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词条 Amifampridine
释义

  1. Medical uses

  2. Contraindications

  3. Adverse effects

  4. Pharmacology

      Mechanism of action    Pharmacokinetics  

  5. Chemistry

  6. History

  7. Research

  8. See also

  9. References

{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477217342
| IUPAC_name = Pyridine-3,4-diamine
| image = Diaminopyridine.png
| image2 = 3,4-diaminopyridine-3D-balls.png
| width = 120
| tradename = Firdapse
| Drugs.com = {{Drugs.com|UK|firdapse}}
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category = No clinical data
| licence_EU = yes
| legal_AU =
| legal_CA =
| legal_UK = POM
| legal_US =
| legal_status =
| routes_of_administration = Oral
| bioavailability = 93–100%[1]
| protein_bound =
| metabolism = Acetylation to 3-N-acetyl­amifampridine
| elimination_half-life = 2.5 hrs (amifampridine)
4 hrs (3-N-acetyl­amifampridine)
| excretion = Renal (19% unmetabolized, 74–81% 3-N-acetyl­amifampridine
| IUPHAR_ligand = 8032
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 54-96-6
| ATC_prefix = N07
| ATC_suffix = XX05
| PubChem = 5918
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5705
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = RU4S6E2G0J
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 354077
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D10228
| C=5 | H=7 | N=3
| smiles = c1cncc(c1N)N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H7N3/c6-4-1-2-8-3-5(4)7/h1-3H,7H2,(H2,6,8)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OYTKINVCDFNREN-UHFFFAOYSA-N
| melting_point = 218
| melting_high = 220
| melting_notes = decomposes
| solubility = 24
}}

Amifampridine (pyridine-3,4-diamine, 3,4-diaminopyridine, 3,4-DAP) is used as a drug, predominantly in the treatment of a number of rare muscle diseases. The free base form of the drug has been used to treat congenital myasthenic syndromes and Lambert–Eaton myasthenic syndrome (LEMS) through compassionate use programs since the 1990s and was recommended as a first line treatment for LEMS in 2006, using ad hoc forms of the drug, since there was no marketed form.

Around 2000 doctors at Assistance Publique – Hôpitaux de Paris created a phosphate salt form, which was developed through a series of companies ending with BioMarin Pharmaceutical which obtained European approval in 2009 under the trade name Firdapse, and which licensed the US rights to Catalyst Pharmaceuticals in 2012. As of January 2017, Catalyst and another US company, Jacobus Pharmaceuticals, which had been manufacturing and giving it away for free since the 1990s, were both seeking FDA approval for their iterations and marketing rights.

Amifampridine phosphate has orphan drug status in the EU for Lambert–Eaton myasthenic syndrome and Catalyst holds both an orphan designation and a breakthrough therapy designation in the US.

Medical uses

Amifampridine is used to treat many of the congenital myasthenic syndromes, particularly those with defects in choline acetyltransferase, downstream kinase 7, and those where any kind of defect causes "fast channel" behaviour of the acetylcholine receptor.[1][2]

It is also used to treat psoriasis.

It is also used to treat symptoms of Lambert–Eaton myasthenic syndrome.[3][5]

Contraindications

Because it affects voltage-gated ion channels, it is contraindicated in people with long QT syndrome and in people taking a drug that might prolong QT like sultopride, disopyramide, cisapride, domperidone, rifampicin or ketoconazol. It is also contraindicated in people with epilepsy or badly controlled asthma.[3]

Adverse effects

The dose-limiting side effects include tingling or numbness, difficulty sleeping, fatigue, and loss of muscle strength.[7]

Interactions via the liver's cytochrome P450 enzyme system are considered unlikely.[3]

Pharmacology

Mechanism of action

In Lambert–Eaton myasthenic syndrome, acetylcholine release is inhibited as antibodies involved in the host response against certain cancers cross-react with Ca2+ channels on the prejunctional membrane. Amifampridine works by blocking potassium channel efflux in nerve terminals so that action potential duration is increased.[4] Ca2+ channels can then be open for a longer time and allow greater acetylcholine release to stimulate muscle at the end plate.[5]

