Flupirtine
{{Short description|Non-opioid analgesic}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 455522860
| IUPAC_name = ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate
| image = Flupirtine Structural Formula V1.svg
| width = 250
| tradename =
| Drugs.com = {{drugs.com|international|flupirtine}}
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| metabolism = Hepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound), para-fluorohippuric acid{{cite journal | vauthors = Narang PK, Tourville JF, Chatterji DC, Gallelli JF | title = Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection | journal = Journal of Chromatography | volume = 305 | issue = 1 | pages = 135–143 | date = January 1984 | pmid = 6707137 | doi = 10.1016/S0378-4347(00)83321-6 }} and a mercapturic acid metabolite, presumably formed from a glutathione adduct{{cite journal | vauthors = Methling K, Reszka P, Lalk M, Vrana O, Scheuch E, Siegmund W, Terhaag B, Bednarski PJ | display-authors = 6 | title = Investigation of the in vitro metabolism of the analgesic flupirtine | journal = Drug Metabolism and Disposition | volume = 37 | issue = 3 | pages = 479–493 | date = March 2009 | pmid = 19074524 | doi = 10.1124/dmd.108.024364 | s2cid = 5661841 }}
| elimination_half-life = 6.5 hrs (average), 11.2-16.8 hrs (average 14 hrs) (elderly), 8.7-10.9 hrs (average 9.8 hrs) (in those with moderate-level renal impairment)
| excretion = 72% of flupirtine and its metabolites appear in urine and 18% appear in feces{{cite journal | vauthors = Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE | title = Retigabine: chemical synthesis to clinical application | journal = CNS Drug Reviews | volume = 11 | issue = 1 | pages = 1–20 | year = 2005 | pmid = 15867950 | pmc = 6741764 | doi = 10.1111/j.1527-3458.2005.tb00033.x }}
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 56995-20-1
| ATC_prefix = N02
| ATC_suffix = BG07
| PubChem = 53276
| IUPHAR_ligand = 2598
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = MOH3ET196H
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07978
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 255044
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 48119
| smiles = Fc1ccc(cc1)CNc2nc(N)c(NC(=O)OCC)cc2
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C15H17FN4O2/c1-2-22-15(21)19-12-7-8-13(20-14(12)17)18-9-10-3-5-11(16)6-4-10/h3-8H,2,9H2,1H3,(H,19,21)(H3,17,18,20)
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = JUUFBMODXQKSTD-UHFFFAOYSA-N
| C=15 | H=17 | F=1 | N=4 | O=2
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Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic that was originally used as an analgesic for acute and chronic pain{{cite journal | vauthors = Harish S, Bhuvana K, Bengalorkar GM, Kumar T | title = Flupirtine: Clinical pharmacology | journal = Journal of Anaesthesiology Clinical Pharmacology | volume = 28 | issue = 2 | pages = 172–177 | date = April 2012 | pmid = 22557738 | pmc = 3339720 | doi = 10.4103/0970-9185.94833 | doi-access = free }} but in 2013 due to issues with liver toxicity, the European Medicines Agency restricted its use to acute pain, for no more than two weeks, and only for people who cannot use other painkillers.{{cite web|title=Flupirtine-containing medicines|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicines/human_referral_prac_000019.jsp&mid=WC0b01ac05805c516f|publisher=European Medicines Agency|date=November 21, 2013}} In March 2018, marketing authorisations for flupirtine were withdrawn following a European Medicines Agency recommendation based on the finding that the restrictions introduced in 2013 had not been sufficiently followed in clinical practice, and cases of serious liver injury still occurred including liver failure.{{Cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicinal_products/human_referral_prac_000069.jsp&mid=WC0b01ac05805c516f|title=European Medicines Agency - Human medicines - Flupirtine-containing medicinal products|website=www.ema.europa.eu|language=en|access-date=2018-03-18|archive-date=2022-01-21|archive-url=https://web.archive.org/web/20220121013335/http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicinal_products/human_referral_prac_000069.jsp&mid=WC0b01ac05805c516f|url-status=dead}}
Flupirtine is a selective neuronal potassium channel opener (SNEPCO) that also has NMDA receptor antagonist and GABAA modulatory properties.{{cite journal | vauthors = Szelenyi I | title = Flupirtine, a re-discovered drug, revisited | journal = Inflammation Research | volume = 62 | issue = 3 | pages = 251–258 | date = March 2013 | pmid = 23322112 | doi = 10.1007/s00011-013-0592-5 | s2cid = 16535456 }}
It first became available in Europe in 1984 under the brand name Katadolon and after it went off patent many generic brands were introduced.
