Flupirtine

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Flupirtine
Flupirtine.svg
Flupirtine3Dan.gif
Systematic (IUPAC) name
ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
?
Pharmacokinetic data
Bioavailability 90% (oral), 70% (rectal)[1]
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[2] and a mercapturic acid metabolite, presumably formed from a glutathione adduct[3]
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)[1]
Excretion 72% of flupirtine and its metabolites appear in urine and 18% appear in feces[4]
Identifiers
CAS number 56995-20-1 N
ATC code N02BG07
PubChem CID 53276
IUPHAR ligand 2598
ChemSpider 48119 N
UNII MOH3ET196H YesY
KEGG D07978 YesY
ChEMBL CHEMBL255044 N
Chemical data
Formula C15H17FN4O2 
Mol. mass 304.32 g/mol
 N (what is this?)  (verify)

Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor.[5] Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine [USAN]) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients.[6] Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine.

History[edit]

Flupirtine was originally developed by Asta Medica, with the synthesis of the compound and the development of the drug described in patents from the 1970s to the 2000s.[7][8][9][10][11][12]

It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. 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.[13]

Mechanism of Action[edit]

Flupirtine is a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties.[14]

Uses[edit]

Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases. [15] Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology.

Flupirtine has been noted for its neuroprotective properties, and it is being investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer's disease, and multiple sclerosis.[16][17] It has also been proposed as a possible treatment for Batten disease.[18]

Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[19] and fibromyalgia.[20] Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: Lyrica (pregabalin), Savella (milnacipran), and Cymbalta (duloxetine).[21] Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.[22] Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.[21]

Side Effects[edit]

The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[23][24]

Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.[25][26]

Abuse and Dependence[edit]

Although some studies have reported flupirtine has no addictive properties,[27][28] there was suggestion that it may possess some abuse potential and liability.[29] There were at least two registered cases of flupirtine abuse.[30] Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.[30]

References[edit]

