Friday, June 13, 2008

What is 4-Aminopyridine?

According to Wikipedia:
4-Aminopyridine is an organic compound with the formula H2NC5H4N. The molecule is one of the three isomeric amines of pyridine. It is used primarily as a research tool and is helpful in characterizing subtypes of potassium channel. 4-Aminopyridine is prepared by the decarbonylation of pyridine-4-carboxyamide.
According to Extoxnet PIP (dated June 1996):
4-Aminopyridine, a pyridine compound, is an extremely effective bird poison. It is one of the most prominent avicides. It is registered with the EPA for use against red-winged blackbirds, blackbirds in agricultural fields, grackles, pigeons, and sparrows around public buildings, and various birds around livestock feeding pens. Avitrol repels birds by poisoning a few members of a flock, causing them to become hyperactive. Their distress calls signal other birds to leave the site. Only a small number of birds need to be affected to cause alarm in the rest of the flock. After one alarming exposure, birds will usually not return to treated areas. Avitrol is available as grain baits or as a powder concentrate.
According to Multiple Sclerosis Encylopaedia:

4-aminopyridine (also known as 4-AP and Fampridine) is a drug that blocks the potassium channels in neurons. This effectively improves the transmission of nerve impulses down damaged axons. It does not replace damaged myelin but users of 4-aminopyridine report dramatic improvement in a number of symptoms especially paraesthesia. It should be born in mind that this is an experimental drug and the side-effects are uncertain. Dosages should be carefully regulated as potassium is a chemical that is used extensively in other parts of the body including heart functions.

Agriculturally, 4-AP is used as an extremely effective bird poison sold under the brand name Avitrol. It is highly toxic to all mammals including humans if dosages are exceeded, and, as an experimental drug, recommended dose data is unavailable.

A slow release formulation of 4-aminopyridine is supplied by the Irish drug company, Elan Corporation, and is currently being tested by Acorda in two phase II trials in the US. It is currently awaiting authorisation by the US Federal Drug Agency (FDA).

Actually, Acorda Therapeutics recently announced Positive Data from their Second Phase III Trial of Fampridine-SR on Walking Ability in People with Multiple Sclerosis. Fampridine-SR is a proprietary slow-release formula of 4-aminopyridine. I'll be taking a closer look at how Acorda is aiming to bring this drug as an FDA-approved option to MS patients worldwide.

Researchers have been looking into the effects of demyelination on nerve conduction for many decades. Here is a sampling of earlier published papers related to conduction, demyelination, ion channels, 4-AP and MS.

Early Research in London, UK (1969-1983):
Bostick, McDonald, Rasminsky, Sears, Sheratt.
  • Nature, Jan 1969 - Effect of demyelination on conduction in the central nervous system. McDonald, Sears.
  • J Physiol, Apr 1970 - Effect of a demyelinating lesion on conduction in the central nervous system studied in single nerve fibres. McDonald, Sears.
  • J Physiol, Aug 1971 - Internodal conduction in normal and demyelinated mammalian single nerve fibres. Rasminsky, Sears.
  • Br Med J, Dec 1972 - Temperature change and multiple sclerosis. McDonald, Sears.
  • Arch Neurol, May 1973 - The effects of temperature on conduction in demyelinated single nerve fibers. Rasminsky.
  • Nature, Oct 1976 - Continuous conduction in demyelinated mammalian nerve fibers. Bostock, Sears.
  • Nature, July 1978 - Overcoming conduction failure in demyelinated nerve fibres by prolonging action potentials. Bostock, Sheratt, Sears.
  • Neurology, Sep 1978 - The pathophysiology of demyelination and its implications for the symptomatic treatment of multiple sclerosis. Sears, Bostock, Sheratt.
  • Nature, Feb 1980 - Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres. Sheratt, Bostock, Sears
  • J Physiol, 1981 - The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres. Bostock, Sears, Sherratt.
  • J Physiol, July 1983 - Potassium channel distribution in spinal root axons of dystrophic mice. Bostock, Rasminsky.
  • J Physiol, Oct 1989 - Functional consequences of demyelination. Rasminsky, Sears.
1983: First clinical study of 4-AP in MS, effects on visual function

  • J Neurol Sci, Aug-Sep 1983 - Effects of 4-aminopyridine in patients with multiple sclerosis. 10 patients. Jones, Heron, Foster, Snelgar, Mason. University of Keele, Staffordshire, England.

