Clavulanic acid

{{Short description|Molecule used to overcome antibiotic resistance in bacteria}} {{cs1 config|name-list-style=vanc}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 460041016 9372 | IUPAC_name = (2''R'',5''R'',''Z'')-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid | image = Clavulanic acid.svg | image_class = skin-invert-image | width = 200 | image2 = Clavulanic-acid-based-on-xtal-3D-bs-17.png | image_class2 = bg-transparent | width2 =  | pronounce = {{IPAc-en|ˌ|k|l|æ|v|j|ʊ|ˈ|l|æ|n|ᵻ|k}} | tradename = | Drugs.com = {{drugs.com|international|clavulanic-acid}} | DailyMedID = Clavulanic acid | pregnancy_US = B | pregnancy_AU = B1 | legal_AU = Schedule 4 | legal_status = rx only | routes_of_administration = By mouth, intravenous

| bioavailability = Oral: 45–64%<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="DrugBank" /> | protein_bound = ~25%<ref name="DrugBank">{{cite web | title=Clavulanic acid: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=8 July 2014 | url=https://go.drugbank.com/drugs/DB00766 | access-date=5 November 2024}}</ref> | metabolism = Unknown<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /> | metabolites = Two minor metabolites<ref name="DrugBank" /> | onset = ≤0.67–2{{nbsp}}hours ({{Abbrlink|Tmax|time to peak concentrations}})<ref name="DrugBank" /> | elimination_half-life = 0.8–1.2{{nbsp}}hours<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="DrugBank" /> | duration_of_action = | excretion = Urine: 35–65% (unchanged; within 6{{nbsp}}hours)<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="DrugBank" />

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 58001-44-8 | ATC_prefix = J01 | ATC_suffix = CR | ATC_supplemental = (combinations with penicillins) | PubChem = 5280980 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00766 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4444466 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 23521W1S24 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D07711 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 48947 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 777 | synonyms = RX-10100; Serdaxin; Zoraxel

| C = 8 | H = 9 | N = 1 | O = 5 | SMILES = O=C2N1[C@H](C(/O[C@@H]1C2)=C/CO)C(=O)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-/t6-,7-/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HZZVJAQRINQKSD-PBFISZAISA-N }}

'''Clavulanic acid''' is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

In its most common preparations, potassium clavulanate (clavulanic acid as a salt of potassium) is combined with:

* amoxicillin (co-amoxiclav, trade names Augmentin, Clavulin, Tyclav, Clavaseptin (veterinary), Clavamox (veterinary), Synulox (veterinary), and others) * ticarcillin (co-ticarclav, trade name Timentin)

Clavulanic acid was patented in 1974.<ref>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=978-3-527-60749-5|page=490|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA490|language=en}}</ref> In addition to its β-lactamase inhibition, clavulanic acid shows off-target activity in the nervous system by upregulating the glutamate transporter 1 (GLT-1) and has been studied in the potential treatment of a variety of central nervous system disorders.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="AdisInsight" />

==Medical uses== Amoxicillin–clavulanic acid is a first-line treatment for many types of infections, including sinus infections, and urinary tract infections, including pyelonephritis. This is, in part, because of its efficacy against gram-negative bacteria which tend to be more difficult to control than gram-positive bacteria with chemotherapeutic antibiotics.{{Clarification needed|date=October 2024}}

== Adverse effects == The use of clavulanic acid with penicillins has been associated with an increased incidence of cholestatic jaundice and acute hepatitis during therapy or shortly after. The associated jaundice is usually self-limiting and very rarely fatal.<ref>Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.</ref><ref>{{cite journal|url=http://livertox.nih.gov/AmoxicillinClavulanate.htm|title=Drug Record - Amoxicillin-Clavulanate|journal=LiverTox - Clinical and Research Information on Drug-Induced Liver Injury|date=2012|pmid=31643176|access-date=April 24, 2013|archive-date=November 23, 2016|archive-url=https://web.archive.org/web/20161123062345/https://livertox.nih.gov/AmoxicillinClavulanate.htm}}</ref> The UK Committee on Safety of Medicines (CSM) recommends that treatments such as amoxicillin/clavulanic acid preparations be reserved for bacterial infections likely to be caused by amoxicillin-resistant β-lactamase-producing strains, and that treatment should not normally exceed 14 days.

