Vigabatrin
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| ( S ) -Vigabatrin (top) and ( R ) -Vigabatrin (bottom) | ||||||||||||||||||||||
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| Non-proprietary name | Vigabatrin | |||||||||||||||||||||
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| Molecular formula | C 6 H 11 NO 2 | |||||||||||||||||||||
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| Molar mass | 129.16 g · mol -1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
209 ° C |
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| solubility |
easily soluble in water |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Vigabatrin (trade name: Sabril ; manufacturer: Sanofi ) is an anti-convulsive drug that is used in the treatment of epilepsy . Chemically, it is structurally very similar to the carrier substance gamma-aminobutyric acid (GABA). Due to the side effect profile, its use is limited to individual special forms of epilepsy or otherwise therapy-resistant cases.
Mechanism of action
Vigabatrin is an enzyme-activated, irreversible inhibitor of the GABA-degrading enzyme GABA aminotransferase. Because of its close structural relationship to the natural substrate, it is also referred to as a suicide substrate. The enzyme inhibition increases the concentration of the inhibitory neurotransmitter GABA. Since the enzyme inhibition is irreversible, the neuronal effect continues even after the drug is discontinued until new GABA aminotransferase is provided by the nerve cells.
application areas
Because of the unfavorable side effects , vigabatrin is only used as the drug of first choice in the case of West syndrome in those children in whom this occurs as symptomatic epilepsy in the context of tuberous sclerosis , because it has proven to be particularly effective here. Otherwise, it can be used in focal epilepsy - including those with secondary generalization - if the first-line agents did not lead to freedom from seizures.
The drug is taken orally and has a half-life of 5 to 8 hours in adolescents and 12 to 13 hours in adults.
In July 2018, the French company Orphelia Pharma received an approval recommendation from the CHMP for a new dosage form , as soluble tablets especially for children. The dosage can be increased in 50 mg steps. Until then, vigabatrin was available in the form of granules and coated tablets that had to be divided or diluted to adjust the dose for children. This drug has been approved in the EU under the trade name Kigabeq since October 12, 2018 .
Side effects
Depending on the dose, fatigue up to drowsiness, headache, dizziness, concentration and memory disorders, blurred vision, nystagmus and balance disorders occur. Irrespective of the dose, allergic reactions can lead to agitation in children and depression or psychosis in adults. These changes usually occur in the first few months of therapy and are reversible. Chronic use can lead to weight gain and aggravation of generalized epilepsies such as absenteeism and myoclonic seizures. Bilateral visual field defects were observed in up to 40% of the treated adults; although only about 5% were symptomatic, they are probably irreversible. They occur regardless of the dose, duration of therapy, age, duration of epilepsy and concomitant anti-epileptic medication. It is true that “tunnel vision” that is really impairing rarely occurs, but this side effect has led to vigabatrin only being used in selected, well-balanced cases after initially broader use.
Stereoisomerism
Vigabatrin is chiral , so it contains a stereocenter. There are thus two enantiomers , the ( R ) -form and the ( S ) -form, of which only the ( S ) -enantiomer is pharmacologically active. The commercial preparations contain the drug as a racemate (1: 1 mixture of enantiomers).
Manufacturing
For vigabatrin, multistage syntheses , starting from diethyl malonate and 1,4-dichloro-2-butene , are described in the literature .
Individual evidence
- ↑ a b The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition, 2006, pp. 1715-1716, ISBN 978-0-911910-00-1 .
- ↑ a b Data sheet Vigabatrin at Sigma-Aldrich , accessed on April 25, 2011 ( PDF ).
- ↑ Lippert, B., Metcalf, BW, Jung, MJ and Casara, P .: 4-aminohex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyrate aminotransferase in mammalian brain. European Journal of Biochemistry No. 74, p. 441 (1977). PDF
- ↑ Kigabeq - Opinion , PM EMA, July 26, 2018, accessed August 5, 2018.
- ↑ Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 23.-26. July 2018 , PM EMA July 27, 2018, accessed August 5, 2018.
- ↑ European Medicines Agency: Kigabeq (vigabatrin) PDF document, accessed on August 18, 2020
- ↑ KD Hägele, PJ Schechter: Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer , Clinical Pharmacology and Therapy 40 (1986) 581-586.
- ^ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances , 4th edition (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .
