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Article ; Online: Impact of refractory and unexplained chronic cough on disease burden: a qualitative study.

Ueda, Naoya / Yakushiji, Anzu / Schelfhout, Jonathan / Tokita, Shigeru / Kubo, Takekazu

2022 Volume 22, Issue 1, Page(s) 372

Abstract: Background: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese ... ...

Abstract	Background: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin). Methods: This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized. Results: A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word ('cough'); etiology ('asthma'); and words associated with change in states ('influence,' 'changing,' 'change') and expressions ('tough,' 'pain,' 'hard,' 'terrible,' 'unpleasant'). The patients experienced 'mental/social burden,' 'physical burden,' 'impact on sleep and meals,' 'impact on work and housework,' 'impact on communication,' 'impact on hobbies and leisure,' and 'economic burden.' By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern. Conclusions: The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted 'mental burden,' on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough. Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110).
MeSH term(s)	Chronic Disease ; Cost of Illness ; Cough/psychology ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Qualitative Research
Language	English
Publishing date	2022-10-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2059871-3
ISSN	1471-2466 ; 1471-2466
ISSN (online)	1471-2466
ISSN	1471-2466
DOI	10.1186/s12890-022-02171-z
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Article ; Online: Proton conductivity in mixed cation phosphate, KMg

Matsuda, Yasuaki / Ueda, Naoya / Funakoshi, Kousei / Nakajima, Jun / Mori, Daisuke / Taminato, Sou / Higashimoto, Shinya

Dalton transactions (Cambridge, England : 2003)

2021 Volume 50, Issue 22, Page(s) 7678–7685

Abstract: Proton solid electrolytes, which exhibit high proton conductivity at a wide range of low-intermediate temperatures (150-300 °C), are key materials for the development of fuel cells for automobiles and cogeneration systems. In this study, a benitoite-type ...

Abstract	Proton solid electrolytes, which exhibit high proton conductivity at a wide range of low-intermediate temperatures (150-300 °C), are key materials for the development of fuel cells for automobiles and cogeneration systems. In this study, a benitoite-type polyphosphate, KMg1-xH2x(PO3)·yH2O, which has a non-combustible and layered structure, was investigated as a new proton conductor. The benitoite-type KMg1-xH2x(PO3)·yH2O was synthesised by a coprecipitation method. The solid solution formed in the range of x = 0-0.100 in KMg1-xH2x(PO3)3·yH2O. Multi-step weight loss due to dehydration was observed for TG/DTA measurement at 30 °C and 150 °C. We observed enhanced peaks of the vibration bands at around 1117 cm-1 and 1229 cm-1, which were attributed to the symmetric and asymmetric PO2 vibration modes, and at 743 cm-1 and 970 cm-1 due to the ns(P-O-P) and nas(P-O-P) modes as well as broad absorbance peaks at 2300 cm-1 and 2700 cm-1 corresponding to the vibration modes of ns(P-O-H) with increasing x for FTIR spectra, which suggest the introduction of protons to the crystal structure. Proton conductivity increased from x = 0 to 0.10 and then decreased at x = 0.125, where the impurity phase was observed. The sample with x = 0.10 in benitoite-type KMg1-xH2x(PO3)3·yH2O exhibited high proton conductivity of 1.4 × 10-3 S cm-1 at 150 °C and 6.5 × 10-3 S cm-1 at 250 °C under a non-humidified N2 gas flow.
Language	English
Publishing date	2021-05-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1472887-4
ISSN	1477-9234 ; 1364-5447 ; 0300-9246 ; 1477-9226
ISSN (online)	1477-9234 ; 1364-5447
ISSN	0300-9246 ; 1477-9226
DOI	10.1039/d1dt01187a
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Article ; Online: Exploring Neurofeedback Training for BMI Power Augmentation of Upper Limbs: A Pilot Study.

Liang, Hongbo / Maedono, Shota / Yu, Yingxin / Liu, Chang / Ueda, Naoya / Li, Peirang / Zhu, Chi

Entropy (Basel, Switzerland)

2021 Volume 23, Issue 4

Abstract: Electroencephalography neurofeedback (EEG-NFB) training can induce changes in the power of targeted EEG bands. The objective of this study is to enhance and evaluate the specific changes of EEG power spectral density that the brain-machine interface (BMI) ...

