This study explored the protective effect of atractylenolide Ⅰ(AO-Ⅰ) against acetaminophen(APAP)-induced acute liver injury(ALI) in mice and its underlying mechanism. C57 BL/6 J mice were randomly divided into a control group, an APAP group(500 mg·kg~(-1)), a low-dose combination group(500 mg·kg~(-1) APAP + 60 mg·kg~(-1) AO-Ⅰ), and a high-dose combination group(500 mg·kg~(-1) APAP + 120 mg·kg~(-1) AO-Ⅰ). ALI was induced by intraperitoneal injection of APAP(500 mg·kg~(-1)). AO-Ⅰ by intragastric administration was performed 2 hours before APAP treatment, and the control group received the same dose of solvent by intragastric administration or intraperitoneal injection. The protective effect of AO-Ⅰ against APAP-induced ALI was evaluated by detecting alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels in the plasma and H&E staining in liver tissues of mice. The malondialdehyde(MDA) and glutathione(GSH) content and catalase(CAT) activity in mouse liver tissues were detected to evaluate the effect of AO-Ⅰ on APAP-induced oxidative stress in the liver. The proteins in the liver p38 mitogen-activated protein kinase(p38 MAPK), c-jun N-terminal kinase(JNK), and nuclear factor kappa-B p65(NF-κB p65) signaling pathways were measured by Western blot, and the liver inflammatory cytokines interleukin-1β(IL-1β) and interleukin-6(IL-6) were detected by real-time PCR. Compared with the APAP group, the combination groups showed reduced APAP-induced ALT level and liver MDA content, potentiated liver CAT activity, and elevated GSH content. Mechanistically, AO-Ⅰ treatment significantly inhibited APAP-up-regulated MAPK phosphorylation and NF-κB p65, and significantly reduced the transcriptional activities of IL-1β and IL-6, downstream targets of NF-κB p65. AO-Ⅰ can improve APAP-induced ALI and the underlying mechanism is related to the inhibition of the MAPK/NF-κB p65 signaling pathway in APAP-challenged mice.
Acetaminophen/adverse effects* ; Animals ; Chemical and Drug Induced Liver Injury/drug therapy* ; Lactones ; Mice ; NF-kappa B/metabolism* ; Sesquiterpenes ; Signal Transduction

Acetaminophen ; adverse effects ; Child ; Female ; Humans ; Integrative Medicine ; Liver Failure, Acute ; blood ; chemically induced ; drug therapy ; Medicine ; Medicine, Chinese Traditional ; Western World

An eight-month-old female infant with severe dengue disease, who was repeatedly given therapeutic paracetamol for severe dengue, developed fulminant liver failure with encephalopathy, gastrointestinal haemorrhage and severe coagulopathy. She responded to supportive measures and N-acetylcysteine infusion. This case highlights the potential danger of administering repeated therapeutic doses of paracetamol in childhood severe dengue disease with hepatitis.
Acetaminophen ; adverse effects ; therapeutic use ; Antipyretics ; adverse effects ; therapeutic use ; Blood Coagulation ; Female ; Hepatic Encephalopathy ; drug therapy ; Humans ; Infant ; Liver Failure, Acute ; chemically induced ; Severe Dengue ; drug therapy ; Treatment Outcome

OBJECTIVE: Long-term use of the analgesic acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis is limited due to the lack of effectiveness and presence of side effects. Celecoxib is a selective inhibitor of cyclo-oxygenase (COX)-2 and expected to help NSAIDs in expressing the effective anti-inflammatory effect by not inhibiting COX-1. Thus, 200 mg of celecoxib and 100 mg of slow releasing diclofenac were compared for their effectiveness and safety in Korean patients with knee osteoarthritis. METHODS: We administered 200 mg of celecoxib or 100 mg of slow releasing diclofenac in 223 randomly selected patients with knee osteoarthritis for 4 weeks. The effectiveness of these drugs on osteoarthritis was assessed by evaluating pain in each patient, making overall evaluation on osteoarthritis by the patient and his/her attending physician, and measuring the severity indices on osteoarthritis before treatment, and 2 weeks and 4 weeks after treatment. Moreover, safety and drug resistance were evaluated by assessing the rate of adverse effects, rate of withdrawal, laboratory tests, and vital signs. RESULTS: The clinical symptoms of osteoarthritis were improved significantly by 4 weeks after treatment with celecoxib and diclofenac. According to the results of overall evaluation made by attending physicians 2 weeks after treatment, the rate of improvement was 49.5% in celecoxib group and 35.7% in diclofenac group, showing a statistically significant difference (p=0.023). Other than this difference, no other significant difference was present between the two groups with other variables used for the evaluation of effectiveness. The rate of adverse effects was significantly lower in celecoxib group compared with diclofenac group. According to laboratory findings, no abnormal figure was found in both groups but total bilirubin, SGOT, and SGPT were consistently higher in patients in diclofenac group. Thirteen patients dropped out of the study due to side effects (10 patients) and treatment failure (3 patients). CONCLUSION: Our findings from the clinical comparison of celecoxib and diclofenac in Korean patients with knee osteoarthritis were similar to those results found in previous studies. Although celecoxib showed similar effectiveness as diclofenac on knee osteoarthritis in the treatment of symptoms, it showed a lower rate of adverse effects; thus, we concluded that celecoxib is safer compared with diclofenac.
Acetaminophen ; Alanine Transaminase ; Anti-Inflammatory Agents, Non-Steroidal ; Aspartate Aminotransferases ; Bilirubin ; Diclofenac* ; Drug Resistance ; Drug-Related Side Effects and Adverse Reactions* ; Humans ; Osteoarthritis* ; Osteoarthritis, Knee ; Prostaglandin-Endoperoxide Synthases ; Treatment Failure ; Vital Signs

OBJECTIVETo evaluate the effects of human mesenchymal stem cells (hMSCs) transplantation via portal vein to treat acute liver injury in mice induced with acetaminophen.

METHODSA model of acute liver injury was established by acetaminophen gavage with a dose of 500 mg/kg. Twenty severe combined immune deficient mice (SCID mice) were randomly divided into 2 groups; one with hMSCs transplantation via their portal veins, the other group served as controls and only saline was infused into their veins. Liver function tests, fluorescein staining and reticular fiber staining of liver histological preparations and fluorescence- and light-microscopy were applied to observe the biochemical and pathological changes in the mice before and after the transplantation of hMSCs.

RESULTSLiver function of the hMSCs group was significantly better than that of the controls (P less than 0.05). Fluorescence microscopy revealed that the hMSCs appeared in the areas of the periportal veins at first and then extended to the central vein areas; the reticular fiber staining indicated that hMSCs could repair the architecture of the hepatic acini. No prominent fibrosis and pseudolobules were found.

CONCLUSIONShMSCs transplantation via portal vein to SCID mice with acute liver injury induced by acetaminophen can improve their liver function effectively; hMSCs growth in their livers and acinus reconstruction can be affected. We think it is a good method to treat acute liver injury.

Acetaminophen ; adverse effects ; Animals ; Bone Marrow Cells ; Chemical and Drug Induced Liver Injury ; surgery ; Disease Models, Animal ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Mice ; Mice, SCID ; Portal Vein ; surgery

Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient.
Acetaminophen ; Aged ; Carbon ; Cetirizine ; Chlorpheniramine ; Common Cold ; Drug Eruptions ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Female ; Guaifenesin ; Histamine Antagonists ; Humans ; Hydroxyzine ; Hypersensitivity ; Loratadine ; Magnesium ; Patch Tests ; Pigmentation ; Pruritus ; Pseudoephedrine ; Triprolidine

OBJECTIVETo explore the effect of hemoperfusion (HP) on tylenol poisoned patients.

METHODSUrgently established the blood access by transfemoral catheterization of femoral vein, we used charcoal hemoperfusion by blood pump and dynamically monitored the plasma concentration of tylenol active ingredients for the 2 patients and the content of tylenol active ingredients in the charcoal was determined.

RESULTSPlasma concentration of tylenol active ingredients of the 2 patients was declined gradually during and after the HP management. The acetaminophen serum concentration of the case 1 was declined from the 13.4 µg/L at the start of HP to the 5.81 µg/L at the end of HP; and the case 2 was declined from 51.1 µg/L to 22.3 µg/L. The adsorption amount of acetaminophen in the blood perfusion device are respectively 119 542 µg of case 1 and 33 2154 µg of case 2.

CONCLUSIONEarly hemoperfusion should be carried out for acute tylenol poisoning patients if there were indications, hemoperfusion can clear the tylenol active ingredients and this is an effective measure to eliminate tylenol active ingredients.

