3,4-Diaminopyridine

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3,4-Diaminopyridine
Diaminopyridine.png
3,4-diaminopyridine-3D-balls.png
Systematic (IUPAC) name
3,4-Diaminopyridine
Clinical data
  • Phase III
Oral
Pharmacokinetic data
Bioavailability 30%,[1][2]
Identifiers
54-96-6 N
N07XX05
PubChem CID 5918
ChemSpider 5705 YesY
UNII RU4S6E2G0J YesY
ChEMBL CHEMBL354077 YesY
Chemical data
Formula C5H7N3
109.13
 N (what is this?)  (verify)

3,4-Diaminopyridine (or 3,4-DAP) is an organic compound with the formula C5H3N(NH2)2. It is formally derived from pyridine by substitution of the 3 and 4 positions with an amino group.

The compound 3,4-diaminopyridine has the International Nonproprietary Name amifampridine and is used as a drug, predominantly in the treatment of a number of rare muscle diseases. Firdapse, the phosphate salt of amifampridine, is marketed in the EU by BioMarin Pharmaceutical and designated as an orphan medicine in the EU.[3] In the United States, Firdapse is under investigation for the treatment of Lambert-Eaton myasthenic syndrome by Catalyst Pharmaceuticals,[4][5] and was granted a breakthrough therapy designation by the FDA in 2013.[6][7] In a Phase 3 clinical trial, Firdapse demonstrated superiority over placebo in both co-primary endpoints.[8][9][10] LEMS patients can receive Firdapse at no cost under an ongoing expanded access program.[11][12] A clinical trial of the free-base form of amifampridine has also been completed, by Jacobus Pharmaceutical Co. This form of amifampridine remains available at no cost to patients with Lambert-Eaton myasthenic syndrome and congenital myasthenic syndromes under a long-standing compassionate use program, with FDA oversight, from Jacobus Pharmaceutical Co. (see also Uses and Cost, below.)

Uses[edit]

In Lambert-Eaton syndrome, acetylcholine release is inhibited as antibodies meant to target certain cancers target Ca2+ channels on the prejunctional membrane instead. Amifampridine works by blocking potassium channel efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for a longer time and allow greater acetylcholine release to stimulate muscle at the end plate. A 2011 systematic review from the Cochrane Collaboration found data favoring its use in LEMS.[13] Although not approved for pharmaceutical use in the United States, amifampridine is available under compassionate use regulations for the treatment of Lambert-Eaton myasthenic syndrome (LEMS).

Amifampridine is also 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.[14] In the US, Firdapse is under development as an orphan drug for congenital myasthenic syndrome [15] and 3,4-diaminopyridine is available at no cost for patients with congenital myasthenic syndromes under a long-standing compassionate use program from Jacobus Pharmaceutical Co.

Amifampridine has also been proposed for the treatment of multiple sclerosis, but a 2002 systematic review found that there was little unbiased data to support its use in MS.[16]

Cost[edit]

The licensing of Firdapse in 2010 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.[17] A group of UK neurologists and pediatricians have petitioned to prime minister David Cameron in an open letter to review the situation.[18] 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.[19] In 2010, Biomarin company scientists published evidence that amifampridine should be the first-line treatment for LEMS.[20]

In the United States, 3,4-diaminopyridine phosphate (Firdapse), a more stable formulation of amifampridine that does not require refrigeration, and 3.4-diaminopyridine free base have completed clinical trials to treat the Lambert-Eaton myasthenic syndrome (LEMS).[21][22][23] Both formulations are available to LEMS patients in the U.S.: the free base is available to patients with LEMS and congenital myasthenic syndromes under a compassionate distribution program by Jacobus Pharmaceutical Company, and the phosphate salt is available to LEMS patients under an expanded access program by Catalyst Pharmaceuticals. Patients must be diagnosed with Lambert-Eaton myasthenic syndrome or congenital myasthenic syndrome and meet appropriate inclusion criteria.[11]

Compounding pharmacies may also be a source of amifampridine in the U.S. In Europe, 3,4-diaminopyridine phosphate is sold by BioMarin under the name Firdapse, and the free base is compounded, usually by hospital pharmacies.

