Cycloserine: Difference between revisions

{{Short description|Tuberculosis medication}}

{{About|the tuberculosis medicine|the nerve agent|Cyclosarin}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 460111047

| image = Cycloserine.svg

| width = 140

| image2 = Cycloserine ball-and-stick model.png

| synonyms = {{sc|d}}-cycloserine, 4-amino-3-isoxazolidinone

| DailyMedID = Seromycin

| =

| ATC_prefix = J04

| ATC_suffix = AB01

| ATC_supplemental =

| legal_US = Rx-only

| legal_status =

| protein_bound =

| metabolism =

| elimination_half-life = 10 hrs (normal function)

| excretion =

| = {{cascite|correct|}}

| NIAID_ChemDB = 007654

| IUPAC_name = (''R'')-4-Amino-1,2-oxazolidin-3-one

| C=3 | H=6 | N=2 | O=2

| melting_point = 155

| melting_high = 156

| melting_notes = (dec.)

<!-- Definition and medical uses -->

'''Cycloserine''', sold under the brand name '''Seromycin''', is a [[GABA transaminase inhibitor]] and an [[antibiotic]], used to treat [[tuberculosis]].<ref name="Polc Pieri Bonetti Scherschlicht 1986 pp. 411–418">{{cite journal | vauthors = Polc P, Pieri L, Bonetti EP, Scherschlicht R, Moehler H, Kettler R, Burkard W, Haefely W | title = L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats | journal = Neuropharmacology | volume = 25 | issue = 4 | pages = 411–418 | date = April 1986 | pmid = 3012401 | doi = 10.1016/0028-3908(86)90236-4 | publisher = Elsevier BV | s2cid = 462885 }}</ref><ref name=AHFS2016/> Specifically it is used, along with other [[antituberculosis medication]]s, for active [[drug resistant tuberculosis]].<ref name=AHFS2016/> It is given by mouth.<ref name=AHFS2016>{{cite web|title=Cycloserine|url=https://www.drugs.com/monograph/cycloserine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231240/https://www.drugs.com/monograph/cycloserine.html|archive-date=20 December 2016}}</ref>

<!-- Side effects and mechanism -->

Common side effects include [[allergic reactions]], [[seizures]], [[sleepiness]], unsteadiness, and [[paresthesia|numbness]].<ref name=AHFS2016/> It is not recommended in people who have [[kidney failure]], [[epilepsy]], [[major depressive disorder|depression]], or are [[alcoholics]].<ref name=AHFS2016/> It is unclear if use during [[pregnancy]] is safe for the baby.<ref name=AHFS2016/> Cycloserine is similar in structure to the [[amino acid]] [[D-alanine|<small>D</small>-alanine]] and works by interfering with the formation of the bacteria's [[cell wall]].<ref name=AHFS2016/>

<!-- History and culture -->

Cycloserine was discovered in 1954 from a type of ''[[Streptomyces]]''.<ref>{{cite book| vauthors = Gottlieb D, Shaw PD |title=Mechanism of Action|date=2012|publisher=Springer Science & Business Media|isbn=9783642460517|page=41|url=https://books.google.com/books?id=xjPtCAAAQBAJ&pg=PA41|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220092417/https://books.google.ca/books?id=xjPtCAAAQBAJ&pg=PA41|archive-date=2016-12-20}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>

== ==

===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, [[depression (mood)|depression]], dizziness, [[vertigo]], confusion, [[paresthesias]], [[dysarthria]], hyperirritability, [[psychosis]], [[convulsions]], and shaking (tremors).<ref name="Nitsche - DCS-bg">{{cite journal | vauthors = Nitsche MA, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W | title = Consolidation of human motor cortical neuroplasticity by D-cycloserine | journal = Neuropsychopharmacology | volume = 29 | issue = 8 | pages = 1573–8 | date = August 2004 | pmid = 15199378 | doi = 10.1038/sj.npp.1300517 | doi-access = free | url = https://publications.goettingen-research-online.de/bitstream/2/47862/1/document.pdf }}</ref><ref name=NIH>{{cite web|title=CYCLOSERINE: Human Health Effects|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+68-41-7|publisher=National Institutes of Health|url-status=live|archive-url=https://web.archive.org/web/20140416080623/http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb%3A%40term+%40rn+68-41-7|archive-date=2014-04-16}}</ref> Overdose of cycloserine may result in [[paresis]], [[seizures]], and [[coma]], while [[alcohol (drug)|alcohol]] consumption may increase the risk of seizures.<ref name=NIH /> Coadministration of [[pyridoxine]] can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.{{citation needed|date=August 2022}}

