Cycloserine

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D-cycloserine
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This article is about the tuberculosis medicine. For the nerve agent, see Cyclosarin.
Cycloserine
Clinical data
Trade namesSeromycin
Other namesD-cycloserine, 4-amino-3-isoxazolidinone
AHFS/Drugs.comMonograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~70% to 90%
MetabolismLiver
Elimination half-life10 hrs (normal kidney function)
ExcretionKidney
Identifiers
  • (R)-4-Amino-1,2-oxazolidin-3-one
JSmol)
Melting point155 to 156 °C (311 to 313 °F) (dec.)
  • O=C1NOC[C@H]1N
  • InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 checkY
  • Key:DYDCUQKUCUHJBH-UWTATZPHSA-N checkY
  (verify)

Cycloserine, sold under the brand name Seromycin, is a

drug resistant tuberculosis.[2] It is given by mouth.[2]

Common side effects include

D-alanine and works by interfering with the formation of the bacteria's cell wall.[2]

Cycloserine was discovered in 1954 from a type of Streptomyces.[3] It is on the World Health Organization's List of Essential Medicines.[4]

Medical uses

Tuberculosis

For the treatment of tuberculosis, cycloserine is classified as a second-line drug. Its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness,

seizures, and coma, while alcohol consumption may increase the risk of seizures.[6] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.[citation needed
]

Psychiatry

A 2015

Cochrane review found no evidence of benefit in anxiety disorders as of 2015.[7] Another review found preliminary evidence of benefit.[8] Evidence for use in addiction is tentative but also unclear.[9]

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall

dipeptide bond between the resulting D-alanine molecules.[11] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined.[11] This effectively leads to inhibition of peptidoglycan synthesis.[11]

Psychiatric use is suggested based on partial NMDA receptor agonism, which improves neural plasticity in lab animals. The degree of clinical usefulness is, as aforementioned, very unclear and still being explored.[8]

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine.[12][13] Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.[citation needed]

Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.[12]

Synthesis

Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from DL‐β‐aminoxyalanine ethyl ester. In 1957, Platter et al. managed to synthesis the pure D-enantiomer by cyclizing the corresponding α‐amino‐β‐chlorohydroxamic acids. Chemical synthesis of the compound was revolutionized in the 2010s, when several approaches starting with the cheap D-serine (mirror form of normal

L-serine) were published by different groups.[14]

The biosynthesis of the compound is defined by a ten-gene cluster. L-serine and L-arginine are converted to O-ureido-L-serine, flipped to O-ureido-D-serine, then turned into the final compound by cyclization. In 2013, Uda et al. successfully used recombinant versions of three enzymes in the cluster to produce the compound.[15]

A 1963 patent describes industrial production of the drug by bacterial fermentation.[16] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.[citation needed]

History

The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces.[17] The same team prepared the molecule synthetically.[18] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.[19]

Economics

In the U.S., the price of cycloserine increased from $500 for 30 pills to $10,800 in 2015 after the Chao Center for Industrial Pharmacy and Contract Manufacturing changed ownership to Rodelis Therapeutics in August 2015.[20]

The price increase was rescinded after the previous owner, the Purdue University Research Foundation, which retained "oversight of the manufacturing operation" intervened and Rodelis returned the drug to an NGO of Purdue University. The foundation now will charge $1,050 for 30 capsules, twice what it charged before". Eli Lilly has been criticised for not ensuring that the philanthropic initiative continued. Due to US antitrust laws, however, no company may control the price of a product after it is outlicensed.[21]

In 2015, the cost in the United States was increased to US$3,150 a month and then decreased to US$1,050 per month.[21]

Research

Some experimental evidence suggests that D-cycloserine aids in learning by helping form stronger neural connections.

acute suicidal ideation/behavior.[29]

References

  1. S2CID 462885
    .
  2. ^ a b c d e f g "Cycloserine". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. ISBN 9783642460517. Archived
    from the original on 2016-12-20.
  4. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. PMID 15199378
    .
  6. ^ a b "CYCLOSERINE: Human Health Effects". National Institutes of Health. Archived from the original on 2014-04-16.
  7. PMID 25957940
    .
  8. ^
    PMID 26364274
    .
  9. PMID 22579305
    .
  10. PMID 4555420
    .
  11. ^
    S2CID 22305408
    .
  12. ^
    PMID 22466372
    .
  13. doi:10.1021/ja972907b
    .
  14. PMID 3459696
    .
  15. PMID 23529730
    .
  16. ^ Harned RL (21 May 1963). "US3090730A Process for the production of cycloserine". Google Patents.
  17. doi:10.1021/ja01613a105
    .
  18. doi:10.1021/ja01613a107
    .
  19. doi:10.1021/ja01613a106
    .
  20. ^ Pollack A (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. Archived from the original on 25 September 2015. Retrieved 21 September 2015.
  21. ^ a b Pollack A (21 September 2015). "Big Price Increase for Tuberculosis Drug Is Rescinded". NYT. Archived from the original on 26 September 2015. Retrieved 24 September 2015.
  22. ^ "Learning and Brain Activity Are Boosted by a Dose of a Small-Molecule Compound". Scientific American. Archived from the original on 2015-12-23.
  23. PMID 26238379
    .
  24. PMID 23768232
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  25. PMID 25550231
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  26. PMID 22368237
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  27. PMID 26132675
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  28. S2CID 201057546
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  29. ^ "Official page about NeuroRX NRX100/NRX101". Archived from the original on 2020-07-09. Retrieved 2023-10-22.
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