• BMB Reports
• /
• v.53 no.8
• /
• pp.437-441
• /
• 2020

In accordance with requirements of the ICH S7B safety pharmacology guidelines, numerous next-generation cardiotoxicity studies using human stem cell-derived cardiomyocytes (CMs) are being conducted globally. Although several stem cell-derived CMs are being developed for commercialization, there is insufficient research to verify if these CMs can replace animal experiments. In this study, in vitro high-efficiency CMs derived from human embryonic stem cells (hESC-CMs) were compared with Sprague-Dawley rats as in vivo experimental animals, and primary cultured in vitro rat-CMs for cardiotoxicity tests. In vivo rats were administrated with two consecutive injections of 100 mg/kg isoproterenol, 15 mg/kg doxorubicin, or 100 mg/kg nifedipine, while in vitro rat-CMs and hESC-CMs were treated with 5 μM isoproterenol, 5 μM doxorubicin, and 50 μM nifedipine. We have verified the equivalence of hESC-CMs assessments over various molecular biological markers, morphological analysis. Also, we have identified the advantages of hESC-CMs, which can distinguish between species variability, over electrophysiological analysis of ion channels against cardiac damage. Our findings demonstrate the possibility and advantage of high-efficiency hESC-CMs as next-generation cardiotoxicity assessment.

• The Journal of Internal Korean Medicine
• /
• v.37 no.3
• /
• pp.467-483
• /
• 2016

Objective: This study was performed to investigate the effect of IUS (Inulsan, an extract of Artemisiae capillaris (茵蔯), Curcumae longae (鬱金), and Crataegi fructus (山査)) on anti-hyperlipidemia, anti-oxidation, and anti-inflammation.Method: We administered water extracts of Artemisiae capillaris, Curcumae longae, and Crataegi fructus for three weeks to db/db mice (C57BL/Ks), animal models induced with type 2 diabetes mellitus. Mice were divided into three groups: normal (C57BL/6J mice group), control group (db/db mice without administration of IUS) and IUS group (db/db mice treated with IUS). Then we measured total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride in the serum after the oral administration of IUS.Results: 1. IUS did not show any cytotoxicity in RAW 264.7 cells. 2. IUS decreased AST, ALP, and creatinine levelsand did not show any liver or renal toxicity in the db/db mice. 3. IUS increased DPPH and ABTS radical scavenging activity and decreased ROS production in RAW 264.7 cells. 4. IUS significantly decreased IL-1β, IL-6, and TNF-α production in RAW 264.7 cells. 5. IUS increased HDL cholesterol and significantly decreased total cholesterol and triglyceride in db/db mice. 6. IUS significantly decreased the atherogenic index and cardiac risk factor. 7. In contrast with the control group, fat infiltration in the liver and aorta decreased in IUS treated mice. The cell nucleus was located in the central area in H&E staining of liver. And endomembranes also were more thinner than the control group in H&E staining of aorta.Conclusions: These results suggest that IUS might be effective in the prevention and treatment of dyslipidemia.

• Toxicological Research
• /
• v.24 no.4
• /
• pp.289-295
• /
• 2008

Toxicology screening following treatment with astemizole, a histamine receptor antagonist, at oral doses of 0, 10, 30 and 60 mg/kg was carried out in male cynomolgus monkeys (Macaca fascicularis). No dose-related changes in mortality, clinical signs, body weight changes, food consumption, or urine analysis occurred in any animal compared to the vehicle control. However, the high-dose group showed a decrease in BUN and ALP compared to vehicle control group. In addition, the levels of TG, AST, ALP and CK increased. Although astemizole did not produce significant toxicological changes at any dose tested, we predict that it can cause toxicological changes of the liver and heart based on the changes in the serum parameters related to the heart and liver. The Action Potential Duration (APD) was prolonged in the heart of 60 mg/kg treatment group compared to the control group. The APD increase in 60 mg/kg treatment group along the other related changes in toxicological parameters imply that astemizole has major cardiotoxic effects in the cynomolgus monkey. This study is a valuable assessment for predicting the general toxicity and cardiotoxic effects of antihistamine drugs using nonhuman primates.

