4-Aminopyridine

4-Aminopyridine
INN: Fampridine
Names
Trade namesAmpyra, Fampyra, others
Other names4-Pyridinamine
4-Pyridylamine
fampridine (INN)
dalfampridine (USAN)
IUPAC name
  • 1,4-dihydropyridin-4-imine
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
MedlinePlusa611005
Legal
License data
Pharmacokinetics
Bioavailability96%
Chemical and physical data
FormulaC5H6N2
Molar mass94.1146 g/mol
3D model (JSmol)
Solubility in waterpolar organic solvents mg/mL (20 °C)
SMILES
  • n1ccc(N)cc1
InChI
  • InChI=1S/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7) checkY
  • Key:NUKYPUAOHBNCPY-UHFFFAOYSA-N checkY

4-Aminopyridine (4-AP, fampridine, dalfampridine) is a medication used to treat symptoms of multiple sclerosis.[1][2] In some forms of the disease it improves walking in adults.[3]

It has the chemical formula C5H4N–NH2. The molecule is one of the three isomeric amines of pyridine. It is used as a research tool in characterizing subtypes of the potassium channel.

4-Aminopyridine was approved for medical use in the United States in 2010.[4] In Canada, it was approved in 2012.[5] Fampridine is also marketed as Ampyra[4][6] and as Fampyra in the European Union, Canada, and Australia.

Medical uses

4-Aminopyridine

Fampridine is used in Lambert-Eaton myasthenic syndrome and multiple sclerosis. It acts by blocking voltage-gated potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction.[7] It reverses saxitoxin and tetrodotoxin toxicity in tissue and animal experiments.[8][9][10][11] In calcium entry blocker overdose, 4-aminopyridine can increase the cytosolic Ca2+ concentration independent of the calcium channels.[8]

Multiple sclerosis

Fampridine has been shown to improve visual function and motor skills and relieve fatigue in patients with multiple sclerosis (MS). However, the effect of the drug is strongly established for walking capacity only.[12] Common side effects include dizziness, nervousness and nausea, and the incidence of adverse effects was shown to be less than 5% in all studies.[13][14]

4-AP works as a potassium channel blocker. Strong potassium currents decrease action potential duration and amplitude, which increases the probability of conduction failure − a well documented characteristic of demyelinated axons. Potassium channel blockade has the effect of increasing axonal action potential propagation and improving the probability of synaptic vesicle release. A study has shown that 4-AP is a potent calcium channel activator and can improve synaptic and neuromuscular function by directly acting on the calcium channel beta subunit.[15]

In MS treated with 4-AP exhibited a response rate of 29.5% to 80%. A long-term study (32 months) indicated that 80-90% of patients who initially responded to 4-AP exhibited long-term benefits. Although improving symptoms, 4-AP does not inhibit progression of MS. Another study, conducted in Brazil, showed that treatment based on fampridine was considered efficient in 70% of the patients.[16]

Overdose

Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures,[17] and atrial fibrillation.[18]

Contraindications

4-aminopyridine is excreted by the kidneys. 4-AP should not be given to people with significant kidney disease (e.g., acute kidney injury or advanced chronic kidney disease) due to the higher risk of seizures with increased circulating levels of 4-AP.

Society and culture

Branding

The drug was originally intended, by Acorda Therapeutics, to have the brand name Amaya, however the name was changed to Ampyra to avoid potential confusion with other marketed pharmaceuticals.[19]

Four of Acorda's patents pertaining to Ampyra were invalidated in 2017 by the United States District Court for the District of Delaware and a fifth patent expired in 2018.[20] Since then, generic alternatives have been developed for the U.S. market.[21]

The drug is marketed by Biogen Idec in Canada as Fampyra[22] and as Dalstep in India by Sun Pharma.[23]

Production

4-phenylethane is prepared by the amine of phenyl-4-amide using sodium via the Hofmann rearrangement. The piperdine amine is generated from the corresponding nitrile, which in turn is obtained from a carbon atom of 4-phenylethane.[24]

Other animals

4-Aminopyridine is a potent convulsant and is used to generate seizures in animal models for the evaluation of antiseizure agents.[25]

4-Aminopyridine is also used under the trade name Avitrol as 0.5% or 1% in bird control bait. It causes convulsions and, infrequently, death, depending on dosage.[26] The manufacturer says the proper dose should cause epileptic-like convulsions which cause the poisoned birds to emit distress calls resulting in the flock leaving the site; if the dose was sub-lethal, the birds will recover after 4 or more hours without long-term ill effect.[27] The amount of bait should be limited so that relatively few birds are poisoned, causing the remainder of the flock to be frightened away with a minimum of mortality. A lethal dose will usually cause death within an hour.[27] The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States.[28]

Research

In the laboratory, 4-AP is a useful pharmacological tool in studying various potassium conductances in physiology and biophysics. It is a relatively selective blocker of members of Kv1 (Shaker, KCNA) family of voltage-activated K+ channels. However, 4-AP has been shown to potentiate voltage-gated Ca2+ channel currents independent of effects on voltage-activated K+ channels.[29]

Parkinson disease

Dalfampridine completed Phase II clinical trials for Parkinson disease in 2014.[30]

Tetrodotoxin poisoning

4-AP maybe capable of reversing the effects of tetrodotoxin poisoning in some animals, however, its effectiveness as an antidote in humans has not yet been determined.[8][9][10]

See also

  • 4-Dimethylaminopyridine, a popular laboratory reagent, is prepared directly from pyridine instead of via methylating this compound.[24]
  • Pyridine
  • 4-Pyridylnicotinamide, useful as a ligand in coordination chemistry, is prepared by the reaction of this compound with nicotinoyl chloride.[31]

