Mesalazine
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| Non-proprietary name | Mesalazine | |||||||||||||||||||||
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| Molecular formula | C 7 H 7 NO 3 | |||||||||||||||||||||
| Brief description |
Powder or crystals, almost white to light gray or light pink in color |
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| Molar mass | 153.14 g · mol -1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
280 ° C (decomposition) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Mesalazine ( INN ), and 5-aminosalicylic acid ( 5-ASA ), a is amine - derivative of salicylic acid and is used as anti-inflammatory drug in the treatment of inflammatory bowel diseases ( Crohn's disease , ulcerative colitis applied).
Mode of action
Inhibition of arachidonic acid metabolism
5-aminosalicylic acid appears to inhibit the production of proinflammatory arachidonic acid metabolites such as prostaglandins and leukotrienes . 5-aminosalicylic acid differs from salicylic acid only in one amino group . Salicylic acid is an active ingredient that acts as an inhibitor of cyclooxygenase-1 and cyclooxygenase-2 . A similar effect of 5-aminosalicylic acid on cyclooxygenase and thus on arachidon metabolism seems likely.
Effect as a "radical catcher"
Increased concentrations of reactive radicals were found in tissue samples from patients with inflammatory bowel disease . In some studies, 5-ASA has been shown to lower the levels of DNA-damaging oxygen and nitrogen radicals by increasing the effects of the protective heat shock protein Hsp72.
Immunosuppressive activity
5-ASA appears to inhibit DNA synthesis and proliferation of potentially pathogenic T and B cell populations. This happens u. a. by inhibiting activating cytokines (see inhibition of cytokine synthesis ). Furthermore, 5-ASA also appears to inhibit the secretion of antibodies . 5-ASA modulates other functions of the immune system by inhibiting important lymphocyte and macrophage functions. These include adhesion , chemotaxis, and phagocytosis . The adhesion seems to be caused by an inhibition of the enzyme AICAR (5-aminoimidazole-4-carboxamide-ribonucleotide) transformylase, which leads to the accumulation of adenosine . The increased adenosine level then dampens the inflammatory process by inhibiting the adhesion of leukocytes to the endothelial cells .
Inhibition of cytokine synthesis
5-ASA inhibits the formation and effect of IL-1, IL-2 , TNF-α and NFκ-B (5-ASA inhibits the phosphorylation of RelA (a mediator of NFκB) and does not inhibit the reduction of the NFκB inhibitor). So here too, 5-ASA has an anti- inflammatory and anti- proliferative effect .
Inhibition of siderophore synthesis by mycobacteria
The biosynthesis of iron-transporting peptides ( siderophores ) in mycobacteria is strongly impaired in vitro by 5-ASA, since the required salicylic acid is displaced. 5-ASA, together with the induction of iron deficiency , is therefore a possible method of treatment for infections with these pathogens. The effectiveness of 5-ASA in Crohn's disease is an indication of a possible involvement of mycobacteria in this disease.
application
5-aminosalicylic acid is only released from the prodrug sulfasalazine in the colon by the bacterial enzyme azoreductase. Another breakdown product is sulfapyridine, which is also anti-inflammatory and is used in the treatment of rheumatoid arthritis. But it is also responsible for a large part of the side effects of sulfasalazine (see below). For this reason, attempts have been made in the recent past to decouple 5-ASA from sulfasalazine. Oral 5-ASA alone is absorbed too quickly in the jejunum and is therefore inefficient for patients with diseases of the small or large intestine. The new developments include drugs that pack 5-ASA molecules in acrylic resins or ethyl cellulose. These only release 5-ASA at a higher pH value and thus ensure a certain delay. Another group relies on delayed release by dimerizing the aminosalicylic acid molecules, e.g. B. olsalazine or balsal azide . Sulfasalazine is no longer recommended as the best therapy due to its side effects, but it is more cost effective than 5-ASA alone. A new form of release has been available since 2008 ( MMX technology ).
Use in ulcerative colitis
With its different dosage forms, 5-ASA is part of the standard therapy for ulcerative colitis. In mild to moderate ulcerative colitis, 5-ASA is dosed with up to 6 g / d. An induction of remission occurs in 50–80% of patients. The different preparations work about equally well here. Topical application is also possible in the case of distal colon involvement.
