• 대한임상독성학회지
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• 제10권2호
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• pp.97-102
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• 2012

Purpose: Serious acetaminophen (AAP) poisoning causes hepatotoxicity. N-acetylcysteine (NAC) is the most effective therapy for AAP poisoning and can be administered orally and intravenously (IV). Several studies have compared the efficacy of these two routes of administration and the results have been controversial. The purpose of this study was to compare the efficacy of oral and IV NAC for the prevention of hepatic toxicity in Korean patients whose serum AAP levels were higher than normal. Methods: A retrospective before/after study was performed, in which the patients presented to the emergency department with an AAP overdose from February 1995 to March 2012. A 3-day oral NAC regimen was used in the beginning, and a 20-hr intravenous regimen was then used from 2007. This study assessed the complications of an AAP overdose, such as hepatotoxicity, hepatic failure and renal failure as well as the side effects of the treatment regimen. Results: A total of 41patients was enrolled in this study. The median ALT and AST were 63 (IU/L) and 57 (IU/L) for the oral NAC treated patients, and 14 (IU/L) and 20 (IU/L) for the IV NAC treated patients (p=0.004 and p=0.001, respectively). The incidence of complications was similar in the treatment groups (p=0.399). Among the patients, 7 patients developed hepatotoxicity and were treated successfully with oral or IV NAC. Conclusion: This study suggests that IV NAC and oral NAC can prevent and successfully treat hepatic toxicity in patients whose serum AAP levels are higher than normal.

• BMB Reports
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• 제46권10호
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• pp.513-518
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• 2013

We investigated the protective effects of Gymnaster koraiensis against oxidative stress-induced hepatic cell damage. We used two different cytotoxicity models, i.e., the administration of tert-butyl hydroperoxide (t-BHP) and acetaminophen, in HepG2 cells to evaluate the protective effects of G. koraiensis. The ethyl acetate (EA) fraction of G. koraiensis and its major compound, 3,5-di-O-caffeoylquinic acid (DCQA), exerted protective effects in the t-BHP-induced liver cytotoxicity model. The EA fraction and DCQA ameliorated t-BHP-induced reductions in GSH levels and exhibited free radical scavenging activity. The EA fraction and DCQA also significantly reduced t-BHP-induced DNA damage in HepG2 cells. Furthermore, the hexane fraction of G. koraiensis and its major compound, gymnasterkoreayne B (GKB), exerted strong hepatoprotection in the acetaminophen-induced cytotoxicity model. CYP 3A4 enzyme activity was strongly inhibited by the extract, hexane fraction, and GKB. The hexane fraction and GKB ameliorated acetaminophen-induced reductions in GSH levels and protected against cell death.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.15-23
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• 2016

Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure. The study aimed to investigate the protective effect of carnosic acid (CA) on APAP-induced acute hepatotoxicity and its underlying mechanism in mice. To induce hepatotoxicity, APAP solution (400 mg/kg) was administered into mice by intraperitoneal injection. Histological analysis revealed that CA treatment significantly ameliorated APAP-induced hepatic necrosis. The levels of both alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum were reduced by CA treatment. Moreover, CA treatment significantly inhibited APAP-induced hepatocytes necrosis and lactate dehydrogenase (LDH) releasing. Western blot analysis showed that CA abrogated APAP-induced cleaved caspase-3, Bax and phosphorylated JNK protein expression. Further results showed that CA treatment markedly inhibited APAP-induced pro-inflammatory cytokines TNF-${\alpha}$, IL-$1{\beta}$, IL-6 and MCP-1 mRNA expression and the levels of phosphorylated $I{\kappa}B{\alpha}$ and p65 protein in the liver. In addition, CA treatment reduced APAP- induced hepatic malondialdehyde (MDA) contents and reactive oxygen species (ROS) accumulation. Conversely, hepatic glutathione (GSH) level was increased by administration of CA in APAP-treated mice. Mechanistically, CA facilitated Nrf2 translocation into nuclear through blocking the interaction between Nrf2 and Keap1, which, in turn, upregulated anti-oxidant genes mRNA expression. Taken together, our results indicate that CA facilitates Nrf2 nuclear translocation, causing induction of Nrf2-dependent genes, which contributes to protection from acetaminophen hepatotoxicity.

• 대한치과교정학회지
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• 제51권5호
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• pp.346-354
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• 2021

Objective: To compare the effectiveness of ibuprofen, acetaminophen, and chewing gum for orthodontic pain relief and to assess if chewing gum can be a non-pharmacological alternative for orthodontic pain relief. Methods: The study enrolled 106 patients of both sexes, aged ≥ 12 years, with body weight > 50 kg, and mild-to-moderate dental crowding in the upper arch. After randomization and allocation concealment, the intervention groups were either administered with ibuprofen (400 mg) or acetaminophen (500 mg) or chewed sugar-free chewing gum immediately after initial archwire placement and every 6 hours for 1 week if the pain persisted. The control group did not receive any pain relief. The pain was assessed on a 100-mm visual analog scale at rest and while biting down at T1 (2 hours), T2 (24 hours), T3 (2 days), T4 (3 days), T5 (7 days), and T6 (21 days). Statistical analyses were performed using the Kruskal-Wallis and post-hoc Mann-Whitney U tests (α = 0.05). Results: The chewing gum group experienced more pain relief than the ibuprofen group at while biting down at T3 (p = 0.04) and at rest at T4 (p < 0.001). The chewing gum group reported more pain relief than the acetaminophen and control groups while biting down at T3 (p = 0.03 and p = 0.0006, respectively) and T4 (both p < 0.001). Conclusions: Chewing gum can be a non-pharmacological alternative for orthodontic pain relief at 2 and 3 days after initial archwire placement.