  1. ^ a b Abrams, SML; L.R.I. Baker, P. Crome, A.S.T. White, A. Johnston, S.I. Ankier, S.J. Warrington, P. Turner, G. Niebch (1988). "Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment". The Fellowship of Postgraduate Medicine 64 (751): 361–363. doi:10.1136/pgmj.64.751.361. PMC 2428663. PMID 3200777. 
  2. ^ Narang, PK; Tourville JF; Chatterji DC; Gallelli JF (1984). "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. doi:10.1016/S0378-4347(00)83321-6. PMID 6707137. 
  3. ^ Methling, K; Reszka P; Lalk M; Vrana O; Scheuch E; Siegmund W; Terhaag B; Bednarski PJ (2008). "Investigation of the in Vitro Metabolism of the Analgesic Flupirtine". Drug Metabolism and Disposition 37: 479–493. doi:10.1124/dmd.108.024364. 
  4. ^ Blackburn-Munro, G; W. Dalby-Brown; N. R. Mirza; J. D. Mikkelsen; R. E. Blackburn-Munro (2005). "Retigabine: Chemical Synthesis to Clinical Application". CNS Drug Reviews 11 (1): 1–20. doi:10.1111/j.1527-3458.2005.tb00033.x. PMID 15867950. 
  5. ^ Flupirtine Drugs.com. Accessed 20 September 2011.
  6. ^ "POTIGA® (ezogabine) Tablets, CV. Full Prescribing Information". GlaxoSmithKline and Valeant Pharmaceuticals. Revised: September, 2013. Initial U.S. Approval: 2011. Retrieved 2 June 2014.  Check date values in: |date= (help)
  7. ^ http://www.freepatentsonline.com/5721258.html Primary and secondary neuroprotective effect of flupirtine in neurodegenerative diseases The synthesis of flupirtine and its pharmaceutically acceptable salts is described in EP 160 865 and 199 951. EP0199951 December, 1986 Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine.
  8. ^ http://patent.ipexl.com/EP/EP0199951.html#reference Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of EPO Patent EP0199951 1986 German.
  9. ^ http://www.patentfish.com/2-amino-3-carbethoxyamino-6-4-fluoro-benzylamino Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine EP 0199951 B1 1986. English.
  10. ^ http://patent.ipexl.com/US/4481205.html 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate United States Patent 4481205. 1981
  11. ^ http://www.freepatentsonline.com/3998834.html Novel N-(4-piperidinyl)-N-phenylamides and -carbamates having very potent analgesic activity, methods of preparing same and useful intermediates therefor. Patent 3998834. 1976.
  12. ^ http://www.faqs.org/patents/app/20090306150 CARBOXYLIC ACID SALTS OF 2-AMINO-3-CARBETHOXYAMINO-6-(4-FLUORO-BENZYLAMINO)-PYRIDINE patent 20090306150. 2009. Flupirtine is commonly used in the form of pharmaceutically acceptable acid addition salts. Commercially, flupirtine is available as its maleate addition salt under the trademark Katadolon®. There are two known polymorphs of flupirtine maleate, designated in the art as flupirtine maleate A and B. European patentEP 0 977 736 discloses pure flupirtine maleate crystalline form A and a process for its preparation. Flupirtine and mixtures of flupirtine maleate polymorphs A and B can be synthesised according to EP 0 199 951.
  13. ^ "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. Retrieved 2 June 2014. 
  14. ^ Kornhuber, J.; Bleich, S.; Wiltfang, J.; Maler, M.; Parsons, C. G. (1999). "Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication". Journal of neural transmission (Vienna, Austria : 1996) 106 (9–10): 857–867. doi:10.1007/s007020050206. PMID 10599868.  edit
  15. ^ McMahon, FG; Arndt WF Jr, Newton JJ, Montgomery PA, Perhach JL. (1987). "Clinical experience with flupirtine in the U.S". Postgraduate Medical Journal 63 (3): 81–85. PMID 3328854. 
  16. ^ Klawe, C; Maschke, M (2009). "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert opinion on pharmacotherapy 10 (9): 1495–500. doi:10.1517/14656560902988528. PMID 19505216. 
  17. ^ Swedberg MD, Shannon HE, Nickel B, Goldberg SR (September 1988). "Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat". J. Pharmacol. Exp. Ther. 246 (3): 1067–74. PMID 2901483. 
  18. ^ Dhar S, Bitting RL, Rylova SN, et al. (April 2002). "Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons". Ann. Neurol. 51 (4): 448–66. doi:10.1002/ana.10143. PMID 11921051. 
  19. ^ Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) Clinical Trials.gov Accessed 20 September 2011.
  20. ^ Pipex Pharmaceuticals (PPXP)' Oral Flupirtine Receives IND With FDA for Phase II Clinical Trial for Fibromyalgia 4/21/2008
  21. ^ a b "Partnered Program. Effirma™ for Fibromyalgia". Synthetic Biologics, Inc. Retrieved 2 June 2014. 
  22. ^ Stoll AL, Belmont MA. (2000) "Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series" Psychosomatics 41:371-372. Accessed 20 September 2011.
  23. ^ EMA information about flupirtine
  24. ^ article in Deutsches Ärzteblatt
  25. ^ Singal, Rikki; Parveen Gupta; Nidhi Jain; Samita Gupta (2012). "Role of Flupirtine in the Treatment of Pain - Chemistry and its Effects". Mædica — a Journal of Clinical Medicine 7 (2): 163–166. PMID 23401726. 
  26. ^ "DRUGDEX® Evaluations - Flupirtine". Retrieved 24 March 2013. 
  27. ^ Preston, KL; Funderburk, FR; Liebson, IA; Bigelow, GE (Mar 1991). "Evaluation of the Abuse Potential of the Novel Analgesic Flupirtine Maleate". Drug and Alcohol Dependence 27 (2): 101–113. doi:10.1016/0376-8716(91)90027-v. PMID 2055157. 
  28. ^ Sofia, RD; Diamantis, W; Gordon, R (1987). "Abuse Potential and Physical Dependence Liability Studies with Flupirtine Maleate in Laboratory Animals". Postgraduate Medical Journal. 63 Suppl 3: 35–40. PMID 3447127. 
  29. ^ Gahr, M; Freudenmann, RW; Connemann, BJ; Hiemke, C; Schönfeldt–Lecuona, C (Dec 2013). "Abuse Liability of Flupirtine Revisited: Implications of Spontaneous Reports of Adverse Drug Reactions". Journal of Clinical Pharmacology 53 (12): 1328–1333. doi:10.1002/jcph.164. PMID 24037995. 
  30. ^ a b Stoessel, C; Heberlein, A; Hillemacher, T; Bleich, S; Kornhuber, J (Aug 16, 2010). "Positive Reinforcing Effects of Flupirtine—Two Case Reports". Progress in Neuro-psychopharmacology & Biological Psychiatry 34 (6): 1120–1121. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. Retrieved 2 June 2014.