See also[edit]

References[edit]

  1. ^ AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. (2001). "Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthena gravis or Lambert-Eaton myasthenic syndrome: summary statement". Muscle Nerve 24 (9): 1236–1238. doi:10.1002/mus.1139. PMID 11494280. 
  2. ^ Lundh H, Nilsson O, Rosen I, Johansson S. (1993). "Practical aspects of 3,4-diaminopyridine treatment of the Lambert-Eaton myasthenic syndrome". Acta Neurol Scand 88 (2): 136–140. doi:10.1111/j.1600-0404.1993.tb04205.x. PMID 8213058. 
  3. ^ "Firdapse". European Medicines Agency. Retrieved 2010-09-28. 
  4. ^ Baker DE (Nov 2013). "Breakthrough Drug Approval Process and Postmarketing ADR Reporting". Hospital Pharmacy 48 (10): 796–8. doi:10.1310/hpj4810-796. PMID 24421428. 
  5. ^ Clinical trial number NCT00265148 for "A Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)" at ClinicalTrials.gov
  6. ^ "Rare Disease: Catalyst Pharmaceutical Receives 20th FDA Breakthrough Therapy Designation". Orphan Druganaut Blog. 2013-08-27. 
  7. ^ Bandell B (2013-08-28). "Shares of Catalyst Pharmaceuticals soar 42% on FDA news". South Florida Business Journal. 
  8. ^ American Neurological Association 2013 Meeting Poster ID: S737WIP
  9. ^ "Special Issue: 2014 Annual Meetings". Annals of Neurology 76 (S18): i–ii, S1–S254. October 2014. doi:10.1002/ana.v76.S18. 
  10. ^ Muscular Dystrophy Association Press Release
  11. ^ a b Clinical trial number NCT02189720 for "Expanded Access Study of Amifampridine Phosphate in LEMS, Congenital Myasthenic Syndrome, or Downbeat Nystagmus Patients (EAP-001)" at ClinicalTrials.gov
  12. ^ Radke J (2014-10-30). "Catalyst Using the Expanded Access Program to Conduct Phase IV Study with LEMS Patients". Rare Disease Report. 
  13. ^ Keogh M, Sedehizadeh S, Maddison P (2011). "Treatment for Lambert-Eaton myasthenic syndrome". The Cochrane Database of Systematic Reviews (2): CD003279. doi:10.1002/14651858.CD003279.pub3. PMID 21328260. 
  14. ^ Argov Z (Oct 2009). "Management of myasthenic conditions: nonimmune issues". Current Opinion in Neurology 22 (5): 493. doi:10.1097/WCO.0b013e32832f15fa. PMID 19593127. 
  15. ^ [1]
  16. ^ Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C (2002). Solari A, ed. "Aminopyridines for symptomatic treatment in multiple sclerosis". The Cochrane Database of Systematic Reviews (4): CD001330. doi:10.1002/14651858.CD001330. PMID 11687106. 
  17. ^ Daniel Martin (2010-09-27). "Hospitals are forced to use unlicensed medicines to save millions". Daily Mail. Archived from the original on 28 September 2010. Retrieved 2010-09-28. 
  18. ^ Nicholl DJ, Hilton-Jones D, Palace J, Richmond S, Finlayson S, Winer J et al. (2010). "Open letter to prime minister David Cameron and health secretary Andrew Lansley". Bmj 341: c6466. doi:10.1136/bmj.c6466. PMID 21081599. 
  19. ^ Hawkes N, Cohen D (2010). "What makes an orphan drug?". Bmj 341: c6459. doi:10.1136/bmj.c6459. PMID 21081607. 
  20. ^ Quartel A, Turbeville S, Lounsbury D (Jun 2010). "Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment". Current Medical Research and Opinion 26 (6): 1363–75. doi:10.1185/03007991003745209. PMID 20377318. 
  21. ^ ANA presentation[2]
  22. ^ Raust, JA et al. (2007). "Stability studies of ionised and non-ionised 3,4-diaminopyridine: hypothesis of degradation pathways and chemical structure of degradation products.". J Pharm Biomed Anal. PMID 16844337. 
  23. ^ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001032/WC500069918.pdf