Euphorbia peplus:18th-Century Insights on a 21st-Century Therapy

Abstract

In 2012, the US Food and Drug Administration approved a new therapeutic agent, ingenolmebutate, for the topical treatmentofactinic keratoses. Ingenolmebutate is a diterpene ester with the chemical formula C25H34O6 and is extracted from the sap of the plant species Euphorbia peplus, alsoknownasthepettyspurge.Euphorbiapeplusextracthasbeen used for centuries as a topical agent for the treatmentof avarietyof skin conditions in traditional medicine systems from around the world. Euphorbia peplus was first taxonomically categorized in the Western scientific community by Carl Linnaeus in the 1750s and presented in a thesis defendedbyhis student JohannesWimanatUppsalaUniversity in Sweden. Linnaeus described a variety of medicinal uses for the genusofEuphorbiaplants as topical treatments andsystemic agents for gastrointestinal tract purging. Members of this genus were known to causeskin irritationoncontactwiththeplant’s sap.Thegenuswasnamed after the ancient Greek physician Euphorbus, who in the first century AD documented the laxative properties of the spurges. A monograph published in London, England, circa 1770 highlights specific insights into several plants, including E peplus. The manuscript (Figure), published inbothLatinandEnglish, likely representsone of theearliestdocumentationsof thedermatologicapplicationsafterLinnaean classification. The monograph authors describe “the milky fluid which it abounds with, is by some applied to Warts, which it is said to destroy.” The other members of the Euphorbia genus, particularly Euphorbiahelioscopia, or sunspurge,werealso recognizedtohavesapwith similar properties in themonograph. A later selection fromthesamemonographdiscusses thesunspurge or “wart-wort” species in greater detail, including its toxicity. “My friend MrWilliamWavell lately informedme of a case which fell under his notice in the Isle of Wight, where from the application of the juice of this Spurge[Ehelioscopia] tosomeWartsnear theeyeofa littlegirl, thewhole face became inflamed to a very great degree,” noted the author of the monograph. Consistent with these case reports frommore than 2 centuries earlier, most patients enrolled in clinical trials demonstrating the efficacy of ingenol mebutate for actinic keratoses developed clinically significant erythema at the site of application. It is also notable that a lower concentrationof thedrug is approved for treatmentof the faceand that themost commonadverseeffectsof ingenolmebutate in theaforementioned clinical trialswerepruritus, irritation, andpain—echoing the cautionary casedescribed in themonograph.As futureworkunfolds examining additional applications for topical ingenolmebutate, looking back into the pastmay help uncover other natural remedies awaiting our rediscovery.