• Radiation Oncology Journal
• /
• v.37 no.3
• /
• pp.201-206
• /
• 2019

Purpose: To observe the effectiveness of the practical instruction sheet and the educational video for left-sided breast treatment in a patient receiving deep inspiration breath hold (DIBH) technique. Two parameters, simulation time and patient satisfaction, were assessed through the questionnaire. Methods: Two different approaches, which were the instruction sheet and educational video, were combinedly used to assist patients during DIBH procedures. The guideline was assigned at least 1 week before the simulation date. On the simulation day, patients would fill the questionnaire regarding their satisfaction with the DIBH instruction. The questionnaire was categorized into five levels: extremely satisfied to dissatisfied, sequentially. The patients were divided into four groups: not DIBH technique, DIBH without instruction materials, the DIBH with instruction sheet or educational video, and DIBH with both of instruction sheet and educational video. Results: Total number of 112 cases of left-sided breast cancer were analyzed. The simulation time during DIBH procedure significantly reduced when patients followed the instruction. There was no significant difference in simulation time on the DIBH procedures between patient compliance via instruction sheet or educational video or even following both of them. The excellent level was found at 4.6 ± 0.1 and 4.5 ± 0.1, for patients coaching via instruction sheet as well as on the educational video, respectively. Conclusion: Patient coaching before simulation could potentially reduce the lengthy time in the simulation process for DIBH technique. Practicing the DIBH technique before treatment is strongly advised.

• The Korea Journal of Herbology
• /
• v.20 no.3
• /
• pp.43-49
• /
• 2005

Objectives : The present study was carried out to determine if Glycyrrhizae Radix extract exerts beneficial effect against the ischemia-induced acute renal failure in rabbits. Glycyrrhizae Radix was known to reinforce the function of the spleen and replenish Qi, remove heat and counteract toxicity, dispel phlegm and relieve cough, alleviate spasmodic pain, and to moderate drug actions. It's indications are weakness of the spleen and the stomach marked by lassitude and weakness; cardiac palpitation and shortness of breath; cough with much phlegm: spasmodic pain in the epigastrium, abdomen and limbs: carbuncles and sores. It is often used for reducing the toxic or drastic actions of other drugs. Methods : Antioxidative effect of 3% concentration of Glycyrrhizae Radix extract was measured. Rabbits were treated with Glycyrrhizae Radix extract via i.v., followed by renal ischemia/reperfusion, and the changes of urine volume, serum creatinine levels, glomerular filtration rate(GFR), fractional Na+ excretion$(FE\;Na^+)\;and\;K^+\;excretion(FE\;K^+)$ in ischemia/reperfusion induced acute renal failure were measured. Results : Renal ischemia/reperfusion caused increase of serum creatinine level, which was accompanied by a reduction in glomerular filtration rate(GFR). The fractional excretion of $Na^+\;and\;K^+$ increased in ischemia-induced animals, which was partially prevented by Glycyrrhizae Radix extract treatment. Conclusions : These results indicate that lipid peroxidation plays a critical role in ischemia-induced acute renal failure. Glycyrrhizae Radix extract exerts the protective effect against acute renal failure induced by renal ischemia/reperfusion, and its effect may be attributed to an antioxidant action.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.20 no.1
• /
• pp.98-102
• /
• 2006

The present stuby was carried out to determine if Radix Glycyrrhizae extract exerts beneficial effect against the ischemia-induced acute renal failure in rabbits. Radix Glycyrrhizae was known to reinforce the function of the spleen and replenish Qi, remove heat and counteract toxicity, dispel phlegm and relieve cough, alleviate spasmodic pain, and to moderate drug actions. It's indications are weakness of the spleen and the stomach marked by lassitude and weakness; cardiac palpitation and shortness of breath; cough with much phlegm; spasmodic pain in the epigastrium, abdomen and limbs; carbuncles and sores. It is often used for reducing the toxic or drastic actions of other drugs. Rabbits were treated with Radix Glycyrrhizae extract via i.v., followed by renal ischemia/reperfusion. Fractional excretion of glucose and phosphate, lipid peroxidation and light microscopy were done to evaluate the beneficial effect of Radix Glycyrrhizae extract on ischemia/reperfusion induced acute renal failure. Renal ischemia/reperfusion caused increase of fractional excretion of glucose and phosphate increased in ischemia-induced animals, which was partially prevented by Radix Glycyrrhizae extract treatment. Ischemia/reperfusion increased lipid peroxidation, which was prevented by Radix Glycyrrhizae extract administration. And the beneficial effect of Radix Glycyrrhizae extract on ischemia/reperfusion induced kidney injury was shown through the light micrographic observation. These results indicate that lipid peroxidation plays a critical role in ischemia-induced acute renal failure. Radix Glycyrrhizae extract exerts the protective effect against acute renal failure induced by renal ischemia/reperfusion.

• Journal of The Korean Society of Clinical Toxicology
• /
• v.6 no.2
• /
• pp.104-109
• /
• 2008

Purpose: Unrefined tablets prepared from Aconitum tubers are occasionally used in Korean folk medicine. This study defines the potential sources, clinical toxicology, and treatment of aconitine poisoning. Methods: A retrospective survey was conducted in 63 patients in the ED of a tertiary University Hospital with suspected toxicity from an unrefined tablet prepared from Aconitum tubers from 1999 to 2007. Results: A total of 63 cases enrolled included 26 men and 37 women, aged 30 to 86 years. Forty-eight patients ingested aconitine tablets as digestives, 26 tablets on average. After a latent period of 30 to 450 minutes, patients developed a combination of neurologic (87.3%), gastrointestinal (82.5%), cardiopulmonary (41.3%), and other (28.6%) features typical of aconitine poisoning. Initial ECG abnormalities revealed dysrhythmia (61.9%), conduction disturbance (42.9%), and abnormal waveforms (39.7%), with 28.6% of patients having normal ECGs. All patients received supportive treatment or close observation regardless of ingestion amounts. Patients with hypotension or ventricular arrhythmia were treated with inotropic agents or amiodarone. Conclusion: Toxicologic signs and symptoms can occur after the consumption of aconitine tablets, regardless of ingestion amount. The risk occurs because of inadequately processed aconitine roots. This study will provide important data for public education and distribution regulations for Aconitum sp. in Korea.

• Journal of The Korean Society of Clinical Toxicology
• /
• v.16 no.2
• /
• pp.108-115
• /
• 2018

Purpose: Glehnia littoralis has been reported to have several pharmacological properties but no in vivo reports describing the protective effects of this plant on${\alpha}$-amanitin-induced hepatotoxicity have been published. ${\alpha}$-Amanitin is a peptide found in several mushroom species that accounts for the majority of severe mushroom poisonings leading to severe hepatonecrosis. In our previous in vitro study, we found that ${\alpha}$-amanitin induced oxidative stress, which may contribute to its severe hepatotoxicity. The aim of this study was to investigate whether Glehnia littoralis acetate extract (GLEA) has protective antioxidant effects on ${\alpha}$-amanitin-induced hepatotoxicity in a murine model. Methods: Swiss mice (n=40 in all groups) were divided into four groups (n=10/group). Three hours after giving ${\alpha}$-amanitin (0.6 mg/kg, i.p.) to the mice, they were administered silibinin (50 mg/kg/d, i.p.) or Glehnia littoralis ethyl acetate extract (100 mg/kg/d, oral) therapies once a day for 3 days. After 72 hours of treatment, each subject was killed, cardiac blood was aspirated for hepatic aminotransferase measurement, and liver specimens were harvested to evaluate the extent of hepatonecrosis. The degree of hepatonecrosis was assessed by a pathologist blinded to the treatment group and divided into 4 categories according to the grade of hepatonecrosis. Results: GLEA significantly improved the beneficial functional parameters in ${\alpha}$-amanitin-induced hepatotoxicity. In the histopathological evaluation, the toxicity that was generated with ${\alpha}$-amanitin was significantly reduced by GLEA, showing a possible hepatoprotective effect. Conclusion: In this murine model, Glehnia littoralis was effective in limiting hepatic injury after ${\alpha}$-amanitin poisoning. Increases of aminotransferases and degrees of hepatonecrosis were attenuated by this antidotal therapy.

• Clinical and Experimental Pediatrics
• /
• v.49 no.4
• /
• pp.417-423
• /
• 2006

Purpose : The objectives of this study were to assess ventricular function by tissue Doppler imaging in children who were receiving chemotherapy or who had received chemotherapy, and to apply repeated tissue Doppler imaging to make an early assessment in cardiac toxicity studies. Methods : This study was conducted on 23 oncology patients on-treatment or off-treatment from April 2005 to July 2005 at Dongsan Medical Center, Keimyung University. All patients(group 1) were divided into two groups, fractional shortening(FS) over 29 percent(group 2) and FS under 28 percent (group 3) in the first category. These same patients were also divided into the following groups : group treated with anthracyclin(group 4) and group treated without anthracyclin(group 5). Deceleration time(DT), isovolumic relaxation time(IVRT), FS, peak early diastolic(E), and peak late diastolic (A) velocity of transmitral flow were measured by M-mode and pulsed wave Doppler. Systolic(Sm), peak early diastolic(Em), and peak late diastolic(Am) velocity in apical 4-chamber and 2-chamber views were measured by tissue Doppler imaging. The author calculated a modified Tei index, E/A, E/Em ratio by using measured values. Results : Twenty three patients were enrolled : 12 boys and 11 girls. The average age of patients was 8 years and 4 months. Thirteen out of 23 patients were in the group treated with anthracyclin (group 4) and 6 had FS under 28 percent(group 3). E/Em ratio showed a significant difference between group 1 and control group($6.46{\pm}1.85$ vs $7.06{\pm}1.64$, P<0.05). Other parameters had no difference statistically. Conclusion : This study showed that the change of cardiac function developed earlier in diastolic function than in systolic function, as E/Em ratio reflecting the mean LV diastolic pressure showed a significant difference between the control group and chemotherapy groups. Echocardiography using tissue Doppler imaging is a non-invasive, comfortable and reliable method for post-chemotherapy follow up.

• Journal of Yeungnam Medical Science
• /
• v.3 no.1
• /
• pp.279-285
• /
• 1986

Carbamazepine is a derivative of iminostilbene with carbamyl group and related chemically to the tricyclic antidepressants. Carbamazepine has been introduced for treatment of trigeminal neuralgia. Recently it is used as an antiepileptic agent such as diphenylhydantoin. Antiepileptic drugs are known to affect experimentally induced cardiac arrhythmia and are now widely used clinically for treatment of ventricular tachyarrhythmias, particularly those produced by digitalis intoxication. Steiner et al.(1970) reported that carbamazepine was found to be very effective in converting ventricular tachycardia due to digitalis toxicity to normal sinus rhythm. Clinically bradycardia, complete heart block, ventricular standstill and Adams-stokes attack were reported in the course of carbamazepine treatment. The purpose of this study was to investigate the effects of carbamazepine on the ouabain-induced arrhythmia in vivo. The rabbits of either sex, weighing from 1.6 to 3.2kg were anesthesized by urethane. After the trachea was cannulated, the rabbits were ventilated with room air using a respirator. Drugs were given into polyethylene cannula in the femoral vein. Blood pressure were recorded by physiograph via pressure tranducer connected with the cannula in the femoral artery. EKG were recorded by Physiograph via electrode implanted in both fore leg and left hind leg. The results are summarized as follows; 1. Arrhythmia was induced by continuous infusion of ouabain.($64{\pm}8.8{\mu}g/kg$) 2. Single administration of ouabain($64{\mu}g/kg$) induced arrhythmia which was persisted for 7-8 min. 3. Ouabain induced arrhythmia was restored to normal sinus rhythm by administration of carbamazepine.(The more dosage, the less frequent and the longer duration) 4. Severe bradycardia, A-V block, atrial fibrillation were seen on the EKG after injection of carbamazepine alone. By the above results, it may be concluded that carbamazepine inhibits the ouabain-induced arrhythmia by dose-dependent.