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Ingenol mebutate

March 13, 2024

Ingenol mebutate, sold under the brand name Picato, is a substance that is found in the sap of the plant Euphorbia peplus,[1] commonly known as petty spurge, and is an inducer of cell death. This compound was isolated first from this plant in 2000.[2] A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA)[3] and by the European Medicines Agency (EMA)[4] for the topical treatment of actinic keratosis. 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use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively.[5] In 2020 the drug was withdrawn from the market in the EU.[6]

Ingenol mebutate
Clinical data
Trade namesPicato
Other namesPEP005, ingenol-3-angelate
AHFS/Drugs.comMonograph
MedlinePlusa613008
License data
  • EU EMA: by INN
Pregnancy
category
  • AU: B3
Routes of
administration		Topical (gel)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
BioavailabilityBelow detection level
Identifiers
  • (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
CAS Number
  • 75567-37-2
PubChem CID
  • 6918670
DrugBank
  • DB05013
ChemSpider
  • 26325194
UNII
  • 7686S50JAH
KEGG
  • D09393
ChEBI
  • CHEBI:66913 Y
ECHA InfoCard100.214.695
Chemical and physical data
FormulaC25H34O6
Molar mass430.541 g·mol−1
3D model (JSmol)
  • Interactive image
  • C/C=C(/C)\C(=O)O[C@H]1C(C)=C[C@]23[C@]1(O)[C@H](O)C(CO)=C[C@H](C3=O)[C@H]4[C@H](C4(C)C)C[C@H]2C
  • InChI=1S/C25H34O6/c1-7-12(2)22(29)31-21-13(3)10-24-14(4)8-17-18(23(17,5)6)16(20(24)28)9-15(11-26)19(27)25(21,24)30/h7,9-10,14,16-19,21,26-27,30H,8,11H2,1-6H3/b12-7-/t14-,16+,17-,18+,19-,21+,24+,25+/m1/s1
  • Key:VDJHFHXMUKFKET-WDUFCVPESA-N

Adverse effects edit

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 (3% of patients in studies), headaches (2%) and nasopharyngitis (running nose, 2%).[7]

Allergic reactions, shingles, changes in pigmentation at application site, chemical conjunctivitis, and corneal burns may also occur.[8][9]

The European Medicines Agency 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 or imiquimod. Physicians were advised to refrain from prescribing ingenol and to use different treatment options.[10] 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.[6]

 
Euphorbia peplus

Interactions edit

As ingenol mebutate is not effectively absorbed through the skin and into the bloodstream, interactions with oral drugs are unlikely.[11][12]

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 by a chemical research group in Denmark in 2012.[13] A 14-step synthesis of (+)-ingenol from (+)-3-carene, which is a relatively inexpensive constituent of turpentine, was published in July 2013.[14]

Mechanism of action edit

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.[15]

Studies edit

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.[16][11]

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.[17]

Research edit

HIV 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.[18]

Tattoo removal edit

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.[19]

Skin cancer risk edit

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.[20]

