• Archives of Pharmacal Research
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• v.27 no.2
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• pp.239-245
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• 2004

KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2 -methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran, is a new neuroprotective agent for preventing ischemia-reperfusion damage. This study was performed to identify the metabolic pathway of KR-31543 in human liver microsomes and to characterize cytochrome P450 (CYP) enzymes that are involved in the metabolism of KR-31543. Human liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of two metabolites, M1 and M2. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC/MS/MS analysis with a synthesized authentic standard, and M2 was suggested to be hydroxy-KR-31543. Correlation analysis between the known CYP enzyme activities and the rates of the formation of M 1 and M2 in the 12 human liver microsomes have showed significant correlations with testosterone 6$\beta$-hydroxylase activity (a marker of CYP3A4). Ketoconazole, a selective inhibitor of CYP3A4, and anti-CYP3A4 monoclonal antibodies potently inhibited both N-hydrolysis and hydroxylation of KR-31543 in human liver microsomes. These results provide evidence that CYP3A4 is the major isozyme responsible for the metabolism of KR-31543 to M1 and M2.

• YAKHAK HOEJI
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• v.49 no.1
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• pp.30-37
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• 2005

Xuesaitong Ruanjiaonang (XR), a soft capsule containing Panax notoginseng saponins as main ingredients, is believed to remove extravasated blood and increase cerebral blood flow by improving blood circulation, and therefore, has been used in China to treat ischemic stroke or hemiplegia caused by cerebral thrombosis. To characterize pharmacological actions of XR, the present study evaluated its effects on neuronal cell damage induced by various oxidative insults or excitotoxic amino acids in primary cultured rat cortical cells. The neuronal cell viability was not affected by XR with the exposure for 2 h at the concentrations tested in this study ($10{\sim}1000\;{\mu}g/ml$). However, significant reduction of the cell viability was observed when the cultured cells were exposed to XR at $1000\;{\mu}g/ml$ for 24 h. XR was found to concentration-dependently inhibit the oxidative neuronal damage induced by $H_{2}O_2$, xanthine/xanthine oxidase or $Fe^{2+}$/ascorbic acid. In addition, it dramatically inhibited the excitotoxic damage induced by glutamate or N-methyl-D-aspartate (NMDA). We found that the NMDA-induced neurotoxicity was inhibited more effectively and potently than the glutamate-induced toxicity. Moreover, XR was found to exert mild inhibition of lipid peroxidation induced by $Fe^{2+}$/ascorbic acid in rat brain homogenates and some 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. Taken together, these results demonstrate neuroprotective and antioxidant effects of XR, showing inhibition of oxidative and excitotoxic damage in the cultured cortical neurons, as well as inhibition of lipid peroxidation and its radical scavenging activity. Considering that excitotoxicity and oxidative stress pl ay crucial roles in neuronal cell damage during ischemia and reperfusion, these results may provide pharmacological basis for its clinical usage to treat ischemic stroke.

• The Korean Journal of Physiology
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• v.22 no.1
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• pp.1-12
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• 1988

The changes in membrane potential and intracellular $Ca^{2+}$ activities along with adenosine triphosphate (ATP) and creatine phosphate (CP) contents of guinea pig hearts were studied during the cardioplegia and recovery phase. The results obtained were summarized as follows: 1) A low concentration of $Ca^{2+}$ in the cardioplegic solution caused significant changes in membrane potential during the cardioplegia and action potential configurations of the first beat after cardioplegia. 2) Intracellular $Ca^{2+}$ activities were decreased significantly during cardioplegia and increased when the cardiac tissue was reperfused with the normal Tyrode solution. The magnitude of increase in intracellular $Ca^{2+}$ activities was larger in the 0.1 mM $Ca^{2+}-cardioplegic$ solution than the 1.8 mM $Ca^{2+}-solution$. 3) ATP and CP contents of cardiac ventricular tissue were decreased during the cardioplegia, regardless of $Ca^{2+}$ concentration in the cardioplegic solutions, and CP contents were recovered with the reperfusion of normal Tyrode solution faster than those of ATP. And, there were no significant differences in the recovery of CP contents with different concentrations of $Ca^{2+}$ in the cardioplegic solutions tested, while the recovery of ATP contents was faster with $15mM\;K^{+},\;0.1mM\;Ca^{2+}$ cardioplegic solution. These results suggest that the $Ca^{2+}$ concentration in the cardioplegic solution is one of major factors influencing the recovery of cardiac tissue from the cardioplegia.

• Journal of radiological science and technology
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• v.24 no.2
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• pp.19-22
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• 2001

The purpose of this study is to evaluate time course of signal enhancement on Gadomer-17 enhance MRI, and to correlate the size of enhanced area with that of the infarct area on 2'3'5'-triphenyl tetrazolium chloride(TTC) histochemical examination for the assessment of myocardial viability in reperfused Myocardial Infarction in a cat model. Tan cats(average weight: 3.8 kg) which had undergone 90 minutes of occlusion of the LAD followed by 90 minutes of reperfusion underwent MR T2-weighted imaging, and T1-weighted imaging, enhanced T1-weighted imaging. We used 1.5T Magneton Vision MRI system(Siemens, Erlangen, Germany). Signal intensities were measured in the enhanced and non-enhanced areas of enhanced T1-weighted imaging. and TTC histochemical staining the size of the abnormal signal area on each image was compared with that of the infarct area. Maximum enhancement was detected during a $40{\sim}60$ minute period with an average enhancement of $168{\pm}9.9%$ of normal myocardium. TTC staining revealed that the size of the high signal area on T2-weighted images and of the enhanced area on enhanced T1-weighted images was greater than that of the infarct area($T2=48.1%{\pm}3.7$, enhanced $T1=47.2%{\pm}2.6$, TTC $staining=38.7%{\pm}3.1$ ; p<0.05). In reperfused Myocardial Infarction in a cat model, enhanced MR imaging delineates reversibly and irreversibly damaged myocardium, with a strong enhancement and a broad temporal window. We may therefore expect that enhanced MR image is useful for demonstrating myocardial injury.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.6
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• pp.1612-1619
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• 2006

This Study was designed to investigate the mechanism of Mixture of Bambusae Caulis in Liquamen and Bamboo Extract on the change of regional cerebral blood flow (rCBF) and blood pressure (BP) in normal rats, and further to investigate cytokines production in serum of cerebral ischemic rats. Mixture were as follows ; Bamboo Extract extracted with distilled water at 98 $^{\circ}C$ for 3 hrs, Mixture of Bambusae Caulis in Liquamen and bamboo Extracts (MLE) mixed at the ratio 1 to 100 (MLE100), 1 to 50 (MLE50), 1 to 20 (MLE20), 1 to 10 (MLE10), 1 to 5 (MLE5). The results were as follows ; The MLE-induced increase in rCBF was significantly inhibited by pretreatment with indomethacin (1 mg/kg, I.p.), an inhibitor of cyclooxygenase as well as methylene blue (10 $^{\mu}g/kg$, I.p.), an inhibitor of guanylate cyclase. The MLE-induced increase in BP was significantly inhibited by pretreatment with methylene blue. In cytokines production in the serum drawn from femoral arterial 1 hr after middle cerebral artery occlusion, MLE5 significantly increased production of TGF-${\beta}$ and increased production of IL-10, but significantly decreased production of TGF-${\alpha}$ compared with control group. In cytokines production in the serum drawn from femoral arterial 1 hr after reperfusion, MLE5 significantly increased production of TGF-${\beta}$ and IL-10, but significantly decreased production of TGF-${\alpha}$ compared with control group. AS results above. And MLE5 had anti-ischemic effect by inhibiting TGF-${\alpha}$ production, and by accelerating IL-10 and TGF-${\beta}$ production.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.1
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• pp.19-25
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• 2012

This study was designed to investigate the effects of a new herbal medicine named CWS-A on the changes in regional cerebral blood flow (rCBF) and mean arterial blood pressure (MABP) in normal rats, and further to determine the mechanism of action. Also, this study was designed to investigate the effects of CWS-A on the changes in rCBF in cerebral ischemic rats and the safety examination of CWS-A in rats regared to body weight change, renal and liver function test, CBC, $LD_{50}$ and histological observation in rats. The rCBF was significantly and stably increased and MABP was significantly decreased by CWS-A during the period of cerebral reperfusion in normal rats. However, there were no here were no significant changes of rCBF in ischemic rats. In additional, there were no significant changes on the safety examination. In conclusion, these results suggest that medication of CWS-A is effective for the improve the cerebral blood flow and CWS-A can be prescribed as vertigo(眩暈) symptoms treatment.

