• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4025-4030
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• 2012

Background and Objective: Cardiotoxicity and oxidative stress is a life-threatening side effect of doxorubicin (DOX). We investigate the effects of short-term exercise as therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity in the rat. Methods: Wistar males (weighing $257{\pm}28g$) were divided into six groups: (1) control+placebo (2) control+DOX $10mg.kg^{-1}$ (3) control+DOX $20mg.kg^{-1}$ (4) training+placebo (5) training+ DOX$10mg.kg^{-1}$ (6) training+DOX $20mg.kg^{-1}$. Cardiotoxicity was induced by DOX (10 and $20mg.kg^{-1}$). The rats in groups 4, 5 and 6 experienced treadmill running of 25 to $39min.day^{-1}$ and 15 to $17m.min^{-1}$, 5 days/wk for 3 wk. At the end of the endurance training program, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, DOX $10mg.kg^{-1}$ and DOX $20mg.kg^{-1}$, respectively. Result: DOX administration (10 and $20mg.kg^{-1}$) caused significant increase in MDA and Apelin, an insignificant increase in NO and a significant decrease in SOD, as compared to the C+P group. Three weeks of the pretreatment endurance exercise resulted in a significant increase of Apelin and SOD, an insignificant increase of NO and an insignificant decrease of MDA, as compared to the C+P group. Furthermore, after three weeks of endurance training and DOX treatment with $10mg.kg^{-1}$ and $20mg.kg^{-1}$, a significant increase in apelin and SOD, and a significant decrease in MDA were detected in comparison to C+DOX10 and/or C+DOX20 groups. There was a significant difference between DOX$10mg.kg^{-1}$ and DOX$20mg.kg^{-1}$ treatments in MDA levels only. Conclusion: Pretreatment exercise may improve myocardial tolerance to DOX-induced cardiotoxicity by inhibition of oxidative stress and up-regulation of antioxidants in heart tissue.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.3
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• pp.267-275
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• 2023

Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (human iPSC-CMs) has become an attractive human-based platform for predicting cardiotoxicity. Moreover, electrophysiological assessment of multiple cardiac ion channel blocks is emerging as an important parameter to recapitulate proarrhythmic cardiotoxicity. Therefore, we aimed to establish a novel in vitro multiple cardiac ion channel screening-based method using human iPSC-CMs to predict the drug-induced arrhythmogenic risk. To explain the cellular mechanisms underlying the cardiotoxicity of three representative TdP high- (sotalol), intermediate- (chlorpromazine), and low-risk (mexiletine) drugs, and their effects on the cardiac action potential (AP) waveform and voltage-gated ion channels were explored using human iPSC-CMs. In a proof-of-principle experiment, we investigated the effects of cardioactive channel inhibitors on the electrophysiological profile of human iPSC-CMs before evaluating the cardiotoxicity of these drugs. In human iPSC-CMs, sotalol prolonged the AP duration and reduced the total amplitude (TA) via selective inhibition of I_Kr and I_Na currents, which are associated with an increased risk of ventricular tachycardia TdP. In contrast, chlorpromazine did not affect the TA; however, it slightly increased AP duration via balanced inhibition of I_Kr and I_Ca currents. Moreover, mexiletine did not affect the TA, yet slightly reduced the AP duration via dominant inhibition of I_Ca currents, which are associated with a decreased risk of ventricular tachycardia TdP. Based on these results, we suggest that human iPSC-CMs can be extended to other preclinical protocols and can supplement drug safety assessments.

• Advances in Traditional Medicine
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• v.5 no.2
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• pp.137-143
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• 2005

Doxorubicin induces oxidative stress leading to cardiotoxicity causing electrocardiogram abnormalities and increases in biomarkers associated with toxicity. Green tea extract (GTE) is reported to possess antioxidant activity mainly via its polyphenolic constituent, catechins. This study was intended to determine the effect of various doses of GTE (25, 50 and 100 mg/kg/day p.o. for 30 days) on doxorubicin-induced electrocardiographic and biochemical changes in rat heart. The latter included lactate dehydrogenase, creatine kinase, and glutamic oxaloacetate transaminase in serum and superoxide dismutase, catalase, and reduced glutathione, as well as membrane bound enzymes like $Na^+K^+ATPase,\;Ca^{2+}ATPase,\;Mg^{2+}ATPase$ and decreased lipid peroxidation in heart tissue Results demonstrated that rats which received GTE were less susceptible to such changes indicating protection afforded by GTE.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.2
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• pp.289-295
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• 2002