Allergic reactions have been reported.<ref name="pmid19080805">{{cite journal | vauthors = Tortajada Girbés M, Ferrer Franco A, Gracia Antequera M, Clement Paredes A, García Muñoz E, Tallón Guerola M | title = Hypersensitivity to clavulanic acid in children | journal = Allergologia et Immunopathologia | volume = 36 | issue = 5 | pages = 308–310 | year = 2008 | pmid = 19080805 | doi = 10.1016/S0301-0546(08)75228-5 | url = http://www.elsevier.es/en/revistas/allergologia-et-immunopathologia-105/hypersensitivity-to-clavulanic-acid-in-children-13130586-research-letters-2008 | access-date = 2011-11-11 | archive-url = https://web.archive.org/web/20120407122437/http://www.elsevier.es/en/revistas/allergologia-et-immunopathologia-105/hypersensitivity-to-clavulanic-acid-in-children-13130586-research-letters-2008 | archive-date = 2012-04-07 | url-access = subscription | doi-access = free }}</ref>

==Sources== The name is derived from strains of ''Streptomyces clavuligerus'', which produces clavulanic acid.<ref name="pmid16251194">{{cite journal | vauthors = Arulanantham H, Kershaw NJ, Hewitson KS, Hughes CE, Thirkettle JE, Schofield CJ | title = ORF17 from the clavulanic acid biosynthesis gene cluster catalyzes the ATP-dependent formation of N-glycyl-clavaminic acid | journal = The Journal of Biological Chemistry | volume = 281 | issue = 1 | pages = 279–287 | date = January 2006 | pmid = 16251194 | doi = 10.1074/jbc.M507711200 | doi-access = free }}</ref><ref name="pmid14982786">{{cite journal | vauthors = Tahlan K, Park HU, Wong A, Beatty PH, Jensen SE | title = Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus | journal = Antimicrobial Agents and Chemotherapy | volume = 48 | issue = 3 | pages = 930–939 | date = March 2004 | pmid = 14982786 | pmc = 353097 | doi = 10.1128/AAC.48.3.930-939.2004 }}</ref>

===Biosynthesis=== class=skin-invert-image|thumbnail|left|The intermediates of the biosynthesis of clavulanic acid<ref name="ReferenceA">{{cite journal | vauthors = Townsend CA | title = New reactions in clavulanic acid biosynthesis | journal = Current Opinion in Chemical Biology | volume = 6 | issue = 5 | pages = 583–589 | date = October 2002 | pmid = 12413541 | doi = 10.1016/S1367-5931(02)00392-7 }}</ref> The β-lactam like structure of clavulanic acid looks structurally similar to penicillin, but the biosynthesis of this molecule involves a different biochemical pathway. Clavulanic acid is produced by the bacterium ''Streptomyces clavuligerus'', using glyceraldehyde-3-phosphate and L-arginine as starting materials.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Reading C, Cole M | title = Clavulanic acid: a beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus | journal = Antimicrobial Agents and Chemotherapy | volume = 11 | issue = 5 | pages = 852–857 | date = May 1977 | pmid = 879738 | pmc = 352086 | doi = 10.1128/AAC.11.5.852 }}</ref> Although each of the intermediates of the pathway is known, the exact mechanism for all of the enzymatic reactions is not fully understood. The process mainly involves 3 enzymes: clavaminate synthase, β-lactam synthetase, and N2-(2-carboxyethyl)-L-arginine (CEA) synthase.<ref name="ReferenceA"/> Clavaminate synthase is a non-heme oxygenase dependent on iron and α-keto-glutarate and is encoded by orf5 of the clavulanic acid gene cluster. The specific mechanism of how this enzyme works is not fully understood, but this enzyme regulates 3 steps in the overall synthesis of clavulanic acid. All 3 steps occur in the same region of the catalytic, iron-containing reaction center, yet do not occur in sequence and affect different areas of the clavulanic acid structure.<ref>{{cite journal | vauthors = Busby RW, Townsend CA | title = A single monomeric iron center in clavaminate synthase catalyzes three nonsuccessive oxidative transformations | journal = Bioorganic & Medicinal Chemistry | volume = 4 | issue = 7 | pages = 1059–1064 | date = July 1996 | pmid = 8831977 | doi = 10.1016/0968-0896(96)00088-0 | doi-access = free }}</ref>