Uses
Flupirtine is used as an analgesic for acute pain, in moderate-to-severe cases.{{cite journal | vauthors = McMahon FG, Arndt WF, Newton JJ, Montgomery PA, Perhach JL | title = Clinical experience with flupirtine in the U.S | journal = Postgraduate Medical Journal | volume = 63 Suppl 3 | issue = 3 | pages = 81–85 | year = 1987 | pmid = 3328854 }} Its muscle relaxant properties make it popular for back pain and other orthopaedic uses, but it is also used for migraines, in oncology, postoperative care, and gynaecology.
In 2013 due to issues with liver toxicity, the European Medicines Agency restricted its use to acute pain, for no more than two weeks, and only for people who cannot use other painkillers.
Side effects
The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicines/human_referral_prac_000019.jsp&mid=WC0b01ac05805c516f EMA information about flupirtine]{{cite web | url = http://www.aerzteblatt.de/nachrichten/53767/Flupirtin-EMA-startet-Risikobewertung-wegen-Leberrisiko | title = Flupirtin: EMA startet Risikobewertung wegen Leberrisiko | work = Deutsches Ärzteblatt | date = 15 March 2013 }}
Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.{{cite journal | vauthors = Singal R, Gupta P, Jain N, Gupta S | title = Role of flupirtine in the treatment of pain - chemistry and its effects | journal = Maedica | volume = 7 | issue = 2 | pages = 163–166 | date = June 2012 | pmid = 23401726 | pmc = 3557425 | url = http://www.maedica.org/articles/2012/2/MAEDICA_art_9.pdf }}{{cite web|title=DRUGDEX Evaluations - Flupirtine|url=https://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/C13ED6/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/9F4E9C/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DisplayDrugdexDocument?docId=1385&contentSetId=31&title=FLUPIRTINE&servicesTitle=FLUPIRTINE&topicId=cautionsSection&subtopicId=adverseReactionsSection|access-date=24 March 2013}}
Abuse and dependence
Although some studies have reported flupirtine has no addictive properties,{{cite journal | vauthors = Preston KL, Funderburk FR, Liebson IA, Bigelow GE | title = Evaluation of the abuse potential of the novel analgesic flupirtine maleate | journal = Drug and Alcohol Dependence | volume = 27 | issue = 2 | pages = 101–113 | date = March 1991 | pmid = 2055157 | doi = 10.1016/0376-8716(91)90027-v }}{{cite journal | vauthors = Sofia RD, Diamantis W, Gordon R | title = Abuse potential and physical dependence liability studies with flupirtine maleate in laboratory animals | journal = Postgraduate Medical Journal | volume = 63 | pages = 35–40 | date = 1987 | issue = Suppl 3 | pmid = 3447127 }} there was suggestion that it may possess some abuse potential and liability.{{cite journal | vauthors = Gahr M, Freudenmann RW, Connemann BJ, Hiemke C, Schönfeldt-Lecuona C | title = Abuse liability of flupirtine revisited: implications of spontaneous reports of adverse drug reactions | journal = Journal of Clinical Pharmacology | volume = 53 | issue = 12 | pages = 1328–1333 | date = December 2013 | pmid = 24037995 | doi = 10.1002/jcph.164 | s2cid = 35299692 }} There were at least two registered cases of flupirtine abuse.{{cite journal | vauthors = Stoessel C, Heberlein A, Hillemacher T, Bleich S, Kornhuber J | title = Positive reinforcing effects of flupirtine--two case reports | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 6 | pages = 1120–1121 | date = August 2010 | pmid = 20362025 | doi = 10.1016/j.pnpbp.2010.03.031 | s2cid = 19710997 }} Drug tolerance does not develop in most cases, but has individually occurred.
Mechanism of action
Flupirtine is a selective neuronal potassium channel opener that also has indirect NMDA receptor antagonist and GABAA receptor modulatory properties.
History
Flupirtine was discovered and developed between the 1970s and the 1990s by Chemiewerk Homburg in Frankfurt am Main, Germany, which became Degussa Pharma Group and then through mergers, ASTA Pharma and Asta Medica. Retigabine, in which the pyridine group in flupirtine is replaced with a phenyl group, was discovered as part of the same program and has a similar mechanism of action.
