Methyl 5-amino-4-oxopentanoate

Structural formula
General
Surname	Methyl 5-amino-4-oxopentanoate
other names	5-Amino-4-oxopentanoic acid methyl ester Methyl (5-amino-4-oxopentanoate) 5-aminolevulinic acid methyl ester δ-aminolevulinic acid methyl ester Methyl 5-aminolevulinate MAOP Metvix (trade name)
Molecular formula	C 6 H 11 NO 3
External identifiers / databases
CAS number 33320-16-0 PubChem 157922 DrugBank DB00992 Wikidata Q619603
Drug information
ATC code	L01 XD03
properties
Molar mass	145.16 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Methyl 5-amino-4-oxopentanoate (MAOP), international non-proprietary name methyl (5-amino-4-oxopentanoate) hydrochloride, is a medicinal substance for photodynamic therapy (PDT) of superficial and nodular basal cell carcinomas and actinic keratoses .

description

MAOP is the methyl ester of 5-aminolevulinic acid . MAOP accumulates preferentially in skin cancer and precancerous cells . As a prodrug , it is by esterases in the cells to 5-aminolevulinic acid (5-ALA) metabolized . The catalytic action of δ-aminolevulinic acid dehydratase in the cells initially produces porphobilinogen (PBG) from two molecules of 5-ALA . Protoporphyrin IX , the actual photosensitizer for photodynamic therapy, is then formed from four PBG molecules via three further intermediate stages .

Protoporphyrin IX makes the cells sensitive to light. Irradiation with light with a wavelength of approx. 630 nm generates free radicals and reactive oxygen species that kill the degenerated cells by triggering apoptosis . The light dose usually administered is in the range of 37 to 75 J / cm². The irradiation takes about eleven minutes, so that the output is in the range of 50 mW / cm².

For recording MAOP and 5-ALA in healthy and diseased skin cells, but also nerve cells of the sensory root ganglia of are gamma-aminobutyric acid (GABA) transporter GAT-3 or amino acid transporters mainly responsible. In contrast, passive diffusion of the very hydrophilic molecules across the cell membrane is insignificant for the accumulation within the cell. Protoporphyrin IX accumulates in various cell types faster after the addition of 5-ALA than after MAOP. Presumably, the cleavage of the methyl radical by cellular esterases, which is necessary in MAOP, occurs rather slowly. After an exposure time in skin cancer cells relevant for photodynamic therapy, an accumulation of protoporphyrin IX was found to be almost twice as intensive as that of MAOP when 5-ALA was added. Protoporphyrin IX from 5-ALA also accumulated more selectively in skin cancer cells than in healthy cells.

Methyl 5-amino-4-oxopentanoate is currently the only drug approved for the photodynamic therapy of superficial and nodular basal cell carcinoma and actinic keratoses .

Administration and application

MAOP is applied as a skin cream about 1 mm thick to the area to be treated. A side safety area of ​​10 mm is also provided with cream beyond the affected area. The cream contains 16% MAOP in the form of its hydrochloride . The actual photodynamic therapy begins after an exposure time of around three hours. Before the irradiation, a pain reliever , such as metamizole , is usually administered orally and a locally anesthetic gel is applied. The local irradiation and the increased accumulation in degenerate cells ensure that the surrounding healthy tissue is largely spared. The treatment is usually outpatient and can be repeated after about three months. Repetition increases the chances of recovery significantly.

Side effects

Up to 80% of patients show local phototoxic reactions, which manifest themselves mainly in the form of pain , edema and erythema . The edema and erythema should not be treated with corticosteroids , as these inflammatory reactions are an integral part of the healing process.

A number of retrospective studies and reports came to different results with regard to the pain intensity caused by PDT with MAOP or 5-ALA, although no clear tendency in favor of either of the two active ingredients was discernible. In the only directly comparative, controlled phase III study, the pain caused by photodynamic therapy with MAOP and 5-ALA occurred with the same frequency and was perceived as equally intense by the patients.

Development history

MAOP was developed by the Norwegian company Photocure. Galderma , then a joint venture between Nestlé and L'Oréal , acquired an exclusive license to manufacture and distribute MAOP in 2001.

further reading

• CB Warren, LJ Karai, A. Vidimos, EV Maytin: Pain associated with aminolevulinic acid-photodynamic therapy of skin disease. In: Journal of the American Academy of Dermatology . Volume 61, Number 6, December 2009, pp. 1033-1043. doi: 10.1016 / j.jaad.2009.03.048 . PMID 19925929 . (Review).
• B. Ortiz-Policarpio, H. Lui: Methyl aminolevulinate-PDT for actinic keratoses and superficial nonmelanoma skin cancers. In: Skin therapy letter. Volume 14, Number 6, Jul-Aug 2009, pp. 1-3. PMID 19609473 . (Review).
• P. Lehmann: Methyl aminolaevulinate-photodynamic therapy: a review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. In: British Journal of Dermatology . Volume 156, Number 5, May 2007, pp. 793-801. doi: 10.1111 / j.1365-2133.2007.07833.x . PMID 17419691 . (Review).
• RM Szeimies: Methyl aminolevulinate-photodynamic therapy for basal cell carcinoma. In: Dermatologic Clinics . Volume 25, Number 1, January 2007, pp. 89-94. doi: 10.1016 / j.det.2006.09.008 . PMID 17126746 . (Review).
• CA Morton: Methyl aminolevulinate: actinic keratoses and Bowen's disease. In: Dermatologic Clinics. Volume 25, Number 1, January 2007, pp. 81-87. doi: 10.1016 / j.det.2006.09.009 . PMID 17126745 . (Review).
• P. Foley: Clinical efficacy of methyl aminolaevulinate photodynamic therapy in basal cell carcinoma and solar keratosis. In: Australasian Journal of Dermatology . Volume 46, Suppl 3, February 2005, pp. S8-S10. PMID 15859301 . (Review).
• CA Morton: Methyl aminolevulinate (Metvix) photodynamic therapy - practical pearls. In: Journal of Dermatological Treatment . Volume 14, Suppl 3, 2003, pp. 23-26. PMID 14522638 . (Review).
• P. Foley: Clinical efficacy of methyl aminolevulinate (Metvix) photodynamic therapy. In: Journal of Dermatological Treatment. Volume 14, Suppl 3, 2003, pp. 15-22. PMID 14522637 . (Review).
• SB Brown: The role of light in the treatment of non-melanoma skin cancer using methyl aminolevulinate. In: Journal of Dermatological Treatment. Volume 14, Suppl 3, 2003, pp. 11-14. PMID 14522636 . (Review).

