Cycloserin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P271：Nur im Freien oder in gut belüfteten Räumen verwenden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

D-Cycloserine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R5:Beim Erwärmen explosionsfähig.
  R20:Gesundheitsschädlich beim Einatmen.

• S-Sätze Betriebsanweisung:

  S38:Bei unzureichender Belüftung Atemschutzgerät anlegen.
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.

• Beschreibung

  D-Cycloserine (68-41-7) is a partial agonist at the glycine modulatory site of NMDA glutamatergic receptors.1?Blocks kainate-induced seizures2?and displays anticonvulsant effects3?in rat models. D-Cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices.4?Second-line drug for the treatment of tuberculosis. ?Enhances activity-dependent plasticity in human adults.5

• Chemische Eigenschaften

  White to pale yellow cryst. powder

• Originator

  Oxamycin,Merck Sharp and Dohme,US,1956

• Verwenden

  antibacterial (tuberculostatic)

• Verwenden

  D-cycloserine has been used to inhibit serine hydroxymethyltransferase.

• Verwenden

  D-Cycloserine inhibits cell wall biosynthesis (D-Ala peptide bond formation). D-Cycloserine also prevents conversion of D-Ala to L-Ala. D-Cycloserine is an bacteriostatic. D-Cycloserine is an antibiot ic against Gram-negative bacteria.

• Definition

  ChEBI: D-cycloserine is a 4-amino-1,2-oxazolidin-3-one that has R configuration. It is an antibiotic produced by Streptomyces garyphalus or S. orchidaceus and is used as part of a multi-drug regimen for the treatment of tuberculosis when resistance to, or toxicity from, primary drugs has developed. An analogue of D-alanine, it interferes with bacterial cell wall synthesis in the cytoplasm by competitive inhibition of L-alanine racemase (which forms D-alanine from L-alanine) and D-alanine--D-alanine ligase (which incorporates D-alanine into the pentapeptide required for peptidoglycan formation and bacterial cell wall synthesis). It has a role as an antitubercular agent, an antiinfective agent, an antimetabolite, a metabolite and a NMDA receptor agonist. It is an organooxygen heterocyclic antibiotic, an organonitrogen heterocyclic antibiotic and a 4-amino-1,2-oxazolidin-3-one. It is a conjugate base of a D-cycloserine(1+). It is an enantiomer of a L-cycloserine. It is a tautomer of a D-cycloserine zwitterion.

• Indications

  Cycloserine is a broad-spectrum antibiotic produced by Streptomyces orchidaceus. It is structural analogue of Dalanine and acts through a competitive inhibition of the D-alanine that is involved in bacterial cell wall synthesis. Cycloserine is inhibitory to M. tuberculosis and active against Escherichia coli, S. aureus, and Enterococcus, Nocardia, and Chlamydia spp. It is used in the treatment of MDR tuberculosis and is useful in renal tuberculosis, since most of the drug is excreted unchanged in the urine.

• Manufacturing Process

  Cycloserine may be made by a fermentation process or by direct synthesis. The fermentation process is described in US Patent 2,773,878. A fermentation medium containing the following proportions of ingredients was prepared:
  Parts by Weight
  Soybean meal
  30.0
  Cornstarch
  5.0
  Corn steep liquor
  3.0
  Sodium nitrate
  3.0
  This material was made up with distilled water to provide 41 g per liter, and the mixture was adjusted to pH 7.0 with potassium hydroxide solution. To the mixture were added per liter 5.0 g of calcium carbonate and 7.5 ml of soybean oil. 2,000 ml portions of this medium were then added to fermentation vessels, equipped with stirrers and aeration spargers, and sterilized at 121°C for 60 minutes. After cooling the flasks were inoculated with a suspension of strain No. ATCC 11924 of Streptomyces lavendulae,obtained from the surface of agar slants. The flasks were stirred for 4 days at 28°C at approximately 1,700 rpm. At the end of this period the broth was found to contain cycloserine in the amount of about 250 C.D.U./ml of broth. The mycelium was separated from the broth by filtration. The broth had a pH of about 7.5. Tests showed it to be highly active against a variety of microorganisms.
  The direct synthetic process is described in US Patent 2,772,280. A solution of 73.3 g (0.332 mol) of β-aminoxyalanine ethyl ester dihydrochloride in 100 ml of water was stirred in a 500 ml 3-necked round-bottomed flask cooled in an ice-bath. To the above solution was added over a 30-minute period 65.6 g (1.17 mols) of potassium hydroxide dissolved in 100 ml of water, While the pH of the reaction mixture was 7 to 10.5, a red color appeared which disappeared when the pH reached 11 to 11.5. The light yellow solution was allowed to stand at room temperature for ? hour and then added to 1,800 ml of 1:1 ethanol-isopropanol. The reaction flask was washed twice with 10 ml portions of water and the washings added to the alcohol solution. The precipitated salts were filtered out of the alcohol solution and the filtrate cooled to 5°C in a 5 liter 3-necked round-bottomed flask. To the cold, well-stirred solution was added dropwise over a 35-minute period sufficient glacial acetic acid to bring the pH of the alcohol solution to 6.0. When the pH of the solution had reached 7 to 7.5, the solution was seeded and no further acetic acid added until crystallization of the oil already precipitated had definitely begun. The crystalline precipitate was collected on a filter, washed twice with 1:1 ethanolisopropanol and twice with ether. The yield of 4-amino-3-isoxazolidone was 22.7 g.