References edit

  1. ^ Fallen RS, Gooderham M (February 2012). "Ingenol mebutate: an introduction". Skin Therapy Letter. 17 (2): 1–3. PMID 22358305.
  2. ^ Hohmann J, Evanics F, Berta L, Bartók T (April 2000). "Diterpenoids from Euphorbia peplus". Planta Medica. 66 (3): 291–294. doi:10.1055/s-2000-8568. PMID 10821064. S2CID 260249228.
  3. ^ "Drugs@FDA: FDA-Approved Drugs". Accessdata.fda.gov. Retrieved 10 April 2022.
  4. ^ "Picato | European Medicines Agency". Ema.europa.eu. 17 September 2018. Retrieved 10 April 2022.
  5. ^ "Picato® Gel label at Drugs@FDA" (PDF). Accessdata.fda.org. Retrieved 10 April 2022.
  6. ^ a b "Picato : Withdrawal of the marketing authorisation in the European Union" (PDF). Ema.europa.eu. Retrieved 10 April 2022.
  7. ^ Drugs.com: Picato Side Effects in Detail
  8. ^ "Picato (ingenol mebutate) Gel: Drug Safety Communication - FDA Warns of Severe Adverse Events, Requires Label Changes". Food and Drug Administration. 2015-08-21. Retrieved 24 August 2015.
  9. ^ "Picato (Ingenol Mebutate): Side Effects, Interactions, Warning, Dosage & Uses". RxList.com. Retrieved 2018-12-06.
  10. ^ "EMA suspends Picato as a precaution while review of skin cancer risk continues | European Medicines Agency". Ema.europa.eu. 17 January 2020. Retrieved 10 April 2022.
  11. ^ a b "Picato". Drugs.com.
  12. ^ Haberfeld H, ed. (2013). Austria-Codex (in German). Haberfeld Vienna: Österreichischer Apothekerverlag.
  13. ^ Liang X, Grue-Sørensen G, Petersen AK, Högberg T (2012). "Semisynthesis of Ingenol 3-Angelate (PEP005): Efficient Stereoconservative Angeloylation of Alcohols" (PDF). Synlett. 23 (18): 2647–2652. doi:10.1055/s-0032-1317415. S2CID 95418968. Retrieved 10 April 2022.
  14. ^ Jørgensen L, McKerrall SJ, Kuttruff CA, Ungeheuer F, Felding J, Baran PS (August 2013). "14-step synthesis of (+)-ingenol from (+)-3-carene". Science. 341 (6148): 878–882. Bibcode:2013Sci...341..878J. doi:10.1126/science.1241606. PMID 23907534. S2CID 26998997.
  15. ^ Freiberger SN, Cheng PF, Iotzova-Weiss G, Neu J, Liu Q, Dziunycz P, et al. (September 2015). "Ingenol Mebutate Signals via PKC/MEK/ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2". Molecular Cancer Therapeutics. 14 (9): 2132–2142. doi:10.1158/1535-7163.mct-15-0023-t. PMID 26116359.
  16. ^ Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B (March 2012). "Ingenol mebutate gel for actinic keratosis". The New England Journal of Medicine. 366 (11): 1010–1019. doi:10.1056/NEJMoa1111170. PMID 22417254.
  17. ^ Lebwohl M, Shumack S, Stein Gold L, Melgaard A, Larsson T, Tyring SK (June 2013). "Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses". JAMA Dermatology. 149 (6): 666–670. doi:10.1001/jamadermatol.2013.2766. PMID 23553119.
  18. ^ Jiang G, Mendes EA, Kaiser P, Wong DP, Tang Y, Cai I, et al. (July 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. PMC 4520526. PMID 26225771.
  19. ^ Cozzi SJ, Le TT, Ogbourne SM, James C, Suhrbier A (2017). "Tattoo removal with ingenol mebutate". Clinical, Cosmetic and Investigational Dermatology. 10: 205–210. doi:10.2147/ccid.s135716. PMC 5448692. PMID 28579816.
  20. ^ "Search Page - Drug and Health Product Register". Hpr-rps.hres.ca. 2014-10-23. Retrieved 2020-10-27.

External links edit

  • "Ingenol mebutate". Drug Information Portal. U.S. National Library of Medicine.

