Reported direct aminopyridine effects on voltage-gated calcium channels is a high-dose pharmacological off-target effect of no clinical relevance

SD Meriney, D Lacomis - The Journal of Biological Chemistry, 2018 - ncbi.nlm.nih.gov
SD Meriney, D Lacomis
The Journal of Biological Chemistry, 2018ncbi.nlm.nih.gov
Wu et al.(1) present high-quality data, but we challenge their interpretation that they relate to
the therapeutic use of aminopyridines (4-aminopyridine (4-AP) and 3, 4-diaminopyridine
(DAP)). They argue that their results highlight an alternative mechanism of action for
aminopyridines that is distinct from the conventional view that these drugs are potassium
channel blockers and discuss their results in the context of therapy for multiple sclerosis,
spinal cord injury, myasthenia gravis, and Lambert-Eaton syndrome. Importantly, the …
Wu et al.(1) present high-quality data, but we challenge their interpretation that they relate to the therapeutic use of aminopyridines (4-aminopyridine (4-AP) and 3, 4-diaminopyridine (DAP)). They argue that their results highlight an alternative mechanism of action for aminopyridines that is distinct from the conventional view that these drugs are potassium channel blockers and discuss their results in the context of therapy for multiple sclerosis, spinal cord injury, myasthenia gravis, and Lambert-Eaton syndrome. Importantly, the concentration range over which Wu et al.(1) studied aminopyridine effects (0.1–10 mM) does not cover the clinically relevant concentration range (0.5–10 μM; 1000 less). Clinical data using 4-AP for multiple sclerosis (2) or DAP for Lambert-Eaton myasthenic syndrome (3) show that patients are given 8–70 mg of 4-AP and 10–20 mg of DAP, which, based on pharmacokinetics (4, 5), would be predicted to produce a maximum plasma concentration 10 μM (and typically 0.3–1 μM). Based on their reported concentration-response relationships (1), we predict no effects of aminopyridines on calcium channels at low micromolar concentrations. Wu et al.’s interpretation of their data is a serious issue for investigators developing therapeutic approaches that employ aminopyridines, as reviewers of new proposals and publications may be unaware of these concentration-dependent effects of aminopyridines. We conclude that the traditional view of aminopyridine action in the clinical context (selective potassium channel antagonists that broaden the neuronal action potential, indirectly increasing the calcium flux and transmitter release) is not challenged by the data presented by Wu et al.(1).
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