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1
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Jiang X, Li W, Chen X, Kuang Y, Jiang S. Oral dydrogesterone versus oral dydrogesterone plus micronized vaginal progesterone for luteal phase support in ovulatory frozen-thawed embryo transfers. Reprod Biomed Online 2025; 51:104844. [PMID: 40413849 DOI: 10.1016/j.rbmo.2025.104844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/21/2025] [Accepted: 01/24/2025] [Indexed: 05/27/2025]
Abstract
RESEARCH QUESTION Is oral dydrogesterone (DYD) alone as effective as DYD + micronized vaginal progesterone (MVP) for luteal phase support (LPS) in ovulatory frozen-thawed embryo transfer (FET) cycles? DESIGN This retrospective cohort study included 22,868 patients undergoing their first FET cycles using an ovulatory protocol between January 2011 and February 2023. Patients were classified into two cohorts according to LPS protocol: oral DYD alone or DYD + MVP. After propensity score matching (PSM), pregnancy and neonatal outcomes were compared to determine the efficacy and safety of oral DYD alone. Further stratification was made to observe the effect of oral DYD alone for each endometrial preparation regimen (natural, letrozole or human menopausal gonadotrophin). Logistic regression and stratified analysis based on maternal age further confirmed the results before PSM. RESULTS After PSM, there were 6153 patients in the oral DYD group and 6153 patients in the DYD + MVP group. No significant differences in the clinical pregnancy rate (CPR) (51.8% versus 52.2%, P = 0.626), live birth rate (LBR) (42.8% versus 43.2%, P = 0.623), miscarriage rate (P = 0.637) and other pregnancy outcomes were observed between the two cohorts. These results were reconfirmed for each endometrial preparation protocol. No significant differences in newborn sex, birth weight or birth defects were found between the two cohorts (P > 0.05). Regression analysis showed no influence of LPS protocol on CPR (P = 0.672). Stratified analysis showed no impact of LPS protocol on CPR, LBR or miscarriage rate in patients aged <35 years and patients aged ≥35 years. CONCLUSIONS Oral DYD alone is comparable to DYD + MVP for LPS in ovulatory FET cycles in terms of pregnancy and neonatal outcomes.
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Affiliation(s)
- Xueyi Jiang
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Wenzhi Li
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xi Chen
- Cardiovascular Research Institute, School of Medicine, University of California, San Francisco, CA, USA
| | - Yanping Kuang
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Shutian Jiang
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
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2
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Patki A. Role of Dydrogesterone for Luteal Phase Support in Assisted Reproduction. Reprod Sci 2024; 31:17-29. [PMID: 37488405 DOI: 10.1007/s43032-023-01302-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 07/10/2023] [Indexed: 07/26/2023]
Abstract
Clinical outcomes of in vitro fertilization (IVF) have significantly improved over the years with the advent of the frozen-thawed embryo transfer (FET) technique. Ovarian hyperstimulation during IVF cycles causes luteal phase deficiency, a condition of insufficient progesterone. Intramuscular or vaginal progesterone and dydrogesterone are commonly used for luteal phase support in FET. Oral dydrogesterone has a higher bioavailability than progesterone and has high specificity for progesterone receptors. Though micronized vaginal progesterone has been the preferred option, recent data suggest that oral dydrogesterone might be an alternative therapeutic option for luteal phase support to improve clinical outcomes of IVF cycles. Dydrogesterone has a good safety profile and is well tolerated. Its efficacy has been evaluated in several clinical studies and demonstrated to be non-inferior to micronized vaginal progesterone in large-scale clinical trials. Oral dydrogesterone may potentially become a preferred drug for luteal phase support in millions of women undergoing IVF.
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Affiliation(s)
- Ameet Patki
- Fertility Associates Khar, 4Th Floor, Gupte House, 81 SV Road, Khar West, Mumbai, 400052, Maharashtra, India.
- Hinduja Group of Hospitals, Khar West, Mumbai, India.
- Surya Hospital Mumbai, Mumbai, India.
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3
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Kucukakcali Z, Colak C, Gozukara Bag HG, Balikci Cicek I, Ozhan O, Yildiz A, Danis N, Koc A, Parlakpinar H, Akbulut S. Modeling Based on Ensemble Learning Methods for Detection of Diagnostic Biomarkers from LncRNA Data in Rats Treated with Cis-Platinum-Induced Hepatotoxicity. Diagnostics (Basel) 2023; 13:1583. [PMID: 37174973 PMCID: PMC10177870 DOI: 10.3390/diagnostics13091583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND The first aim of this study is to perform bioinformatic analysis of lncRNAs obtained from liver tissue samples from rats treated with cisplatin hepatotoxicity and without pathology. Another aim is to identify possible biomarkers for the diagnosis/early diagnosis of hepatotoxicity by modeling the data obtained from bioinformatics analysis with ensemble learning methods. METHODS In the study, 20 female Sprague-Dawley rats were divided into a control group and a hepatotoxicity group. Liver samples were taken from rats, and transcriptomic and histopathological analyses were performed. The dataset achieved from the transcriptomic analysis was modeled with ensemble learning methods (stacking, bagging, and boosting). Modeling results were evaluated with accuracy (Acc), balanced accuracy (B-Acc), sensitivity (Se), specificity (Sp), positive predictive value (Ppv), negative predictive value (Npv), and F1 score performance metrics. As a result of the modeling, lncRNAs that could be biomarkers were evaluated with variable importance values. RESULTS According to histopathological and immunohistochemical analyses, a significant increase was observed in the sinusoidal dilatation and Hsp60 immunoreactivity values in the hepatotoxicity group compared to the control group (p < 0.0001). According to the results of the bioinformatics analysis, 589 lncRNAs showed different expressions in the groups. The stacking model had the best classification performance among the applied ensemble learning models. The Acc, B-Acc, Se, Sp, Ppv, Npv, and F1-score values obtained from this model were 90%, 90%, 80%, 100%, 100%, 83.3%, and 88.9%, respectively. lncRNAs with id rna-XR_005492522.1, rna-XR_005492536.1, and rna-XR_005505831.1 with the highest three values according to the variable importance obtained as a result of stacking modeling can be used as predictive biomarker candidates for hepatotoxicity. CONCLUSIONS Among the ensemble algorithms, the stacking technique yielded higher performance results as compared to the bagging and boosting methods on the transcriptomic data. More comprehensive studies can support the possible biomarkers determined due to the research and the decisive results for the diagnosis of drug-induced hepatotoxicity.