To certify the protective effect of herbal medicine against oxygen free radical-induced myocardiotoxicity, cytotoxicity was measured using MTT, LDH activity and Beating rate assay in the presence of Guaruhaebaekbanha-tang(GHBT) extracts or single constituents of this prescription. Myocardial toxicity was evaluated in neonatal rat myocardiocytes in cultures. In the present study, xanthine oxidase/hypoxanthine(XO/HX) resulted in a decrease in cell viability, increases in LDH activity in culture medium and decreases in beating rate in cultured myocardial cells. In the effect of GHBT extract, it showed the prevention from the XO/HX-induced cardiotoxicity by the increases of cell viability and beating rate as well as the decrease of LDH activity. In the protective effect of Fructus Trichosanthis(FT), Bulbus Allii Macrostemi(BAM) and Rhizoma Pinelliae(RP), all the extracts were significantly effective in the protection of XO/HX-induced cardiotoxocity in cultured myocardial cells by the increase of beating rate as well as th decrease of LDH activity. From these results, they show that XO/HX is cardiotoxic in cultured myocardial cells derived from neonatal rat, and it suggests that GHBT, FT, SAM, RP extracts are positively effective in the blocking in XO/HX-induced cardiotoxicity.

• Journal of The Korean Society of Clinical Toxicology
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• v.10 no.1
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• pp.1-7
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• 2012

Purpose: Herbal preparations have long been used for medical purposes by traditional cultures, and their use is increasing in modern societies. However, many herbal agents produce specific cardiovascular toxicities in humans. We performed this study in order to investigate the clinical characteristics of the cardiac toxicities associated with herbal remedies. Methods: We conducted a retrospective study of 45 patients (mean age $57{\pm}10$ years) who presented with cardiotoxicity between January 2007 and May 2011 due to ingestion of herbal remedy substances. Patients were identified as suffering cardiotoxicity if they presented with chest pain, EKG abnormality, and elevation of cardiac enzyme. Results: Of the 45 total cases, 17 included hemodynamic instability (37.8%), 7 with increasing cardiac enzyme (15.6%), 2 with cardiac arrest (4.4%) and one case of mortality (2.2%). The cardiotoxic herb group that demonstrated the worst clinical course was Ranunculaceae. Conclusions: In our study results, 57.6% of the herbal intoxication patients demonstrated the effects of cardiotoxicity. Thus, we recommend careful monitoring of herbal intoxication patients.

• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.2
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• pp.486-492
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• 2003

To certify the protective effect of herbal medicine on myocardial damage against oxygen free radical-induced myocardiotoxicity, cytotoxicity was measured using by MTT assay, LDH activity and thiobarbituric acid reactive substances(TBARS) assay in the presence of Guaruhaebaekbaekju-tang(GHBT) extracts or single constituents of this prescription, Myocardial toxicity was evaluated in neonatal rat myocardiocytes in cultures. In the present study, xanthine oxidase/hypoxanthine (XO/HX) resulted in a decrease in cell viability, an increase in LDH activity in culture medium and lipid peroxidation in cultured myocardial cells, In the effect of GHBT extract, it showed the prevention from the XO/HX-induced cardiotoxicity such as the decrease of LDH activity and lipid peroxidation. In the protective effect of Fructus Trichosanthis (FT) and Bulbus Allii Macrostemi (BAM), all the extracts were significantly effective in the protection of XO/HX-induced cardiotoxocity in cultured myocardial cells. From these results, they show that XO/HX is cardiotoxic in cultured myocardial cells derived from neonatal rats, and it suggests that GHBT, FT and BAM extracts are positively effective in the blocking XO/HX-induced cardiotoxicity.

