Chemistry:Flupirtine

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Short description: Non-opioid analgesic
Flupirtine
Flupirtine Structural Formula V1.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
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Pharmacokinetic data
Bioavailability90% (oral), 70% (rectal)[1]
MetabolismHepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound), para-fluorohippuric acid[3] and a mercapturic acid metabolite, presumably formed from a glutathione adduct[4]
Elimination half-life6.5 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)[1]
Excretion72% of flupirtine and its metabolites appear in urine and 18% appear in feces[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
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KEGG
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Chemical and physical data
FormulaC15H17FN4O2
Molar mass304.325 g·mol−1
3D model (JSmol)
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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[5] 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and only for people who cannot use other painkillers.[6] In March 2018, marketing authorisations for flupirtine were withdrawn following a European Medicines Agency recommendation based on the finding that the restrictions introduced in 2013 had not been sufficiently followed in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.[7]

Flupirtine is a selective neuronal potassium channel opener (SNEPCO) that also has NMDA receptor antagonist and GABAA modulatory properties.[8]

It first became available in Europe in 1984 under the brand name Katadolon and after it went off patent many generic brands were introduced.[9]

Uses

Flupirtine is used as an analgesic for acute pain, in moderate-to-severe cases.[5][10] 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.[6]

Side effects

The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[11][12]

Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.[13][14]

Abuse and dependence

Although some studies have reported flupirtine has no addictive properties,[15][16] there was suggestion that it may possess some abuse potential and liability.[17] There were at least two registered cases of flupirtine abuse.[18] Drug tolerance does not develop in most cases, but has individually occurred.[18]

Mechanism of action

Flupirtine is a selective neuronal potassium channel opener that also has indirect NMDA receptor antagonist and GABAA receptor modulatory properties.[8][5]

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.[8] 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.[8]

It was approved for the treatment of pain in 1984 in Europe[19] under the brand name Katadolon.[20]

As of 2013 it was used in 11 member countries: Bulgaria, Estonia, Germany, Hungary, Italy, Latvia, Lithuania, Poland, Portugal, Romania and Slovak Republic.[19] Many generics entered the European market around 2011.[21]

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.[22]

In 2010 retigabine was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients.[23]

As of 2016 it is marketed under many brand names, including Efiret, Flupigil, Flupirtin, Flupirtina, Flupirtine, Flupizen, Fluproxy, Katadolon, Metanor, Trancolong, and Zentiva.[9]

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.[24][25] It has also been proposed as a possible treatment for Batten disease.[26]

Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[27] and fibromyalgia.[28] Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: pregabalin, milnacipran, and duloxetine.[29] Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.[30] Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.[29]

