• Journal of Korean Neurosurgical Society
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• v.40 no.4
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• pp.267-272
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• 2006

Objective : There have been recent reports that mesenchymal stromal cells that are harvested from adipose tissue are able to differentiate into neurons. In the present study, we administered adipose tissue derived stem cells in rats with cerebral infarction in order to determine whether those stem cells could enhance the recovery of motor function. Methods : Cerebral infarction was induced by intraluminal occlusion of middle cerebral artery in rats. The adipose tissue-derived mesenchymal stem cells were harvested from inguinal fat pad and proliferated for 2 weeks in DMEM media. Approximately $1{\times}10^6$ cells were injected intravenously or into subdural space of the peri-lesional area. The rotor rod test was performed at preoperative state[before MCA occlusion], and 1, 2, 3, 4, 6, 8 and 10 weeks after the cell therapy. Results : The motor functions that were assessed by rotor rod test at 1 week of the cell therapy were nearly zero among the experimental groups. However, there was apparent motor function recovery after 2 weeks and 4 weeks of cell injection in intravenously treated rats and peri-lesionaly treated rats, respectively, while there was no significant improvement till 8 weeks in vehicle treated rats. Conclusion : These results demonstrate that the adipose derived stem cell treatment improves motor function recovery in rats with cerebral infarction.

• Journal of Pharmaceutical Investigation
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• v.41 no.5
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• The Korean Journal of Physiology
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• v.23 no.1
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• pp.129-138
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• 1989

In an attempt to characterize the ventral root afferent fibers, arterial blood pressure responses to stimulation of the ventral root (VR) were observed in anesthetized cats. Effects of the morphine administered either intravenously or direct spinally and of the spinal lesions on the pressor responses were compared. Followings are the results obtained. 1) Stimulation of the VR with C-strength, high frequency stimuli evoked a marked pressor response. No depressor response, which had been reported during peripheral nerve stimulation, was observed during VR stimulation with low frequency. 2) Acute cervical spinalization abolished the pressor response, indicating the involvement of supraspinal mechanism. 3) The ascending spinal pathways of the pressor response were located in the dorsolateral funiculus bilaterally. 4) Intravenously administered morphine exaggerated the pressor response to VR stimulation, while direct spinally administered morphine suppressed it. From the above results it was concluded that the ventral root afferent fibers have more similar properties to muscular C-afferent fibers than to cutaneous C-fibers.

• YAKHAK HOEJI
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• v.40 no.4
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• pp.468-477
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• 1996

Vasopressin which is an antidiuretic hormone in human body produced the diuretic action in dog. This study was investigated in order to certify the diuretic action and to search out the mechanism of the action on the vasopressin. Vasopressin, when given in a dose of 10.0mU/kg, bolus+1.0mU/kg/min intravenously, exhibited the increase of urine flow(Vol), renal plasma flow(RPF), osmolar clearance (Cosm) and amounts of sodium and potassium excreted in urine ($E_{Na},\;E_K$), the decrease of reabsorption rate of sodium and potassium in renal tubules ($R_{Na},\;R_K$), and then elevated the mean arterial pressure(MAP). Vasopressin given in a increased dose to 30.0mU/kg, bolus+1.0mU/kg/min intravenously elicited the same aspect with that exhibited by a small dose in changes of Vol. and all renal function and potentiated the change rates, whereas this time MAP did not change at all when compared with control value. Vasopressin, when administered into a renal artery, did not induce the changes of Vol and all renal function in experimental (administered) kidney, but increased slightly the Vol, glomerular filtration rate(GFR), $E_{Na},\;and\;E_K$ expected the no change of $R_{Na}\;and\;R_K$ in the control (not administered) kidney. Vasopressin, when infused into carotid artery, showed the increase of Vol. GFR, $E_{Na},\;and\;E_K$ and no change of $R_{Na}\;and\;R_K$ in a dose of 1/5 of intravenous dose. Diuretic action of vasopressin administered into carotid artery was not influenced by renal denervation. Above results suggest that vasopressin produced diuretic action by hemodynamic changes in dogs. These hemodynamic changes may be mediated by central endogenous substances not associated with renal nerve.

• Tuberculosis and Respiratory Diseases
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• v.78 no.3
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• pp.239-245
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• 2015

Background: Chronic obstructive pulmonary disease is characterized by emphysema, chronic bronchitis, and small airway remodeling. The alveolar destruction associated with emphysema cannot be repaired by current clinical practices. Stem cell therapy has been successfully used in animal models of cigarette smoke- and elastase-induced emphysema. However, the optimal dose of mesenchymal stem cells (MSCs) for the most effective therapy has not yet been determined. It is vital to determine the optimal dose of MSCs for clinical application in emphysema cases. Methods: In the present study, we evaluated the therapeutic effects of various doses of MSCs on elastase-induced emphysema in mice. When 3 different doses of MSCs were intravenously injected into mice treated with elastase, only $5{\times}10^4$ MSCs showed a significant effect on the emphysematous mouse lung. We also identified action mechanisms of MSCs based on apoptosis, lung regeneration, and protease/antiprotease imbalance. Results: The MSCs were not related with caspase-3/7 dependent apoptosis. But activity of matrix metalloproteinase 9 increased by emphysematous lung was decreased by intravenously injected MSCs. Vascular endothelial growth factor were also increased in lung from MSC injected mice, as compared to un-injected mice. Conclusion: This is the first study on the optimal dose of MSCs as a therapeutic candidate. This data may provide important basic data for determining dosage in clinical application of MSCs in emphysema patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6595-6597
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• 2015

Objective: To investigate short- and long-term treatment effects and side reactions of lobaplatin plus 5-Fu combined and concurrent radiotherapy in treating patients with inoperable middle-advanced stage esophageal cancer. Methods: Sixty patients with middle-advanced stage esophageal squamous cell cancer were retrospectively analyzed. All patients were administered lobaplatin (50 mg intravenously) for 2 h on day 1, and 5-Fu ($500mg/m^2$) injected intravenously from day 1 to 5 for 1 cycle, in an interval of 21 days for totally 4 cycles. At the same time, late-course accelerated hyperfractionated three-dimensional conformal radiotherapy was performed. Patients were firstly treated with conventional fractionated irradiation (1.8 Gy/d, 5 times/week, a total of 23 treatments, and DT41.4 Gy), and then treated with accelerated hyperfractionated irradiation (1.5 Gy, 2 times/d, a total of 27 Gy in 9 days, an entire course of 6-7 weeks, and DT 68.4Gy). Results: All patients completed treatment, including 10 complete response (CR), 41 partial response (PR), 7 stable disease (SD), and 2 progressive disease (PD). The total effective rate was 85.0% (51/60). Thirty-nine patients had an increased KPS score. One-, 2-, and 3-year survival rates were 85.3%, 57.5%, and 41.7%, respectively. The median survival time was 27 months. The adverse reactions included myelosuppression, which was mainly degree I and II. The occurrence rate of radiation esophagitis was 17.5%. No significant hepatic or renal toxicity was observed. Conclusion: Lobaplatin plus 5-Fu combined with concurrent radiotherapy is safe and effective in treating patients with middle-advanced stage esophageal cancer. However, this result warrants further evaluation by randomized clinical studies.

• Biomolecules & Therapeutics
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• v.1 no.1
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• pp.9-19
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• 1993

DA-125, a new anthracycline antibiotic, showed antitumor activity against animal tumors and human tumors. Therefore we studied the cardiotoxic potential of DA-125 in hamsters and rats as a part of safety research, and compared it with that of doxorubicin(DXR). In acute cardiotoxicity test model used hamsters DA-125 was administered intravenously at a dose of 6, 9, 12 mg/kg, and DXR at 3 mg/kg was given. The electrocardiogram(ECG) of hamsters was recorded for 30 minutes after administration. The DA-125 caused slight ECG alterations at a dose of 6 mg/kg. At a dose of 12 mg/kg DA-125 induced moderate to remarkable changes in ECG like decrease of heart rate, widening of PR interval and 07 interval, and A-V block in 3 out of 5 animals. The severity of ECG alteration at 12 mg/kg of DA-125 was similar to that at 3mg/kg of DXR and these changes caused by DA-125 and DXR recovered within 10 minutes after injection. In chronic cardiotoxicity test model used rats, DA-125 was administered intravenously once a week for three weeks at a dose of 6, 9mg/kg and DXR was given at a dose of 6mg/kg. Electrocardiogram was recorded every week from the start of administration to 2 weeks after the last administration and the animals were sacrificed for histological heart examination at 1 week or 2 weeks after the last administration. DA-125 did not cause any abnormal changes in ECG and in histological heart examination due to administration, but DXR caused widening of ST segment, QRS complex, and QT interval from 1 week after administration and these changes were continued to necropsy. These alterations in ECG were accompanied by cardiac histological lesions such as vacuolation in myocardiac cells, interstitial edema and necrosis of myocytes. These results suggest that DA-125 is less cardiotoxic than DXR.

• Journal of Korean Neurosurgical Society
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• v.60 no.3
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• pp.355-361
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• 2017

Objective : The aim of this study to investigate the normal values of erythropoietin (EPO) and neuroprotective effects of quercetin and mannitol on EPO and hematocrit levels after acute severe traumatic brain injury (TBI) in rat model. Methods : A weight-drop impact acceleration model of TBI was used on 40 male Wistar rats. The animals were divided into sham (group I), TBI (group II), TBI+quercetin (50 mg/kg intravenously) (group III), and TBI+mannitol (1 mg/kg intravenously) (group IV) groups. The malondialdehyde, glutathione peroxidase, catalase, EPO, and hematocrit levels were measured 1 and 4 hour after injury. Two-way repeated measures analysis of variance and Tukey's test were used for statistical analysis. Results : The malondialdehyde levels decreased significantly after administration of quercetin and mannitol compared with those in group II. Catalase and glutathione peroxidase levels increased significantly in groups III and IV. Serum EPO levels decreased significantly after mannitol but not after quercetin administration. Serum hematocrit levels did not change significantly after quercetin and mannitol administration 1 hour after trauma. However, mannitol administration decreased serum hematocrit levels significantly after 4 hour. Conclusion : This study suggests that quercetin may be a good alternative treatment for TBI, as it did not decrease the EPO levels.

• Journal of Pharmaceutical Investigation
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• v.40 no.5
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• pp.291-296
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• 2010

This study was to investigate the effect of baicalein, an antioxidant, on the bioavailability of nicardipine after orally or intravenously administered nicardipine in rats. Nicardipine was administered orally (12 mg/kg) or intravenously (4 mg/kg) with or without orally administered baicalein (0.4, 2 or 10 mg/kg) to rats. In the inhibitory effect of baicalein on CYP3A4 activity, baicalein inhibited CYP3A4 activity with $IC_{50}$ values of 9.2 ${\mu}M$. The cell-based P-gp activity test using rhodamine-123 also showed that baicalein (30-10 ${\mu}M$, p<0.01) significantly inhibited P-gp activity. Compared with the control group (given nicardipine alone), the area under the plasma concentration-time curve (AUC) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 25.9-60.0%, and the peak concentration ($C_{max}$) was significantly (10 mg/kg, P<0.01) increased by 40.0% in the presence of baicalein after orally administration of nicardipine. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.26- to 1.60-fold and the absolute bioavailability (A.B.) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 26.0-59.9%. Compared to the i.v. control, baicalein did not significantly change pharmacokinetic parameters of nicardipine in i.v. administration. Accordingly, the enhanced oral bioavailability of nicardipine might be mainly due to increased intestinal absorption caused by P-gp inhibition rather than to reduced elimination of nicardipine by baicalein. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the small intestine via the inhibition of P-gp and reduced first-pass metabolism of nicardipine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by baicalein. Based on these results, nicardipine dosage should be adjusted when given concomitantly with baicalein.

• Biomolecules & Therapeutics
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• v.10 no.1
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• pp.59-69
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• 2002

Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. YHB216 is a new rHu-EPO developed by Yuhan Research Institute. In this study, we investigated the single dose and 4-week repeated dose toxicity of YHB216 in Beagle dogs. In the single dose toxicity study, YHB216 was administered intravenously at single dose levels of 0 and 25,000 IU/kg to dogs (2 dogs/sex/group). There were no treament-related changes in survivals, clinical signs, body weight gain, hematological values, blood chemical values, and necropsy finding during experimental period. In the repeated dose toxicity study, YHB216 was administered intravenously to dogs for 4 weeks at the dose levels of 0, 100, 500, and 2,500IU／kg (3 dogs/sex／group). There were no toxicologically significant changes in clinical signs, body weights, food and water consumptions, ophthalmoscopy, urinalysis and blood chemistry. There were increased values of red blood cell, hemoglobin, and hematocrit at all treated groups. Spleen revealed increased weight and extramedullary hematopoiesis at 500 IU/kg or more. These changes are all considered to be Pharmacology-related effects and were recovered after 4-week recovery period. From these results, it is concluded that LD50 value was above 25,000 IU/kg in the single dose toxicity study of YHB216 in dogs and the no observed adverse effect level (NOAEL) was 100 IU/kg day in the repeated dose toxicity study of YHB216 in dogs.