It was approved for the treatment of pain in 1984 in Europe under the brand name Katadolon.{{cite book| vauthors = Allen RC | veditors = Hesp B |title=Annual Reports in Medicinal Chemistry, Volume 21|date=1986|publisher=Academic Press|location=Orlando|isbn=9780080583655|page=328|chapter-url=https://books.google.com/books?id=qsFCGskRHZQC&pg=PA328|chapter=To Market, To Market - 1985}}
As of 2013 it was used in 11 member countries: Bulgaria, Estonia, Germany, Hungary, Italy, Latvia, Lithuania, Poland, Portugal, Romania and Slovak Republic.{{cite web|title=Assessment report for flupirtine containing medicinal products|url=http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Flupirtine-containing_medicines/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500146103.pdf|publisher=EMA|date=June 24, 2013}} Many generics entered the European market around 2011.{{cite web|title=Rationale for the triggering of procedure under Article 107i of Directive 2001/83/EC on flupirtine presented by the Federal Institute for Drugs and Medicinal Devices/BfArM, Germany|url=http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Flupirtine-containing_medicines/Procedure_started/WC500139760.pdf|publisher=EMA|date=March 8, 2013}}
It was never introduced to the United States market for any indication but in 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine's use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.{{cite web|title=Adeona Pharmaceuticals and National Neurovision Research Institute (NNRI) Collaborate to Test Flupirtine for Retinitis Pigmentosa|url=http://www.syntheticbiologics.com/index.php?s=43&item=38|publisher=Synthetic Biologics, Inc.|access-date=2 June 2014|location=Ann Arbor, MI and Owings Mills, MD|date=December 2, 2008|archive-url=https://web.archive.org/web/20140606203650/http://www.syntheticbiologics.com/index.php?s=43&item=38|archive-date=6 June 2014|url-status=dead}}
In 2010 retigabine was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients.{{cite web|title=POTIGA (ezogabine) Tablets, CV. Full Prescribing Information Revised: September, 2013. Initial U.S. Approval: 2011.|url=https://www.gsksource.com/gskprm/htdocs/documents/POTIGA-PI-MG.PDF|publisher=GlaxoSmithKline and Valeant Pharmaceuticals|access-date=2 June 2014}}
As of 2016 it is marketed under many brand names, including Efiret, Flupigil, Flupirtin, Flupirtina, Flupirtine, Flupizen, Fluproxy, Katadolon, Metanor, Trancolong, and Zentiva.[https://www.drugs.com/international/flupirtine.html Flupirtine] Drugs.com. Accessed 30 August 2016
Research
Flupirtine has been noted for its neuroprotective properties, and has been investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer's disease, and multiple sclerosis.{{cite journal | vauthors = Klawe C, Maschke M | title = Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 9 | pages = 1495–1500 | date = June 2009 | pmid = 19505216 | doi = 10.1517/14656560902988528 | s2cid = 11597721 }}{{cite journal | vauthors = Swedberg MD, Shannon HE, Nickel B, Goldberg SR | title = Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 246 | issue = 3 | pages = 1067–1074 | date = September 1988 | pmid = 2901483 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2901483 }} It has also been proposed as a possible treatment for Batten disease.{{cite journal | vauthors = Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, Amalfitano A, Boustany RM | display-authors = 6 | title = Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons | journal = Annals of Neurology | volume = 51 | issue = 4 | pages = 448–466 | date = April 2002 | pmid = 11921051 | doi = 10.1002/ana.10143 | s2cid = 23653281 }}
Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[http://clinicaltrials.gov/ct2/show/NCT00623415 Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS)] Clinical Trials.gov Accessed 20 September 2011. and fibromyalgia.[http://www.biospace.com/news_story.aspx?NewsEntityId=93287 Pipex Pharmaceuticals (PPXP)' Oral Flupirtine Receives IND With FDA for Phase II Clinical Trial for Fibromyalgia] {{Webarchive|url=https://web.archive.org/web/20170830235052/http://www.biospace.com/news_story.aspx?NewsEntityId=93287 |date=2017-08-30 }} 4/21/2008 Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: pregabalin, milnacipran, and duloxetine.{{cite web|title=Partnered Program. Effirma for Fibromyalgia|url=http://www.syntheticbiologics.com/fibromyalgia|publisher=Synthetic Biologics, Inc.|access-date=2 June 2014|archive-url=https://web.archive.org/web/20140606210655/http://www.syntheticbiologics.com/fibromyalgia|archive-date=6 June 2014|url-status=dead}} Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.Stoll AL, Belmont MA. (2000) "[http://psy.psychiatryonline.org/cgi/content/full/41/4/371 Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series] {{Webarchive|url=https://web.archive.org/web/20100902172130/http://psy.psychiatryonline.org/cgi/content/full/41/4/371 |date=2010-09-02 }}" Psychosomatics 41:371-372. Accessed 20 September 2011. Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.
References
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{{Analgesics}}
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Category:Potassium channel openers
Category:4-Fluorophenyl compounds
Category:GABAA receptor positive allosteric modulators