4-Aminopyridine Explained

4-Aminopyridine (4-AP, fampridine, dalfampridine) is an organic compound with 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. It has also been used as a drug, to manage some of the symptoms of multiple sclerosis,[1] [2] and is indicated for symptomatic improvement of walking in adults with several variations of the disease.[3] It was undergoing Phase III clinical trials,[4] and the U.S. Food and Drug Administration (FDA) approved the compound on January 22, 2010.[5] Fampridine is also marketed as Ampyra (pronounced "am-PEER-ah," according to the maker's website) in the United States by Acorda Therapeutics[6] and as Fampyra in the European Union, Canada, and Australia. In Canada, the medication has been approved for use by Health Canada since February 10, 2012.[7]

Applications

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.[8]

Convulsant activity

4-Aminopyridine is a potent convulsant and is used to generate seizures in animal models for the evaluation of antiseizure agents.[9]

Vertebrate pesticide

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.[10] 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.[11] 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.[11] The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States.[12]

Medical use

Drug Name:Fampridine
Tradename:Ampyra, Fampyra, others
Dailymedid:Dalfampridine
Drugbank:DB06637
Iupac Name:1,4-dihydropyridin-4-imine

Fampridine has been used clinically 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.[13] The drug has been shown to reverse saxitoxin and tetrodotoxin toxicity in tissue and animal experiments.[14] [15] [16] [17] In calcium entry blocker overdose in humans, 4-aminopyridine can increase the cytosolic Ca2+concentration very efficiently independent of the calcium channels.

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.[18] Common side effects include dizziness, nervousness and nausea, and the incidence of adverse effects was shown to be less than 5% in all studies.[19]

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.[20]

MS patients 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.[21]

Spinal cord injury

Spinal cord injury patients have also seen improvement with 4-AP therapy. These improvements include sensory, motor and pulmonary function, with a decrease in spasticity and pain.[22]

Tetrodotoxin poisoning

Clinical studies have shown that 4-AP is capable of reversing the effects of tetrodotoxin poisoning in animals, however, its effectiveness as an antidote in humans has not yet been determined.[14] [15] [16]

Overdose

Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures,[23] and atrial fibrillation.[24]

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.

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.[25]

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.[26] Since then, generic alternatives have been developed for the U.S. market.[27]

The drug is marketed by Biogen Idec in Canada as Fampyra[28] and as Dalstep in India by Sun Pharma.[29]

Research

Parkinson's disease

Dalfampridine completed Phase II clinical trials for Parkinson's disease in July 2014.