Web links

• MAOP at onmeda .de

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ↑ Ordinance on the prescription of medicinal products (Medicinal Prescription Ordinance - AMVV). 21 December 2005.
3. ↑ A. Casas, A. Batlle: Aminolevulinic acid derivatives and liposome delivery as strategies for improving 5-aminolevulinic acid-mediated photodynamic therapy. In: Current Medicinal Chemistry . Volume 13, Number 10, 2006, pp. 1157-1168. PMID 16719777 . (Review).
4. ↑ ^{a b c d e} H. Weisser, D. Meyer-Rogge, E. Meyer-Rogge: First experiences in private practice with the new topical photosensitizer MAOP for actinic keratoses and basaliomas. (PDF; 697 kB). In: Akt Dermatol. Volume 30, 2004, pp. 306-311. doi : 10.1055 / s-2004-825849 .
5. ↑ ^{a b} M. A. Siddiqui, CM Perry, LJ Scott: Topical methyl aminolevulinate. In: American Journal of Clinical Dermatology . Volume 5, Number 2, 2004, pp. 127-137. PMID 15109276 . (Review).
6. ↑ B. Novak, R. Schulten, H. Lübbert: δ-Aminolevulinic acid and its methyl ester induce the formation of Protoporphyrin IX in cultured sensory neurones. In: Naunyn Schmiedebergs Arch Pharmacol. 384 (6), Dec 2011, pp. 583-602. doi: 10.1007 / s00210-011-0683-1 . Epub 2011 Sep 25. PMID 21947250
7. ↑ ^{a b c d} R. Schulten, B. Novak, B. Schmitz, H. Lübbert: Comparison of the uptake of 5-aminolevulinic acid and its methyl ester in keratinocytes and skin. In: Naunyn Schmiedebergs Arch Pharmacol. 385 (10), Oct 2012, pp. 969-979. doi: 10.1007 / s00210-012-0777-4 . Epub 2012 Jul 17. PMID 22801976
8. ^ R. Washbrook, H. Fukuda, A. Battle, P. Riley: Stimulation of tetrapyrrole synthesis in mammalian epithelial cells in culture by exposure to aminolaevulinic acid. In: Br J Cancer. 75, 1997, pp. 381-387.
9. ↑ P. Uehlinger, M. Zellweger, G. Wagnieres, L. Juillerat-Jeanneret, H. van den Berg, N. Lange: 5-Aminolevulinic acid and its derivatives: physical chemical properties and protoporphyrin IX formation in cultured cells. In: J Photochem Photobiol B. 54, 2000, pp. 72-80.
10. ↑ JM Gaullier, K. Berg, Q. Peng, H. Anholt, PK Selbo, LW Ma, J. Moan: Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture. In: Cancer Res. 57, 1997, pp. 1481-1486.
11. ^ RG Tunstall, AA Barnett, J. Schofield, J. Griffiths, DI Vernon, SB Brown, DJ Roberts: Porphyrin accumulation induced by 5-aminolaevulinic acid esters in tumor cells growing in vitro and in vivo. In: Br J Cancer. 87, 2002, pp. 246-250.
12. ↑ L. Rodriguez, A. Batlle, G. Di Venosa, S. Battah, P. Dobbin, AJ Macrobert, A. Casas: Mechanisms of 5-aminolevulinic acid ester uptake in mammalian cells. In: Br J Pharmacol. 147, 2006, pp. 825-833.
13. ↑ JB Lee, JY Choi, JS Chun, S. J Yun, SC Lee, J. Oh, HR Park: Relationship of protoporphyrin IX synthesis to photodynamic effects by 5-aminolaevulinic acid and its esters on various cell lines derived from the skin. In: Br J Dermatol. 159, 2008, pp. 61-67.
14. ↑ ^{a b} T. Dirschka, P. Radny, R. Dominicus, H. Mensing, H. Brüning, L. Jenne, L. Karl, M. Sebastian, C. Oster-Schmidt, W. Klövekorn, U. Reinhold, M Tanner, D. Gröne, M. Deichmann, M. Simon, F. Huebinger, G. Hofbauer, G. Krähn-Senftleben, F. Borrosch, K. Reich, C. Berking, P. Wolf, P. Lehmann, M Moers-Carpi, H. Hönigsmann, K. Wernicke-Panten, S. Hahn, G. Pabst, D. Voss, M. Foguet, B. Schmitz, H. Lübbert, RM Szeimies; AK-CT002 Study Group; AK-CT003 Study Group: Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. In: Br J Dermatol. 168 (4), 2013, pp. 825-836. PMID 21910711
15. ↑ galderma.com: Our History. ( September 3, 2011 memento in the Internet Archive ) Retrieved August 4, 2011.

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