• Journal of Environmental Health Sciences
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• v.31 no.3
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• pp.227-233
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• 2005

This study was conducted to determine the endorcrine disruption effects of the several major pharmaceutical residues in water using adult Japanese medaka (Oryzias latipes). Four frequently used pharmaceuticals including caffeine, ketoconazole, acetaminophen, and diltiazem were investigated for the vitellogenin(Vtg) induction in the medaka using Western blotting and ELISA. $17\beta$,-estradiol was used as a positive control. Vtg was qualified and quantified through Western blot and ELISA. Following SDS gel electrophoresis, the dominant protein band was identified to molecular weight approximately 205 kDa in whole body samples of vitellogenic female. With female medaka exposed to $17\beta,-estradiol$, no significant difference in total protein induction was noted. In contrast, three to five day exposure of male fish to $17\beta,-estradiol$ resulted in $63.07\%o$, increase of total protein comparing to that of control males (p<0.01). Vtg induction in male fish was observed with all the test pharmaceuticals: At concentrations greater than 1ppm of diltiazem, 2 ppm of caffeine, 4 ppm of acetaminophen, and 10 ppm of ketoconazole, Vtg induction was monotonously increased in a dose dependent manner. This study is one of the first reports suggesting potential endocrine disruption mechanism of common human pharmaceutical products in aquatic ecosystem. Although the effect concentrations obtained from this investigation are environmentally unrealistically high, endocrine disruption should be considered as one of the important consequences of pharmaceutical pollution in aquatic environment, and warrants due attention in future researches.

• Preventive Nutrition and Food Science
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• v.8 no.3
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• pp.239-244
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• 2003

Recently, we reported (J Korean Soc Food Sci Nutr, 31(3): 516-520, 2002) that Semisulcospira libertina (Marsh Snail) pretreatment has a hepatoprotective effect on $CCl_4$-induced liver damage in rats. The purpose of this study was to investigate the possible mechanisms of hepatoprotection by S. libertina (SL) on liver injury induced by acetaminophen (AA). Male ICR mice were pretreated with dehydrated powder of SL once daily for three consecutive days, given a single toxic dose of AA (450 mg/kg) and liver function determined 24 h later. Liver damage was assessed by quantifying serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH) activities, and by measuring hepatic lipid peroxidation. To confirm possible mechanism(s), the content of hepatic glutathione (GSH) and gene expression of tumor necrosis factor a (TNF $\alpha$) mRNA by reverse transcription-polymerase chain reaction (RTPCR) were also measured. Pretreatment with SL dramatically lowered AA-elevated ALT, AST and SDH activities. SL pretreatment decreased AA-produced lipid peroxidation by 11% and restored the AA-depleted hepatic GSH by 27%. Furthermore, SL markedly suppressed the expression of TNF $\alpha$ mRNA induced by AA. Our findings revealed that the possible hepatoprotective mechanisms of SL could be attributed, at least in part, to the glutathione-mediated detoxification as well as the regulation of TNF $\alpha$ mRNA expression.

• Journal of Pharmacopuncture
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• v.22 no.4
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• pp.239-247
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• 2019

Objectives: Allium jesdianum (Aj) is a medicinal plant that has highlighted pharmacological features. In this study, the effects of Aj extract were examined on acetaminophen (APAP)-induced hepatic failure in rats. Methods: Methanolic fraction of hydro-alcoholic extract of Aj was obtained by silica gel column chromatography method. Animals were randomly divided into four groups each containing six rats and treated by gavage as follows: the first and second groups received normal saline, the third and fourth groups were received with 50 and 100 mg/kg of Aj extract, respectively. After two consecutive weeks, the groups 2-4 were given a single dose of APAP (2 g/kg). After 48 hours, blood and liver samples were collected for biochemical and histological examinations. Results: The findings of the study demonstrated that APAP caused a significant increase in ALT (P < 0.001), AST (P < 0.001), LDH (P < 0.001), ALP (P < 0.001) serum levels, hepatic lipid peroxidation (LPO; P < 0.001) and nitric oxide (NO; P < 0.001). In this regard, APAP led to the depletion of the total antioxidant capacity (TAC; P < 0.001), glutathione and total thiol groups (TTGs; P < 0.001), and structural change in the liver. In the Aj extract groups, a considerable improvement was found in the hepatic function alongside the histopathologic changes. Conclusion: This investigation indicated that the influential effects of Aj extract in APAP-induced hepatic failure might depend on its effect on improving oxidant/antioxidant balance in hepatic tissue.