• Journal of Korean Neurosurgical Society
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• v.56 no.3
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• pp.188-193
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• 2014

Objective : Moyamoya disease (MMD) is a chronic cerebrovascular occlusive disease of unknown etiology. In addition, the neurocognitive impairment of adults with MMD is infrequently reported and, to date, has not been well described. We attempted to determine both the neurocognitive profile of adult moyamoya disease and whether a superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis can improve the neurocognitive impairment in exhibiting hemodynamic disturbance without stroke. Methods : From September 2010 through November 2012, 12 patients with angiographically diagnosed MMD underwent STA-MCA anastomosis for hemodynamic impairment. Patients with hypoperfusion and impaired cerebrovascular reserve (CVR) capacity but without evidence of ischemic stroke underwent a cognitive function test, the Seoul Neuropsychological Screening Battery (SNSB). Five patients agreed to undergo a follow-up SNSB test. Data from preoperative and postoperative neurocognitive function tests were compared and analyzed. Results : Five of 12 patients were enrolled. The median age was 45 years (range, 24-55 years). A comparison of preoperative to postoperative status of SNSB, memory domain, especially delayed recall showed significant improvement. Although most of the domains showed improvement after surgery, the results were not statistically significant. Conclusion : In our preliminary study, large proportions of adult patients with MMD demonstrate disruption of cognitive function. This suggests the possibility of chronic hypoperfusion as a primary cause of the neurocognitive impairment. When preoperative and postoperative status of cognitive function was compared, memory domain showed remarkable improvement. Although further study is needed, neurocognitive impairment may be an indication for earlier intervention with reperfusion procedures that can improve cognitive function.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.4
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• pp.281-296
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• 2021

The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetes-induced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholine-induced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O₂ for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (L-NAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3β/GSK-3β ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IR-induced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3β and Nrf2 signaling pathway to confer protection.

• Journal of The Korean Society of Emergency Medicine
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• v.29 no.5
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• pp.437-448
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• 2018

Objective: Acute ischemic stroke (AIS) requires time-dependent reperfusion therapy, and early recognition of AIS is important to patient outcomes. This study was conducted to identify the clinical features and risk factors of AIS patients that are missed during the early stages of diagnosis. Methods: We retrospectively reviewed AIS patients admitted to a hospital through the emergency department. AIS patients were defined as ischemic stroke patients who visited the emergency department within 6 hours of symptom onset. Patients were classified into two groups: an activation group (A group), in which patients were identified as AIS and the stroke team was activated, and a non-activation group (NA group), for whom the stroke team was not activated. Results: The stroke team was activated for 213 of a total of 262 AIS patients (81.3%), while it was not activated for the remaining 49 (18.7%). The NA group was found to be younger, have lower initial National Institutes of Health Stroke Scale scores, lower incidence of previous hypertension, and a greater incidence of cerebellum and cardio-embolic infarcts than the A group. The chief complaints in the A group were traditional stroke symptoms, side weakness (61.0%), and speech disturbance (17.8%), whereas the NA group had non-traditional symptoms, dizziness (32.7%), and decreased levels of consciousness (22.4%). Independent factors associated with missed stroke team activation were nystagmus, nausea/vomiting, dizziness, gait disturbance, and general weakness. Conclusion: A high index of AIS suspicion is required to identify such patients with these findings. Education on focused neurological examinations and the development of clinical decision tools that could differentiate non-stroke and stroke are needed.

• Archives of Plastic Surgery
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• v.46 no.2
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• pp.108-113
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• 2019

Background The aim of this study was to assess the safety of one-per-mil tumescent injections into viable skin flaps that had survived an ischemic insult, in order to assess the potential suitability of one-per-mil tumescent injections in future secondary reconstructive procedures such as flap revision and refinements after replantation. Methods Forty groin flaps harvested from 20 healthy Wistar rats weighing 220 to 270 g were subjected to acute ischemia by clamping the pedicle for 15 minutes. All flaps showing total survival on the 7th postoperative day were randomly divided into group A (one-per-mil tumescent infiltration; n=14), group B (normal saline infiltration; n=13), and group C (control, with no infiltration; n=13) before being re-elevated. Transcutaneous oxygen tension ($TcPO_2$) was measured before and after infiltration, and changes in $TcPO_2$ were statistically analyzed using analysis of variance, the paired t-test, and the independent t-test. The viability of flaps was also assessed using the Analyzing Digital Images software at 7 days after the second elevation. Results Thirty-nine flaps survived to the final assessment, with the sole exception of a flap from group A that did not survive the first elevation. $TcPO_2$ readings showed significant decreases (P<0.05) following both one-per-mil tumescent ($99.9{\pm}5.7mmHg$ vs. $37.2{\pm}6.3mmHg$) and normal saline ($103{\pm}8.5mmHg$ vs. $48.7{\pm}5.9mmHg$) infiltration. Moreover, all groin flaps survived with no signs of tissue necrosis. Conclusions One-per-mil tumescent infiltration into groin flap tissue that had survived ischemia did not result in tissue necrosis, although the flaps experienced a significant decrease of cutaneous oxygenation.