Differential Inhibition by Cenobamate of Canonical Human Nav1.5 Ion Channels and Several Point Mutants.

Cenobamate is a new and highly effective antiseizure compound used for the treatment of adults with focal onset seizures and particularly for epilepsy resistant to other antiepileptic drugs. It acts on multiple targets, as it is a positive allosteric activator of γ-aminobutyric acid type A (GABA) receptors and an inhibitor of neuronal sodium channels, particularly of the late or persistent Na current. We recently evidenced the inhibitory effects of cenobamate on the peak and late current component of the human cardiac isoform hNav1.

Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences.

Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABA receptors (EC 42-194 µM) and persistent neuronal Na currents (IC 59 µM). Side effects include QT interval shortening with >20 ms, but not <300 ms. Our in vitro cardiac safety pharmacology study was performed via whole-cell patch-clamp on HEK293T cells with persistent/inducible expression of human cardiac ion channel isoforms hNav1.

Kinetics methods for clinical epidemiology problems.

Calculating the probability of each possible outcome for a patient at any time in the future is currently possible only in the simplest cases: short-term prediction in acute diseases of otherwise healthy persons. This problem is to some extent analogous to predicting the concentrations of species in a reactor when knowing initial concentrations and after examining reaction rates at the individual molecule level. The existing theoretical framework behind predicting contagion and the immediate outcome of acute diseases in previously healthy individuals is largely analogous to deterministic kinetics of chemical systems consisting of one or a few reactions.

Proposed principles of maximum local entropy production.

Articles have appeared that rely on the application of some form of "maximum local entropy production principle" (MEPP). This is usually an optimization principle that is supposed to compensate for the lack of structural information and measurements about complex systems, even systems as complex and as little characterized as the whole biosphere or the atmosphere of the Earth or even of less known bodies in the solar system. We select a number of claims from a few well-known papers that advocate this principle and we show that they are in error with the help of simple examples of well-known chemical and physical systems.

Stability and sustained oscillations in a ventricular cardiomyocyte model.

The Luo-Rudy I model, describing the electrophysiology of a ventricular cardiomyocyte, is associated with an 8-dimensional discontinuous dynamical system with logarithmic and exponential non-linearities depending on 15 parameters. The associated stationary problem was reduced to a nonlinear system in only two unknowns, the transmembrane potential V and the intracellular calcium concentration [Ca]( i ). By numerical approaches appropriate to bifurcation problems, sections in the static bifurcation diagram were determined.

Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. A simulation study.

Background: Increasing the predictability and reducing the rate of side effects of oral anticoagulant treatment (OAT) requires further clarification of the cause of about 50% of the interindividual variability of OAT response that is currently unaccounted for. We explore numerically the hypothesis that the effect of the interindividual expression variability of coagulation proteins, which does not usually result in a variability of the coagulation times in untreated subjects, is unmasked by OAT.

Results: We developed a stochastic variant of the Hockin-Mann model of the tissue factor coagulation pathway, using literature data for the variability of coagulation protein levels in the blood of normal subjects.

Kinetic laws, phase-phase expansions, renormalization group, and INR calibration.

We introduce systematic approaches to chemical kinetics based on the use of phase-phase (log-log) representations of the rate equations. For slow processes, we obtain a corrected form of the mass-action law, where the concentrations are replaced by kinetic activities. For fast reactions, delay expressions are derived.

Incremental parameter evaluation from incomplete data with application to the population pharmacology of anticoagulants.

We develop a method for parameter evaluation from incomplete data. Improved estimates of the desired parameters are evaluated step by step, from experiment to experiment by using both Bayesian and informational methods. We make dynamical, improved predictions while the experiments are still going on and keep and interpret information about local fluctuations, which is lost on applying global techniques.

On anti-portfolio effects in science and technology with application to reaction kinetics, chemical synthesis, and molecular biology.

The portfolio effect is the increase of the stability of a system to random fluctuations with the increase of the number of random state variables due to spreading the risk among these variables; many examples exist in various areas of science and technology. We report the existence of an opposite effect, the decrease of stability to random fluctuations due to an increase of the number of random state variables. For successive industrial or biochemical processes of independent, random efficiencies, the stability of the total efficiency decreases with the increase of the number of processes.

Susceptibility for ventricular tachycardia and the correlation between depolarization and orthogonal components of repolarization.

Objective: There is a continuing need of methods to identify subgroups of patients at high risk of ventricular arrhythmias, in particular after myocardial infarction (MI).

Methods: We performed a singular value decomposition of repolarization potentials in individual recordings in 134 healthy males, in 203 males with old MI and without documented sustained ventricular tachycardia (VT) and in 104 MI males with documented VT. We considered the absolute correlation coefficient between the first orthogonal component, constructed by matrix multiplication of the first left and right singular vectors and the QRS integral (RT1) and a similar index for the second component (RT2).

Clinical use of body surface potential mapping in cardiac arrhythmias.

The electrocardiology and specifically body surface potential maps (BSPM) have two main objectives in the arrhythmologic field: 1) identification of signs of susceptibility to arrhythmias, and 2) identification of site of origin of the arrhythmias. In order to detect the susceptibility to ventricular arrhythmias, maps were recorded with different lead systems by different authors and, in particular, various methods of analysis of BSPM have been used to study repolarization potentials: QRST integral maps, eigenvector analysis, principal component analysis, autocorrelation analysis. From these analyses several markers of vulnerability to arrhythmias were identified, which demonstrated a predictive accuracy of various degree in selected patient populations.

The effect of intrathoracic heart position on electrocardiogram autocorrelation maps.

We studied the influence of the heart position in the thorax on the autocorrelation (AC) maps consisting of correlation coefficients between each pair of instantaneous electrocardiogram potential distributions over a time interval. We used a thorax-shaped electrolytic-filled tank with an isolated and perfused dog heart placed at positions spanning 5 cm on each space direction. The correlation coefficient between QRST AC maps was in the range of 0.

Prognostic value of heart rate variability after acute myocardial infarction.

Background: Prognosis after acute myocardial infarction (AMI) may be influenced by autonomic dysfunction that can be evaluated by assessment of heart rate variability (HRV). Its predictive value resulted from studies performed prior to large scale use of reperfusion therapy. We assessed the prognostic value of HRV parameters 1 year after AMI in patients treated conventionally or by a reperfusion method in the first 12 hours from onset.