Flupirtine

Last updated
Flupirtine
Flupirtine Structural Formula V1.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
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]
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) [1]
Excretion 72% of flupirtine and its metabolites appear in urine and 18% appear in feces [4]
Identifiers
  • ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.054.986 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H17FN4O2
Molar mass 304.325 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)CNc2nc(N)c(NC(=O)OCC)cc2
  • InChI=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) X mark.svgN
  • Key:JUUFBMODXQKSTD-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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 [6] In March 2018, marketing authorisations for flupirtine were withdrawn following a European Medicines Agency recommendation based on the finding that the restrictions introduced in 2013 had not been sufficiently followed in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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Any member of the group of drugs used to achieve analgesia, relief from pain

An analgesic drug, also called simply an analgesic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Hydrocodone</span> Opioid drug used in pain relief

Hydrocodone, also known as dihydrocodeinone, is a semisynthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug: in the United States a Schedule II Controlled Substance.

<span class="mw-page-title-main">Paracetamol</span> Common medication for pain and fever

Paracetamol is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.

<span class="mw-page-title-main">Tramadol</span> Medication of the opioid type, patented 1972

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for treatment of anxiety and chronic pain

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive-compulsive disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

<span class="mw-page-title-main">Dantrolene</span> Chemical compound

Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia or drugs. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis), and poisoning by 2,4-dinitrophenol or by the related compounds dinoseb and dinoterb.

<span class="mw-page-title-main">Oxymorphone</span> Opioid analgesic drug

Oxymorphone is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets. The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally. Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.

<span class="mw-page-title-main">Riluzole</span> Medication used to treat amyotrophic lateral sclerosis

Riluzole is a medication used to treat amyotrophic lateral sclerosis and other motor neuron diseases. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Riluzole is available in tablet and liquid form.

<span class="mw-page-title-main">Octreotide</span> Octapeptide that mimics natural somatostatin pharmacologically

Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.

<span class="mw-page-title-main">Nimesulide</span> Anti-inflammatory drug

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in adolescents and adults above 12 years old.

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<span class="mw-page-title-main">Pregabalin</span> Anticonvulsant medication

Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal, and generalized anxiety disorder (GAD). Pregabalin also has antiallodynic properties. Its use in epilepsy is as an add-on therapy for partial seizures. It is a gabapentinoid medication and acts by inhibiting certain calcium channels. When used before surgery, it reduces pain but results in greater sedation and visual disturbances. It is taken by mouth.

<span class="mw-page-title-main">Metamizole</span> Medication

Metamizole or dipyrone is a painkiller, spasm reliever, and fever reliever drug. It is most commonly given by mouth or by intravenous infusion. It belongs to the ampyrone sulfonate family of medicines and was patented in 1922. Metamizole is marketed under various trade names. It was first used medically in Germany under the brandname "Novalgin".

<span class="mw-page-title-main">Agomelatine</span> Atypical antidepressant classified primarily as a melatonin receptor agonist

Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.

<span class="mw-page-title-main">Thiocolchicoside</span> Chemical compound

Thiocolchicoside is a muscle relaxant with anti-inflammatory and analgesic effects. Its mechanism of action is unknown, but it is believed to be act via antagonism of nicotinic acetylcholine receptors (nAchRs). However, it also appears to be a competitive antagonist of GABAA and glycine receptors. As such, it has powerful convulsant activity and should not be used in seizure-prone individuals.

<span class="mw-page-title-main">Retigabine</span> Anticonvulsant, which works as a potassium-channel opener

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017.

<span class="mw-page-title-main">Arylcyclohexylamine</span> Class of chemical compounds

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.

<span class="mw-page-title-main">Ulipristal acetate</span> Chemical compound

Ulipristal acetate, sold under the brand name Ella among others, is a medication used for emergency contraception and uterine fibroids. As emergency contraception it should be used within 120 hours of vaginally penetrating intercourse. For fibroids it may be taken for up to six months. It is taken by mouth.

<span class="mw-page-title-main">Difelikefalin</span> Chemical compound

Difelikefalin, sold under the brand name Korsuva, is an opioid peptide used for the treatment of moderate to severe itch. It acts as a peripherally-restricted, highly selective agonist of the κ-opioid receptor (KOR).