Early Research in New England, USA (1977-1994):
Bowe, Kocsis, Targ, Waxman, et al.

  • Arch Neurol, Oct 1977 - Conduction in myelinated, unmyelinated, and demyelinated fibers. Waxman.
  • Brain Res, Aug 1980 - Effects of 4-aminopyridine on the frequency following properties of the parallel fibers of the cerebellar cortex. Kocsis, Malenka, Waxman.
  • Exp Neurol, Mar 1983 - Effects of 4-aminopyridine on rapidly and slowly conducting axons of rat corpus callosum. Preston, Waxman, Kocsis.
  • J Neurophysiol, Aug 1983 - Maturation of mammalian myelinated fibers: changes in action-potential characteristics following 4-aminopyridine application. Kocsis, Ruiz, Waxman.
  • Nature, Aug 1983 - Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents. Kocsis, Waxman.
  • Exp Brain Res, 1985 - Aminopyridine-sensitivity of spinal cord white matter studied in vitro. Kocsis.
  • Brain Res, Mar 1985 - 4-Aminopyridine leads to restoration of conduction in demyelinated rat sciatic nerve. Targ, Kocsis.
  • Neurology, Jan 1986 - Different effects of 4-aminopyridine on sensory and motor fibers: pathogenesis of paresthesias. Kocsis, Bowe, Waxman.
  • Neurosci Lett, Mar 1987 - Functional differences between 4-aminopyridine and tetraethylammonium-sensitive potassium channels in myelinated axons. Kocsis, Eng, Gordon, Waxman.
  • Ann Neurol, Aug 1987 - Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Bowe, Kocsis, Targ, Waxman. Brown University, Providence.
  • J Neurophysiol, Dec 1988 - Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers. Eng, Gordon, Kocsis, Waxman. Yale University School of Medicine, New Haven.
  • J Neurol Sci, June 1989 - Demyelination in spinal cord injury. Waxman. Yale University School of Medicine, New Haven.
  • J Neurotrauma, Mar 1992 - Demyelination in spinal cord injury and multiple sclerosis: what can we do to enhance functional recovery? Waxman. Yale University School of Medicine, New Haven.
  • J Neurotrauma, Spring 1993 - Aminopyridines and the treatment of spinal cord injury. Waxman. Yale University School of Medicine, New Haven.
  • Res Publ Assoc Res Nerv Ment Dis, 1993 - Pharmacological modification of axon membrane molecules and cell transplantation as approaches to the restoration of conduction in demyelinated axons. Kocsis, Black, Waxman. Yale University School of Medicine, New Haven.
  • Prog Brain Res, 1994 - Enhancement of action potential conduction following demyelination: experimental approaches to restoration of function in multiple sclerosis and spinal cord injury. Waxman, Utzschneider, Kocsis. Yale University School of Medicine, New Haven.
Early Research in Chicago, USA (1974-1991):
Schauf, Davis, Stefoski, et al.
  • J Neurol Neurosurg Psychiatry, Feb 1974 - Impulse conduction in multiple sclerosis: a theoretical basis for modification by temperature and pharmacological agents. Schauf, Davis.
  • J Pharmacol Exp Ther, 1976 - Aminopyridines and sparteine as inhibitors of membrane potassium conductance: effects on Myxicola giant axons and the lobster neuromuscular junction. Schauf, Colton, Colton, Davis.
  • Adv Neurol, 1981 - Approaches to the development of pharmacological interventions in multiple sclerosis. Davis, Schauf.
  • Experientia, Feb 1987 - Selective blockade of components of potassium activation in Myxicola axons. Chauman, Schauf, Davis, Stefoski. Rush Multiple Sclerosis Center, Chicago.