References

  1. ↑ 1.0 1.1 "Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment". Postgraduate Medical Journal 64 (751): 361–363. May 1988. doi:10.1136/pgmj.64.751.361. PMID 3200777. 
  2. ↑ "Retigabine: chemical synthesis to clinical application". CNS Drug Reviews 11 (1): 1–20. 2005. doi:10.1111/j.1527-3458.2005.tb00033.x. PMID 15867950. 
  3. ↑ "Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection". Journal of Chromatography 305 (1): 135–143. January 1984. doi:10.1016/S0378-4347(00)83321-6. PMID 6707137. 
  4. ↑ "Investigation of the in vitro metabolism of the analgesic flupirtine". Drug Metabolism and Disposition 37 (3): 479–493. March 2009. doi:10.1124/dmd.108.024364. PMID 19074524. 
  5. ↑ 5.0 5.1 5.2 "Flupirtine: Clinical pharmacology". Journal of Anaesthesiology Clinical Pharmacology 28 (2): 172–177. April 2012. doi:10.4103/0970-9185.94833. PMID 22557738. 
  6. ↑ 6.0 6.1 "Flupirtine-containing medicines". European Medicines Agency. November 21, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicines/human_referral_prac_000019.jsp&mid=WC0b01ac05805c516f. 
  7. ↑ "European Medicines Agency - Human medicines - Flupirtine-containing medicinal products" (in en). http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Flupirtine-containing_medicinal_products/human_referral_prac_000069.jsp&mid=WC0b01ac05805c516f. 
  8. ↑ 8.0 8.1 8.2 8.3 "Flupirtine, a re-discovered drug, revisited". Inflammation Research 62 (3): 251–258. March 2013. doi:10.1007/s00011-013-0592-5. PMID 23322112. 
  9. ↑ 9.0 9.1 Flupirtine Drugs.com. Accessed 30 August 2016
  10. ↑ "Clinical experience with flupirtine in the U.S". Postgraduate Medical Journal 63 Suppl 3 (3): 81–85. 1987. PMID 3328854. 
  11. ↑ EMA information about flupirtine
  12. ↑ "Flupirtin: EMA startet Risikobewertung wegen Leberrisiko". Deutsches Ärzteblatt. 15 March 2013. http://www.aerzteblatt.de/nachrichten/53767/Flupirtin-EMA-startet-Risikobewertung-wegen-Leberrisiko. 
  13. ↑ "Role of flupirtine in the treatment of pain - chemistry and its effects". Maedica 7 (2): 163–166. June 2012. PMID 23401726. PMC 3557425. http://www.maedica.org/articles/2012/2/MAEDICA_art_9.pdf. 
  14. ↑ "DRUGDEX Evaluations - Flupirtine". 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. 
  15. ↑ "Evaluation of the abuse potential of the novel analgesic flupirtine maleate". Drug and Alcohol Dependence 27 (2): 101–113. March 1991. doi:10.1016/0376-8716(91)90027-v. PMID 2055157. 
  16. ↑ "Abuse potential and physical dependence liability studies with flupirtine maleate in laboratory animals". Postgraduate Medical Journal 63 (Suppl 3): 35–40. 1987. PMID 3447127. 
  17. ↑ "Abuse liability of flupirtine revisited: implications of spontaneous reports of adverse drug reactions". Journal of Clinical Pharmacology 53 (12): 1328–1333. December 2013. doi:10.1002/jcph.164. PMID 24037995. 
  18. ↑ 18.0 18.1 "Positive reinforcing effects of flupirtine--two case reports". Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (6): 1120–1121. August 2010. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. 
  19. ↑ 19.0 19.1 "Assessment report for flupirtine containing medicinal products". EMA. June 24, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Flupirtine-containing_medicines/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500146103.pdf. 
  20. ↑ "To Market, To Market - 1985". Annual Reports in Medicinal Chemistry, Volume 21. Orlando: Academic Press. 1986. p. 328. ISBN 9780080583655. https://books.google.com/books?id=qsFCGskRHZQC&pg=PA328. 
  21. ↑ "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". EMA. March 8, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Flupirtine-containing_medicines/Procedure_started/WC500139760.pdf. 
  22. ↑ "Adeona Pharmaceuticals and National Neurovision Research Institute (NNRI) Collaborate to Test Flupirtine for Retinitis Pigmentosa". Ann Arbor, MI and Owings Mills, MD: Synthetic Biologics, Inc.. December 2, 2008. http://www.syntheticbiologics.com/index.php?s=43&item=38. 
  23. ↑ "POTIGA (ezogabine) Tablets, CV. Full Prescribing Information Revised: September, 2013. Initial U.S. Approval: 2011.". GlaxoSmithKline and Valeant Pharmaceuticals. https://www.gsksource.com/gskprm/htdocs/documents/POTIGA-PI-MG.PDF. 
  24. ↑ "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert Opinion on Pharmacotherapy 10 (9): 1495–1500. June 2009. doi:10.1517/14656560902988528. PMID 19505216. 
  25. ↑ "Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat". The Journal of Pharmacology and Experimental Therapeutics 246 (3): 1067–1074. September 1988. PMID 2901483. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2901483. 
  26. ↑ "Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons". Annals of Neurology 51 (4): 448–466. April 2002. doi:10.1002/ana.10143. PMID 11921051. 
  27. ↑ Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) Clinical Trials.gov Accessed 20 September 2011.
  28. ↑ Pipex Pharmaceuticals (PPXP)' Oral Flupirtine Receives IND With FDA for Phase II Clinical Trial for Fibromyalgia 4/21/2008
  29. ↑ 29.0 29.1 "Partnered Program. Effirma for Fibromyalgia". Synthetic Biologics, Inc.. http://www.syntheticbiologics.com/fibromyalgia. 
  30. ↑ Stoll AL, Belmont MA. (2000) "Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series " Psychosomatics 41:371-372. Accessed 20 September 2011.



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