3,4-Diaminopyridine
Encyclopedia
3,4-Diaminopyridine 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.
With the International Nonproprietary Name
amifampridine, it is used as a drug, predominantly in the treatment of a number of rare muscle diseases. In Europe, the phosphate salt of amifampridine has been licenced as Firdapse (BioMarin Pharmaceutical
) in 2010 as an orphan drug
.
(LEMS). In Lambert-Eaton syndrome, acetylcholine
release is inhibited as antibodies meant to target characteristic cancers target Ca2+ channels on the prejunctional membrane instead. 3,4-Diaminopyridine works by blocking potassium channel
efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for longer time and allow greater acetylcholine release to stimulate muscle at end plate. A 2005 systematic review
from the Cochrane Collaboration
found some data favouring its use in LEMS.
It is also used to treat many of the congenital myasthenic syndrome
s, 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
.
3,4-Diaminopyridine 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.
in an open letter to review the situation. The company has 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 2010, company scientists published evidence that amifampridine should be the first-line treatment for LEMS.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
with the formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
C5H3N(NH2)2. It is formally derived from pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
by substitution of the 3 and 4 positions with an amino group.
With the International Nonproprietary Name
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
amifampridine, it is used as a drug, predominantly in the treatment of a number of rare muscle diseases. In Europe, the phosphate salt of amifampridine has been licenced as Firdapse (BioMarin Pharmaceutical
BioMarin Pharmaceutical
BioMarin Pharmaceutical Inc. is a biotechnology firm based in Novato, California. It has offices and facilities in the US, South America, Asia and Europe. BioMarin's core business and research is in enzyme replacement therapies...
) in 2010 as an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
.
Uses
3,4-Diaminopyridine is used for the treatment of Lambert-Eaton myasthenic syndromeLambert-Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome is a rare autoimmune disorder that is characterised by muscle weakness of the limbs...
(LEMS). In Lambert-Eaton syndrome, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
release is inhibited as antibodies meant to target characteristic cancers target Ca2+ channels on the prejunctional membrane instead. 3,4-Diaminopyridine works by blocking potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for longer time and allow greater acetylcholine release to stimulate muscle at end plate. A 2005 systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
from the Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
found some data favouring its use in LEMS.
It is also used to treat many of the congenital myasthenic syndrome
Congenital myasthenic syndrome
Congenital myasthenic syndrome is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction...
s, particularly those with defects in choline acetyltransferase
Choline acetyltransferase
Choline acetyltransferase is an enzyme that is synthesized within the body of a neuron. It is then transferred to the nerve terminal via axoplasmic flow. The role of choline acetyltransferase is to join Acetyl-CoA to choline, resulting in the formation of the neurotransmitter acetylcholine...
, downstream kinase 7
Dok-7
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
, and those where any kind of defect causes "fast channel" behaviour of the acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
.
3,4-Diaminopyridine has also been proposed for the treatment of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, but a 2002 systematic review found that there was little unbiased data to support its use in MS.
Cost
The licensing of 3,4-diaminopyridine in 2010 led to a sharp increase in price for the drug. In some cases, this has led to hospitals using an unlicenced form rather than the licensed agent, as the price difference proved prohibitive. The drug company has been criticised for licencing the drug on the basis of previously conducted research, and yet charging exorbitantly for it. A group of UK neurologists and pediatricians have petitioned to prime minister David CameronDavid Cameron
David William Donald Cameron is the current Prime Minister of the United Kingdom, First Lord of the Treasury, Minister for the Civil Service and Leader of the Conservative Party. Cameron represents Witney as its Member of Parliament ....
in an open letter to review the situation. The company has 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 2010, company scientists published evidence that amifampridine should be the first-line treatment for LEMS.