5-ASA is also dosed at 1–2 g / d to maintain remission. Studies have shown that a dose of 2 g / d leads to a reduction in recurrence of 30–70%. In more severe illness, 5-ASA can also be used in combination with steroids.
Use in Crohn's disease
At a dosage of about 4 g / d, the disease activity is reduced in the case of mild to moderate attacks of Crohn's disease. However, 5-ASA works better in Crohn's induced colitis than in ileitis. Here too, 5-ASA can be used to maintain returns. There is no value in maintaining remission after an attack. A daily dose of 3–4 g can be administered permanently to maintain remission.
Lowering the risk of colon cancer
Depending on the severity and duration of the disease, ulcerative colitis increases the risk of colon cancer. A positive family history also increases the risk. The antiproliferative properties of COX, NFkappaB, bcl2, MAPK, and, through COX, PPARgamma inhibition have a direct effect. Furthermore 5-ASA lowers the concentration of DNA-damaging radicals (see above). On average, the risk of carcinoma should be reduced by up to 50% (in the case of ulcerative colitis).
Side effects
The following side effects occur with treatment with sulfasalazine and 5-ASA alone, but they are much more often caused by sulfapyridine: 20% of patients cannot tolerate sulfasalazine, only pure 5-ASA products. Agranulocytosis , the most serious side effect, is believed to be caused only by sulfapyridine. In general, serious side effects are very rare.
- Gastrointestinal: nausea, vomiting , diarrhea (especially osalazine)
- Skin reactions: itching , exanthema
- rare hematopoietic disorders : leukopenia , agranulocytosis
- in men: oligospermia , azoospermia
- Hypersensitivity: pancreatitis , pneumonitis
- rare: interstitial nephritis (<1: 500)
- possibly reversible hair loss at high dose
Pregnancy, breastfeeding and the desire to have children
In a study that continued taking 5-aminosalicylic acid supplements during pregnancy, no negative effects on pregnancy or the fetus were found. However, consultation with the doctor is strongly recommended. Male fertility does not appear to be affected by mesalazine or 5-aminosalicylic acid medication. In studies in animals, where much higher doses are administered, no effect on fertility could be found. Mesalazine therapy can be continued during pregnancy, as teratogenic damage can be virtually excluded.
synthesis
5-aminosalicylic acid can be produced on an industrial scale by reducing 5-nitrosalicylic acid .
Trade names
Asacol (D, CH), Asazine (CH), Claversal (D, A), Mesagran (A), Mesazin (CH), Mezavant (D), Pentasa (D, A, CH), Salofalk (D, A, CH )
Individual evidence
- ↑ a b c European Pharmacopoeia Commission (Ed.): EUROPÄISCHE PHARMACOPÖE 5th EDITION . tape 5.0-5.8 , 2006.
- ↑ a b Entry on mesalazine in the ChemIDplus database of the United States National Library of Medicine (NLM)
- ↑ a b c Entry on 5-aminosalicylic acid in the GESTIS substance database of the IFA , accessed on February 14, 2017(JavaScript required) .
- ↑ LJ Egan et al. a .: Inhibition of Interleukin-1-stimulated NF-κB RelA / p65 Phosphorylation by Mesalamine Is Accompanied by Decreased Transcriptional Activity. In: The Journal of Biological Chemistry 274, 1999, pp. 26448-26453, doi : 10.1074 / jbc.274.37.26448 PMID 10473604 .
- ↑ Brown KA, Ratledge C: The effect of p-aminosalicyclic acid on iron transport and assimilation in mycobacteria . In: Biochim. Biophys. Acta . 385, No. 2, April 1975, pp. 207-20. PMID 1092357 .
- ↑ a b c Treatment with mesalazine / olsalazine - information for patients ( memento of the original from March 9, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 148 kB). As of December 17, 2007.
- ↑ Falk Foundation e. V. . As of 2008, page 11.
- ↑ Summary of Product Claversal_250 Merck .
- ↑ G.Breviglieri, B.Giacomo, C.Sergio, A.Cinzia, E.Campanab, M.Panunzio: Reduction of 5-Nitrosalicylic acid in water to give 5-Aminosalicylic acid . Molecules 2001, 6, M260.