===Psychiatry===

A 2015 [[Cochrane review]] found no evidence of benefit in anxiety disorders as of 2015.<ref>{{cite journal | vauthors = Ori R, Amos T, Bergman H, Soares-Weiser K, Ipser JC, Stein DJ | title = Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 5 | pages = CD007803 | date = May 2015 | pmid = 25957940 | doi = 10.1002/14651858.CD007803.pub2 | pmc = 8939046 }}</ref> Another review found preliminary evidence of benefit.<ref name=pmid26364274>{{cite journal | vauthors = Schade S, Paulus W | title = D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review | journal = The International Journal of Neuropsychopharmacology | volume = 19 | issue = 4 | pages = pyv102 | date = April 2016 | pmid = 26364274 | pmc = 4851259 | doi = 10.1093/ijnp/pyv102 }}</ref> Evidence for use in addiction is tentative but also unclear.<ref>{{cite journal | vauthors = Myers KM, Carlezon WA | title = D-cycloserine effects on extinction of conditioned responses to drug-related cues | journal = Biological Psychiatry | volume = 71 | issue = 11 | pages = 947–55 | date = June 2012 | pmid = 22579305 | pmc = 4001849 | doi = 10.1016/j.biopsych.2012.02.030 }}</ref>

==Mechanism of action==

Cycloserine works as an antibiotic by inhibiting cell-wall [[biosynthesis]] in bacteria.<ref name="Lambert-tuberculosis">{{cite journal | vauthors = Lambert MP, Neuhaus FC | title = Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W | journal = Journal of Bacteriology | volume = 110 | issue = 3 | pages = 978–87 | date = June 1972 | doi = 10.1128/JB.110.3.978-987.1972 | pmid = 4555420 | pmc = 247518 }}</ref><ref name=Prosser>{{cite journal | vauthors = Prosser GA, de Carvalho LP | title = Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine | journal = The FEBS Journal | volume = 280 | issue = 4 | pages = 1150–66 | date = February 2013 | pmid = 23286234 | doi = 10.1111/febs.12108 | s2cid = 22305408 | doi-access = free }}</ref> As a cyclic analogue of [[alanine|<small>D</small>-alanine]], cycloserine acts against two crucial enzymes important in the [[cytosolic]] stages of [[peptidoglycan]] synthesis: [[alanine racemase]] (Alr) and [[D-alanine—D-alanine ligase|<small>D</small>-alanine:<small>D</small>-alanine ligase]] (Ddl).<ref name=Prosser /> The first [[enzyme]] is a pyridoxal 5'-phosphate-dependent enzyme which converts the <small>L</small>-alanine to the <small>D</small>-alanine form.<ref name=Prosser /> The second enzyme is involved in joining two of these <small>D</small>-alanine residues together by catalyzing the formation of the [[Adenosine triphosphate|ATP]]-dependent <small>D</small>-alanine-<small>D</small>-alanine [[dipeptide bond]] between the resulting <small>D</small>-alanine molecules.<ref name=Prosser /> If both of these enzymes are inhibited, then <small>D</small>-alanine residues cannot form and previously formed <small>D</small>-alanine molecules cannot be joined.<ref name=Prosser /> This effectively leads to inhibition of peptidoglycan synthesis.<ref name=Prosser />

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.<ref name=pmid26364274/>

==Chemical properties==

Under mildly acidic conditions, cycloserine hydrolyzes to give [[hydroxylamine]] and [[serine|<small>D</small>-serine]].<ref name=Kaushal /><ref name="Silverman-GABA">{{cite journal| vauthors = Silverman R |title=An Aromatization Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase for the Antibiotic l-Cycloserine|journal=Journal of the American Chemical Society|year=1998|volume=120|issue=10|pages=2256–2267|doi=10.1021/ja972907b}}</ref> Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.{{citation needed|date=August 2022}}

Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.<ref name=Kaushal>{{cite journal | vauthors = Kaushal G, Ramirez R, Alambo D, Taupradist W, Choksi K, Sirbu C | title = Initial characterization of D-cycloserine for future formulation development for anxiety disorders | journal = Drug Discoveries & Therapeutics | volume = 5 | issue = 5 | pages = 253–60 | date = October 2011 | pmid = 22466372 | doi = 10.5582/ddt.2011.v5.5.253 | doi-access = free }}</ref>

== Synthesis ==

Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from {{sc|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 {{sc|d}}-serine (mirror form of normal [[L-serine]]) were published by different groups.<ref>{{cite journal | vauthors = Holt GR | title = Principles of plastic surgery of congenital facial abnormalities | journal = Facial Plastic Surgery | volume = 3 | issue = 3 | pages = 147–154 | date = 6 December 2021 | pmid = 3459696 | pmc = 9293202 | doi = 10.1002/cmdc.202100503 }}</ref>