β-lactam synthetase is a 54.5 kDa protein that is encoded by orf3 of the clavulanic acid gene cluster, and shows similarity to asparagine synthase – Class B enzymes. The exact mechanism on how this enzyme works to synthesize the β-lactam is not proven, but is believed to occur in coordination with a CEA synthase and ATP.<ref>{{cite journal | vauthors = Bachmann BO, Townsend CA | title = Kinetic mechanism of the beta-lactam synthetase of Streptomyces clavuligerus | journal = Biochemistry | volume = 39 | issue = 37 | pages = 11187–11193 | date = September 2000 | pmid = 10985764 | doi = 10.1021/bi000709i }}</ref> class=skin-invert-image|thumbnail|left|Proposed mechanism of beta-lactam synthetase in the biosynthesis of clavulanic acid.<ref name="ReferenceA"/> CEA synthase is a 60.9 kDA protein and is the first gene found in the clavulanic acid biosynthesis gene cluster, encoded by orf2 of the clavulanic acid gene cluster. The specific mechanism of how this enzyme works is still under investigation; however, it is known that this enzyme has the ability to couple together glyceraldehyde-3-phosphate with L-arginine in the presence of thiamine diphosphate (TDP or thiamine pyrophosphate), which is the first step of the clavulanic acid biosynthesis.<ref>{{cite journal| vauthors = Khaleeli N, Li R, Townsend CA |title=Origin of the β-Lactam Carbons in Clavulanic Acid from an Unusual Thiamine Pyrophosphate-Mediated Reaction|journal=Journal of the American Chemical Society|year=1999|volume=121|issue=39|pages=9223–9224|doi=10.1021/ja9923134|bibcode=1999JAChS.121.9223K }}</ref> class=skin-invert-image|thumbnail|center|Proposed mechanism of CEA synthetase in the biosynthesis of clavulanic acid.<ref name="ReferenceA"/>

== History == Clavulanic acid was discovered around 1974-75 by British scientists working at the drug company Beecham from the bacteria ''Streptomyces clavuligerus''.<ref>{{cite journal | vauthors = Sutherland R | title = Beta-lactamase inhibitors and reversal of antibiotic resistance | journal = Trends in Pharmacological Sciences | volume = 12 | issue = 6 | pages = 227–232 | date = June 1991 | pmid = 2048218 | doi = 10.1016/0165-6147(91)90557-9 }}</ref> After several attempts, Beecham finally filed for US patent protection for the drug in 1981, and U.S. Patents 4,525,352, 4,529,720, and 4,560,552 were granted in 1985.

== Mechanism of action == Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic of β-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme β-lactamase secreted by certain bacteria to confer resistance to β-lactam antibiotics.

Clavulanic acid is a suicide inhibitor, covalently bonding to a serine residue in the active site of the β-lactamase. This restructures the clavulanic acid molecule, creating a much more reactive species that attacks another amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme.

This inhibition restores the antimicrobial activity of β-lactam antibiotics against lactamase-secreting resistant bacteria. Despite this, some bacterial strains that are resistant even to such combinations have emerged.<ref>{{cite journal | vauthors = Weber DJ, Tolkoff-Rubin NE, Rubin RH | title = Amoxicillin and potassium clavulanate: an antibiotic combination. Mechanism of action, pharmacokinetics, antimicrobial spectrum, clinical efficacy and adverse effects | journal = Pharmacotherapy | volume = 4 | issue = 3 | pages = 122–136 | date = May 1984 | pmid = 6739312 | doi = 10.1002/j.1875-9114.1984.tb03333.x }}</ref>

