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  1. Article ; Online: Chloroquine and hydroxychloroquine provoke arrhythmias at concentrations higher than those clinically used to treat COVID‐19

    Jun‐ichi Okada / Takashi Yoshinaga / Takumi Washio / Kohei Sawada / Seiryo Sugiura / Toshiaki Hisada

    Clinical and Translational Science, Vol 14, Iss 3, Pp 1092-

    A simulation study

    2021  Volume 1100

    Abstract: Abstract The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID‐19), but the reported number of life‐threatening arrhythmic events or deaths is relatively small. ... ...

    Abstract Abstract The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID‐19), but the reported number of life‐threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 μM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L‐type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch‐clamp system. Using the concentration–inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life‐threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 μM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. ...
    Keywords Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
    Subject code 610
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Effect of myofibril passive elastic properties on the mechanical communication between motor proteins on adjacent sarcomeres

    Takumi Washio / Seine A. Shintani / Hideo Higuchi / Seiryo Sugiura / Toshiaki Hisada

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 17

    Abstract: Abstract Rapid sarcomere lengthening waves propagate along a single muscle myofibril during spontaneous oscillatory contraction (SPOC). In asynchronous insect flight muscles, SPOC is thought to be almost completely synchronized over the entire myofibril. ...

    Abstract Abstract Rapid sarcomere lengthening waves propagate along a single muscle myofibril during spontaneous oscillatory contraction (SPOC). In asynchronous insect flight muscles, SPOC is thought to be almost completely synchronized over the entire myofibril. This phenomenon does not require Ca2+ regulation of the dynamics of the motor proteins, and cannot be explained simply by the longitudinal mechanical equilibrium among sarcomeres in the myofibril. In the present study, we rationalize these phenomena by considering the lateral mechanical equilibrium, in which two tensions originating from the inverse relationship between sarcomere length and lattice spacing, along with the lattice alignment, play important roles in the mechanical communication between motor proteins on adjacent filaments via the Z-disc. The proposed model is capable of explaining various SPOC phenomena based on the stochastic power-stroke mechanism of motor proteins, which responds to temporal changes in longitudinal mechanical load.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Enhancement of force generated by individual myosin heads in skinned rabbit psoas muscle fibers at low ionic strength.

    Haruo Sugi / Takahiro Abe / Takakazu Kobayashi / Shigeru Chaen / Yoshiki Ohnuki / Yasutake Saeki / Seiryo Sugiura

    PLoS ONE, Vol 8, Iss 5, p e

    2013  Volume 63658

    Abstract: Although evidence has been presented that, at low ionic strength, myosin heads in relaxed skeletal muscle fibers form linkages with actin filaments, the effect of low ionic strength on contraction characteristics of Ca(2+)-activated muscle fibers has not ...

    Abstract Although evidence has been presented that, at low ionic strength, myosin heads in relaxed skeletal muscle fibers form linkages with actin filaments, the effect of low ionic strength on contraction characteristics of Ca(2+)-activated muscle fibers has not yet been studied in detail. To give information about the mechanism of muscle contraction, we have examined the effect of low ionic strength on the mechanical properties and the contraction characteristics of skinned rabbit psoas muscle fibers in both relaxed and maximally Ca(2+)-activated states. By progressively decreasing KCl concentration from 125 mM to 0 mM (corresponding to a decrease in ionic strength μ from 170 mM to 50 mM), relaxed fibers showed changes in mechanical response to sinusoidal length changes and ramp stretches, which are consistent with the idea of actin-myosin linkage formation at low ionic strength. In maximally Ca(2+)-activated fibers, on the other hand, the maximum isometric force increased about twofold by reducing KCl concentration from 125 to 0 mM. Unexpectedly, determination of the force-velocity curves indicated that, the maximum unloaded shortening velocity Vmax, remained unchanged at low ionic strength. This finding indicates that the actin-myosin linkages, which has been detected in relaxed fibers at low ionic strength, are broken quickly on Ca(2+) activation, so that the linkages in relaxed fibers no longer provide any internal resistance against fiber shortening. The force-velocity curves, obtained at various levels of steady Ca(2+)-activated isometric force, were found to be identical if they are normalized with respect to the maximum isometric force. The MgATPase activity of muscle fibers during isometric force generation was found not to change appreciably at low ionic strength despite the two-fold increase in Ca(2+)-activated isometric force. These results can be explained in terms of enhancement of force generated by individual myosin heads, but not by any changes in kinetic properties of cyclic actin-myosin interaction.
    Keywords Medicine ; R ; Science ; Q
    Subject code 796 ; 612
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Definite differences between in vitro actin-myosin sliding and muscle contraction as revealed using antibodies to myosin head.

    Haruo Sugi / Shigeru Chaen / Takakazu Kobayashi / Takahiro Abe / Kazushige Kimura / Yasutake Saeki / Yoshiki Ohnuki / Takuya Miyakawa / Masaru Tanokura / Seiryo Sugiura

    PLoS ONE, Vol 9, Iss 2, p e

    2014  Volume 93272

    Abstract: Muscle contraction results from attachment-detachment cycles between myosin heads extending from myosin filaments and actin filaments. It is generally believed that a myosin head first attaches to actin, undergoes conformational changes to produce force ... ...

    Abstract Muscle contraction results from attachment-detachment cycles between myosin heads extending from myosin filaments and actin filaments. It is generally believed that a myosin head first attaches to actin, undergoes conformational changes to produce force and motion in muscle, and then detaches from actin. Despite extensive studies, the molecular mechanism of myosin head conformational changes still remains to be a matter for debate and speculation. The myosin head consists of catalytic (CAD), converter (CVD) and lever arm (LD) domains. To give information about the role of these domains in the myosin head performance, we have examined the effect of three site-directed antibodies to the myosin head on in vitro ATP-dependent actin-myosin sliding and Ca2+-activated contraction of muscle fibers. Antibody 1, attaching to junctional peptide between 50K and 20K heavy chain segments in the CAD, exhibited appreciable effects neither on in vitro actin-myosin sliding nor muscle fiber contraction. Since antibody 1 covers actin-binding sites of the CAD, one interpretation of this result is that rigor actin-myosin linkage is absent or at most a transient intermediate in physiological actin-myosin cycling. Antibody 2, attaching to reactive lysine residue in the CVD, showed a marked inhibitory effect on in vitro actin-myosin sliding without changing actin-activated myosin head (S1) ATPase activity, while it showed no appreciable effect on muscle contraction. Antibody 3, attaching to two peptides of regulatory light chains in the LD, had no significant effect on in vitro actin-myosin sliding, while it reduced force development in muscle fibers without changing MgATPase activity. The above definite differences in the effect of antibodies 2 and 3 between in vitro actin-myosin sliding and muscle contraction can be explained by difference in experimental conditions; in the former, myosin heads are randomly oriented on a glass surface, while in the latter myosin heads are regularly arranged within filament-lattice structures.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612 ; 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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