• Food Science and Biotechnology
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• v.16 no.3
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• pp.463-469
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• 2007

We examined the hepatoprotective effects of colored potato flakes on acetaminophen (AAP)-induced liver damage in rats. F344/DuCrj (8 week-old) rats were fed a cholesterol-free diet with 54.9486 g of ${\alpha}$-corn starch/100g diet and were orally treated with 25% colored flakes of Kitamurasaki (KM: light purple), Northern Ruby (NR: red), and Shadow Queen (SQ: medium purple) potatoes co-administered with AAP (0.5 g/100 g diet) for 4 weeks. The hepatic thiobarbituric acid-reactive substances (TBARS) values in the KM, NR, and SQ groups were significantly lower (p<0.05) than those in the control groups with and without AAP. Furthermore, the hepatic catalase, Mn-superoxide dismutase (SOD), and Cu/Zn-SOD mRNA levels in the KM, NR, and SQ groups were higher than those in the control groups with and without AAP. The present findings suggest that colored potato flakes are useful as a prophylactic agent against oxidative liver damage.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.235-235
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• 1996

1. 초산 writhing법에서 DA-5018, morphine, capsaicin 및 acetaminophen의 E $D_{50}$ 은 각각 0.1, 0.3, 1.4 및 45.4 mg/kg이었으며, formalin법에서 DA-5018과 morphine의 E $D_{50}$은 0.17과 4.3 mg/kg이었다. Randall-Selitto법에서 DA-5018, morphine, capsaicin 및 acetaminophen의 E $D_{50}$은 0.66, 3.9, 4.2 및 643 mg/kg이었다. Tail flick법에서 DA-5018, morphine 및 capsaicin의 E $D_{50}$ 은 2.0, 2.6 및 14.2 mg/kg이었고 hot plate법에서 DA-5018과 capsaicin의 E $D_{50}$은 1.7 및 26.5mg/kg이었다. 그러나 열자극에 의한 동통모델에서 acetaminophen은 진통효과가 없었다. 2. Streptozotocin유발 당뇨랫드에 DA-5018 0.2, 0.5 및 1.0mg/kg 또는 capsaicin 10 mg/kg 투여시 1, 3, 7 일째에서 각각 유의성있는 동통역치의 증가를 나타내었으나 ketoprofen(10 mg/kg) 및 desipramin(10 mg/kg) 투여시는 동통역치의 유의성있는 증가가 나타내지 않았다. 관절염 동통모델에서 DA-5018, ketoprofen 및 capsaicin을 투여한 후 7일째에 동통역치를 2배 증가시키는 용량은 각각 0.66, 3.76 및 17.38 mg/kg이었다. 3. 이상의 결과로부터 DA-5018은 morphine 및 capsaicin에 비해 동등 이상의 효력을 갖고 있으며, 비스테로이드성 진통제보다 효능이 우수함을 확인하였다.

• Proceedings of the Korean Environmental Health Society Conference
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• 2005.06a
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• pp.345-350
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• 2005

Acute toxicities of five pharmaceutical products were evaluated with aquatic microbes, invertebrates, and fish. The test pharmaceuticals, i.e., cimetidine, carbamazepine, diltiazem, acetaminophene, and metformin have been often detected in aquatic environment, but theire cological hazard on receptors of various trophic levels has seldom been evaluated. In the present study, we conducted acute toxicity assays with a marine bacterium, Vibrio fischeri, an invertebrate, Daphnia magna, and a fish, Japanese medake (Oryzias latipes). In general, D. magna, showed the most sensitive response to the test chemicals. Diltiazem exhibited the lowest EC50 value after 96 hr of exposure at 7.6 mg/L, followed by cimetidine >acetaminophen > metformin = carbamazepine in an order of decreasing susceptibility. With the fish, diltiazem and carbamazepine showed the 96 hr EC50 values at 14.1${\sim}$35.4 mg/L while acetaminophen, cimetidine, and metformin did not cause 50% mortality at 100 mg/L. Similar pattern was noted with the Microtox Assay, with which the median effective concentrations for acetaminophen, cimetidine, and metformin were found at the range between 301.8 and 755.4 mg/L. Carbamazepine and diltiazem exposure to the microbes resulted in EC50 values around 50 mg/L. Predicted no effect concentrations (PECs) of these pharmaceuticals derived from the EC5O values obtained from this study, and predicted environmental concentrations (PECs) obtained from available literatures were utilized to estimate ecological risks of the test compounds. No test pharmaceuticals resulted in risk quotients (PEC/PNEC) greater than 1, which suggests no serious potential ecological concerns. It should be noted however that further studies including the refinement of PEC derivation, identification and toxicity assessment of the metabolites and/or their interactions with other stressors may be warranted to better understand the environmental consequences of the residual pharmaceutical discharge to the waterway.