References

  1. ↑ Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C (2002). Solari A (ed.). "Aminopyridines for symptomatic treatment in multiple sclerosis". Cochrane Database Syst Rev (4): CD001330. doi:10.1002/14651858.CD001330. PMC 7047571. PMID 12804404.
  2. ↑ Korenke AR, Rivey MP, Allington DR (October 2008). "Sustained-release fampridine for symptomatic treatment of multiple sclerosis". Ann Pharmacother. 42 (10): 1458–65. doi:10.1345/aph.1L028. PMID 18780812. S2CID 207263182.
  3. ↑ "New Drugs: Fampridine". Australian Prescriber (34): 119–123. August 2011. Archived from the original on 2012-02-27.
  4. 1 2 "FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on Jan 12, 2017.
  5. ↑ "Notice of Decision for FAMPYRA". hc-sc.gc.ca. Archived from the original on 2012-05-02. Retrieved 2012-04-21.
  6. ↑ "Ampyra". National Multiple Sclerosis Society. Archived from the original on 2021-04-27. Retrieved 2021-06-30.
  7. ↑ Judge S, Bever C (2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
  8. 1 2 3 van der Voort, P.H; Wilffert, B; van Roon, E.N.; Uges, D.R. (2016). "4-Aminopyridine as a life-saving treatment in calcium channel antagonist intoxication". Neth. J. Med. 74 (6): 276. PMID 27571731. Archived from the original on 2020-09-15. Retrieved 2021-06-30.
  9. 1 2 Chang, F. C.; Spriggs, D. L.; Benton, B. J.; Keller, S. A.; Capacio, B. R. (1997). "4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs". Fundamental and Applied Toxicology. 38 (1): 75–88. doi:10.1006/faat.1997.2328. PMID 9268607.
  10. 1 2 Chen, H.; Lin, C.; Wang, T. (1996). "Effects of 4-Aminopyridine on Saxitoxin Intoxication". Toxicology and Applied Pharmacology. 141 (1): 44–48. doi:10.1006/taap.1996.0258. PMID 8917674.
  11. ↑ Octopus Envenomations Archived 2008-10-06 at the Wayback Machine at eMedicine.com
  12. ↑ Valet, Maxime; Quoilin, Mélanie; Lejeune, Thierry; Stoquart, Gaëtan; Van Pesch, Vincent; El Sankari, Souraya; Detrembleur, Christine; Warlop, Thibault (14 October 2019). "Effects of Fampridine in People with Multiple Sclerosis: A Systematic Review and Meta-analysis". CNS Drugs. 33 (11): 1087–1099. doi:10.1007/s40263-019-00671-x. PMID 31612418. S2CID 204543081.
  13. ↑ Fampyra: EPAR - Product Information (PDF), London: European Medicines Agency, 1 Jun 2017, archived (PDF) from the original on 11 February 2018, retrieved 11 Feb 2018
  14. ↑ "Fampyra EPAR". European Medicines Agency (EMA). Archived from the original on 11 August 2020. Retrieved 24 August 2020.
  15. ↑ Wu, ZZ; Li, DP; Chen, SR; Pan, HL (2009). "Aminopyridines Potentiate Synaptic and Neuromuscular Transmission by Targeting the Voltage-activated Calcium Channel β Subunit". The Journal of Biological Chemistry. 284 (52): 36453–61. doi:10.1074/jbc.M109.075523. PMC 2794761. PMID 19850918.
  16. ↑ "Real-life experience with fampridine (Fampyra) for patients with multiple sclerosis and gait disorders". NeuroRehabilitation. August 1, 2016.
  17. ↑ Pickett T, Enns R (1996). "Atypical presentation of 4-aminopyridine overdose". Annals of Emergency Medicine. 27 (3): 382–5. doi:10.1016/S0196-0644(96)70277-9. PMID 8599505.
  18. ↑ Johnson N, Morgan M (2006). "An unusual case of 4-aminopyridine toxicity". The Journal of Emergency Medicine. 30 (2): 175–7. doi:10.1016/j.jemermed.2005.04.020. PMID 16567254.
  19. ↑ Jeffrey, Susan (January 22, 2010). "FDA Approves Dalfampridine to Improve Walking in Multiple Sclerosis". Medscape. Archived from the original on September 18, 2020. Retrieved June 30, 2021.
  20. ↑ "US courts invalidates Dalfampridine patents". Acorda. Archived from the original on 2020-09-15. Retrieved 2021-06-30.
  21. ↑ House, Douglas W. (7 October 2019). "Supreme Court declines to hear Acorda appeal of adverse Ampyra patent ruling". Seeking Alpha. Archived from the original on 15 September 2020. Retrieved 8 October 2019.
  22. ↑ "Fampyra Drug Monograph" (PDF). Health Canada Drug Product Database. Biogen Idec Canada Inc. 26 November 2014. Archived (PDF) from the original on 11 October 2017. Retrieved 10 October 2017.
  23. ↑ "Dalstep 10mg Registration Details". Registrationwala. Archived from the original on 2020-09-15. Retrieved 2021-06-30.
  24. 1 2 Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura "Pyridine and Pyridine Derivatives" in "Ullmann's Encyclopedia of Industrial Chemistry" 2007; John Wiley & Sons: New York.
  25. ↑ Yamaguchi S, Rogawski MA (1992). "Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice". Epilepsy Res. 11 (1): 9–16. doi:10.1016/0920-1211(92)90016-m. PMID 1563341. S2CID 5772125.
  26. ↑ EPA Reregistration Eligibility Decision for 4-aminopyridine, pg.23, September 27, 2007.
  27. 1 2 "What is Avitrol?". Avitrol Corporation, Tulsa, Oklahoma, USA. Archived from the original on 9 November 2012. Retrieved 15 August 2012.
  28. ↑ Brasted, Maggie (May 13, 2008). "Poisonous Solution: The Avitrol Problem". Humane Society of the United States. Archived from the original on December 25, 2008. Retrieved December 23, 2008. Retrieved on December 23, 2008.
  29. ↑ Wu, Zi-Zhen; Li, De-Pei; Chen, Shao-Rui; Pan, Hui-Lin (25 December 2009). "Aminopyridines Potentiate Synaptic and Neuromuscular Transmission by Targeting the Voltage-activated Calcium Channel β Subunit". Journal of Biological Chemistry. 284 (52): 36453–36461. doi:10.1074/jbc.M109.075523. PMC 2794761. PMID 19850918.
  30. ↑ "A Randomized Trial to Evaluate Ampyra for Gait Impairment in Parkinson's Disease - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Archived from the original on 2014-08-05. Retrieved 2021-06-30.
  31. ↑ Gardner, T. S.; Wenis, E.; Lee, J. (1954). "The Synthesis of Compounds for the Chemotherapy of Tuberculosis. Iv. The Amide Function". The Journal of Organic Chemistry. 19 (5): 753. doi:10.1021/jo01370a009.
Identifiers:
  • "Dalfampridine". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-08-27. Retrieved 2021-06-30.
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