Ingenol mebutate, sold under the brand name Picato, is a substance that is found in the sap of the plant ''

Euphorbia peplus ''Euphorbia peplus'' (petty spurge, radium weed, cancer weed, or milkweed), is a species of ''Euphorbia'', native to most of Europe, northern Africa and western Asia, where it typically grows in cultivated arable land, gardens and other disturb ...

'', commonly known as milkweed, and is an inducer of cell death. A gel formulation of the drug has been approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) and by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

(EMA) for the topical treatment of

actinic keratosis Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Actinic k ...

. Two different strengths of the gel have been approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively. In 2020 the drug was withdrawn from the market in the EU.

Adverse effects

Irritation of the application site is very common. The various types of irritation include redness, scaling, crusting, pain, severe itching, and sometimes infection. Additional possible side effects include eye irritation, such as

periorbital edema Periorbital puffiness, also known as puffy eyes, or swelling around the eyes, is the appearance of swelling in the tissues around the eyes, called the orbits. It is almost exclusively caused by fluid buildup around the eyes, or periorbital edem ...

(3% of patients in studies), headaches (2%) and

nasopharyngitis The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exp ...

(running nose, 2%). Allergic reactions,

shingles Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or fac ...

, changes in pigmentation at application site, chemical conjunctivitis, and corneal burns may also occur. The

recommended suspending the marketing authorisation of ingenol mebutate due to concerns regarding increased incidence of skin cancer in patients treated with topical ingenol mebutate compared to

vehicle A vehicle (from la, vehiculum) is a machine that transports people or cargo. Vehicles include wagons, bicycles, motor vehicles (motorcycles, cars, trucks, buses, mobility scooters for disabled people), railed vehicles (trains, trams), ...

or imiquimod. Physicians were advised to refrain from prescribing ingenol and to use different treatment options. Subsequently, the marketing authorization holder requested withdrawal of the manufacturing authorization for commercial reasons. The withdrawal was granted and therefore, ingenol mebutate is no longer registered in the EU. Euphorbia peplus3 ies

Interactions

As ingenol mebutate is not effectively absorbed through the skin and into the bloodstream, interactions with oral drugs are unlikely.

Chemistry

The substance is an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

of the

diterpene Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being ...

ingenol and angelic acid. A 3-step semisynthesis of ingenol mebutate starting from ingenol was described by a chemical research group in Denmark in 2012. A 14-step synthesis of (+)-ingenol from (+)-3-carene, which is a relatively inexpensive constituent of

turpentine Turpentine (which is also called spirit of turpentine, oil of turpentine, terebenthene, terebinthine and (colloquially) turps) is a fluid obtained by the distillation of resin harvested from living trees, mainly pines. Mainly used as a special ...

, was published in July 2013.

Mechanism of action

The mechanism by which ingenol mebutate causes cell death is still not fully understood. One study on squamous cell carcinoma, the precursor of which is actinic keratosis, cultures found that the PKC/MEK/ERK signaling pathway is involved in causing cell death after treatment with ingenol mebutate. In addition, the interleukin decoy receptors IL1R2 and IL13RA2 were induced, resulting in a reduction in the long-term viability of the cells, which could help prevent recurrence.

Studies

Results from four multicenter, randomized, double-blind studies have shown that ingenol mebutate gel applied topically, for 2 to the trunk or 3 days to the face or scalp, is effective for field treatment of actinic keratoses. A twelve-month follow-up study was performed on actinic keratosis patients who had been treated with ingenol mebutate, 108 of which had been treated for face or scalp and 71 for trunk or extremities and the study found that of those treated for the face or scalp 46.1% had sustained clearance, and of those treated for the trunk 44.0% had sustained clearance for the period of the study.

Research

HIV

Ingenol mebutate has also been found to be useful for reactivating latent HIV virus in cells taken from individuals who have tested negative for signs of the disease following extended courses of anti-retroviral drugs, raising the possibility that this drug may be used to expose the last traces of virus, and thus potentially provide a permanent cure for HIV infection. Research is ongoing to determine whether the effects observed ''in vitro'' are also seen in animal models, with a view to eventual human trials for this application.

Tattoo removal

A placebo-controlled study on hairless mice found that 0.1% ingenol mebutate gel was able to remove two-week-old tattoos consistently. It was observed that the microspheres within the skin containing the dye would exude into the scab intact and slough off as the skin healed about 20 days after treatment began. This mechanism appears to be independent of ink color, unlike laser tattoo removal, which is less effective for certain colors. There are no reports of human trials having been conducted.

Skin cancer risk

Health Canada assessed twelve studies published in scientific and medical literature in order to determine the link between the use of ingenol mebutate and skin cancer. Health Canada's review found that six of the twelve studies had evidence of skin cancer with the use of ingenol mebutate. The European Medicines Agency (EMA) has also reviewed this safety issue. In April 2020, it concluded that ingenol mebutate may increase the risk of skin cancer and that its risks outweigh its benefits. On February 11, 2020, the manufacturer voluntarily withdrew the product from the European Union market.

References

External links

* {{Portal bar , Medicine Dermatologic drugs Antineoplastic drugs Diterpenes Cyclopropanes Triols Alkene derivatives Ketones Carboxylate esters Withdrawn drugs