References

  1. 1 2 Abrams SM, Baker LR, Crome P, White AS, Johnston A, Ankier SI, et al. (May 1988). "Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment". Postgraduate Medical Journal. 64 (751): 361–363. doi:10.1136/pgmj.64.751.361. PMC   2428663 . PMID   3200777.
  2. ↑ Narang PK, Tourville JF, Chatterji DC, Gallelli JF (January 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, et al. (March 2009). "Investigation of the in vitro metabolism of the analgesic flupirtine". Drug Metabolism and Disposition. 37 (3): 479–493. doi:10.1124/dmd.108.024364. PMID   19074524. S2CID   5661841.
  4. ↑ Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005). "Retigabine: chemical synthesis to clinical application". CNS Drug Reviews. 11 (1): 1–20. doi:10.1111/j.1527-3458.2005.tb00033.x. PMC   6741764 . PMID   15867950.
  5. 1 2 3 Harish S, Bhuvana K, Bengalorkar GM, Kumar T (April 2012). "Flupirtine: Clinical pharmacology". Journal of Anaesthesiology Clinical Pharmacology. 28 (2): 172–177. doi: 10.4103/0970-9185.94833 . PMC   3339720 . PMID   22557738.
  6. 1 2 "Flupirtine-containing medicines". European Medicines Agency. November 21, 2013.
  7. ↑ "European Medicines Agency - Human medicines - Flupirtine-containing medicinal products". www.ema.europa.eu. Archived from the original on 2022-01-21. Retrieved 2018-03-18.
  8. 1 2 3 4 Szelenyi I (March 2013). "Flupirtine, a re-discovered drug, revisited". Inflammation Research. 62 (3): 251–258. doi:10.1007/s00011-013-0592-5. PMID   23322112. S2CID   16535456.
  9. 1 2 Flupirtine Drugs.com. Accessed 30 August 2016
  10. ↑ McMahon FG, Arndt WF, Newton JJ, Montgomery PA, Perhach JL (1987). "Clinical experience with flupirtine in the U.S". Postgraduate Medical Journal. 63 Suppl 3 (3): 81–85. PMID   3328854.
  11. ↑ EMA information about flupirtine
  12. ↑ "Flupirtin: EMA startet Risikobewertung wegen Leberrisiko". Deutsches Ärzteblatt . 15 March 2013.
  13. ↑ Singal R, Gupta P, Jain N, Gupta S (June 2012). "Role of flupirtine in the treatment of pain - chemistry and its effects" (PDF). Maedica. 7 (2): 163–166. PMC   3557425 . PMID   23401726.
  14. ↑ "DRUGDEX Evaluations - Flupirtine" . Retrieved 24 March 2013.
  15. ↑ Preston KL, Funderburk FR, Liebson IA, Bigelow GE (March 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.
  16. ↑ 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.
  17. ↑ Gahr M, Freudenmann RW, Connemann BJ, Hiemke C, Schönfeldt-Lecuona C (December 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. S2CID   35299692.
  18. 1 2 Stoessel C, Heberlein A, Hillemacher T, Bleich S, Kornhuber J (August 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. S2CID   19710997.
  19. 1 2 "Assessment report for flupirtine containing medicinal products" (PDF). EMA. June 24, 2013.
  20. ↑ Allen RC (1986). "To Market, To Market - 1985". In Hesp B (ed.). Annual Reports in Medicinal Chemistry, Volume 21. Orlando: Academic Press. p. 328. ISBN   9780080583655.
  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" (PDF). EMA. March 8, 2013.
  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. Archived from the original on 6 June 2014. Retrieved 2 June 2014.
  23. ↑ "POTIGA (ezogabine) Tablets, CV. Full Prescribing Information Revised: September, 2013. Initial U.S. Approval: 2011" (PDF). GlaxoSmithKline and Valeant Pharmaceuticals. Retrieved 2 June 2014.
  24. ↑ Klawe C, Maschke M (June 2009). "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert Opinion on Pharmacotherapy. 10 (9): 1495–1500. doi:10.1517/14656560902988528. PMID   19505216. S2CID   11597721.
  25. ↑ 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". The Journal of Pharmacology and Experimental Therapeutics. 246 (3): 1067–1074. PMID   2901483.
  26. ↑ Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, et al. (April 2002). "Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons". Annals of Neurology. 51 (4): 448–466. doi:10.1002/ana.10143. PMID   11921051. S2CID   23653281.
  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 Archived 2017-08-30 at the Wayback Machine 4/21/2008
  29. 1 2 "Partnered Program. Effirma for Fibromyalgia". Synthetic Biologics, Inc. Archived from the original on 6 June 2014. Retrieved 2 June 2014.
  30. ↑ Stoll AL, Belmont MA. (2000) "Fibromyalgia Symptoms Relieved by Flupirtine: An Open-Label Case Series Archived 2010-09-02 at the Wayback Machine " Psychosomatics41:371-372. Accessed 20 September 2011.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.