|Systematic (IUPAC) name|
|Bioavailability||90% (oral), 70% (rectal)|
|Metabolism||Hepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound) and Para-fluorohippuric acid.|
|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 faeces.|
|Mol. mass||304.32 g/mol|
|(what is this?)|
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. Flupirtine is sold by Intas Pharma under the brand name Pruf in India. It is unique as a non-opioid, non-NSAID, non-steroidal 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 partial seizures. Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine.
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. obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications.
Mechanism of action
Flupirtine is used as an analgesic for acute and chronic pain, in moderate to severe cases. Mass by mass flupirtine has approximately one third the analgesic potency of codeine. 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.
Flupirtine has been noted for its neuro-protective properties, and it is being investigated for possible use in Creutzfeld-Jakob disease, Alzheimer's disease, and multiple sclerosis. It has also been proposed as a possible treatment for Batten disease.
Flupirtine underwent a clinical trial as a treatment for multiple sclerosis and fibromyalgia. Flupirtine showed promise for fibromyalgia due to its different action than the three approved US Food and Drug Administration drugs: Lyrica, Savella, and Cymbalta. Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia. Adeona sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.
Flupirtine is notably devoid of any addictive properties, negative psychological or motor function effects, or effects on reproductive function. Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.
Peripheral Side Effects
- Blurred vision (up to 12% in one study)
- Dry mouth
- Flu-like symptoms
- Gastric & abdominal discomfort
- Gastric fullness
- Nausea (in ≤15% of patients)
- Pruritus (pruritus was associated with long-term flupirtine therapy in 9% of patients treated in 1 study)
- Slight decreases in systolic blood pressure have been reported in patients receiving chronic flupirtine therapy.
- Isolated instances of arrhythmias, such as supraventricular extrasystoles, atrial fibrillation and left bundle branch block have been reported during chronic flupirtine therapy. However, it is unclear if any of these effects are drug-related.
- Elevated liver enzymes (although a cause-effect relationship has not been clearly demonstrated).
- Deterioration of hepatic function in patients with preexisting liver disease (cirrhosis and/or hepatitis) has been noted.
Elevations in blood urea nitrogen and serum creatinine have been observed in some patients treated with flupirtine, although it is unclear if these effects were drug-related.
CNS Side Effects
- Depression (39% in some study, vs. 8.3% for dihydrocodeine)
- Dizziness/light-headedness (around 3-24%)
- Elevated mood
- Impaired Concentration
- Sedation/somnolence (reported in 10-15% of patients)
- Tremors (~2% of patients complain of this side effect)
- 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. PMID 3200777.
- 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.
- 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.
- Flupirtine Drugs.com. Accessed 20 September 2011.
- 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.
- 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.
- 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.
- http://patent.ipexl.com/US/4481205.html 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate United States Patent 4481205. 1981
- 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.
- 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.
- Effirma Adeona Pharmaceuticals. Accessed 20 September 2011.
- 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. PMID 10599868.
- 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.
- 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.
- 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.
- 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.
- Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) Clinical Trials.gov Accessed 20 September 2011.
- Pipex Pharmaceuticals (PPXP)' Oral Flupirtine Receives IND With FDA for Phase II Clinical Trial for Fibromyalgia 4/21/2008
- Stoll AL, Belmont MA. (2000) "Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series" Psychosomatics 41:371-372. Accessed 20 September 2011.
- Stoessel, C.; Heberlein, A.; Hillemacher, T.; Bleich, S.; Kornhuber, J. (2010). "Positive reinforcing effects of flupirtine — Two case reports". Progress in Neuro-Psychopharmacology and Biological Psychiatry 34 (6): 1120–1121. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025.
- 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.
- "DRUGDEX® Evaluations - Flupirtine". Retrieved 24 March 2013.