==Research== ===Neuromodulation=== In 2005, it was discovered via screening of 1,040 Food and Drug Administration (FDA)-approved drugs and neutraceuticals that many β-lactams, such as ceftriaxone, upregulate astrocytic glutamate transporter 1 (GLT-1) expression.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024">{{cite journal | vauthors = Balcazar-Ochoa LG, Ventura-Martínez R, Ángeles-López GE, Gómez-Acevedo C, Carrasco OF, Sampieri-Cabrera R, Chavarría A, González-Hernández A | title = Clavulanic Acid and its Potential Therapeutic Effects on the Central Nervous System | journal = Arch Med Res | volume = 55 | issue = 1 | article-number = 102916 | date = January 2024 | pmid = 38039802 | doi = 10.1016/j.arcmed.2023.102916 | url = https://www.researchgate.net/publication/376168515}}</ref><ref name="AbulseoudAlasmariHussein2022">{{cite journal | vauthors = Abulseoud OA, Alasmari F, Hussein AM, Sari Y | title = Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation | journal = Front Neurosci | volume = 16 | issue = | article-number = 841036 | date = 2022 | pmid = 35864981 | pmc = 9294323 | doi = 10.3389/fnins.2022.841036 | doi-access = free | url = }}</ref><ref name="RothsteinPatelRegan2005">{{cite journal | vauthors = Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB | title = Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression | journal = Nature | volume = 433 | issue = 7021 | pages = 73–77 | date = January 2005 | pmid = 15635412 | doi = 10.1038/nature03180 | bibcode = 2005Natur.433...73R | url = }}</ref> Subsequently, it was discovered that clavulanic acid, likewise a β-lactam, shares this action.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="KimKingZuccarelli2009" /> The associated effects include enhanced GLT-1 expression in the nucleus accumbens, medial prefrontal cortex, and spinal cord, modulation of glutamatergic, dopaminergic, and serotonergic neurotransmission, and anti-inflammatory effects via modulation of cytokines tumor necrosis factor α (TNF-α) and interleukin-10 (IL-10).<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="MilenkovicCampbellRoussel2018" /><ref name="AdisInsight" /> Ceftriaxone lacks oral bioavailability, has poor brain permeability, and has concomitant antibiotic activity.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /> These limitations have resulted in more interest in clavulanic acid, which does not share these drawbacks and is more potent than ceftriaxone ''in vivo''.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /> The mechanism of action underlying the upregulation of GLT-1 expression by β-lactams is unknown.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="RothsteinPatelRegan2005" /> However, interactions with the SNARE proteins Munc18-1 and Rab4 may be involved in some of clavulanic acid's effects, such as increased dopamine release.<ref name="Ochoa-AguilarVentura-MartinezSotomayor-Sobrino2016">{{cite journal | vauthors = Ochoa-Aguilar A, Ventura-Martinez R, Sotomayor-Sobrino MA, Gómez C, Morales-Espinoza MR | title = Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules | journal = Anti-Inflamm Anti-Allergy Agents Med Chem | volume = 15 | issue = 1 | pages = 3–14 | date = 2016 | pmid = 27185396 | doi = 10.2174/1871523015666160517114027 | url = }}</ref><ref name="KostSelvarajLee2011">{{cite journal | vauthors = Kost GC, Selvaraj S, Lee YB, Kim DJ, Ahn CH, Singh BB | title = Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking | journal = Neurosci Lett | volume = 504 | issue = 2 | pages = 170–175 | date = October 2011 | pmid = 21964384 | pmc = 3195833 | doi = 10.1016/j.neulet.2011.09.032 | url = }}</ref>