• Trademarks

  Seromycin (Lilly).

• Therapeutic Function

  Antitubercular

• Synthesis Reference(s)

  Journal of the American Chemical Society, 79, p. 3236, 1957 DOI: 10.1021/ja01569a065

• Allgemeine Beschreibung

  Chemical structure: amino acid derivatives

• Pharmazeutische Anwendungen

  A fermentation product of Strep. orchidaceus and other related organisms now produced synthetically. Aqueous solutions are stable at pH 7.8 but the agent is rapidly destroyed in acid conditions. It is active against a wide range of Gram-negative and Grampositive bacteria, including Staphylococcus aureus, streptococci, including Enterococcus faecalis, various enterobacteria, Nocardia and Chlamydia spp. M. tuberculosis is inhibited by 8–16 mg/L. Some environmental mycobacteria, including M. avium, are also susceptible. Its action is specifically antagonized by d-alanine, from which media for in-vitro tests should be free. Its use is limited by neurological and psychiatric side effects. Primary resistance in M. tuberculosis is rare and develops only slowly in patients treated with cycloserine alone. Its inclusion in combinations deters the development of resistance to other drugs. There is no cross-resistance with other therapeutic antibiotics.
  It is well absorbed when given orally, achieving a concentration of c. 10 mg/L 3–4 h after a 250 mg dose. Doubling the dose approximately doubles the plasma level. Some accumulation occurs over the first 3 or 4 days of treatment. In children receiving 20 mg/kg orally, plasma levels of 20–35 mg/L have been found. It is widely distributed throughout the body fluids, including the CSF. About 50% is excreted unchanged in the glomerular filtrate over 24 h and 65–70% over the subsequent 2 days. The remainder is metabolized. There is no tubular secretion and no effect of probenecid. Cycloserine accumulates in renal failure, reaching toxic levels if dosage is uncontrolled. It can be removed by hemodialysis.
  Evidence of central nervous system toxicity, including headache, somnolence, vertigo, visual disturbances, confusion, depression, acute psychotic reactions and tremors, may develop over the first 2 weeks of treatment. The effects may be exacerbated by alcohol and can be reduced, to some extent, by administering pyridoxine. Treatment should be stopped promptly if any mental or neurological signs develop. Convulsions are said to occur in about 50% of patients when the plasma concentration exceeds 20–25 mg/L, but the relationship to dose is not particularly close. No permanent damage appears to be caused. Cycloserine inhibits mammalian transaminases and this and the convulsant effects of the drug have been attributed to a metabolite, amino-oxyalanine. Use of the drug should be avoided in patients with previous fits or other neurological or psychiatric abnormalities. Rare side effects include rashes, cardiac arrhythmia and deficiency in folate and vitamin B₁₂ leading to peripheral neuritis.
  It is occasionally used in MDR tuberculosis (with other antituberculosis drugs) and other mycobacterioses (with appropriate additional drugs).

• Biochem/physiol Actions

  Mode of Action: Inhibits cell wall biosynthesis (D-Ala peptide bond formation). Also prevents conversion of D-Ala to L-Ala. Bacteriostatic.Partial agonist at the glycine modulatory site of NMDA glutamatergic receptors; antibiotic against Gram-negative bacteria.Mode of Resistance: D-Ala transport interference.

• Mechanism of action

  D-Cycloserine is considered to be the active form of the drug, having its action associated with the ability to inhibit two key enzymes, D-alanine racemase and D-alanine ligase. D-Alanine is an important component of the peptidoglycan portion of the mycobacterial cell wall. Mycobacterium are capable of utilizing natural occurring L-alanine and converting the L-alanine to D-alanine via the enzyme D-alanine racemase. The resulting D-alanine is coupled with itself to form a D-alanine–D-alanine complex under the influence of D-alanine ligase, and this complex is incorporated into the peptidoglycan of the mycobacterial cell wall . D-Cycloserine is a rigid analogue of D-alanine; therefore, it competitively inhibits the binding of D-alanine to both of these enzymes and its incorporation into the peptidoglycan. Resistance is associated with an over expression of D-alanine racemase.