Abstract	Electroencephalography neurofeedback (EEG-NFB) training can induce changes in the power of targeted EEG bands. The objective of this study is to enhance and evaluate the specific changes of EEG power spectral density that the brain-machine interface (BMI) users can reliably generate for power augmentation through EEG-NFB training. First, we constructed an EEG-NFB training system for power augmentation. Then, three subjects were assigned to three NFB training stages, based on a 6-day consecutive training session as one stage. The subjects received real-time feedback from their EEG signals by a robotic arm while conducting flexion and extension movement with their elbow and shoulder joints, respectively. EEG signals were compared with each NFB training stage. The training results showed that EEG beta (12-40 Hz) power increased after the NFB training for both the elbow and the shoulder joints' movements. EEG beta power showed sustained improvements during the 3-stage training, which revealed that even the short-term training could improve EEG signals significantly. Moreover, the training effect of the shoulder joints was more obvious than that of the elbow joints. These results suggest that NFB training can improve EEG signals and clarify the specific EEG changes during the movement. Our results may even provide insights into how the neural effects of NFB can be better applied to the BMI power augmentation system and improve the performance of healthy individuals.
Language	English
Publishing date	2021-04-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2014734-X
ISSN	1099-4300 ; 1099-4300
ISSN (online)	1099-4300
ISSN	1099-4300
DOI	10.3390/e23040443
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Article ; Online: Functional Evaluation of a Force Sensor-Controlled Upper-Limb Power-Assisted Exoskeleton with High Backdrivability.

Liu, Chang / Liang, Hongbo / Ueda, Naoya / Li, Peirang / Fujimoto, Yasutaka / Zhu, Chi

Sensors (Basel, Switzerland)

2020 Volume 20, Issue 21

Abstract: A power-assisted exoskeleton should be capable of reducing the burden on the wearer's body or rendering his or her work improved and efficient. More specifically, the exoskeleton should be easy to wear, be simple to use, and provide power assistance ... ...

Abstract	A power-assisted exoskeleton should be capable of reducing the burden on the wearer's body or rendering his or her work improved and efficient. More specifically, the exoskeleton should be easy to wear, be simple to use, and provide power assistance without hindering the wearer's movement. Therefore, it is necessary to evaluate the backdrivability, range of motion, and power-assist capability of such an exoskeleton. This evaluation identifies the pros and cons of the exoskeleton, and it serves as the basis for its subsequent development. In this study, a lightweight upper-limb power-assisted exoskeleton with high backdrivability was developed. Moreover, a motion capture system was adopted to measure and analyze the workspace of the wearer's upper limb after the exoskeleton was worn. The results were used to evaluate the exoskeleton's ability to support the wearer's movement. Furthermore, a small and compact three-axis force sensor was used for power assistance, and the effect of the power assistance was evaluated by means of measuring the wearer's surface electromyography, force, and joint angle signals. Overall, the study showed that the exoskeleton could achieve power assistance and did not affect the wearer's movements.
MeSH term(s)	Biomechanical Phenomena ; Electromyography ; Exoskeleton Device ; Humans ; Movement ; Range of Motion, Articular ; Upper Extremity
Language	English
Publishing date	2020-11-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2052857-7
ISSN	1424-8220 ; 1424-8220
ISSN (online)	1424-8220
ISSN	1424-8220
DOI	10.3390/s20216379
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Article ; Online: Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance.

Ueda, Naoya / Tomita, Taisuke / Yanagisawa, Katsuhiko / Kimura, Nobuyuki

Journal of neurochemistry

2016 Volume 137, Issue 4, Page(s) 647–658

Abstract: Accumulating evidence suggests that endocytic pathway deficits are involved in Alzheimer's disease pathogenesis. Several reports show that endocytic disturbance affects β-amyloid peptide (Aβ) cleavage from β-amyloid precursor protein (APP). Presenilin-1 ( ...

