/extremities.
  Reports of periocular pain, edema, ptosis have been docu-mented. Prompt hand washing after application and avoid-ance of contact with the eyes is recommended.
  No evidence of skin sensitization, photoirritation, or pho-toallergic potential has been demonstrated.
  Ingenol mebutate is pregnancy category C. It is unknown if ingenol mebutate is secreted in the breast milk of lactating women. ;

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