• Toxicological Research
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• v.20 no.4
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• pp.375-380
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• 2004

The toxicity of CKD-602 was investigated at doses of 0, 3, 9, and 27 mg/kg in rats, by administering the same total dose over 24-hr continuous infusion or bolus injection. CKD-602 treatment caused gastrointestinal symptoms such as diarrhea, soft stool, and soiled perineal region. It also decreased body weight at doses of 9 and 27 mg/kg in a dose-dependant manner. At 3 mg/ kg, clinical signs and body weight decrease were more severe in the infusion group than in the bolus group. In the bolus group, mortalities were 0/8, 0/8, 1/8, and 3/8 at 0, 3, 9, and 27 mg/kg, respectively, whereas those were 0/8, 1/8, 8/8, and 8/8 in the infusion group. $LD_{50}$ values were 36.25 mg/kg for bolus and 3.50 mg/kg for infusion, respectively. This finding indicates that the toxic potency of CKD-602 by continuous infusion is about 10 times higher than by bolus injection. Our findings suggest that the toxic effects of CKD-602 are dependant upon the duration of intravenous administration.

• YAKHAK HOEJI
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• v.42 no.4
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• pp.431-436
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• 1998

The pharmacokinetics of CKD-602, a new camptothecin anticancer derivative, were studied in mice, rats and dogs following a single or multiple intravenous administration, and the following results were obtained. The blood levels of CKD-602 declined in biphasic fashions with peak plasma levels $(C_0)$ of $2.63{\mu}g/ml$ in mice, $2.27{\mu}g/ml$ in tumor bearing mice, $2.84{\mu}g/ml$ in rats at a dose of 20mg/kg, and of 0.02mcg/ml in dogs at a dose of 0.5mg/kg. The plasma half-lives $(t_{1/2}{\beta})$ were 9.55hr in mice, 9.94hr in tumor bearing mice, 9.98hr in rats and 12.75hr in dogs. AUC of CKD-602 was increased linearly with the dose at a range from 5 to 20mg/kg. Moreover, Cltot and Vdss were also not significantly changed with increasing the dose. On the other hand, after 5 daily intravenous bolus injection of CKD-602 (5mg/kg) in rats, $t_{1/2}{\beta}$, AUC and MRT of CKD-602 were 11.90hr, $3.19{\mu}g{\cdot}hr/ml$, and 11.61hr, respectively, which were slightly higher than after the single bolus injection.

• Toxicological Research
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• v.20 no.4
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• pp.381-389
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• 2004

The toxicity of CKD-602 was investigated at doses of 3, 9, and 27 mg/kg in rats, when the same total dose of CKD-602 was administered over 24 hr-continuous infusion or bolus injection. At 3 and 9 mg/kg, the 24-hr infusion group showed a more decreased WBC count on day 3, compared with the bolus group. Administration of CKD-602 caused more toxic effects such as the significant decreases of RBC counts, hematocrit, hemoglobin, and platelet count on day 7 post-administarion in the 24-hr infusion group than in the bolus group. Administration of CKD-602 also caused histopathological changes such as extramedullary hemopoiesis of liver and spleen, hyperplasia of femoral bone marrow, and caecal dilation. These toxic effects were more severe in the 24-hr infusion group than in the bolus injection group, indicating that the toxicity of CKD-602 may be dependant upon the duration of administration.

• The Korean Journal of Pain
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• v.10 no.1
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• pp.42-47
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• 1997