• 대한약침학회지
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• 제21권4호
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• pp.249-257
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• 2018

Objectives: The hepatotoxicity induced by Acetaminophen (AAP) mostly mediated by effect on oxidative stress parameters. The Zataria multiflora (Z.M) is an herbal medicine with well-known antioxidant effect. The aim of this study is investigation of preventive effects of Z.M and Carvacrol (CAR) on AAP-induced hepatotoxicity in rats. Methods: Rats were randomly divided into four groups including: 1) Control, 2) Acetaminophen (AAP), 3) and 4) CAR. The saline, Z.M (200 mg/kg) and CAR (20 mg/kg) were administrated orally for 6 days, after that AAP (600 mg/kg) was administrated in the $7^{th}$ day. Blood sampling was performed on the first and last days. Also, the liver tissue was removed for evaluation of Malondyaldehide (MDA), Thiol content, Superoxide dismutase (SOD) and Catalase (CAT). Total Protein (tPro), Glutamic Oxaloacetic Transaminase (GOT), Glutamic Pyruvic Transaminase (GPT) and Alkaline Phosphatase (ALP) in liver tissue were evaluated. The changes (${\Delta}$) of enzymes activities were presented. Results: The ${\Delta}GOT$, ${\Delta}GPT$ and ${\Delta}ALP$ in CAR group significantly decreased compared to AAP group (P < 0.01 to P < 0.001) and ${\Delta}GPT$ in Z.M group was significantly reduced in comparison with AAP group (P < 0.05). Also, MDA, Thiol, SOD and CAT levels in treated groups were attenuated compared to AAP group (P < 0.05 to P < 0.001). Conclusion: Z.M and CAR have a powerful hepatoprotective effect. CAR is more effective than Z.M. Based on the results. Z.M and CAR could be potent supplementary agents against hepatotoxicity of AAP in patients.

• Food Science and Biotechnology
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• 제15권5호
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• pp.752-755
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• 2006

This study was carried out to investigate the effects of ash tree leaf extract (ALE) on acetaminophen (APAP)-induced hepatotoxicity in mice. Hepatoprotective effects were detected by biochemical analysis of hepatic enzymes and histopathological examination of the liver. BALB/c mice were divided into three groups: 'normal' control mice, APAP-treated control mice, and mice pretreated with ALE and treated with APAP. A single dose of APAP markedly increased levels of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Light micrographs of liver cells stained with hematoxylin and eosin showed that APAP induced severe centrilobular necrosis, degeneration, and infiltration by inflammatory cells. Moreover, APAP caused the numbers of TUNEL-positive hepatocytes to increase and caused glycogen content to decrease as observed by Periodic acid-Schiff stain. However, pretreatment with ALE for 7 days prior to the administration of APAP significantly decreased plasma levels of AST and ALT. Histological findings demonstrated that ALE pretreatment alleviated APAP-induced liver damage, and induced the regeneration of liver tissue and restoration of glycogen. These results indicate that ash tree leaf extract exerts a protective effect against APAP-hepatotoxicity induced injury.

• 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.

• Advances in Traditional Medicine
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• 제10권1호
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• pp.29-36
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• 2010

The present study was aimed to investigate the hepatoprotective and antioxidant activities of ethanol extract from Monochoria vaginalis (250 mg/kg and 500 mg/kg B/W) on acetaminophen (APAP) induced rat hepatic injury. Monochoria vaginalis is a traditional medicinal plant that is commonly used to treat and improve liver conditions in India and other Asian countries. The development of hepatotoxicity induced by APAP is promoted by oxidative stress. APAP treated group significantly (P < 0.01) elevated the serum enzymatic levels like glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, alkaline phosphatase (SALP), total bilirubin and malondialdehyde (MDA), which were restored towards normalization significantly (P < 0.01) thanol extract of yonochoria vagin is (EEMV). In addition, the EEMV significantly (P < 0.01) elevated the decreased level of total protein and antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase and reduced glutathione. Apart from these, histopathological changes also showed the protective nature of the EEMV against APAP induced hepatic damage in liver tissues. The activity of EEMV at 500 mg/kg B/W was comparable to the standard drug silymarin (25 mg/kg B/W). In conclusion, these data suggest that the EEMV possess hepatoprotective and antioxidant effects against APAP-induced hepatotoxicity and oxidative stress in rats.

• Biomolecules & Therapeutics
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• 제1권2호
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• pp.160-165
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• 1993

The effects of Glycyrrhizae Radix (GR) on the metabolism of acetaminophen (AA) were examined in male Sprague-Dawley rats. The methanol extract of GR (500 mg/kg) was administered orally to rats for 6 days. AA and its metabolites excreted in bile, urine and blood within 120 min after dosing of AA (150 mg/kg, i.v.) were assayed by HPLC. Treatment of rats with the methanol extract of GR significantly increased the cumulative biliary excretion of AA-glucuronide (156% of the control) and decreased that of AA-sulfate (63% of the control). The cumulative urinary excretion of AA-glucuronide was also significantly increased to 132% of the control. GR treatment significantly increased total (biliary plus urinary) excretion of AA-glucuronide (172% of the control) without influencing thioether and sulfate conjugates of AA. The results clearly show that GR enhances UDP-glucuronosyl transferase-mediated detoxication of AA, but may not influence sulfotrans-ferase-mediated and cytochrome P-450-mediated metabolites formation.

• BMB Reports
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• 제50권2호
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• pp.91-96
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• 2017

Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamil-induced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity.