Ingenol mebutate

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Ingenol mebutate
Ingenol 3-angelate.svg
Systematic (IUPAC) name
(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-Dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen-6-yl (2Z)-2-methylbut-2-enoate
Clinical data
Trade names Picato
AHFS/Drugs.com picato
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Topical (gel)
Legal status
Legal status
Pharmacokinetic data
Bioavailability Below detection level
Identifiers
CAS Number 75567-37-2
ATC code D06BX02 (WHO)
PubChem CID 6918670
ChemSpider 26325194
ChEBI CHEBI:66913 YesY
Synonyms PEP005, ingenol-3-angelate
Chemical data
Formula C25H34O6
Molar mass 430.534 g/mol

Ingenol mebutate (ingenol-3-angelate, PEP005, LEO Pharma trade name Picato) is a substance found in the sap of the plant Euphorbia peplus[1] and an inducer of cell death. A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA)[2] and by the European Medicines Agency (EMA)[3] for the topical treatment of actinic keratosis. Two different strengths of the gel are approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively.[4]

Results from four multicenter, randomized, double-blind studies have shown that ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses.[5]

Adverse effects[edit]

Irritations of the application site are very common. This includes redness, scaling, crusting, pain, pruritus, and sometimes infection. Other side effects include eye irritation such as periorbital edema (3% of patients in studies), headache (2%) and nasopharyngitis (running nose, 2%).[6]

Allergic reactions or shingles may also occur.[7]

Interactions[edit]

As ingenol mebutate is practically not absorbed through the skin, interactions with oral drugs are unlikely.[8][9]

Chemistry[edit]

The substance is an ester of the diterpene ingenol and angelic acid. A 3-step semisynthesis of ingenol mebutate starting from ingenol was described.[10] A 14-step synthesis of (+)-ingenol from (+)-3-carene, which is a relatively inexpensive constituent of turpentine, was published in July 2013.[11]

Research[edit]

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.[12]

References[edit]

  1. ^ Fallen RS, Gooderham M (2012). "Ingenol mebutate: An introduction". Skin Therapy Lett. 17 (2): 1–3. PMID 22358305. 
  2. ^ Picato Drug Details at Drugs@FDA
  3. ^ European Public Assessment Report (EPAR) for Picato
  4. ^ Picato® Gel label at Drugs@FDA
  5. ^ Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B (2012). "Ingenol Mebutate Gel for Actinic Keratosis". N Engl J Med. 336 (11): 1010–1019. doi:10.1056/NEJMoa1111170. PMID 22417254. 
  6. ^ Drugs.com: Picato Side Effects in Detail
  7. ^ "Picato (ingenol mebutate) Gel: Drug Safety Communication - FDA Warns of Severe Adverse Events, Requires Label Changes". 2015-08-21. Retrieved 24 August 2015. 
  8. ^ Picato FDA Professional Drug Information
  9. ^ Haberfeld, H, ed. (2013). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. 
  10. ^ Liang, X.; Grue-Sørensen, G.; Petersen, A. K.; Högberg, T. (2012), "Semisynthesis of Ingenol 3-Angelate (PEP005): Efficient Stereoconservative Angeloylation of Alcohols", SYNLETT (23): 2647–2652. https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0032-1317415.pdf
  11. ^ Jorgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. (2013). "14-Step Synthesis of (+)-Ingenol from (+)-3-Carene". Science. 341 (6148): 878–882. doi:10.1126/science.1241606. PMID 23907534. 
  12. ^ Jiang G, Mendes EA, Kaiser P, Wong DP, Tang Y, Cai I, et al. (2015) Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation. PLoS Pathogens 11(7): e1005066. doi:10.1371/journal.ppat.1005066