Background : This study was designed to evaluate the continuous effects of single intravenous injection of antiemetics on nausea and vomiting during continuous morphine injection for postoperative pain control. Methods : Prior to the study, we divided patients into two major groups according to the type of surgery performed intra-abdominal(Open: O) and non intra-abdominal(Close: C). When patients regained orientation after routine general anesthesia, enflurane-$O_2-N_2O$, we injected bolus dose of morphine and started continuous injection of morphine for postoperative pain control(Group I; Control). After bolus injection and just before continuous injection, we injected single dose of droperidol(Group II) or ondansetron(Group III). Mean arterial blood pressure, heart rate, pain score and symptom-therapy score were checked at 10 minutes, 4, 8, 16, 24, 36 hours after continuous morphine injection. Results : The pain score of group III was lower than group II(10 min.) and group I(24, 36 hours) in the open group. Symptom-therapy score of group III(10 min., 4, 24 hours) and group II(10 min.) were lower than group I in the open group. In the close group, symptom-therapy score of group III(8 hours) was lower than group I. Conclusions : Single intravenous injection of antiemetics have a tendency of lowering symptom-therapy score for 36 hours in spite of their relatively short elimination half-life.

• Journal of Veterinary Science
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• v.21 no.4
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• pp.55.1-55.11
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• 2020

Background: Computed tomography urography (CTU), based on the excretion of contrast medium after its injection, allows visualization of the renal parenchyma and the renal collecting system. Objectives: To determine the optimal contrast medium dose allocation ratio to apply in split-bolus CTU in dogs. Methods: This prospective, experimental, exploratory study used 8 beagles. In 3-phase CTU, unenhanced-, nephrographic-, and excretory-phase images were obtained with a single injection of 600 mg iodine/kg iohexol. In split-bolus CTU, two different contrast medium allocation ratios (30% and 70% for split CTU 1; 50% and 50% for split CTU 2) were used. Unenhanced phase image and a synchronous nephrographic-excretory phase image were acquired. Results: Although the attenuation of the renal parenchyma was significantly lower when using both split CTUs than the 3-phase CTU, based on qualitative evaluation, the visualization score of the renal parenchyma of split CTU 1 was as high as that of the 3-phase CTU, whereas the split CTU 2 score was significantly lower than those of the two others. Artifacts were not apparent, regardless of CTU protocol. The diameter and opacification of the ureter in both split CTUs were not significantly different from those using 3-phase CTU. Conclusions: Split-bolus CTU with a contrast medium allocation ratio of 30% and 70% is feasible for evaluating the urinary system and allows sufficient enhancement of the renal parenchyma and appropriate distention and opacification of the ureter, with similar image quality to 3-phase CTU in healthy dogs. Split-bolus CTU has the advantages of reducing radiation exposure and the number of CT images needed for interpretation.

• Journal of Gastric Cancer
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• v.16 no.3
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• pp.177-181
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• 2016

Purpose: The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods: We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin ($250mg/m^2/2h$) and bolus 5-FU ($600mg/m^2$) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results: A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3~2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7~7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions: Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.

• Journal of Pharmaceutical Investigation
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• v.29 no.3
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• pp.211-216
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• 1999

To evaluate the thrombolytic activity of streptokinase-dextran conjugate, a rat model of arterial thrombosis was used. Briefly, the femoral artery was exposed and a filter paper saturated with 70% $FeCl_3$ solution was placed around the femoral artery in order to stop the blood flow. Six minutes after the stop of the blood flow in the femoral artery, streptokinase $(10000{\sim}30000\;units\;per\;rat)$ or streptokinase-dextran conjugate $(5000{\sim}17000\;units\;per\;rat)$ was administered by i.v. bolus injection through the femoral vein. Then the blood flow in the femoral artery was monitored using a Doppler laser flow meter. The i.v. bolus administration of streptokinase could not restore the blood flow in the femoral artery in the dose range of $10000{\sim}30000$ units per rat. The i.v. bolus administration of streptokinase-dextran conjugate could restore the blood flow in the femoral artery in the dose range of $5000{\sim}17000$ units per rat. A good correlation between the dose of streptokinase-dextran conjugate and the total thrombolytic effect was observed. In addition, the lag time between the injection of streptokinase-dextran conjugate and the restoring of the blood flow was decreased as the i.v. dose of streptokinase dextran conjugate increased. These results show the superior beneficial effect of streptokinase-dextran conjugate compared with the unconjugated streptokinase with respect to the elongation of thrombolytic activity, the administration method (single injection versus continuous infusion), and the reduced dose necessary for a equivalent thrombolytic effect.

