Miglustat

Structural formula
General
Non-proprietary name	Miglustat
other names	(2 R , 3 R , 4 R , 5 S ) -1-Butyl-2- (hydroxymethyl) piperidine-3,4,5-triol ( IUPAC ) 1,5- (butylimino) -1,5-dideoxy-D-glucitol n -Butyldeoxynojirimycin n -butylmoranoline NB-DNJ SC 48334 (development code) OGT 918 (development code)
Molecular formula	C 10 H 21 NO 4
Brief description	hygroscopic white solid ( hydrochloride )
External identifiers / databases
CAS number 72599-27-0 210110-90-0 ( hydrochloride ) EC number 689-232-7 ECHA InfoCard 100.216.074 PubChem 51634 ChemSpider 46764 DrugBank DB00419 Wikidata Q425911
Drug information
ATC code	A16 AX06
properties
Molar mass	219.28 g mol −1
Physical state	firmly
Melting point	170-171 ° C
solubility	Easily soluble in water (75 mM in water and DMSO)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Miglustat is a drug that is used in the treatment of two rare hereditary metabolic diseases, Gaucher's disease type 1 and Niemann-Pick disease type C. Both are lysosomal storage diseases .

description

Is considered chemically Miglustat an iminosugar and the n -butyl derivative of the natural product moranoline , a D - Glucopiperidinose . As glucose - analogue , it is a reversible inhibitor of the enzyme glucosylceramide synthase (GCS). GCS catalyzes the first step in the biosynthesis of glucosylceramide . Miglustat, reduces the activity of glucosylceramide synthase, which means that less glucosylceramide can be produced in the cells ( substrate reduction therapy ).

The drug is approved for the treatment of Niemann-Pick disease type C and Gaucher disease type 1 in the European Union . In the latter, however, only in patients for whom enzyme replacement therapy is not a treatment option.

Pharmacokinetics

Unlike the in enzyme replacement therapy administered proteins for the treatment of Gaucher disease, miglustat is orally bioavailable. This means that the active ingredient can be taken as a tablet and does not have to be administered parenterally , for example intravenously . Oral bioavailability is 40 to 60%. The active ingredient is distributed in a large number of organs and tissues . The central nervous system , the skeleton and the lungs are therapeutically important . Miglustat can cross the blood-brain barrier and is eliminated by the kidneys . In the latter, there is a combination of glomerular filtration and active secretion. Only small amounts of miglustat are eliminated from the organism via the liver .

Side effects

By inhibiting several disaccharidases , miglustat causes diarrhea (84% in one study), weight loss (64%), gas (43%) and abdominal pain (40%) in most patients . Other common side effects affect the nervous system . These include tremors (29%), paresthesias (10%) and amnesias (6%). A disruption of spermatogenesis reduces fertility in male patients. It is also recommended that men use effective contraception while taking miglustat and for up to three months after stopping it.

costs

The treatment costs for a patient weighing 60 kg are around 125,000 euros per year (as of 2003). Compared to the more expensive enzyme replacement therapy with Imiglucerase , the costs are lower by a factor of 4.3. The miglustat tablets with 100 mg of active ingredient are to be taken three times a day.

Finished medicinal products

Zavesca (D, A, CH)

Web links

• Swiss Medicines Compendium: Miglustat Preparations

further reading

• A. Mehta: Gaucher disease: unmet treatment needs. In: Acta paediatrica. Volume 97, Number 457, April 2008, pp. 83-87, doi : 10.1111 / j.1651-2227.2008.00653.x . PMID 18339195 .
• GM Pastores, P. Giraldo et al. a .: Goal-oriented therapy with miglustat in Gaucher disease. In: Current medical research and opinion. Volume 25, Number 1, January 2009, pp. 23-37, doi : 10.1185 / 03007990802576518 . PMID 19210136 .
• FM Platt, M. Jeyakumar: Substrate reduction therapy. In: Acta paediatrica. Volume 97, Number 457, April 2008, pp. 88-93, doi : 10.1111 / j.1651-2227.2008.00656.x . PMID 18339196 .
• PL van Giersbergen, J. Dingemanse: Influence of food intake on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. In: Journal of Clinical Pharmacology . Volume 47, Number 10, October 2007, pp. 1277-1282, doi : 10.1177 / 0091270007305298 . PMID 17720777 .
• GM Pastores: Miglustat: substrate reduction therapy for lysosomal storage disorders associated with primary central nervous system involvement. In: Recent patents on CNS drug discovery. Volume 1, Number 1, January 2006, pp. 77-82, PMID 18221193 .
• J. Jakóbkiewicz-Banecka, A. Wegrzyn, G. Wegrzyn: Substrate deprivation therapy: a new hope for patients suffering from neuronopathic forms of inherited lysosomal storage diseases. In: Journal of applied genetics. Volume 48, number 4, 2007, pp. 383-388, doi : 10.1007 / BF03195237 . PMID 17998597 .
• RH Lachmann: Miglustat: substrate reduction therapy for glycosphingolipid lysosomal storage disorders. In: Drugs of Today . Volume 42, number 1, January 2006, pp. 29-38, doi : 10.1358 / dot.2006.42.1.937457 . PMID 16511609 .
• PL McCormack, KL Goa: Miglustat. In: Drugs . Volume 63, Number 22, 2003, pp. 2427-2434, PMID 14609352 .

Individual evidence

1. ↑ ^{a b} Tocris: Miglustat hydrochloride  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. (PDF file; 107 kB)  
2. ↑ ^{a b} Merck: N-Butyldeoxynojirimycin, Hydrochloride
3. ↑ ^{a b} Data sheet N-Butyldeoxynojirimycin from Sigma-Aldrich , accessed on August 10, 2011 ( PDF ).
4. ↑ JS Primacombe: Syntheses of antibiotic sugars. In: Angewandte Chemie . Volume 83, Number 8, 1971, pp. 261-274. doi : 10.1002 / anie.19710830802
5. ↑ ^{a b} A.reiber, O. Morand, M. Clozel: The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. In: Xenobiotica . Volume 37, Number 3, March 2007, pp. 298-314, doi : 10.1080 / 00498250601094543 . PMID 17624027 .
6. ^ MT Vanier: Niemann-Pick disease type C. In: Orphanet Journal of Rare Diseases. Volume 5, 2010, p. 16, doi : 10.1186 / 1750-1172-5-16 . PMID 20525256 . PMC 2902432 (free full text).
7. ↑ information about Zavesca on the website of the European Medicines Agency .
8. ↑ B. Hoffmann, M. Schwarz a. a .: Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. In: Clinical Gastroenterology and Hepatology . Volume 5, number 12, December 2007, pp. 1447-1453, doi : 10.1016 / j.cgh.2007.08.012 . PMID 17919989 .
9. ↑ GM Pastores, NL Barnett, EH Kolodny: An open-label, noncomparative study of miglustat in type I Gaucher disease: efficacy and tolerability over 24 months of treatment. In: Clinical Therapeutics . Volume 27, Number 8, August 2005, pp. 1215-1227, doi : 10.1016 / j.clinthera.2005.08.004 . PMID 16199246 .
10. ↑ CE Hollak, D. Hughes et al. a .: Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of a post-authorization safety surveillance program. In: Pharmacoepidemiology and Drug Safety . Volume 18, Number 9, September 2009, pp. 770-777, doi : 10.1002 / pds.1779 . PMID 19507165 .
11. ↑ ^{a b} Miglustat (Zavesca) in M. Gaucher. (PDF file; 61 kB) In: arznei-telegram. Volume 34, number 5, 2003, p. 4.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !