Effects of 4-aminopyridine on neuromuscular transmission

doi:10.1016/0006-8993(78)90409-2

Brain Research

Volume 153, Issue 2, 22 September 1978, Pages 307-318

https://doi.org/10.1016/0006-8993(78)90409-2 Get rights and content

Summary

4-Aminopyridine (4-AP) powerfully increases transmitter release from motor nerve terminals of rat and frog skeletal muscle in response to single nerve impulses. The drug also enhances transmitter release during repititive nerve activity but, atd-tubocurarine-blocked endplates, only the first impulses cause increased transmitter release at stimulation frequencies at or above 50 Hz. At magnesium- and botulinum-poisoned endplates, 4-AP potentiates transmitter release at every stimulus during tetanic nerve stimulation and restores neuromuscular transmission. Spontaneous transmitter release in the rat is not affected by the drug, but at some frog endplates miniature endplate potential (mepp) frequency increases. The drug has no post-synaptic action, as evidenced by its lack of effect on amplitude or time course of meps. Decreasing the temperature from 37 to 15°C does not abolish the effect of 4-AP on neuromuscular transmission. In the presence of 4-AP, single nerve impulses produce repetitive spontaneous activity in the nerve terminal of the frog nerve-muscle preparation.

Experiments on the mode of action of 4-AP suggest that the drug increases transmitter release by enhancing the influx of calcium ions during depolarization of the nerve terminal.

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Cited by (140)