Abstract	Accumulating evidence suggests that endocytic pathway deficits are involved in Alzheimer's disease pathogenesis. Several reports show that endocytic disturbance affects β-amyloid peptide (Aβ) cleavage from β-amyloid precursor protein (APP). Presenilin-1 (PS1) is the catalytic core of the γ-secretase complex required for Aβ generation. Previously, we showed that aging induces endocytic disturbance, resulting in the accumulation of Aβ and APP in enlarged endosomes. It remains unclear, however, whether PS1 localization and function are affected with endocytic disturbance. Here, we report that in endocytic disturbance, PS1 is transported from endosomes to ER/Golgi compartments via retromer trafficking, and that PS1 interacts with vacuolar protein sorting-associated protein 35 both in vitro and in vivo. Moreover, PS1 is degraded by proteasomes via a Rab2-dependent trafficking pathway, only during endocytic disturbance. These findings suggest that PS1 levels and localization in endosomes are regulated by retromer trafficking and ER-associated degradation system, even if endocytic disturbance significantly induces the endosomal accumulation of APP and β-site APP-cleaving enzyme 1. Results of this study also suggest that retromer deficiency can affect PS1 localization in endosomes, where Aβ cleavage mainly occurs, possibly leading to enhanced Aβ pathology. We proposed the following mechanism for intracellular transport of presenilin-1 (PS1). When endosome/lysosome trafficking is disturbed, PS1 is transported from endosome to endoplasmic reticulum (ER)/Golgi compartments via retromer and Rab2-mediated trafficking, and then degraded by endoplasmic reticulum-associated degradation (ERAD). Perturbations in this trafficking can cause abnormal endosomal accumulation of PS1, and then may lead to exacerbated Aβ pathology. Cover Image for this issue: doi: 10.1111/jnc.13318.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cells, Cultured ; Endocytosis/physiology ; Endoplasmic Reticulum/metabolism ; Female ; Golgi Apparatus/metabolism ; Macaca fascicularis ; Mice ; Mice, Inbred C57BL ; Presenilin-1/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Transport/physiology ; Proteolysis ; Rats ; Rats, Sprague-Dawley ; rab2 GTP-Binding Protein/metabolism
Chemical Substances	Presenilin-1 ; Psen1 protein, rat ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; rab2 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.13586
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Article ; Online: Demographic and clinical characteristics of patients with delirium: analysis of a nationwide Japanese medical database.

Ueda, Naoya / Igarashi, Masakazu / Okuyama, Kotoba / Sano, Hideki / Takahashi, Kanae / P Qureshi, Zaina / Tokita, Shigeru / Ogawa, Asao / Okumura, Yasuyuki / Okuda, Shoki

BMJ open

2022 Volume 12, Issue 9, Page(s) e060630

Abstract: Objectives: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese ... ...

Abstract	Objectives: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data. Design: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation. Setting: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge. Participants: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium. Primary and secondary outcome measures: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium. Results: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days. Conclusions: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients.
MeSH term(s)	Aged ; Antipsychotic Agents/therapeutic use ; Cross-Sectional Studies ; Delirium/chemically induced ; Delirium/drug therapy ; Delirium/epidemiology ; Demography ; Female ; Haloperidol/therapeutic use ; Humans ; Japan/epidemiology ; Male ; Retrospective Studies
Chemical Substances	Antipsychotic Agents ; Haloperidol (J6292F8L3D)
Language	English
Publishing date	2022-09-14
Publishing country	England
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2021-060630
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Article ; Online: Incremental medical cost of delirium in elderly patients with cognitive impairment: analysis of a nationwide administrative database in Japan.

Igarashi, Masakazu / Okuyama, Kotoba / Ueda, Naoya / Sano, Hideki / Takahashi, Kanae / P Qureshi, Zaina / Tokita, Shigeru / Ogawa, Asao / Okumura, Yasuyuki / Okuda, Shoki

BMJ open

2022 Volume 12, Issue 12, Page(s) e062141

Abstract: Objectives: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of ... ...

Abstract	Objectives: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of delirium in hospitalised elderly Japanese patients with cognitive impairment. Design: Retrospective, cross-sectional, observational study. Setting: Administrative data collected from acute care hospitals in Japan between April 2012 and September 2020. Participants: Hospitalised patients ≥65 years old with cognitive impairment were categorised into groups-with and without delirium. Delirium was identified using a delirium identification algorithm based on the International Classification of Diseases 10 Outcome measures: Total medical costs during hospitalisation were compared between the groups using a generalised linear model. Results: The study identified 297 600 hospitalised patients ≥65 years of age with cognitive impairment: 39 836 had delirium and 257 764 did not. Patient characteristics such as age, sex, inpatient department and comorbidities were similar between groups. Mean (SD) unadjusted total medical cost during hospitalisation was 979 907.7 (871 366.4) yen for patients with delirium and 816 137.0 (794 745.9) yen for patients without delirium. Adjusted total medical cost was significantly greater for patients with delirium compared with those without delirium (cost ratio=1.09, 95% CI: 1.09 to 1.10; p<0.001). Subgroup analyses revealed significantly higher total medical costs for patients with delirium compared with those without delirium in most subgroups except patients with hemiplegia or paraplegia. Conclusions: Medical costs during hospitalisation were significantly higher for patients with delirium compared with those without delirium in elderly Japanese patients with cognitive impairment, regardless of patient subgroups such as age, sex, intensive care unit admission and most comorbidities. These findings suggest that delirium prevention strategies are critical to reducing the economic burden as well as psychological/physiological burden in cognitively impaired elderly patients in Japan.
Language	English
Publishing date	2022-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2022-062141
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Article ; Online: Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce β-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of β-Amyloid Pathology by Type 2 Diabetes Mellitus.

