Cycloserine

Structural formula
General
Non-proprietary name	Cycloserine
other names	D -4-amino-3-isoxazolidinone ( R ) -4-amino-1,2-oxazolidin-3-one Oxamycin
Molecular formula	C 3 H 6 N 2 O 2
Brief description	white to pale yellow, crystalline solid
External identifiers / databases
CAS number 68-41-7 EC number 200-688-4 ECHA InfoCard 100,000,626 PubChem 6234 DrugBank DB00260 Wikidata Q418508
Drug information
ATC code	J04 AB01
Drug class	antibiotic
properties
Molar mass	102.09 g mol −1
Physical state	firmly
Melting point	155–156 ° C ( decomposition )
pK s value	4.5
solubility	readily soluble in water: 100 g l −1 (20 ° C)
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
Toxicological data	560 mg kg −1 ( TD Lo ,  human ,  oral ) 60 mg kg −1 ( LD 50 ,  woman ,  oral ) 5,290 mg kg −1 ( LD 50 ,  mouse ,  oral ) 5 g kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cycloserine (trade name in the USA: Seromycin ) is a heterocyclic organic compound that belongs to the oxazolidinones and is chiral . The substance is used as an antibiotic effective drug for the treatment of tuberculosis used. Cycloserine is considered the second choice and is only used if the pathogen is resistant to other antibiotics .

Natural occurrence and production

Cycloserine, first isolated in 1955 and then traded under the name D-cycloserine by Hoffmann-La Roche as a tuberculostatic mainly effective against tubercle bacteria , is produced by various streptomycetes such as Streptomyces garyphalus , S. archidaceus and S. lavedulae , from which it is obtained by fermentation can. Technically, the compound is produced from the amino acid D- serine by reaction with methanol and hydrogen chloride and subsequent reaction with phosphorus pentachloride PCl ₅ and cyclization with hydroxylamine . A simple laboratory method is now known.

properties

Cycloserine is a readily water-soluble , hygroscopic , crystalline powder with a white to light yellow color. In aqueous solution - at pH values of 7 and less - cycloserine decomposes quickly. The solution is acidic ( pK _s ≈4.5).

Use as a medicine

In the treatment of tuberculosis, the D - enantiomer ( D - cycloserine ) is administered orally in doses of 0.5 g (children) to 1 g per day (adults). The absorption takes place almost completely; Elimination occurs renally . The plasma half-life is around 10 hours. The optimum effect of cycloserine is at a pH value of 6.4 to 7.4. Depending on the concentration, cycloserine shows bacteriostatic or bactericidal action against correspondingly sensitive strains of Gram- positive and Gram-negative bacteria and against Mycobacterium tuberculosis . D -Cycloserine inhibits both alanine racemase and D -alanyl- D -alanine synthetase, both enzymes that are essential for the synthesis of the bacterial cell wall . The L enantiomer inhibits a number of vitamin B ₆ -dependent enzymes and is more toxic to humans.

The use of cycloserine in behavior therapy has only just begun to be researched. The psychotherapy of certain anxiety disorders was significantly more effective with accompanying treatment with cycloserine. Cycloserine does not have an anxiety-suppressing effect, but increases the effect of the psychotherapeutic procedure used in the form of an exposure to fear. Here the patient is repeatedly confronted with the fear-inducing situation and gradually learns that his fear is in fact unfounded: he loses the fear. Few, low-dose doses of cycloserine meant that this learning process was completed more quickly. Preclinical studies indicate that this effect of cycloserine is caused by influencing NMDA receptors in the amygdala . NMDA receptors play an essential role in the biochemical mechanism for learning and memory .

Side effects and safety information

Cycloserine acts as an antagonist for vitamin B6 (pyridoxine) and, through its inactivation, leads to pyridoxine deficiencies or, consequently, to some extent. a. Malfunctions in the amino acid - metabolism (see pyridoxal phosphate ) and u. a. increased nervous excitability (see studies on use in behavior therapy). Background: enzymes in eukaryotes called glutamate decarboxylase (GAD) catalyze the decarboxylation of glutamate to γ-aminobutyric acid (GABA), the most important inhibitory (inhibitory) neurotransmitter in the central nervous system . For this only known way for the biosynthesis of the neurotransmitter GABA these enzymes (GAD) need as a cofactor pyridoxal phosphate, the active form of pyridoxine (vitamin B6), its precursor is inactivated by cycloserine.

