Nitisinone
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| Surname | Nitisinone | ||||||||||||||||||
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| Molecular formula | C 14 H 10 F 3 NO 5 | ||||||||||||||||||
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| Molar mass | 329.2 g · mol -1 | ||||||||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Nitisinone - also known as NTBC , the abbreviation of 2- (2-nitro-4-trifluoromethyl-benzoyl) -1,3-cyclohexanedione - is a drug used to treat the congenital metabolic disorders tyrosinemia type I and alkaptonuria , since 2005 under the trade name Orfadin ( Swedish Orphan Biovitrum , SOBI) approved by the EMA .
history
Nitisinone was originally developed as a herbicide . During compatibility tests by the developing company, an adverse effect in rats in the form of a massive increase in the concentration of the amino acid tyrosine in the blood was discovered.
synthesis
Nitisinone is made by acylating 1,3-cyclohexanedione with 2-nitro-4-trifluoromethylbenzoyl chloride. As a 1,3-dicarbonyl compound, it is in equilibrium with its tautomers .
properties
Nitisinone reversibly inhibits the second enzyme in the catabolism (breakdown) of tyrosine, 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), so that tyrosine can only be broken down up to the level of 4-hydroxyphenylpyruvate. The excretion of all subsequent metabolites such as homogentisic acid or succinylacetone with the urine is reduced or can no longer be detected.
application areas
Nitisinone is used to treat type I tyrosinemia (fumarylacetoacetase defect). This is a congenital metabolic disorder in the breakdown of the phenolic amino acid tyrosine (and phenylalanine). The administration of nitisinone automatically increases the tyrosine concentration in the blood, which is why treatment with nitisinone usually has to be coupled with a special diet (reduced phenylalanine and tyrosine). After administration of nitisinone, the excretion of homogentisic acid is drastically reduced, which is why it is suitable for the treatment of another congenital metabolic disorder, alkaptonuria (lack of homogentisate dioxygenase ). In animal experiments, the pigment deposits of alkaptonuria do not appear. For this purpose, lower doses are necessary than for the treatment of tyrosinemia type I. Nitisinone (Orfadin) is not yet approved for the treatment of alkaptonuria. To date, there are no long-term scientific studies that prove the clinical effect of the treatment.
dosage
It is recommended to take nitisinone (Orfadin) at a dose of 1 to 2 mg / kg body weight (body weight) and day, orally before or after a meal in 2 doses per day (although the biological half-life is 54 hours).
Use during pregnancy and breastfeeding
Research results on the effects of nitisinone in pregnant or breastfeeding women are not available. In animal experiments, impairment of the fetuses was seen, but no experience in humans is available [pregnancy risk categories (PRC) C of the American Food and Drug Administration (FDA)]. In a severe clinical course of type I tyrosinaemia, the expected benefit of nitisinone medication can be so great that the possible risks can be accepted. Since nitisinone has also been found in milk in animal experiments, either breastfeeding should not be carried out or medication should not be administered during breastfeeding.
Therapy controls
The concentration of nitisinone in the blood for therapy control can be quantified using tandem mass spectrometry. The treatment begins with a dose of 1 mg / kg body weight and the excretion of succinylacetone in the urine is first checked. If succinylacetone is still to be found in measurable amounts in the urine after months, the dose is initially increased from 1.5, then to 2 mg / kg body weight. Long-term controls consist of quantifications of nitisinone in the blood and / or succinylacetone in the urine. To control the protein-reduced diet, the blood concentrations of tyrosine and phenylalanine should be determined regularly.
Side effects
Nitisinone has various side effects, the most common of which are transient leukocytopenia and / or thrombocytopenia (low levels of white blood cells and platelets). In addition, side effects have been reported so far: headache, conjunctivitis, keratitis, corneal opacity, photophobia (photophobia), eye pain, loss of appetite and vomiting, etc. a. The incidence of liver carcinomas occurring in patients with type I tyrosinemia is not influenced by nitisinone therapy.
Interactions
Interactions of nitisinone with other drugs or substances are not yet known.
Individual evidence
- ↑ Data sheet Nitisinone, ≥95% (HPLC) from Sigma-Aldrich , accessed on July 4, 2013 ( PDF ).
- ↑ a b c d Information on Orfadin on the website of the European Medicines Agency.
- ^ S. Lindstedt, E. Holme, EA Lock, O. Hjalmarson, B. Strandvik: Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase . In: The Lancet . tape 340 , no. 8823 , October 3, 1992, p. 813-817 , doi : 10.1016 / 0140-6736 (92) 92685-9 .
- ↑ Wendy J. Introne et al .: A 3-year randomized therapeutic trial of nitisinone in alkaptonuria . In: Molecular Genetics and Metabolism . tape 103 , no. 4 , August 2011, p. 307-314 , doi : 10.1016 / j.ymgme.2011.04.016 .
- ↑ Johannes Sander et al.: Monitoring tyrosinaemia type I: Blood spot test for nitisinone (NTBC) . In: Clinica Chimica Acta . tape 412 , no. 1-2 , January 14, 2011, pp. 134-138 , doi : 10.1016 / j.cca.2010.09.027 .