• Pharmakologie

  Cycloserine is readily absorbed orally and distributes throughout body fluids including the cerebrospinal fluid. The concentrations of cycloserine in tissues, body fluids, and the cerebrospinal fluid are approximately equal to the plasma level. Cycloserine is partially metabolized, and 60 to 80% is excreted unchanged by the kidney.

• Clinical Use

  D-(+)-4-Amino-3-isoxazolidinone (Seromycin) is an antibioticthat has been isolated from the fermentation beer of threedifferent Streptomyces species: S. orchidaceus, S. garyphalus,and S. lavendulus. It occurs as a white to pale yellow crystallinematerial that is very soluble in water. It is stable in alkaline,but unstable in acidic, solutions. The compoundslowly dimerizes to 2,5-bis(aminoxymethyl)-3,6-diketopiperazinein solution or standing.
  The structure of cycloserine was reported simultaneouslyby Kuehl et al. and Hidy et al.81 to be D-( +)-4-amino-3-isoxazolidinone. It has been synthesized byStammer et al. and by Smart et al.83 Cycloserine is stereochemicallyrelated to D-serine. However, the L-form hassimilar antibiotic activity.
  Although cycloserine exhibits antibiotic activity invitro against a wide spectrum of both Gram-negative andGram-positive organisms, its relatively weak potency andfrequent toxic reactions limit its use to the treatment of tuberculosis.It is recommended for patients who fail to respondto other tuberculostatic drugs or who are known tobe infected with organisms resistant to other agents. It isusually administered orally in combination with otherdrugs, commonly isoniazid.

• Clinical Use

  Neurological symptoms, which tend to appear in the first week of therapy, consist of dizziness, confusion, irritability, psychotic behavioral changes, and even suicidal ideation. Cycloserine is contraindicated in patients with underlying psychiatric and seizure disorders.Other side effects include occasional peripheral neuropathy and low magnesium levels.

• Nebenwirkungen

  Cycloserine is readily absorbed after oral administration and is widely distributed, including the CNS. Unfortunately, D-cycloserine binds to neuronal N-methylasparate receptors and, in addition, affects synthesis and metabolism of γ-aminobutyric acid, leading to complex series of CNS effects. As a second-line agent, cycloserine should only be used when retreatment is necessary or when the organism is resistant to other drugs. Cycloserine should not be used as a single drug; it must be used in combination.

• Synthese

  Cycloserine, 4-amino-3-isoxalidinone (34.1.19), can be synthesized both biosynthetically from the actinomycetes Streptomyces garyphalus, Streptomyces orchidaceus, and Streptomyces lavenduale as well as synthetically from the methyl ester of D-serine, the hydroxyl group of which is replaced with a chlorine atom when reacted with phosphorous pentachloride, and subsequent reaction of the resulting product (34.1.19) with hydroxylamine results in heterocyclization to the desired cycloserine (34.1.20).

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Alcohol: Increased risk of seizures.

• Stoffwechsel

  Cycloserine is excreted largely unchanged by glomerular filtration. About 50% of a single 250 mg dose is excreted unchanged in the urine within 12 hours and about 70% is excreted within 72 hours. As negligible amounts of cycloserine appear in the faeces, it is assumed that the remainder of a dose is metabolised to unidentified metabolites.

• läuterung methode

  Purify cycloserine by recrystallisation from aqueous EtOH or MeOH or aqueous NH3/EtOH or isoPrOH. Also recrystallise it from aqueous ammoniacal solution at pH 10.5 (100mg/mL) by diluting with 5 volumes of isopropanol and then adjusting to pH 6 with acetic acid. An aqueous solution, buffered to pH 10 with Na2CO3, can be stored in a refrigerator for 1week without decomposition. UV: max at 226nm (A1cm 1% 4.02). The tartrate salt has m 165-166o (dec), 166-168o (dec), and [] D 24 -41o (c 0.7, H2O). [Stammer et al. J Am Chem Soc 79 3236 1959, UV: Kuehl J Am Chem Soc 77 2344 1955, Beilstein 27 III/IV 5549.]

• Einzelnachweise

  1) Watson?et al. (1990),?D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes; Brain Res.,?510?158 2) Baran?et al. (1994),?The glycine/NMDA receptor partial agonist D-cycloserine blocks kainite-induced seizures in rats. Comparison with MK-801 and diazepam; Brain Res.,?652?195 3) L?scher?et al. (1994),?Anticonvulsant effects of the glycine/NMDA receptor ligands D-cycloserine and D-serine but not R(+)-HA-966 in amygdala-kindled rats; Br. J. Pharmacol., 112?97 4) Rouaud and Billard (2003),?D-cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices; Br. J. Pharmacol.,?140?1051 5) Forsyth?et al. (2015),?Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain; Proc. Natl. Acad. Sci. USA,?112?15331

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