A deficiency in GABA resulting from the administration of cycloserine or, as a result, vitamin B6 leads to a. to increased excitability of the nerves, which results in numerous neurotoxic side effects (e.g. main cause of concentration disorders) and can therefore be treated with pyridoxine (Vit. B6). Cycloserine already shows - mainly neurotoxic - side effects in therapeutic doses of 12 to 15 mg / kg body weight, which makes up about 75% of all undesirable effects. Symptoms include rash , drowsiness, dizziness , disorientation , over-excitability, headache and euphoria up to seizures and depression - also with a suicidal tendency. In Germany, cycloserine itself is not approved as a medicinal substance because of its strong side effects; The cycloserine derivative terizidone is used as a tuberculosis drug , but only as a second choice.

The side effects usually occur with long-term administration of high doses. In recent research, which u. a. investigating the reinforcing properties of cycloserine on behavior therapy , low doses are used for a very short time. Usually one or two doses of 50–500 mg cycloserine are given at least one week apart. Accordingly, severe side effects are to be assessed as rather unlikely.

Lethal doses between 60 and 560 mg / kg body weight have been reported for humans , while the toxicity for mice and rats is low (LD ₅₀ ≈5 g / kg).

Individual evidence

1. ↑ ^{a b} Datasheet cycloserine at Acros, accessed on January 7, 2008.
2. ↑ ^{a b c d e} A. W. Frahm, HHJ Hager, F. v. Bruchhausen, M. Albinus, H. Hager: Hager's Handbook of Pharmaceutical Practice: Volume 4: Substances AK. , Birkhäuser, 1999, ISBN 978-3-540-52688-9 .
3. ^ Entry on cycloserine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
4. ↑ D-Cycloserine data sheet from Sigma-Aldrich , accessed on May 9, 2017 ( PDF ).
5. ↑ ^{a b} Diseases of the Chest. Vol. 29, p. 241, 1956.
6. ^ ^{A b} British Medical Journal . Vol. 1, pp. 907, 1965.
7. ↑ ^{a b c} Antibiotics and Chemotherapy. Vol. 6, p. 360, 1956.
8. ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 9–223, here: p. 55.
9. ↑ X Li, X Meng, H Duan H et al .: Original and efficient synthesis of D-cycloserine . In: Arch Pharm (Weinheim) . 343, No. 8, August 2010, pp. 473-5. doi : 10.1002 / ardp.200900316 . PMID 20803624 .
10. ↑ ^{a b} Friedrich Kummer, Nikolaus Konietzko, Tullio C. Medici (Ed.): Pharmacotherapy of bronchopulmonary diseases. Springer, Vienna / New York 1999, ISBN 3-211-83061-8 , p. 236.
11. ↑ SG Hofmann et al .: Augmentation Treatment of Psychotherapy for Anxiety Disorders with D-Cycloserine . In: CNS Drug Rev , 12 (3-4), 2006, pp. 208-217, PMID 17227287 , PMC 2151200 (free full text) (English).
12. ↑ ^{a b} Detlev Schneider: Checklist Medicines A – Z. Georg Thieme Verlag, 2013, ISBN 978-3-13-160226-8 , p. 564 ( limited preview in Google book search).
13. ↑ Gabriele Schünke: workbook orthomolecular medicine. Georg Thieme Verlag, 1997, ISBN 978-3-7773-1237-8 , p. 54 ( limited preview in Google book search).
14. ^ Entry on cycloserine in Flexikon , a wiki from DocCheck , accessed on November 26, 2015.
15. ↑ Entry on drug-based tuberculosis therapy in Flexikon , a wiki from DocCheck , accessed on November 26, 2015.
16. ↑ Technical information terivalidin capsules (PDF) in: pharmazie.com .
17. ↑ MW Otto, SL Basden, TM Leyro, RK McHugh, SG Hofmann: Clinical perspectives on the combination of D-cycloserine and cognitive-behavioral therapy for the treatment of anxiety disorders . In: CNS Spectrums . 12, No. 1, January 2007, pp. 51-66, 59-61. PMID 17192764 . Retrieved November 27, 2009.

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