Pharmacokinetics

Amifampridine is quickly and almost completely (93–100%) absorbed from the gut. In a study with 91 healthy subjects, maximum amifampridine concentrations in blood plasma were reached after 0.6 (±0.25) hours when taken without food, or after 1.3 (±0.9) hours after a fatty meal, meaning that the speed of absorption varies widely. Biological half-life (2.5±0.7 hrs) and the area under the curve (AUC = 117±77 ng∙h/ml) also vary widely between subjects, but are nearly independent of food intake.[3]

The substance is deactivated by acetylation via N-acetyltransferases to the single metabolite 3-N-acetylamifampridine. Activity of these enzymes (primarily N-acetyltransferase 2) in different individuals seems to be primarily responsible for the mentioned differences in half-life and AUC: the latter is increased up to 9-fold in slow metabolizers as compared to fast metabolizers.[3]

Amifampridine is eliminated via the kidneys and urine to 74–81% as N-acetylamifampridine and to 19% in unchanged form.[3]

Chemistry

3,4-Diaminopyridine is a pale yellow to pale brown crystalline powder that melts at about {{convert|218|-|220|C}} under decomposition. It is readily soluble in methanol, ethanol and hot water, but only slightly in diethyl ether.[6][7] Solubility in water at {{convert|20|C}} is 25 g/L.

The drug formulation amifampridine phosphate contains the phosphate salt, more specifically 4-aminopyridine-3-ylammonium dihydrogen phosphate.[7] This salt forms prismatic, monoclinic crystals (space group C2/c)[8] and is readily soluble in water.[9] The phosphate salt is stable, and does not require refrigeration.[19]

History

The development of amifampridine and its phosphate has brought attention to orphan drug policies that grant market exclusivity as an incentive for companies to develop therapies for conditions that affect small numbers of people.[20][10][11]

Amifampridine, also called 3,4-DAP, was discovered in Scotland in the 1970s, and doctors in Sweden first showed its use in LEMS in the 1980s.[12]

In the 1990s, doctors in the US, on behalf of Muscular Dystrophy Association, approached a small family-owned manufacturer of active pharmaceutical ingredients in New Jersey, Jacobus Pharmaceuticals, about manufacturing amifampridine so they could test it in clinical trials. Jacobus did so, and when the treatment turned out to be effective, Jacobus and the doctors were faced with a choice — invest in clinical trials to get FDA approval or give the drug away for free under a compassionate use program. Jacobus elected to give the drug away, and did so for about twenty years.[13][14]

Doctors at the Assistance Publique – Hôpitaux de Paris had created a phosphate salt of 3,4-DAP (3,4-DAPP), and obtained an orphan designation for it in Europe in 2002.[15] The hospital licensed the intellectual property on the phosphate form to the French biopharma company OPI, which was acquired by EUSA Pharma in 2007,[16] and the orphan application was transferred to EUSA in 2008.[15] In 2008 EUSA submitted an application for approval to market the phosphate form to the European Medicines Agency under the brand name, Zenas.[17] EUSA, through a vehicle called Huxley Pharmaceuticals, sold the rights to 3,4-DAPP to Biomarin in 2009,[18] the same year that 3,4-DAPP was approved in Europe under the new name Firdapse.[15] BioMarin launched the drug in Europe in April 2010 and through the first nine months of 2012 year had sales of $10.8 million.[32]

The licensing of Firdapse in 2010 in Europe led to a sharp increase in price for the drug. In some cases, this has led to hospitals using an unlicensed form rather than the licensed agent, as the price difference proved prohibitive. BioMarin has been criticized for licensing the drug on the basis of previously conducted research, and yet charging exorbitantly for it.[19] A group of UK neurologists and pediatricians petitioned to prime minister David Cameron in an open letter to review the situation.[20] The company responded that it submitted the licensing request at the suggestion of the French government, and points out that the increased cost of a licensed drug also means that it is monitored by regulatory authorities (e.g. for uncommon side effects), a process that was previously not present in Europe.[21] A 2011 Cochrane review compared the cost of the 3,4-DAP and 3,4-DAPP in the UK and found an average price for 3,4-DAP base of £1/tablet and an average price for 3,4-DAP phosphate of £20/tablet; and the authors estimated a yearly cost per person of £730 for the base versus £29,448 for the phosphate formulation.[22][23]

