• 대한임상독성학회지
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• 제20권2호
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• pp.39-44
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• 2022

N-Acetylcysteine (NAC) is the standard antidote treatment for preventing hepatotoxicity caused by acetaminophen (AAP) poisoning. This review summarizes the recent evidence for the treatment of AAP poisoning. Several alternative intravenous regimens of NAC have been suggested to improve patient safety by reducing adverse drug reactions and medication errors. A two-bag NAC infusion regimen (200 mg/kg over 4 h, followed by 100 mg/kg over 16 h) is reported to have similar efficacy with significantly reduced adverse reactions compared to the traditional 3-bag regimen. Massive AAP poisoning due to high concentrations (more than 300-lines in the nomogram) needs to be managed with an increased maintenance dose of NAC. In addition to NAC, the combination therapy of hemodialysis and fomepizole is advocated for severe AAP poisoning cases. In the case of a patient presenting with an altered mental status, metabolic acidosis, elevated lactate, and an AAP concentration greater than 900 mg/L, hemodialysis is recommended even if NAC is used. Fomepizole decreases the generation of toxic metabolites by inhibiting CYP2E1 and may be considered an off-label use by experienced clinicians. Since the nomogram cannot be applied to sustained-release AAP formulations, all potentially toxic sustained-release AAP overdoses should receive a full course of NAC regimen. In case of ingesting less than the toxic dose, the AAP concentration is tested twice at an interval of 4 h or more; NAC should be administered if either value is above the 150-line of the nomogram.

• Journal of Pharmaceutical Investigation
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• 제38권4호
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• pp.229-234
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• 2008

In the present study, chitosan-glycerophosphate sodium salt solution as a thermosensitive system (TSS) was used to formulate a temperature-sensitive drug delivery system (TSDDS) containing acetaminophen (AAP). The optimized TSS was prepared by measuring gelation temperature, gelation time and rheological properties of TSS. The optimized gelation temperature and time of TSS were $36^{\circ}C$ and 100 seconds, respectively. The viscosity of TSS was also suitable for maintaining gel structure at $37.2^{\circ}C$. The release profiles of TSDDS in PBS/pH 7.4 with various apparatuses and mass loss of TSDDS were investigated. The time required to release 50% of AAP from TSDDS ($t_{50%}$) was 120 min with the formation of pore on the surfaces, which was 2 times longer than that from AAP-chitosan gel. In addition, TSDDS was degraded approximately 80% within 4 hr and then degraded slowly for 20 hrs. In conclusion, AAP-TSS (TSDDS) formulated in this study might be suitable for some specific uses such as subcutaneous injection and rectal formulation.

• 대한한의학회지
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• 제37권3호
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• pp.47-61
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• 2016

Objectives: The objective of this research is to develop new animal-experimental model for Sasang Constitutional Medicine, especially for partial Taeyangin(one of four constitution which has good pulmonary function and poor hepatic function) by AAP intraperitoneal injection, and to estimate from the viewpoint of obesity and lipid metabolism. Methods: The C57bl/6J mice was divided into 4 groups ; Normal group, AAP group, High-Fat-Diet(HFD) group, and HFD+AAP group. 200mg AAP was injected intraperitoneally to the AAP group twice a week for six weeks, and HFD group was fed with 60%-High-fat Diet for six weeks. HFD+AAP group got both AAP injection and 60%-High-fat Diet at the same time for the same period. In this period, We measured the weight and Food Efficiency Ratio(FER, %) once a week. After six weeks, We conducted the blood chemical test from the groups, and extracted the fat tissue to measure weight. Results & conclusion: In the liver function test, two AAP groups had higher AST and ALP, and normal LDH. The blood level of creatinine from all groups were normal. The rate in weight was lesser by 7.8% in HFD+AAP group, and had lesser FER than HFD group. Also They had lesser Total cholesterol and LDL cholesterol, and had more HDL cholesterol than HFD group. HFD+AAP group hadmore glucose in serum and lesser Insulin-like Growth Factor 1(IGF-1) than HFD group.

• 대한임상독성학회지
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• 제16권2호
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• pp.149-156
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• 2018

Purpose: The purpose of this study was to determine whether hepatotoxicity could be predicted early using biochemical markers in patients with acetaminophen (AAP) poisoning and to assess the usefulness of predictive factors for acute liver injury or hepatotoxicity. Methods: This study was a retrospective observational study involving a medical records review. The participants were patients who were admitted to the emergency department (ED) with AAP overdose at two hospitals over a 10-year period. Demographic data, age, time from ingestion to visit, initial AAP level, initial hepatic aminotransferases, and initial prothrombin time were recorded. Acute liver injury was defined as a peak serum ALT >50 U/L or double the admission value, and hepatotoxicity was defined as a peak ALT >1,000 U/L. Receiver operating characteristic curve analyses were performed to compare the prognostic performance among variables. Results: A total of 97 patients were admitted to the ED with AAP overdose, of whom 26 had acute liver injury and 6 had hepatotoxicity. Acute liver injury was associated with the time interval after taking the drug, and hepatotoxicity was associated with the initial PT and the ALT level. The scoring system proposed by the authors has a significant ability to predict both acute liver injury and hepatotoxicity. Conclusion: To predict the prognosis of AAP poisoning patients, the time interval after taking AAP was important, and initial prothrombin time and ALT level were useful tests. Also a scoring system combining variables may be useful.

