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, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors).[5][6] Overdose of cycloserine may result in paresis, 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 biosynthesis in bacteria.[10][11] As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).[11] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.[11] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine 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, unclear and still being explored, as of 2016.[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]
A. W. Frahm, H. H. J. Hager, F. v. Bruchhausen, M. Albinus, H. Hager: Hagers Handbuch der pharmazeutischen Praxis: Folgeband 4: Stoffe A–K., Birkhäuser, 1999, ISBN978-3-540-52688-9
References
^Polc P, Pieri L, Bonetti EP, Scherschlicht R, Moehler H, Kettler R, et al. (April 1986). "L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats". Neuropharmacology. 25 (4). Elsevier BV: 411–418. doi:10.1016/0028-3908(86)90236-4. PMID3012401. S2CID462885.
^ abcdefg"Cycloserine". Drugs.com, The American Society of Health-System Pharmacists. 2024. Retrieved 28 November 2024.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Silverman R (1998). "An Aromatization Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase for the Antibiotic l-Cycloserine". Journal of the American Chemical Society. 120 (10): 2256–2267. doi:10.1021/ja972907b.
^Kuehl Jr FA, Wolf FJ, Trenner NR, Peck RL, Buhs RP, Howe E, et al. (1955). "D-4-Amino-3-isoxazolidinone, a new antibiotic". Journal of the American Chemical Society. 77 (8): 2344–5. doi:10.1021/ja01613a105.
^Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, et al. (1955). "Synthesis of D-4-amino-3-isoxazolidinone". Journal of the American Chemical Society. 77 (8): 2346–7. doi:10.1021/ja01613a107.
^Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, et al. (1955). "Structure and reactions of cycloserine". Journal of the American Chemical Society. 77 (8): 2345–6. doi:10.1021/ja01613a106.