Meanwhile, in Europe, a task force of neurologists had recommended 3,4-DAP as the firstline treatment for LEMS symptoms in 2006, even though there was no approved form for marketing; it was being supplied ad hoc.[17]{{rp|5}}[24] In 2007 the drug's international nonproprietary name was published by the WHO.[25]

In the US, an orphan drug designation for 3,4-DAPP had been granted in 2009[26] and clinical trials were well under way by 2012.[32]

In the face of the 7 year exclusivity that an orphan approval would give to Biomarin, and of the increase in price that would accompany it, Jacobus began racing to conduct formal clinical trials in order to get approval for the free base form before BioMarin; its first Phase II trial was opened in January 2012.[27]

In October 2012, while BioMarin had a Phase III trial ongoing in the US, it licensed the US rights to 3,4-DAPP, including the orphan designation and the ongoing trial, to Catalyst Pharmaceuticals.[28] Catalyst anticipated that it could earn $300 to $900 million per year in sales for treatment of people with LEMS and other indications, and analysts anticipated the drug would be priced at around. $100,000 in the US.[12] Catalyst went on to obtain a breakthrough therapy designation for 3,4-DAPP in LEMS in 2013,[29] an orphan designation for congenital myasthenic syndromes in 2015[30] and an orphan designation for myasthenia gravis in 2016.[31]

In August 2013, analysts anticipated that FDA approval would be granted to Catalyst in LEMS by 2015.[32]

In October 2014, Catalyst began making available under an expanded access program.[33]

In March 2015 Catalyst obtained an orphan designation for the use of 3,4-DAPP to treat of congenital myasthenic syndromes, causing its stock to rise a bit.[34][35] In April 2015, Jacobus presented clinical trial results with 3,4-DAP at a scientific meeting, causing Catalyst shares to fall by 42%.[14]

In December 2015 a group of 106 neuromuscular doctors who had worked with both Jacobus and BioMarin/Catalyst published an editorial in the journal, Muscle & Nerve, expressing concern about the potential for the price of the drug to be dramatically increased should Catalyst obtain FDA approval, and stating that 3,4-DAPP represented no real innovation and didn't deserve exclusivity under the Orphan Drug Act, which was meant to spur innovation to meet unmet needs.[12][36] Other commentators noted, however, that Jacobus was not able to meet the needs of all people who could benefit from the drug via its free program, and that its manufacturing practices had quality control problems, with 483 FDA citations in 2011 and 2012.[13] Similarly, at the urging of Assistance Publique-Hôpitaux de Paris, the French drug authority had reviewed the use of the free base in light of the manufactured phosphate form in 2006, and had urged doctors in France not to use the free base form due to quality issues.[37]

In December 2015 Catalyst submitted its new drug application to the FDA,[38] and in February 2016 the FDA refused to accept it, on the basis that it wasn't complete and in April 2016 the FDA told Catalyst it would have to gather further data.[39][40] Catalyst cut 30% of its workforce to save money to conduct the trials.[41] In March 2018 the company re-submitted its NDA.[42] The FDA approved amifampridine for the treatment of adults with Lambert-Eaton myasthenic syndrome on November 29, 2018.[43]

In February 2019, U.S. Senator Bernie Sanders questioned the high price charged by Catalyst Pharmaceuticals for Firdapse.[44][45]

Research

Amifampridine has also been proposed for the treatment of multiple sclerosis (MS). A 2002 Cochrane systematic review found that there was no unbiased data to support its use for treating MS.[46] There was no change as of 2012.[47]