In relation to its central nervous system actions, clavulanic acid has been studied preclinically in models of anxiety, sexual behavior, addiction, neuropathic pain, inflammatory pain, epilepsy, Parkinson's disease, dementia, and stroke.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="MilenkovicCampbellRoussel2018" /><ref name="Esmaili-Shahzade-Ali-AkbariGhaderiHosseini2023">{{cite journal | vauthors = Esmaili-Shahzade-Ali-Akbari P, Ghaderi A, Hosseini SM, Nejat F, Saeedi-Mofrad M, Karimi-Houyeh M, Ghattan A, Etemadi A, Rasoulian E, Khezri A | title = β_lactam antibiotics against drug addiction: A novel therapeutic option | journal = Drug Dev Res | volume = 84 | issue = 7 | pages = 1411–1426 | date = November 2023 | pmid = 37602907 | doi = 10.1002/ddr.22110 | url = }}</ref><ref name="Ochoa-AguilarVentura-MartinezSotomayor-Sobrino2016" /> In animals, including in rodents and/or monkeys, clavulanic acid has shown anxiolytic-like, antidepressant-like, pro-sexual, memory-enhancing, analgesic, antiaddictive, pro-dopaminergic, pro-oxytocinergic, and neuroprotective effects.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="Ochoa-AguilarVentura-MartinezSotomayor-Sobrino2016" /><ref name="KimKingZuccarelli2009">{{cite journal | vauthors = Kim DJ, King JA, Zuccarelli L, Ferris CF, Koppel GA, Snowdon CT, Ahn CH | title = Clavulanic acid: a competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects | journal = Pharmacol Biochem Behav | volume = 93 | issue = 2 | pages = 112–120 | date = August 2009 | pmid = 19394358 | doi = 10.1016/j.pbb.2009.04.013 | url = }}</ref><ref name="ArabAlasmariAlbaker2023">{{cite journal | vauthors = Arab AO, Alasmari F, Albaker AB, Alhazmi HA, Alameen AA, Alagail NM, Alwaeli SA, Rizwan Ahamad S, AlAsmari AF, AlSharari SD | title = Clavulanic Acid Improves Memory Dysfunction and Anxiety Behaviors through Upregulating Glutamatergic Transporters in the Nucleus Accumbens of Mice Repeatedly Exposed to Khat Extract | journal = Int J Mol Sci | volume = 24 | issue = 21 | date = October 2023 | article-number = 15657 | pmid = 37958641 | pmc = 10648086 | doi = 10.3390/ijms242115657 | doi-access = free | url = }}</ref> The drug has been studied clinically in humans in the treatment of erectile dysfunction,<ref name="MilenkovicCampbellRoussel2018">{{cite journal | vauthors = Milenkovic U, Campbell J, Roussel E, Albersen M | title = An update on emerging drugs for the treatment of erectile dysfunction | journal = Expert Opin Emerg Drugs | volume = 23 | issue = 4 | pages = 319–330 | date = December 2018 | pmid = 30507329 | doi = 10.1080/14728214.2018.1552938 | url = }}</ref> depression,<ref name="ConnollyThase2012" /><ref name="Belzung2014">{{cite journal | vauthors = Belzung C | title = Innovative drugs to treat depression: did animal models fail to be predictive or did clinical trials fail to detect effects? | journal = Neuropsychopharmacology | volume = 39 | issue = 5 | pages = 1041–1051 | date = April 2014 | pmid = 24345817 | pmc = 3957126 | doi = 10.1038/npp.2013.342 | url = }}</ref><ref name="RiesenbergRosenthalMoldauer2012">{{cite journal | vauthors = Riesenberg R, Rosenthal J, Moldauer L, Peterson C | title = Results of a proof-of-concept, dose-finding, double-blind, placebo-controlled study of RX-10100 (Serdaxin®) in subjects with major depressive disorder | journal = Psychopharmacology (Berl) | volume = 221 | issue = 4 | pages = 601–610 | date = June 2012 | pmid = 22203317 | doi = 10.1007/s00213-011-2604-x | url = }}</ref> substance dependence,<ref name="CallansPhilogene-KhalidJagannathan2024">{{cite journal | vauthors = Callans LS, Philogene-Khalid H, Jagannathan K, Cunningham R, Yu D, Lu X, Walters MI, Morrison MF | title = Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study | journal = Psychopharmacol Bull | volume = 54 | issue = 2 | pages = 8–14 | date = April 2024 | pmid = 38601830 | doi = 10.64719/pb.4485| pmc = 11003254 | url = }}</ref> and pain,<ref name="Ochoa-AguilarVentura-MartinezSotomayor-Sobrino2016" /> with positive or mixed preliminary results for these conditions reported.<ref name="AdisInsight" /><ref name="MilenkovicCampbellRoussel2018" /><ref name="ConnollyThase2012" /><ref name="RiesenbergRosenthalMoldauer2012" />

Clavulanic acid was under formal development by Revaax Pharmaceuticals (now Ocuphire Pharma) for the treatment of erectile dysfunction, anxiety disorders, major depressive disorder, neurodegenerative disorders, and Parkinson's disease.<ref name="AdisInsight" /><ref name="MilenkovicCampbellRoussel2018" /><ref name="ConnollyThase2012">{{cite journal | vauthors = Connolly KR, Thase ME | title = Emerging drugs for major depressive disorder | journal = Expert Opin Emerg Drugs | volume = 17 | issue = 1 | pages = 105–126 | date = March 2012 | pmid = 22339643 | doi = 10.1517/14728214.2012.660146 | url = }}</ref> However, development for these indications was discontinued by 2014.<ref name="AdisInsight">{{cite web | title=Clavulanic acid | website=AdisInsight | date=29 December 2021 | url=https://adisinsight.springer.com/drugs/800027171 | access-date=27 September 2024}}</ref> The developmental code name of clavulanic acid was RX-10100 and its tentative brand names were Serdaxin and Zoraxel.<ref name="AdisInsight" /> Although its development was discontinued, interest in clavulanic acid for potential nervous system-related uses has continued as of 2024.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024" /><ref name="CallansPhilogene-KhalidJagannathan2024" />

== References == {{Reflist}}

{{DEFAULTSORT:Clavulanic Acid}} Category:Azetidines Category:Beta-lactamase inhibitors Category:Carboxylic acids Category:Drugs with unknown mechanisms of action Category:Experimental antidepressants Category:Experimental anxiolytics Category:Experimental drugs Category:Heterocyclic compounds with 2 rings Category:Neuroprotective agents Category:Oxazolidinones