See also

Notes and References

  1. Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C . Aminopyridines for symptomatic treatment in multiple sclerosis . The Cochrane Database of Systematic Reviews . 4 . CD001330 . 2002 . 12804404 . 7047571 . 10.1002/14651858.CD001330 . Solari A .
  2. Korenke AR, Rivey MP, Allington DR . Sustained-release fampridine for symptomatic treatment of multiple sclerosis . The Annals of Pharmacotherapy . 42 . 10 . 1458–1465 . October 2008 . 18780812 . 10.1345/aph.1L028 . 207263182 .
  3. Australian Prescriber . August 2011 . New Drugs: Fampridine . 34 . 119–123 . dead . https://web.archive.org/web/20120227164713/http://www.australianprescriber.com/magazine/34/4/119/123/new-drugs-962/fampridine . 2012-02-27 .
  4. Web site: Acorda Clinical Development and Product Pipeline . Acorda.
  5. FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis. U.S. Food and Drug Administration (FDA). https://wayback.archive-it.org/7993/20170112032146/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm198463.htm. Jan 12, 2017.
  6. Web site: Ampyra. National Multiple Sclerosis Society.
  7. Web site: Notice of Decision for FAMPYRA. hc-sc.gc.ca. 2012-04-21. https://web.archive.org/web/20120502012046/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/nd_ad_2012_fampyra_132859-eng.php. 2012-05-02. dead.
  8. Wu ZZ, Li DP, Chen SR, Pan HL . Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit . The Journal of Biological Chemistry . 284 . 52 . 36453–36461 . December 2009 . 19850918 . 2794761 . 10.1074/jbc.M109.075523 . free .
  9. Yamaguchi S, Rogawski MA . Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice . Epilepsy Research . 11 . 1 . 9–16 . March 1992 . 1563341 . 10.1016/0920-1211(92)90016-m . 5772125 .
  10. Web site: EPA Reregistration Eligibility Decision for 4-aminopyridine . U.S. Environmental Protection Agency . 23 . 27 September 2007 .
  11. Web site: What is Avitrol? . Avitrol Corporation, Tulsa, Oklahoma, US . 15 August 2012.
  12. Web site: Poisonous Solution: The Avitrol Problem . Brasted M . May 13, 2008 . . December 23, 2008 . https://web.archive.org/web/20081225152227/http://www.hsus.org/wildlife/urban_wildlife_our_wild_neighbors/solving_problems/avitrol.html . December 25, 2008 . dead . mdy-all .
  13. Judge SI, Bever CT . Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment . Pharmacology & Therapeutics . 111 . 1 . 224–259 . July 2006 . 16472864 . 10.1016/j.pharmthera.2005.10.006 .
  14. van der Voort PH, Wilffert B, van Roon EN, Uges DR . 4-Aminopyridine as a life-saving treatment in calcium channel antagonist intoxication . The Netherlands Journal of Medicine . 74 . 6 . 276 . July 2016 . 27571731 .
  15. Chang FC, Spriggs DL, Benton BJ, Keller SA, Capacio BR . 4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs . Fundamental and Applied Toxicology . 38 . 1 . 75–88 . July 1997 . 9268607 . 10.1006/faat.1997.2328 . 17185707 .
  16. Chen HM, Lin CH, Wang TM . Effects of 4-aminopyridine on saxitoxin intoxication . Toxicology and Applied Pharmacology . 141 . 1 . 44–48 . November 1996 . 8917674 . 10.1006/taap.1996.0258 .
  17. http://www.emedicine.com/emerg/topic342.htm Octopus Envenomations
  18. Valet M, Quoilin M, Lejeune T, Stoquart G, Van Pesch V, El Sankari S, Detrembleur C, Warlop T . 6 . Effects of Fampridine in People with Multiple Sclerosis: A Systematic Review and Meta-analysis . CNS Drugs . 33 . 11 . 1087–1099 . November 2019 . 31612418 . 10.1007/s40263-019-00671-x . 204543081 .
  19. Web site: Fampyra EPAR . European Medicines Agency (EMA) . 17 September 2018 . 24 August 2020.
  20. Wu ZZ, Li DP, Chen SR, Pan HL . Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit . The Journal of Biological Chemistry . 284 . 52 . 36453–36461 . December 2009 . 19850918 . 2794761 . 10.1074/jbc.M109.075523 . free .
  21. August 1, 2016. Real-life experience with fampridine (Fampyra) for patients with multiple sclerosis and gait disorders. NeuroRehabilitation.
  22. Van Diemen HA, Polman CH, Koetsier JC, Van Loenen AC, Nauta JJ, Bertelsmann FW . 4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety . Clinical Neuropharmacology . 16 . 3 . 195–204 . June 1993 . 8504436 . 10.1097/00002826-199306000-00002 .
  23. Pickett TA, Enns R . Atypical presentation of 4-aminopyridine overdose . Annals of Emergency Medicine . 27 . 3 . 382–385 . March 1996 . 8599505 . 10.1016/S0196-0644(96)70277-9 .
  24. Johnson NC, Morgan MW . An unusual case of 4-aminopyridine toxicity . The Journal of Emergency Medicine . 30 . 2 . 175–177 . February 2006 . 16567254 . 10.1016/j.jemermed.2005.04.020 .
  25. News: FDA Approves Dalfampridine to Improve Walking in Multiple Sclerosis. Jeffrey S . January 22, 2010. Medscape.
  26. Web site: US courts invalidates Dalfampridine patents. Acorda.
  27. News: House DW . Supreme Court declines to hear Acorda appeal of adverse Ampyra patent ruling . Seeking Alpha . 8 October 2019 . en . 7 October 2019.
  28. Web site: Fampyra Drug Monograph. Health Canada Drug Product Database. Biogen Idec Canada Inc.. 10 October 2017. 26 November 2014.
  29. Web site: Dalstep 10mg Registration Details. Registrationwala. 2018-11-25. 2020-09-15. https://web.archive.org/web/20200915071209/https://www.registrationwala.com/trademark/3613942-dalstep. dead.
  30. 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.
  31. Gardner TS, Wenis E, Lee J . 10.1021/jo01370a009 . The Synthesis of Compounds for the Chemotherapy of Tuberculosis. Iv. The Amide Function . The Journal of Organic Chemistry . 19 . 5 . 753 . 1954 .

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