• Molecular & Cellular Toxicology
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• v.4 no.4
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• pp.323-330
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• 2008

Surrogate tissue analysis incorporating -omics technologies has emerged as a potential alternative method for evaluating toxic effect of the tissues which are not accessible for sampling. Among the recent applications, blood including whole blood, peripheral blood lymphocytes and peripheral blood mononuclear cells (PBMCs) was suggested as a suitable surrogate tissue in determining toxicant exposure and effect at the pre- or early clinical stage. In this application, we investigated transcriptomic profiles in astemizole treated Cynomolgus monkey's PBMCs. PBMCs were isolated from 4-6 years old male monkeys at 24 hr after administration45 Helvetica Light (10 mg/kg, 30 mg/kg). Gene expression profiles of astemizole treated monkey's PBMCs were determined using Affymetrix $GeneChip^{(R)}$ Human Genome U133 plus 2.0 arrays. The expression levels of 724 probe sets were significantly altered in PBMCs at 10 or 30 mg/kg after astemizole administration following determination of paired t-test using statistical criteria of ${\geq}$$1.5-fold changes at P<0.05. Gene expression patterns in PBMCs showed a considerable difference between astemizole 10 and 30 mg/kg administration groups in spite of an administration of the same chemical. However, close examination using Ingenuity Pathway Analysis (IPA) software revealed that several gene sets related to cardiotoxicity were deregulated at astemizole 10 and 30 mg/kg administration groups. The deregulation of cardiac hypertrophy related genes such as TXN, GNAQ, and MAP3K5 was observed at 10 mg/kg group. In astemizole 30 mg/kg group, genes involved in cardiotoxicity including cardiac necrosis/cell death, dilation, fibrosis, and hypertrophy were also identified. These results suggest that toxicogenomic approach using PBMCs as surrogate tissues will contribute to assess toxicant exposures and identify biomarkers at the pre-clinical stage.

• Journal of The Korean Society of Clinical Toxicology
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• v.19 no.2
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• pp.133-138
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• 2021

Glufosinate-containing herbicides is a non-selective herbicide commonly used worldwide. As the use of them increased gradually since paraquat was banned in 2012, the number of suicides by their ingestion is also increasing continuously. Complications of glufosinate-containing herbicide poisoning include various central nervous system (CNS) toxicities such as convulsions, loss of consciousness, memory impairment, and respiratory depression, which may be accompanied by hemodynamic changes such as bradycardia and hypotension. However, it is very rare that arrhythmias other than bradycardia occurred and Takotsubo cardiomyopathy was combined due to cardiotoxicity. A 71-year-old female patient was transferred to our hospital after ingesting 500 mL of glufosinate-containing herbicide and receiving 5 L of gastric lavage at a local hospital. A few hours later, she presented stuporous mentality, respiratory depression, and convulsions, and was accompanied by hypotension and bradycardia. On the second day of admission, electrocardiogram (ECG) showed bradycardia and QTc prolongation with hemodynamic Instability. Accordingly, we conducted the early treatment with continuous renal replacement therapy (CRRT) and the application of temporary cardiac pacemaker. An echocardiogram demonstrated decreased ejection fraction (EF) and Takotsubo cardiomyopathy on the third day of admission. Then, she was discharged safely with conservative treatment. At the follow-up after 1 year, Takotsubo cardiomyopathy, EF and QTc prolongation were recovered on echocardiogram and ECG. Because cardiac toxicity after glufosinate-containing herbicide poisoning may cause life-threatening consequences, caution is required while treating the patient. Therefore, if electrocardiogram changes are seen in the elderly with a large amount of glufosinate herbicide ingestion, additional cardiac function test through echocardiography should be concerned, and early treatment through CRRT or artificial cardiac pacing should be considered.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.05a
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• pp.85-85
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• 2004

• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.1
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• pp.136-139
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• 2003

Cytotoxicity of glucose oxidase(GO) and cardioprotective effect of Salviae Multiorrhizae Radix(SMR) against GO-induced cardiotoxicity were measured for evaluation of cardiotoxicity on cultured mouse pulmonary endotherial cells(PEC) by MTT assay after PEC were cultured for 8 hours at various concentrations of GO. GO was toxic in a time and dose-dependent manner on cultured PEC after PEC were grown for 8 hours in media containing 1～60mU/ml GO. While, cultures were pretreated with 60 μg/ml SMR for 2 hours increased remarkably cell viability. From the above results, it is suggested that GO is toxic on cultured PEC by the decrease of cell viability, and herb medicine such as SMR is very effective in the prevention of vascular toxicity induced by GO.