Acetaminophen ; blood ; pharmacokinetics ; poisoning ; Adult ; Anti-Inflammatory Agents, Non-Steroidal ; blood ; pharmacokinetics ; poisoning ; Drug Overdose ; therapy ; Drug-Related Side Effects and Adverse Reactions ; blood ; Female ; Hemoperfusion ; Humans ; Metabolic Clearance Rate ; Young Adult

Acetaminophen (APAP) is the most common antipyretic, analgesic and anti-inflammatory drug, but its overdose often leads to acute liver injury, even acute liver failure, and death in some severe cases. At present, there is still a lack of specific treatments. The c-Jun N-terminal kinase (JNK) signal pathway is one of the potential therapeutic targets identified in recent years in overdose APAP-induced acute liver injury. This article reviews the JNK signaling pathway of APAP in liver metabolism, the activation of JNK signaling pathway and the amplification of oxidative stress, other pathways or cellular processes related to JNK signaling pathway, and the possible challenges of drugs targeting JNK, so as to provide direction and feasibility analysis for further research and clinical application of JNK signaling pathway targets in APAP hepatotoxicity, and to provide reference for searching for other targets.
Animals ; Mice ; Acetaminophen/adverse effects* ; Chemical and Drug Induced Liver Injury ; Chemical and Drug Induced Liver Injury, Chronic/metabolism* ; JNK Mitogen-Activated Protein Kinases/metabolism* ; Liver ; Mice, Inbred C57BL ; Signal Transduction

The present study was designed to evaluate protective activity of an ethanol extract of the stems of Schisandra chinensis (SCE) and explore its possible molecular mechanisms on acetaminophen (APAP) induced hepatotoxicity in a mouse model. The results of HPLC analysis showed that the main components of SCE included schisandrol A, schisandrol B, deoxyschisandrin, schisandrin B, and schisandrin C and their contents were 5.83, 7.11, 2.13, 4.86, 0.42 mg·g, respectively. SCE extract was given for 7 consecutive days before a single hepatotoxic dose of APAP (250 mg·kg) was injected to mice. Our results showed that SCE pretreatment ameliorated liver dysfunction and oxidative stress, which was evidenced by significant decreases in aspartate transaminase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) contents and elevations in reduced glutathione (GSH) and superoxide dismutase (SOD) levels. These findings were associated with the result that the SCE pretreatment significantly decreased expression levels of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT). SCE also significantly decreased the expression levels of Bax, mitogen- activated protein kinase (MAPK), and cleaved caspase-3 by APAP exposure. Furthermore, supplementation with SCE suppressed the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), suggesting alleviation of inflammatory response. In summary, these findings from the present study clearly demonstrated that SCE exerted significant alleviation in APAP-induced oxidative stress, inflammation and apoptosis mainly via regulating MAPK and caspase-3 signaling pathways.
Acetaminophen ; adverse effects ; Alanine Transaminase ; metabolism ; Animals ; Apoptosis ; drug effects ; Aspartate Aminotransferases ; metabolism ; Caspase 3 ; genetics ; metabolism ; Chemical and Drug Induced Liver Injury ; genetics ; metabolism ; physiopathology ; prevention & control ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Glutathione ; metabolism ; Humans ; Liver ; drug effects ; metabolism ; Male ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred ICR ; Mitogen-Activated Protein Kinases ; chemistry ; genetics ; metabolism ; Oxidative Stress ; drug effects ; Schisandra ; chemistry ; Signal Transduction ; drug effects

Traditional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors are among the most widely used drugs. However, their significant side effects in gastrointestinal and cardiovascular systems limited the use of these drugs. Recently, research and development of NO-donating NSAIDs (NO-NSAIDs) have become one of the most important strategies to reduce these side effects. NO-NSAIDs may exert a broad range of positive effects in terms of NO-mediated gastrointestinal and cardiovascular safety as well as comparable or increased anti-inflammatory, analgesic properties relative to NSAIDs. This review briefly deals with chemistry of NO-NSAIDs, more details are focused on biological significance, mechanism of action, and therapeutic potential of this novel class of drugs.
Acetaminophen ; analogs & derivatives ; chemistry ; pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal ; adverse effects ; pharmacology ; Aspirin ; analogs & derivatives ; chemistry ; pharmacology ; Cardiotonic Agents ; pharmacology ; Cyclooxygenase Inhibitors ; adverse effects ; pharmacology ; Flurbiprofen ; analogs & derivatives ; chemistry ; pharmacology ; Gastrointestinal Diseases ; chemically induced ; prevention & control ; Humans ; Ibuprofen ; analogs & derivatives ; chemistry ; pharmacology ; Naproxen ; analogs & derivatives ; chemistry ; pharmacology ; Nitrates ; chemistry ; pharmacology ; Nitric Oxide Donors ; pharmacology