See also

  • 4-Aminopyridine

References

1. ^{{cite journal | vauthors = Argov Z | title = Management of myasthenic conditions: nonimmune issues | journal = Current Opinion in Neurology | volume = 22 | issue = 5 | pages = 493–7 | date = Oct 2009 | pmid = 19593127 | doi = 10.1097/WCO.0b013e32832f15fa }}
2. ^{{cite web|last1=Abicht|first1=Angela|last2=Müller|first2=Juliane|last3=Lochmüller|first3=Hanns|title=Congenital Myasthenic Syndromes |url=https://www.ncbi.nlm.nih.gov/books/NBK1168/ |website=GeneReviews|publisher=University of Washington, Seattle|date=July 14, 2016}}
3. ^1 2 3 4 5 6 {{cite web|title=Firdapse Summary of Product Characteristics|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001032/WC500069915.pdf|publisher=EMA|date=February 11, 2010}} See EMA Index page, product tab
4. ^{{cite journal|journal=Biophys J|title=3,4-diaminopyridine. A potent new potassium channel blocker|date=June 1978|volume=22|issue=3|pages=507–12|vauthors=Kirsch GE, Narahashi T|pmc=1473482|pmid=667299|doi=10.1016/s0006-3495(78)85503-9}}
5. ^1 {{cite journal|last1=Tarr|first1=TB|last2=Wipf|first2=P|last3=Meriney|first3=SD|title=Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome.|journal=Molecular Neurobiology|date=August 2015|volume=52|issue=1|pages=456–63|pmid=25195700|pmc=4362862|doi=10.1007/s12035-014-8887-2}}
6. ^{{cite web|url=http://www.fda.gov/ohrms/dockets/dockets/98n0182/nom007b.pdf|title=Diaminopyridine (3,4-)|publisher=FDA|access-date=28 November 2015}}. Index page: FDA Docket 98N-0812: Bulk Drug Substances to be Used in Pharmacy Compounding
7. ^1 {{cite book|title=Arzneistoff-Profile|editor=Dinnendahl, V |editor2=Fricke, U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2015|edition=28th|volume=1|isbn=978-3-7741-9846-3|language=German}}
8. ^{{cite journal|title=Crystal Structure and Solid-State Properties of 3,4-Diaminopyridine Dihydrogen Phosphate and Their Comparison with Other Diaminopyridine Salts|journal=Cryst Growth Des|year=2013|volume=13|issue=2|pages=708–715|doi=10.1021/cg3014249|last1=Mahé|first1=Nathalie|last2=Nicolaï|first2=Béatrice|last3=Allouchi|first3=Hassan|last4=Barrio|first4=Maria|last5=Do|first5=Bernard|last6=Céolin|first6=René|last7=Tamarit|first7=Josep-Lluis|last8=Rietveld|first8=Ivo B.}}
9. ^{{cite journal| author = A. Klement| date = 9 November 2015| title = Firdapse| journal = Österreichische Apothekerzeitung| issue = 23/2015| page = 10f| language = German}}
10. ^{{cite journal |last1=Drummond |first1=M |last2=Towse |first2=A |title=Orphan drugs policies: a suitable case for treatment. |journal=The European Journal of Health Economics : HEPAC : Health Economics in Prevention and Care |date=May 2014 |volume=15 |issue=4 |pages=335–40 |doi=10.1007/s10198-014-0560-1 |pmid=24435513}}
11. ^{{cite news |last1=Lowe |first1=Derek |title=Catalyst Pharmaceuticals And Their Business Plan |url=http://blogs.sciencemag.org/pipeline/archives/2013/10/21/catalyst_pharmaceuticals_and_their_business_plan |work=In the Pipeline |date=21 October 2013}}
12. ^1 2 {{cite news|last1=Deak|first1=Dalia|title=Jacobus and Catalyst Continue to Race for Approval of LEMS Drug|url=http://blogs.harvard.edu/billofhealth/2016/02/22/jacobus-and-catalyst-approval/|work=Bill of Health|date=February 22, 2016}}
13. ^1 {{cite news|last1=Silverman|first1=Ed|title=A family-run drug maker tries to stay afloat in the Shkreli era|url=https://www.statnews.com/pharmalot/2016/04/05/jacobus-pharmaceuticals-martin-shkreli/|work=STAT News|date=5 April 2016}}
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15. ^1 2 {{cite web|title=Public summary of opinion on orphan designation|url=http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500005405.pdf|publisher=EMA|date=14 June 2010}}