4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis
2013, Experimental Neurology
Citation Excerpt :
Therefore it may be speculated that 4-AP induces the expression of ion channels that facilitates action potential conduction in demyelinated fibers. Alternative mechanisms of actions of 4-AP including increased presynaptic transmitter release, which in turn enhance postsynaptic response, have been discussed (Kim et al., 1980; Lundh, 1978; Smith et al., 2000). The finding that 4-AP potentiates neuromuscular transmission by targeting the voltage-activated Ca2 + channel β subunit raises the possibility that 4-AP may directly stimulate Ca2 + channel in addition to its effect on KV channels thereby exerting synergistic effects (Wu et al., 2009).
Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (K_V) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the K_V-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG_35–55 immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties.
Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4⁺ T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, K_V channel inhibition neither influenced CD4⁺ T cell effector functions (proliferation, IL17 or IFNγ production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 ± 0.03, n = 7 versus 0.399 ± 0.08, n = 14, p < 0.001, respectively).
Our data suggest that 4-AP while having no apparent immunomodulatory or direct neuroprotective effects, significantly ameliorates conduction abnormalities thereby improving gait and coordination. Improvement of mobility in this experimental model supports trial data and clinical experience with 4-AP in the symptomatic treatment of MS.
The Safety Profile of Dalfampridine Extended Release in Multiple Sclerosis Clinical Trials
2012, Clinical Therapeutics
Citation Excerpt :
Although it has been extensively used for the investigation and characterization of potassium channels in laboratory studies for many decades, most of this work has involved millimolar concentrations that are not directly relevant to clinical experience, which is associated with plasma concentrations typically <1 μM. A number of laboratory studies have suggested that dalfampridine is able to relieve conduction block in demyelinated axons,9–12 as well as potentiate synaptic and neuromuscular transmission in some conditions,13–15 although the concentration dependence of these effects has not been fully elucidated. During the past 30 years, published studies have reported on the use of dalfampridine, initially in simple, immediate-release (IR) formulations, for treatment of various neurologic conditions.16–26
Dalfampridine (fampridine outside the United States) is a broad-spectrum potassium channel blocker. Dalfampridine extended-release tablets have been approved by the US Food and Drug Administration to improve walking in patients with multiple sclerosis (MS).
The objective of this article is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in patients with MS.
We reviewed published data relevant to patient safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the US Food and Drug Administration.
The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and “other” (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes. However, in patients with renal impairment (creatinine clearance [CrCl], ≤80 mL/min), mean peak plasma concentrations were 68%–101% higher and apparent clearance was 43%–73% lower relative to those without impairment, precluding dalfampridine use in patients with moderate (CrCl, 30–50 mL/min) or severe renal impairment (CrCl, <30 mL/min). Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system. A thorough QT study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses. Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in patients with no history of seizure, is not likely to be higher than background rates in MS.
In patients with MS, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily.
Pharmacokinetics of <sup>14</sup>C-radioactivity after oral intake of a single dose of <sup>14</sup>C-labeled fampridine (4-aminopyridine) in healthy volunteers
2009, Clinical Therapeutics
Background: Fampridine (4-aminopyridine) is a potassium channel blocker that has been evaluated as a treatment for patients with spinal cord injury and multiple sclerosis.
Objective: The purpose of this study was to determine the pharmacokinetics of a single dose of an orally administered solution of ¹⁴C-labeled fampridine in healthy volunteers.
Methods: In this open-label, single-dose study conducted in an inpatient setting, healthy adult men were administered an oral solution containing 15 mg of ¹⁴C-labeled fampridine (100 μCi) in a fasted state. In addition to blood sampling for analysis of plasma ¹⁴C-radioactivity at prescribed intervals over 7 days, all urine and feces were collected for analysis of drug recovery and disposition. Urine samples were also analyzed for metabolic profiling. Plasma pharmacokinetic parameters of the ¹⁴C-radiolabeled drug were determined using standard liquid-scintillation techniques. Recovery was calculated to provide the total amount of radioactivity excreted as a proportion of the original dose. Nonhydrolyzed and hydrolyzed urine extracts were analyzed for radioactivity and metabolites using reverse-phase, isocratic high-performance liquid chromatography with spectrophotometric and radioactive detection. Tolerability was assessed through evaluation of vital signs, hematologic and other laboratory parameters, and electrocardiography.
Results: The 4 white male subjects had a mean (SD) age of 21 (2) years. No clinically significant abnormalities in vital signs, clinical chemistry, hematology, urinalysis, or electrocardiography were observed either before or during the study. Peak plasma radioactivity was reached at 1 hour after dosing, with a median concentration of 72.9 ng · mL⁻¹. There was complete disappearance of radioactivity by 24 hours (limit of quantitation, 400 disintegrations/min per peak), and the calculated median t_1/2 was 3.14 hours. Total cumulative recovery of ¹⁴C-radioactivity was 96.36%, with only 0.51% of drug recovered in feces. On chromatography, 2 metabolites accounted for a low proportion of total urinary radioactivity (3% and 6% of total radioactivity in the interval from 0 to 4 hours after dosing; 17% and 9% in the interval from 8 to 12 hours after dosing). Three subjects reported mild and transient dizziness occurring 1 half-hour after dosing; this was considered possibly related to the study drug.
Conclusion: Fampridine administered as an oral solution was rapidly absorbed and was nearly completely and rapidly eliminated as unchanged drug via urinary excretion, suggesting that it is unlikely to undergo substantial metabolic transformation.
Seizures are a druggable mechanistic link between tbi and subsequent tauopathy
2021, eLife
Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice
2020, Neural Regeneration Research
Seizures are a druggable mechanistic link between TBI and subsequent tauopathy
2020, bioRxiv

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Effects of 4-aminopyridine on neuromuscular transmission

Summary

Neuropharmacology

J. neurol. Sci.

Europ. J. Pharmacol.

Biophys. J.

The nature of the neuromuscular block produced by magnesium

J. Physiol. (Lond.)

Quantal components of the end-plate potential

J. Physiol. (Lond.)

Effects of botulinum toxin on neuromuscular transmission in the rat

J. Physiol. (Lond.)

A quantitative study of end-plate potentials in isolated human muscle

J. Physiol. (Lond.)

The analysis of the mode of action of curare on neuromuscular transmission; the effect of temperature changes

J. Pharmacol. exp. Ther.

Synaptic transmission in the sixth ganglion of the cockroach: action of 4-aminopyridine

J. exp. Biol.

The release of acetylcholine from nerve endings by graded electric pulses