March 13, 2024
ingenol, mebutate, sold, under, brand, name, picato, substance, that, found, plant, euphorbia, peplus, commonly, known, petty, spurge, inducer, cell, death, this, compound, isolated, first, from, this, plant, 2000, formulation, drug, been, approved, food, drug. Ingenol mebutate sold under the brand name Picato is a substance that is found in the sap of the plant Euphorbia peplus 1 commonly known as petty spurge and is an inducer of cell death This compound was isolated first from this plant in 2000 2 A gel formulation of the drug has been approved by the U S Food and Drug Administration FDA 3 and by the European Medicines Agency EMA 4 for the topical treatment of actinic keratosis 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 5 In 2020 the drug was withdrawn from the market in the EU 6 Ingenol mebutateClinical dataTrade namesPicatoOther namesPEP005 ingenol 3 angelateAHFS Drugs comMonographMedlinePlusa613008License dataEU EMA by INNPregnancycategoryAU B3Routes ofadministrationTopical gel ATC codeD06BX02 WHO Legal statusLegal statusAU S4 Prescription only UK POM Prescription only US only EU Rx onlyPharmacokinetic dataBioavailabilityBelow detection levelIdentifiersIUPAC 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 enoateCAS Number75567 37 2PubChem CID6918670DrugBankDB05013ChemSpider26325194UNII7686S50JAHKEGGD09393ChEBICHEBI 66913 YECHA InfoCard100 214 695Chemical and physical dataFormulaC 25H 34O 6Molar mass430 541 g mol 13D model JSmol Interactive imageSMILES C C C C C O O C H 1C C C C 23 C 1 O C H O C CO C C H C3 O C H 4 C H C4 C C C C H 2CInChI InChI 1S C25H34O6 c1 7 12 2 22 29 31 21 13 3 10 24 14 4 8 17 18 23 17 5 6 16 20 24 28 9 15 11 26 19 27 25 21 24 30 h7 9 10 14 16 19 21 26 27 30H 8 11H2 1 6H3 b12 7 t14 16 17 18 19 21 24 25 m1 s1Key VDJHFHXMUKFKET WDUFCVPESA N Contents 1 Adverse effects 2 Interactions 3 Chemistry 4 Mechanism of action 5 Studies 6 Research 6 1 HIV 6 2 Tattoo removal 6 3 Skin cancer risk 7 References 8 External linksAdverse effects editIrritation 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 3 of patients in studies headaches 2 and nasopharyngitis running nose 2 7 Allergic reactions shingles changes in pigmentation at application site chemical conjunctivitis and corneal burns may also occur 8 9 The European Medicines Agency 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 or imiquimod Physicians were advised to refrain from prescribing ingenol and to use different treatment options 10 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 6 nbsp Euphorbia peplusInteractions editAs ingenol mebutate is not effectively absorbed through the skin and into the bloodstream interactions with oral drugs are unlikely 11 12 Chemistry editThe substance is an ester of the diterpene 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 13 A 14 step synthesis of ingenol from 3 carene which is a relatively inexpensive constituent of turpentine was published in July 2013 14 Mechanism of action editThe 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 15 Studies editResults 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 16 11 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 17 Research editHIV 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 18 Tattoo removal edit 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 19 Skin cancer risk edit 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 20 References edit Fallen RS Gooderham M February 2012 Ingenol mebutate an introduction Skin Therapy Letter 17 2 1 3 PMID 22358305 Hohmann J Evanics F Berta L Bartok T April 2000 Diterpenoids from Euphorbia peplus Planta Medica 66 3 291 294 doi 10 1055 s 2000 8568 PMID 10821064 S2CID 260249228 Drugs FDA FDA Approved Drugs Accessdata fda gov Retrieved 10 April 2022 Picato European Medicines Agency Ema europa eu 17 September 2018 Retrieved 10 April 2022 Picato Gel label at Drugs FDA PDF Accessdata fda org Retrieved 10 April 2022 a b Picato Withdrawal of the marketing authorisation in the European Union PDF Ema europa eu Retrieved 10 April 2022 Drugs com Picato Side Effects in Detail Picato ingenol mebutate Gel Drug Safety Communication FDA Warns of Severe Adverse Events Requires Label Changes Food and Drug Administration 2015 08 21 Retrieved 24 August 2015 Picato Ingenol Mebutate Side Effects Interactions Warning Dosage amp Uses RxList com Retrieved 2018 12 06 EMA suspends Picato as a precaution while review of skin cancer risk continues European Medicines Agency Ema europa eu 17 January 2020 Retrieved 10 April 2022 a b Picato Drugs com Haberfeld H ed 2013 Austria Codex in German Haberfeld Vienna Osterreichischer Apothekerverlag Liang X Grue Sorensen G Petersen AK Hogberg T 2012 Semisynthesis of Ingenol 3 Angelate PEP005 Efficient Stereoconservative Angeloylation of Alcohols PDF Synlett 23 18 2647 2652 doi 10 1055 s 0032 1317415 S2CID 95418968 Retrieved 10 April 2022 Jorgensen L McKerrall SJ Kuttruff CA Ungeheuer F Felding J Baran PS August 2013 14 step synthesis of ingenol from 3 carene Science 341 6148 878 882 Bibcode 2013Sci 341 878J doi 10 1126 science 1241606 PMID 23907534 S2CID 26998997 Freiberger SN Cheng PF Iotzova Weiss G Neu J Liu Q Dziunycz P et al September 2015 Ingenol Mebutate Signals via PKC MEK ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2 Molecular Cancer Therapeutics 14 9 2132 2142 doi 10 1158 1535 7163 mct 15 0023 t PMID 26116359 Lebwohl M Swanson N Anderson LL Melgaard A Xu Z Berman B March 2012 Ingenol mebutate gel for actinic keratosis The New England Journal of Medicine 366 11 1010 1019 doi 10 1056 NEJMoa1111170 PMID 22417254 Lebwohl M Shumack S Stein Gold L Melgaard A Larsson T Tyring SK June 2013 Long term follow up study of ingenol mebutate gel for the treatment of actinic keratoses JAMA Dermatology 149 6 666 670 doi 10 1001 jamadermatol 2013 2766 PMID 23553119 Jiang G Mendes EA Kaiser P Wong DP Tang Y Cai I et al July 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 PMC 4520526 PMID 26225771 Cozzi SJ Le TT Ogbourne SM James C Suhrbier A 2017 Tattoo removal with ingenol mebutate Clinical Cosmetic and Investigational Dermatology 10 205 210 doi 10 2147 ccid s135716 PMC 5448692 PMID 28579816 Search Page Drug and Health Product Register Hpr rps hres ca 2014 10 23 Retrieved 2020 10 27 External links edit Ingenol mebutate Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Ingenol mebutate amp oldid 1183999181, wikipedia, wiki, book, books, library,

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