16. ^{{cite news|last1=Chapelle|first1=François-Xavier|title=OPi ou comment construire une biopharma en moins de dix ans - Private Equity Magazine|url=http://www.pemagazine.fr/MTQ3NQ/opi-ou-comment-construire-une-biopharma-en-moins-de-dix-ans|work=Private Equity Magazine|date=November 4, 2008|language=Fr}}
17. ^1 {{cite web|title=Assessment report: Zenas|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001032/WC500069918.pdf|publisher=EMA CHMP committee|date=2009}}
18. ^{{cite news|title=Huxley Acquisition Lands Biomarin New LEMS Treatment|url=http://www.pharmaceutical-technology.com/news/news68256.html|work=Pharmaceutical Technology|date=October 28, 2009}}
19. ^{{cite news|last1=Goldberg|first1=Adrian|title=Drug firms accused of exploiting loophole for profit|url=https://www.bbc.com/news/health-11798183|work=BBC News|date=21 November 2010}}
20. ^{{cite journal | vauthors = Nicholl DJ, Hilton-Jones D, Palace J, Richmond S, Finlayson S, Winer J, Weir A, Maddison P, Fletcher N, Sussman J, Silver N, Nixon J, Kullmann D, Embleton N, Beeson D, Farrugia ME, Hill M, McDermott C, Llewelyn G, Leonard J, Morris M | title = Open letter to prime minister David Cameron and health secretary Andrew Lansley | journal = BMJ | volume = 341 | issue = | pages = c6466 | year = 2010 | pmid = 21081599 | doi = 10.1136/bmj.c6466 | url = http://www.bmj.com/content/341/bmj.c6466.full }}
21. ^{{cite journal | vauthors = Hawkes N, Cohen D | title = What makes an orphan drug? | journal = BMJ | volume = 341 | issue = | pages = c6459 | year = 2010 | pmid = 21081607 | doi = 10.1136/bmj.c6459 }}
22. ^1 {{cite journal | vauthors = Keogh M, Sedehizadeh S, Maddison P | title = Treatment for Lambert-Eaton myasthenic syndrome | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003279 | year = 2011 | pmid = 21328260 | doi = 10.1002/14651858.CD003279.pub3 }}
23. ^1 {{cite web|title=Evidence Review: Amifampridine phosphate for the treatment of Lambert–Easton Myasthenic Syndrome|url=https://www.engage.england.nhs.uk/consultation/clinical-commissioning-wave2/user_uploads/d04-x01-amifampridine-ev-review.pdf|publisher=NHS England|date=December 2015}}
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27. ^{{cite news|last1=Wahl|first1=Margaret|title=Jacobus Begins Invitation-Only Trial of 3,4-DAP in LEMS|url=http://quest.mda.org/news/jacobus-begins-invitation-only-trial-34-dap-lems|work=Muscular Dystrophy Association Quest Magazine Online|date=January 25, 2012}}
28. ^1 2 {{cite news|last1=Leuty|first1=Ron|title=BioMarin licenses North American rights to rare disease drug, invests $5M in Florida company|url=http://www.bizjournals.com/sanfrancisco/blog/biotech/2012/10/biomarin-catalyst-firdapse-lems.html|work=San Francisco Business Journal|date=October 31, 2012}}
29. ^{{cite journal | vauthors = Baker DE | title = Breakthrough Drug Approval Process and Postmarketing ADR Reporting | journal = Hospital Pharmacy | volume = 48 | issue = 10 | pages = 796–8 | date = Nov 2013 | pmid = 24421428 | doi = 10.1310/hpj4810-796 | pmc=3859287}}
30. ^{{cite web|title=Orphan Drug Designations: amifampridine phosphate for congenital myasthenic syndromes|url=http://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=464814|publisher=FDA|accessdate=14 January 2017}}
31. ^{{cite web|title=Orphan Drug Designations: amifampridine phosphate for myasthenia gravis|url=http://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=534916|website=www.accessdata.fda.gov|publisher=FDA|accessdate=14 January 2017}}