• Biomolecules & Therapeutics
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• v.3 no.2
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• pp.97-103
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• 1995

The purpose of this study was to determine pharmacokinetic parameters of BR-28702-2, a new antineoplastic agent which is the conjugate of nucleotide and phospholipid, and to compare them with those of ara-C. Male rats were cannulated in the left femoral vein and received a single i.v. bolus dose of either BR-28702-2 or ara-C. BR-28702-2 was also administered i.p. and plasma samples were analyzed by reversedphase HPLC. The t$_{1}$2($\beta$)/ of ara-C(1.22 hr.) was significantly smaller than that of BR-28702-2(4.420 hr.). The absolute bioavailability of BR-28702-2 after i.p. injection was 1.125%. This lower bioavailability, together with previous reports that marked antineoplastic activity was observed when given i.p., indicates that BR-28702-2 would act as a depot system to release active moieties. Further works, therefore, need to be done to characterize active metabolites.

• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.171-178
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• 2000

To evaluate the pharmacokinetic properties and tissue distribution of a newly developed recombinant human erythropoietin (GC-rhEPO), we analyzed the plasma and tissue levels of erythropoietin by an ELISA after intravenous (IV) and subcutaneous (SC) adminstration to the male rats at the doses of 20, 100, 500 or 2,500 unit/kg. After single IV bolus injection of GC-rhEPO, the plasma concentration was rapidly increased and decreased with two phases with half-lives of 13.4 min and 2.94 hours. AUC was increased dose- dependently but plasma half-lives remained constant regardless of GC-rhEPO doses. Following SC administration, the plasma concentration increased slowly with half-life of 9.2 hours and reached peak at 8 hours. Mean residence time and bioavailability were 18.2 hours and 44%, respectively. After single IV dose of 100 unit/kg, tissue GC-rhEPO level was higher in bone marrow and spleen, while the depletion rate was slower in liver and bone marrow, indicating the higher affinity of GC-rhEPO to bone marrow. Taken together, the experimental results indicate that GC-rhEPO contained the typical pharmacokinetic properties and the tissue distribution patterns inherent to human erythropoietin.

• The Korean Journal of Pain
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• v.22 no.3
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• pp.199-205
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• 2009

Background: A major ingredient of green tea is epigallocatechin-3-gallate (EGCG), and this is known to have many beneficial effects for cancer prevention and also on the cardiovascular system and neurodegenerative diseases through its anti-oxidant, anti-angiogenic, anti-inflammatory, lipid-lowering and neuroprotective properties. Its actions on nociception and the spinal nervous system have been examined in only a few studies, and in these studies EGCG showed an antinociceptive effect on inflammatory and neuropathic pain, and a neuroprotective effect in motor neuron disease. This study was performed to investigate the effect of EGCG on acute thermal pain and the development of morphine tolerance at the spinal level. Methods: The experimental subjects were male Sprague-Dawley rats and the Hot-Box test was employed. A single or double-lumen intrathecal catheter was implanted at the lumbar enlargement for drug administration. An osmotic pump was used to infuse morphine for 7 days for induction of morphine tolerance. EGCG was injected repeatedly for 7 days at twice a day through the intrathecal catheter. Results: Intrathecal EGCG increased the paw withdrawal latency (PWL) after repeated administration for 7 days at twice a day, but this did not happen with administering on single bolus injection of EGCG. In addition, the antinociceptive effect of intrathecal morphine was not affected by co-administration with EGCG. A continuous 7-day infusion of morphine caused a significant decrease of the PWL in the control group (M + S, morphine plus saline). In contrast, intrathecal EGCG injection over 7 days blocked the decrease of the PWL in the experiment group (M + E, morphine plus EGCG). Conclusions: Intrathecal ECGC produced a weak antinociceptive effect for acute thermal pain, but it did not change the morphine's analgesic effect. However, the development of antinociceptive tolerance to morphine was attenuated by administering intrathecal EGCG.