Takeuchi, Shingo / Ueda, Naoya / Suzuki, Keiko / Shimozawa, Nobuhiro / Yasutomi, Yasuhiro / Kimura, Nobuyuki

The American journal of pathology

2018 Volume 189, Issue 2, Page(s) 391–404

Abstract: The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid (Aβ) protein, a key molecule in AD pathogenesis. It is widely accepted that ... ...

Abstract	The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid (Aβ) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aβ pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aβ pathology. Herein, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aβ in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aβ pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.
MeSH term(s)	Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism ; Brain/pathology ; Cell Line ; Cholesterol/metabolism ; Diabetes Complications/metabolism ; Diabetes Complications/pathology ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Female ; Humans ; Lysosomes/metabolism ; Lysosomes/pathology ; Macaca fascicularis ; Male
Chemical Substances	Amyloid beta-Peptides ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2018-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2018.10.011
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Article: Feature Extraction of Shoulder Joint's Voluntary Flexion-Extension Movement Based on Electroencephalography Signals for Power Assistance.

Liang, Hongbo / Zhu, Chi / Iwata, Yu / Maedono, Shota / Mochita, Mika / Liu, Chang / Ueda, Naoya / Li, Peirang / Yu, Haoyong / Yan, Yuling / Duan, Feng

Bioengineering (Basel, Switzerland)

2018 Volume 6, Issue 1

Abstract: Brain-Machine Interface (BMI) has been considered as an effective way to help and support both the disabled rehabilitation and healthy individuals' daily lives to use their brain activity information instead of their bodies. In order to reduce costs and ... ...

Abstract	Brain-Machine Interface (BMI) has been considered as an effective way to help and support both the disabled rehabilitation and healthy individuals' daily lives to use their brain activity information instead of their bodies. In order to reduce costs and control exoskeleton robots better, we aim to estimate the necessary torque information for a subject from his/her electroencephalography (EEG) signals when using an exoskeleton robot to perform the power assistance of the upper limb without using external torque sensors nor electromyography (EMG) sensors. In this paper, we focus on extracting the motion-relevant EEG signals' features of the shoulder joint, which is the most complex joint in the human's body, to construct a power assistance system using wearable upper limb exoskeleton robots with BMI technology. We extract the characteristic EEG signals when the shoulder joint is doing flexion and extension movement freely which are the main motions of the shoulder joint needed to be assisted. Independent component analysis (ICA) is used to extract the source information of neural components, and then the average method is used to extract the characteristic signals that are fundamental to achieve the control. The proposed approach has been experimentally verified. The results show that EEG signals begin to increase at 300⁻400 ms before the motion and then decrease at the beginning of the generation of EMG signals, and the peaks appear at about one second after the motion. At the same time, we also confirmed the relationship between the change of EMG signals and the EEG signals on the time dimension, and these results also provide a theoretical basis for the delay parameter in the linear model which will be used to estimate the necessary torque information in future. Our results suggest that the estimation of torque information based on EEG signals is feasible, and demonstrate the potential of using EEG signals via the control of brain-machine interface to support human activities continuously.
Language	English
Publishing date	2018-12-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering6010002
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Article ; Online: Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs.

Izumi-Nakaseko, Hiroko / Nakamura, Yuji / Cao, Xin / Ohara, Hiroshi / Yamazaki, Yukiko / Ueda, Naoya / Ando, Kentaro / Sugiyama, Atsushi

European journal of pharmacology

2014 Volume 740, Page(s) 263–270

Abstract: An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to ... ...

Abstract	An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias.
MeSH term(s)	Action Potentials/drug effects ; Anesthetics, Inhalation ; Animals ; Anti-Arrhythmia Agents/blood ; Anti-Arrhythmia Agents/pharmacokinetics ; Anti-Arrhythmia Agents/pharmacology ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Delayed Rectifier Potassium Channels/antagonists & inhibitors ; Delayed Rectifier Potassium Channels/physiology ; Dogs ; Female ; Halothane ; Heart Rate/drug effects ; Heart Ventricles/drug effects ; Male ; Myocardial Contraction/drug effects ; Piperidines/blood ; Piperidines/pharmacokinetics ; Piperidines/pharmacology ; Potassium Channel Blockers/blood ; Potassium Channel Blockers/pharmacokinetics ; Potassium Channel Blockers/pharmacology ; Pyridines/blood ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Ventricular Function/drug effects
Chemical Substances	Anesthetics, Inhalation ; Anti-Arrhythmia Agents ; Delayed Rectifier Potassium Channels ; Piperidines ; Potassium Channel Blockers ; Pyridines ; E 4031 (113558-89-7) ; Halothane (UQT9G45D1P)
Language	English
Publishing date	2014-10-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2014.06.064
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