1987-1991: Series of Clinical Studies of 4-AP in MS, effects on motor function

  • Ann Neurol, Jan 1987 - 4-Aminopyridine improves clinical signs in multiple sclerosis. 12 male heat-sensitive patients. IV treatment. Stefoski, Davis, Faut, Schauf. Rush Multiple Sclerosis Center, Chicago.
  • Ann Neurol, Feb 1990 - Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. 20 heat-sensitive male patients. Davis, Stefoski, Rush. Rush Multiple Sclerosis Center, Chicago.
  • Neurology, Sep 1991 - 4-Aminopyridine in multiple sclerosis: prolonged administration. 17 heat-sensitive male patients. Stefoski, Davis, Fitzsimmons, Luskin, Rush, Parkhurst. Rush Multiple Sclerosis Center, Chicago.
In 1990, Elan licensed from Rush-Presbyterian Hospital in Chicago the Know-How related to fampridine (4-aminopyridine) for treatment of multiple sclerosis.

Research in Amsterdam, The Netherlands (1990-1996):
First large study of 4-AP in MS, broad effects on disability (EDSS) dose and serum level related to efficacy and safety plasma levels variable and difficult to control with Immediate Release form
van Diemen, Polman, Bertelsmann, et al.
  • Ann Neurol, Oct 1990 - 4-Aminopyridine in multiple sclerosis.
    Polman, van Diemen, van Dongen, Koetsier, van Loenen, van Walbeek.
  • J Chromatogr, Feb 1992 - Determination of 4-aminopyridine in serum by solid-phase extraction and high-performance liquid chromatography. van der Horst, de Goede, van Diemen, Polman, Martens. Free University Hospital, Amsterdam.
  • Ann Neurol, Aug 1992 - The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. 70 patients. van Diemen, Polman, van Dongen, van Loenen, Nauta, Taphoorn, van Walbeek, Koetsier. Free University Hospital, Amsterdam.
  • J Neurol Sci, Jun 1993 - 4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. 70 patients. van Diemen, Polman, van Dongen, Nauta, Strijers, van Loenen, Bertelsmann, Koetsier. Free University Hospital, Amsterdam.
  • Clin Neuropharmacol, Jun 1993 - 4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety. 70 patients. van Diemen, Polman, Koetsier, Van Loenen, Nauta, Bertelsmann. Free University Hospital, Amsterdam.
  • Arch Neurol, Mar 1994 - 4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. 31 patients. Polman, Bertelsmann, van Loenen, Koetsier. Free University Hospital, Amsterdam.
  • Neurology, Sep 1994 - The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. 20 patients. Smits, Emmen, Bertelsmann, Kulig, van Loenen, Polman. Free University Hospital, Amsterdam.
  • Arch Neurol, Nov 1994 - 4-Aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis. 24 patients. Polman, Bertelsmann, de Waal, van Diemen, Uitdehaag, van Loenen, Koetsier. Free University Hospital, Amsterdam.
  • Mult Scler, Feb 1996 - Magnetic resonance imaging of epilepsy in multiple sclerosis: a case control study. Implications for treatment trials with 4-aminopyridine. Truyen, Barkhof, Frequin, Polman, Tobi, Hommes, Valk. Free University Hospital, Amsterdam.
Later in September 2003, Acorda Therapeutics entered into agreements with Rush and Elan terminating the Rush license to Elan with mutual releases. In the process Rush granted Acorda worldwide license to the Know-How and Orphan Drug Designation to fampridine for treatment in MS.

More to come...

3 comments:

  1. Wow, that sure is a lot of years of research, and what to show for it? This is the course of MS research...slow, labored, chronic and progessively causes agony. No, wait---that's MY course. Hmmmm

    ReplyDelete
  2. Wow, you have done your homework. I should probably do the same.

    ReplyDelete
  3. Interesting, I am have to come back and read all the links. Thanks for the time you put in researching this.

    ReplyDelete