eprintid: 10151845
rev_number: 22
eprint_status: archive
userid: 699
dir: disk0/10/15/18/45
datestamp: 2022-07-12 09:32:54
lastmod: 2024-10-25 15:45:38
status_changed: 2022-12-08 17:33:28
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Ruijs, Titia Q
creators_name: Koopmans, Ingrid W
creators_name: de Kam, Marieke L
creators_name: van Esdonk, Michiel J
creators_name: Koltzenburg, Martin
creators_name: Groeneveld, Geert Jan
creators_name: Heuberger, Jules AAC
title: Effects of mexiletine and lacosamide on nerve excitability in healthy subjects: a randomized, double-blind, placebo-controlled, crossover study
ispublished: pub
subjects: UCH
divisions: C07
divisions: F84
divisions: B02
divisions: UCL
divisions: D07
note: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. See: http://creativecommons.org/licenses/by-nc-nd/4.0/
abstract: Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double-blind, 3-way crossover study, effects of single oral doses of 333 mg mexiletine and 300 mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd40 (40–60 ms)) decreased by mexiletine (estimated difference (ED) −1.37% (95% confidence interval (CI): −2.20, −0.547; P = 0.002) and lacosamide (ED −1.27%, 95% CI: −2.10, −0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength-duration time constant decreased after lacosamide in motor- (ED −0.0342 ms, 95% CI: −0.0571, −0.0112; P = 0.005) and sensory nerves (ED −0.0778 ms, 95% CI: −0.116, −0.0399; P < 0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.
date: 2022-07-19
date_type: published
publisher: Wiley
official_url: https://doi.org/10.1002/cpt.2694
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1964458
doi: 10.1002/cpt.2694
medium: Print-Electronic
lyricists_name: Koltzenburg, Martin
lyricists_id: MKOLT33
actors_name: Koltzenburg, Martin
actors_id: MKOLT33
actors_role: owner
full_text_status: public
publication: Clinical Pharmacology & Therapeutics
volume: 112
number: 5
pagerange: 1008-1019
event_location: United States
citation:        Ruijs, Titia Q;    Koopmans, Ingrid W;    de Kam, Marieke L;    van Esdonk, Michiel J;    Koltzenburg, Martin;    Groeneveld, Geert Jan;    Heuberger, Jules AAC;      (2022)    Effects of mexiletine and lacosamide on nerve excitability in healthy subjects: a randomized, double-blind, placebo-controlled, crossover study.                   Clinical Pharmacology & Therapeutics , 112  (5)   pp. 1008-1019.    10.1002/cpt.2694 <https://doi.org/10.1002/cpt.2694>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10151845/1/Koltzenburg_Clin%20Pharma%20and%20Therapeutics%20-%202022%20-%20Ruijs%20-%20Effects%20of%20Mexiletine%20and%20Lacosamide%20on%20Nerve%20Excitability%20in%20Healthy.pdf