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| Trade names | Seromycin |
| Other names | D-cycloserine, 4-amino-3-isoxazolidinone |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | ~70% to 90% |
| Metabolism | Liver |
| Eliminationhalf-life | 10 hrs (normal kidney function) |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.626 |
| Chemical and physical data | |
| Formula | C3H6N2O2 |
| Molar mass | 102.093 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 155 to 156 °C (311 to 313 °F) (dec.) |
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Cycloserine, sold under the brand nameSeromycin, is aGABA transaminase inhibitor and anantibiotic, used to treattuberculosis.[1][2] Specifically it is used, along with otherantituberculosis medications, for activedrug resistant tuberculosis.[2] It isgiven by mouth.[2]
Common side effects includeallergic reactions,seizures,sleepiness, unsteadiness, andnumbness.[2] It is not recommended in people who havekidney failure,epilepsy,depression, or arealcoholics.[2] It is unclear if use duringpregnancy is safe for the baby.[2] Cycloserine is similar in structure to theamino acidD-alanine and works by interfering with the formation of the bacteria'scell wall.[2]
Cycloserine was discovered in 1954 from a type ofStreptomyces.[3] It is on theWorld Health Organization's List of Essential Medicines.[4]
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 ofM. 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 inparesis,seizures, andcoma, whilealcohol consumption may increase the risk of seizures.[6] Coadministration ofpyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.[citation needed]
Cycloserine works as an antibiotic by inhibiting cell-wallbiosynthesis in bacteria.[7][8] As a cyclic analogue ofD-alanine, cycloserine acts against two crucial enzymes important in thecytosolic stages ofpeptidoglycan synthesis:alanine racemase (Alr) andD-alanine:D-alanine ligase (Ddl).[8] The firstenzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts theL-alanine to theD-alanine form.[8] The second enzyme is involved in joining two of theseD-alanine residues together by catalyzing the formation of theATP-dependentD-alanine-D-alaninedipeptide bond between the resultingD-alanine molecules.[8] If both of these enzymes are inhibited, thenD-alanine residues cannot form and previously formedD-alanine molecules cannot be joined.[8] This effectively leads to inhibition of peptidoglycan synthesis.[8]
Psychiatric use is suggested based on partialNMDA 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.[9]
Under mildly acidic conditions, cycloserine hydrolyzes to givehydroxylamine andD-serine.[10][11] 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.[10]
Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis fromDL‐β‐aminoxyalanine ethyl ester. In 1957, Platteret 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 cheapD-serine (mirror form of normalL-serine) were published by different groups.[12]
The biosynthesis of the compound is defined by a ten-gene cluster.L-serine andL-arginine are converted to O-ureido-L-serine, flipped to O-ureido-D-serine, then turned into the final compound by cyclization. In 2013, Udaet al. successfully used recombinant versions of three enzymes in the cluster to produce the compound.[13]
A 1963 patent describes industrial production of the drug by bacterial fermentation.[14] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.[citation needed]
The compound was first isolated nearly simultaneously by two teams. Workers atMerck isolated the compound, which they called oxamycin, from a species ofStreptomyces.[15] The same team prepared the molecule synthetically.[16] Workers atEli Lilly isolated the compound from strains ofStreptomyces orchidaceus. It was shown to hydrolyze to serine andhydroxylamine.[17]
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.[18]
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.[19]
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.[19]
A 2015Cochrane review found no evidence of benefit in anxiety disorders as of 2015.[20] Another review found preliminary evidence of benefit.[9] Evidence for use in addiction is tentative but also unclear.[21]
Reviews in 2016-17 found that cycloserine produced a small improvement incognitive behavioral therapy foranxiety,obsessive-compulsive disorder, andpost-traumatic stress disorder,[22] and had potential for use as a therapy inpsychiatric diseases.[9]
Cycloserine is closelystructurally related tomuscimol, aGABAA receptoragonist andhallucinogen found inAmanita muscaria.[23] It has been said to produce effects in humans, includingmental confusion,acute psychosis,convulsions, and other abnormal behavioral states, which are reminiscent of those of muscimol.[23]
However, the closely related antibiotic oxamycin [(d-cycloserine)] (7.6) produces mental confusion, acute psychotic episodes, convulsions, and other abnormal behavioural states in man reminiscent of the isoxazoles [like muscimol and ibotenic acid] contained in Amanita muscaria (Farnsworth, 1968).