32. ^{{cite web | url = http://www.bizjournals.com/southflorida/news/2013/08/27/shares-of-catalyst-pharmaceuticals.html | title = Shares of Catalyst Pharmaceuticals soar 42% on FDA news | work = South Florida Business Journal | date = August 28, 2013 | author = Bandell B }}
33. ^{{cite news |last1=Radke |first1=James |title=Catalyst Using the Expanded Access Program to Conduct Phase IV Study with LEMS Patients |url=http://www.raredr.com/news/catalyst-expanded-access-program-lems-patients |work=Rare Disease Report |date=October 29, 2014}}
34. ^{{cite web |title=Orrphan designation congenital myasthenic syndromes |url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=464814 |publisher=FDA |archiveurl=https://web.archive.org/web/20150726000108/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=464814 |archivedate=July 26, 2015}}
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38. ^{{cite news |last1=Tavernise |first1=Sabrina |title=Patients Fear Spike in Price of Old Drugs |url=https://www.nytimes.com/2015/12/23/health/patients-fear-spike-in-price-of-old-drugs.html |work=New York Times |date=December 22, 2015 |language=en}}
39. ^{{cite news|last1=Adams|first1=Ben|title=Catalyst Pharmaceuticals hit by FDA extra studies request for Firdapse|url=http://www.fiercebiotech.com/biotech/catalyst-pharmaceuticals-hit-by-fda-extra-studies-request-for-firdapse|work=FierceBiotech|date=April 26, 2016}}
40. ^1 {{cite news |last1=Tavernise |first1=Sabrina |title=F.D.A. Deals Setback to Catalyst in Race for Drug Approval |url=https://www.nytimes.com/2016/02/18/health/fda-deals-setback-to-catalyst-in-race-for-drug-approval.html |work=New York Times |date=February 17, 2016 |language=en}}
41. ^{{cite news |last1=Adams |first1=Ben |title=Catalyst to ax 30% of workforce in wake of FDA trial demands |url=https://www.fiercebiotech.com/biotech/catalyst-to-ax-30-workforce-wake-fda-trial-demands |work=FierceBiotech |date=May 17, 2016 |language=en}}
42. ^{{cite news |last1=Lima |first1=Debora |title=Catalyst Pharmaceuticals files new drug application with FDA |url=https://www.bizjournals.com/southflorida/news/2018/03/29/catalyst-files-new-drug-application-with-fda.html |work=South Florida Business Journa |date=March 29, 2018}}
43. ^{{cite web|url=https://www.drugs.com/history/firdapse.html|title=Firdapse (amifampridine phosphate) FDA Approval History|website=Drugs.com|accessdate=5 February 2019}}
44. ^{{cite web|url=https://www.nbcnews.com/politics/2020-election/bernie-sanders-asks-why-drug-once-free-now-costs-375-n966746|title=Bernie Sanders asks why drug, once free, now costs $375K|website=NBC News|accessdate=5 February 2019}}
45. ^{{cite web|url=https://www.nbcnews.com/health/health-news/family-outraged-over-life-changing-treatment-going-free-375-000-n968906|title=Family outraged over life-changing treatment going from free to $375,000 a year|website=NBC News}}
46. ^{{Cite journal|last=Solari|first=A.|last2=Uitdehaag|first2=B.|last3=Giuliani|first3=G.|last4=Pucci|first4=E.|last5=Taus|first5=C.|date=2002|title=Aminopyridines for symptomatic treatment in multiple sclerosis|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=4|pages=CD001330|doi=10.1002/14651858.CD001330|issn=1469-493X|pmid=12804404|via=}}
47. ^{{cite journal|last1=Sedehizadeh|first1=S|last2=Keogh|first2=M|last3=Maddison|first3=P|title=The use of aminopyridines in neurological disorders.|journal=Clinical Neuropharmacology|date=2012|volume=35|issue=4|pages=191–200|doi=10.1097/WNF.0b013e31825a68c5|pmid=22805230}}
{{Other nervous system drugs}}{{Potassium channel blockers}}{{DEFAULTSORT:Diaminopyridine, 3, 4-}}

4 : Orphan drugs|Potassium channel blockers|Pyridines|Aromatic amines
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