The biosynthesis of the compound is defined by a ten-gene cluster. {{sc|l}}-serine and {{sc|l}}-arginine are converted to O-ureido-{{sc|l}}-serine, flipped to O-ureido-{{sc|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.<ref>{{cite journal | vauthors = Uda N, Matoba Y, Kumagai T, Oda K, Noda M, Sugiyama M | title = Establishment of an in vitro D-cycloserine-synthesizing system by using O-ureido-L-serine synthase and D-cycloserine synthetase found in the biosynthetic pathway | journal = Antimicrobial Agents and Chemotherapy | volume = 57 | issue = 6 | pages = 2603–2612 | date = June 2013 | pmid = 23529730 | pmc = 3716191 | doi = 10.1128/AAC.02291-12 }}</ref>

A 1963 patent describes industrial production of the drug by bacterial fermentation.<ref>{{cite web | vauthors = Harned RL |title= US3090730A Process for the production of cycloserine |website=Google Patents |url=https://patents.google.com/patent/US3090730A/en |date=21 May 1963}}</ref> It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.{{citation needed|date=December 2022}}

==History==

The compound was first isolated nearly simultaneously by two teams. Workers at [[Merck & Co.|Merck]] isolated the compound, which they called oxamycin, from a species of ''Streptomyces''.<ref>{{cite journal | vauthors = Kuehl Jr FA, Wolf FJ, Trenner NR, Peck RL, Buhs RP, Howe E, Putter I, Hunnewell BD, Ormond R, Downing G, Lyons JE | year = 1955 | title = D-4-Amino-3-isoxazolidinone, a new antibiotic | journal = Journal of the American Chemical Society | volume = 77 | issue = 8| pages = 2344–5 | doi = 10.1021/ja01613a105 }}</ref> The same team prepared the molecule synthetically.<ref>{{cite journal | vauthors = Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, Runge WF, Stavely HE, Pohland A, Boaz H, Sullivan HR | author-link4 = Karl Folkers | year = 1955 | title = Synthesis of D-4-amino-3-isoxazolidinone | journal = Journal of the American Chemical Society | volume = 77 | issue = 8| pages = 2346–7 | doi = 10.1021/ja01613a107 }}</ref> Workers at [[Eli Lilly]] isolated the compound from strains of ''Streptomyces orchidaceus''. It was shown to hydrolyze to serine and [[hydroxylamine]].<ref>{{cite journal | vauthors = Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, Runge WF, Stavely HE, Pohland A, Boaz H, Sullivan HR | year = 1955 | title = Structure and reactions of cycloserine | journal = Journal of the American Chemical Society | volume = 77 | issue = 8| pages = 2345–6 | doi = 10.1021/ja01613a106 }}</ref>

==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.<ref name=NYT2015>{{cite news | vauthors = Pollack A |title=Drug Goes From $13.50 a Tablet to $750, Overnight|work=The New York Times |url=https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html?ref=health&_r=0|access-date=21 September 2015|date=20 September 2015|url-status=live|archive-url=https://web.archive.org/web/20150925195708/http://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html?ref=health&_r=0|archive-date=25 September 2015}}</ref>

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.<ref name=NYT2015B/>

In 2015, the cost in the United States was increased to {{Currency|3,150|USD|linked=no}} a month and then decreased to {{Currency|1,050|USD|linked=no}} per month.<ref name=NYT2015B>{{cite news | vauthors = Pollack A |title=Big Price Increase for Tuberculosis Drug Is Rescinded|url=https://www.nytimes.com/2015/09/22/business/big-price-increase-for-tb-drug-is-rescinded.html?_r=0|access-date=24 September 2015|work=NYT|date=21 September 2015|url-status=live|archive-url=https://web.archive.org/web/20150926033207/http://www.nytimes.com/2015/09/22/business/big-price-increase-for-tb-drug-is-rescinded.html?_r=0|archive-date=26 September 2015}}</ref>

==Research==

Some experimental evidence suggests that <small>D</small>-cycloserine aids in learning by helping form stronger neural connections.<ref name=SA>{{cite web|title=Learning and Brain Activity Are Boosted by a Dose of a Small-Molecule Compound|url=http://www.scientificamerican.com/article/learning-and-brain-activity-are-boosted-by-a-dose-of-a-small-molecule-compound/|website=Scientific American|url-status=live|archive-url=https://web.archive.org/web/20151223052929/http://www.scientificamerican.com/article/learning-and-brain-activity-are-boosted-by-a-dose-of-a-small-molecule-compound/|archive-date=2015-12-23}}</ref> It has been investigated as an aid to facilitate [[exposure therapy]] in people with [[PTSD]] and anxiety disorders,<ref>{{cite journal | vauthors = Bowers ME, Ressler KJ | title = An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials | journal = Biological Psychiatry | volume = 78 | issue = 5 | pages = E15-27 | date = September 2015 | pmid = 26238379 | pmc = 4527085 | doi = 10.1016/j.biopsych.2015.06.008 }}</ref><ref>{{cite journal | vauthors = Hofmann SG, Wu QJ, Boettcher H | title = D-cycloserine as an augmentation strategy for cognitive behavioral therapy for anxiety disorders | journal = Biology of Mood & Anxiety Disorders | volume = 3 | pages = 11 | date = May 2013 | issue = 1 | doi = 10.1186/2045-5380-3-11 | pmid = 23768232 | pmc = 3686620 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ | title = Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders | journal = Pharmacology & Therapeutics | volume = 149 | pages = 150–90 | date = May 2015 | pmid = 25550231 | pmc = 4380664 | doi = 10.1016/j.pharmthera.2014.12.004 }}</ref> and treatment with schizophrenia.<ref>{{cite journal | vauthors = Goff DC | title = D-cycloserine: an evolving role in learning and neuroplasticity in schizophrenia | journal = Schizophrenia Bulletin | volume = 38 | issue = 5 | pages = 936–41 | date = September 2012 | pmid = 22368237 | pmc = 3446239 | doi = 10.1093/schbul/sbs012 | url = }}</ref> In a clinical trial, a course of <small>D</small>-cycloserine combined with a single dose of ketamine was investigated for treatment resistant bipolar depression. When administered for 8 weeks after a ketamine infusion, cycloserine appeared to potentiate the antidepressant effects in all trial participants.<ref>{{cite journal | vauthors = Kantrowitz J, Halberstam B, Gangwisch J| title = Single-Dose Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant Bipolar Depression | journal = The Journal of Clinical Psychiatry | volume = 76| issue = 6| pages = 737–738| date = June 2015 | pmid = 26132675| pmc = | doi = 10.4088/JCP.14l09527 | url = https://www.psychiatrist.com/jcp/bipolar/single-dose-ketamine-followed-daily-d-cycloserine/| doi-access = free}}</ref> However, a 2019 clinical trial showed no statistically significant difference between the <small>D</small>-cycloserine and placebo groups when it came to maintaining the antidepressant effect of a single ketamine infusion. The authors suggest several possible explanations for this nonsignificance, namely the inclusion of high-risk or severely treatment-resistant participants as well as a possible confounding [[carryover effect]] from the ketamine infusion phase. Although the results point to <small>D</small>-cycloserine having a stronger antisuicidal effect than placebo, the authors caution that this difference might be attributed to the placebo group feeling worse than the <small>D</small>-cycloserine feeling better.<ref>{{cite journal | vauthors = Chen MH, Cheng CM, Gueorguieva R, Lin WC, Li CT, Hong CJ, Tu PC, Bai YM, Tsai SJ, Krystal JH, Su TP | title = Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo-control study | journal = Neuropsychopharmacology | volume = 44 | issue = 12 | pages = 2112–2118 | date = November 2019 | pmid = 31421635 | pmc = 6898334 | doi = 10.1038/s41386-019-0480-y | publisher = [[Springer Nature]] | s2cid = 201057546 | doi-access = free | publication-date = 2019-08-17 }}</ref> A [[combination drug]], [[cycloserine/lurasidone]], containing <small>D</small>-cycloserine and the atypical antipsychotic [[lurasidone]] is being developed for [[Suicidality|acute suicidal ideation/behavior]].<ref>{{cite web |title=Official page about NeuroRX NRX100/NRX101 |url=http://www.neurorxpharma.com/nrx-100nrx-101-overview.html |access-date=2023-10-22 |archive-date=2020-07-09 |archive-url=https://web.archive.org/web/20200709061738/http://www.neurorxpharma.com/nrx-100nrx-101-overview.html |url-status=dead }}</ref>

{{Reflist}}

{{GABA metabolism and transport modulators}}

{{Ionotropic glutamate receptor modulators}}

{{Glutamate metabolism and transport modulators}}

{{Portal bar | Medicine}}

{{Authority control}}

[[Category:]]

[[Category:NMDA receptor agonists]]

[[Category:GABA transaminase inhibitors]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Aldols]]