• Journal of Pharmaceutical Investigation
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• v.20 no.1
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• pp.29-33
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• 1990

Plasma and saliva concentrations of acetaminophen (AAP) were determined at various time points by HPLC after oral administration of AAP tablets (AAP 500 mg) to four healthy male Korean subjects. Saliva concentrations (S) of AAP were significantly correlated with plasma AAP concentrations (P). The S/P ratio of AAP was calculated to be 1.05 (r =0.944, $p<10^{-6}$) for all the data points from the subjects. It showed a little intersubject variation and ranged from 0.89 to 1.46 in each subject. Bioavailability parameters such as AUC, $C_{max}$ and $T_{max}$ which are usually obtained from the plasma concentration data will be predictable approximately by saliva concentration data. Saliva seems to be very convinient and useful samples for the preliminary studies of bioavailability and bioequivalence of AAP preparations, since it can be collected frequently without any painful venipuncture to the subjects, that is inevitable in plasma sampling. Evaluation of the bioavailability of a preparation by saliva samples will reduce the cost, time and safety risk greatly in developing a new drug delivery system for AAP.

• Journal of The Korean Society of Clinical Toxicology
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• v.9 no.2
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• pp.71-76
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• 2011

Purpose: The Rumack-Matthew nomogram cannot be applied in managing overdose by extended release (ER) preparation acetaminophen (AAP). This study analyzed the clinical characteristics of ER preparation AAP overdose in order to develop a treatment recommendation. Methods: We retrospectively reviewed the medical records of patients presented to the emergency department as a result of AAP overdose from Jan 2008 to Dec 2010. Only those patients who ingested an ER preparation of AAP were included in the study. Their blood AAP concentrations were measured at 4 and 8 hours after ingestion. Clinical variables related to AAP intoxication were analyzed. Results: Of the total 108 AAP overdose patients identified during the 3-year period, 20 suffered specifically with ER preparation AAP overdose. The mean estimated ingestion amount was 167.5 mg/kg. Treatments including gastric lavage, activated charcoal, and N-acetyl cysteine (NAC) were performed on 10, 14, and 11 patients, respectively. Hepatotoxicity was diagnosed in only one patient who was then successfully treated with NAC. In another case, blood AAP concentration continued to increase until at least 11-hours after ingestion. Conclusion: This study suggested that blood AAP concentrations associated with ingestion of ER formulations of AAP, may increase in an extended manner. Therefore, multiple sampling and longer periods between samples assessing AAP blood concentration may be required for incidences of extended release overdose.

• Archives of Pharmacal Research
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• v.13 no.2
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• pp.151-160
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• 1990

In order to develop a controlled-release oral drug delivery system (DDS) which sustains the plasma acetaminophen (AAP) concentration for a certain period of time, microporous membrane-coated tablets were prepared and evaluated in vitro. Firstly, highly water-soluble core tablet of AAP were prepared with various formulations by wet granulation and compression technique. Then the core tablets were coated with polyvinychloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of core tablets and coating suspensions on the pharmaceutical characteristics such as drug release kinetics and membrane stability of the coated tablets was investigated in vitro. AAP was released from the coated tablets as a zero-order rate in a pH-independent manner. This independency of AAP release to pH change from 1.2 to 7.2 is favorable for the controlled oral drug delivery, since it will produce a constant drug release in the stomach and intestine regardless of the pH change in the GI tract. Drug release could be extended upto 10 h according to the coating condition. The release rate could be controlled by changing the formula compositions of the core tablets and coating suspensions, coat weight per each tablet, and especially PVC/sucrose ratio and particle size of the sucrose in the coating suspension. The coated tablets prepared in this study had a fairly good pharmaceutical characteristics in vitro, however, overall evaluation of the coated tablet should await in vivo absorption study in man.

• Molecules and Cells
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• v.38 no.10
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• pp.843-850
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• 2015

The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.