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.455-460
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• 2009

Foods of plant origin, especially fruits and vegetables, have attracted attention because of their potential benefits to human health. In this report, Rubi Fructus (RF), the dried unripe fruit of Rubus coreanus Miq (Rosaceae) and ellagic acid (EA) purified from RF were used to test their potential hepatoprotective effect against acetaminophen (AAP)-induced hepatotoxicity in rats. RF extract (RFext) and EA reduced the elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum and the content of lipid peroxide in liver by AAP administration, while the increment of the cellular glutathione (GSH) content and the induction of glutathione S-transferase (GST) and glutathione peroxidase (GSH-PX) which were decreased by AAP administration. RFext and EA from RFext did not affect the two major form of cytochrome P450s, cytochrome P450 2E1 (CYP2E1) and cytochrome P450 1A2 (CYP1A2), but downregulated the cytochrome P450 3A4 (CYP3A4) related to the conversion of AAP to N-acetyl-P-benzoquinone imine (NAPQI). These results suggest that RFext and EA from RF exhibit a hepatoprotective effect not only by increasing antioxidant activities but also by down-regulating CYP3A4 in the AAP-intoxicated rat.

• Nutrition Research and Practice
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• 제11권2호
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• pp.97-104
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• 2017

BACKGROUND/OBJECTIVE: Although Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Asian, its functionality and mechanism of action. The aim of this study was to determine the protective effect of ethanol extract of AK (AK-Ex) on acute hepatotoxicity induced by acetaminophen (AAP) in HepG2 human hepatocellular liver carcinoma cells and HepaRG human hepatic progenitor cells. MATERIALS/METHODS: AK-Ex was prepared HepG2 and HepaRG cells were cultured with various concentrations and 30 mM AAP. The protective effects of AK-Ex against AAP-induced hepatotoxicity in HepG2 and HepaRG cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, lactate dehydrogenase (LDH) assay, flow cytometry, and Western blotting. RESULTS: AK-Ex, when administered prior to AAP, increased cell growth and decreased leakage of LDH in a dose-dependent manner in HepG2 and HepaRG cells against AAP-induced hepatotoxicity. AK-Ex increased the level of Bcl-2 and decreased the levels of Bax, Bok and Bik decreased the permeability of the mitochondrial membrane in HepG2 cells intoxicated with AAP. AK-Ex decreased the cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of caspase-9, -7, and -3. CONCLUSIONS: These results demonstrate that AK-Ex downregulates apoptosis via intrinsic and extrinsic pathways against AAP-induced hepatotoxicity. We suggest that AK could be a useful preventive agent against AAP-induced apoptosis in hepatocytes.

• Natural Product Sciences
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• 제15권3호
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• pp.156-161
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• 2009

Rubus coreanus, commonly known as 'red raspberry' is used as a traditional oriental medicine in Korea for the management of diseases such as impotence, spermatorrhea and athsma, and for allergies, in combination with other herbal preparations, in many centuries. We undertook a comparison of the hepatoprotective effect of ethanol extracts of the unripe (UREx) and ripe (RREx) R. coreanus extract against acetaminophen (AAP) induced hepatotoxicity in rats. UREx reduced the elevated alanine aminotransferase (ALP), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (AP), lipid peroxide and nitric oxide content which had been increased by AAP administration. UREx also increased the cellular glutathione (GSH) content and induced the glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px) content which had been decreased by AAP. RREx did not exhibit strong hepatoprotective effect or antioxidant activity under the same conditions. The experimental results show that the degree of the ripening of R. coreanus affects the hepatoprotective activity in the AAP-intoxicated rats. These findings of a protective mechanism are supportive evidence for the utility of unripened R. coreanus in traditional medicine for liver ailments.

• Food Science and Biotechnology
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• 제16권3호
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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.

• Archives of Pharmacal Research
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• 제13권2호
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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.

• 한국식품과학회지
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• 제42권2호
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• pp.217-222
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• 2010

본 연구에서는 널리 섭취되는 식이 폴리페놀 화합물인 resveratrol과 일반의약품 성분 AAP, Asp 및 Ibu와의 혼용 시 일어날 수 있는 상호작용에 의한 세포독성 변화를 조사하였다. Resveratrol은 장관계 HCT 116 세포와 간 HepG2 세포에 농도의존적인 세포활성 감소를 초래하였고 각각 113.8 및 $135.7\;{\mu}M$의 $IC_{50}$ 수치를 보였다. 농도별 resveratrol과 AAP, Asp 또는 Ibu를 각 세포에 24시간 복합투여하였을 때 일부 유의적인 resvertrol 독성의 감소나 증가가 나타났지만 전체적으로 10% 이내의 미미한 변화를 보였다. AAP, Asp 및 Ibu의 고농도 처리시 발생하는 세포독성에 대한 resveratrol의 효과를 HepG2 세포와 IEC-6 정상장관계 세포에서 비교하였을 때 현저한 약물 독성의 변화 또한 관찰되지 않았다. HepG2 세포에 저농도의 resveratrol을 48, 72시간 처리하였을 때 유의적인 세포증식 촉진효과가 나타났으나, AAP와 복합투여시 그 효과는 소멸되었다. 한편 일반의약품 성분과 resveratrol을 각각 순서를 달리하여 전후로 세포에 처리하였을 때에도 현저한 독성의 변화는 나타나지 않았다. Resveratrol과 빈번히 복용되는 일반의약품 AAP, Asp, Ibu를 여러 조합에 의해 복합처리하여 세포독성을 평가한 결과, 이들의 상호작용에 의한 두드러진 독성발현 및 활성변화는 발견되지 않았다.