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Affiliation(s)
- Zeynep Kucukakcali
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Harika Gozde Gozukara Bag
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Ipek Balikci Cicek
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Onural Ozhan
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (O.O.)
| | - Azibe Yildiz
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey;
| | - Nefsun Danis
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (N.D.); (A.K.)
| | - Ahmet Koc
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (N.D.); (A.K.)
| | - Hakan Parlakpinar
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (O.O.)
| | - Sami Akbulut
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
- Department of Surgery, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey
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4
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Messelmani T, Le Goff A, Souguir Z, Maes V, Roudaut M, Vandenhaute E, Maubon N, Legallais C, Leclerc E, Jellali R. Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix. Bioengineering (Basel) 2022; 9:bioengineering9090443. [PMID: 36134989 PMCID: PMC9495334 DOI: 10.3390/bioengineering9090443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/23/2022] [Accepted: 08/31/2022] [Indexed: 12/12/2022] Open
Abstract
The 3Rs guidelines recommend replacing animal testing with alternative models. One of the solutions proposed is organ-on-chip technology in which liver-on-chip is one of the most promising alternatives for drug screening and toxicological assays. The main challenge is to achieve the relevant in vivo-like functionalities of the liver tissue in an optimized cellular microenvironment. Here, we investigated the development of hepatic cells under dynamic conditions inside a 3D hydroscaffold embedded in a microfluidic device. The hydroscaffold is made of hyaluronic acid and composed of liver extracellular matrix components (galactosamine, collagen I/IV) with RGDS (Arg-Gly-Asp-Ser) sites for cell adhesion. The HepG2/C3A cell line was cultured under a flow rate of 10 µL/min for 21 days. After seeding, the cells formed aggregates and proliferated, forming 3D spheroids. The cell viability, functionality, and spheroid integrity were investigated and compared to static cultures. The results showed a 3D aggregate organization of the cells up to large spheroid formations, high viability and albumin production, and an enhancement of HepG2 cell functionalities. Overall, these results highlighted the role of the liver-on-chip model coupled with a hydroscaffold in the enhancement of cell functions and its potential for engineering a relevant liver model for drug screening and disease study.
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Affiliation(s)
- Taha Messelmani
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
| | - Anne Le Goff
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
- Correspondence: (A.L.G.); (R.J.)
| | - Zied Souguir
- HCS Pharma, 250 rue Salvador Allende, Biocentre Fleming Bâtiment A, 59120 Loos, France
| | - Victoria Maes
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
- HCS Pharma, 250 rue Salvador Allende, Biocentre Fleming Bâtiment A, 59120 Loos, France
| | - Méryl Roudaut
- HCS Pharma, 250 rue Salvador Allende, Biocentre Fleming Bâtiment A, 59120 Loos, France
| | - Elodie Vandenhaute
- HCS Pharma, 250 rue Salvador Allende, Biocentre Fleming Bâtiment A, 59120 Loos, France
| | - Nathalie Maubon
- HCS Pharma, 250 rue Salvador Allende, Biocentre Fleming Bâtiment A, 59120 Loos, France
| | - Cécile Legallais
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
| | - Eric Leclerc
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
- CNRS IRL 2820, Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
| | - Rachid Jellali
- CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60319, Université de Technologie de Compiègne, 60203 Compiègne, France
- Correspondence: (A.L.G.); (R.J.)
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5
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Khan Z, Karataş Y, Kıroğlu O. Evaluation of Adverse Drug Reactions in Paediatric Patients: A Retrospective Study in Turkish Hospital. Front Pharmacol 2021; 12:786182. [PMID: 34867419 PMCID: PMC8638749 DOI: 10.3389/fphar.2021.786182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/25/2021] [Indexed: 12/28/2022] Open
Abstract
Drug safety in paediatric patients is a serious public health concern around the world. The paediatric patients are more prone to adverse drug reactions (ADRs) than adults. Moreover, there is a scarcity of information about ADRs in paediatric patients. This study was conducted to determine the frequency, causality, severity, preventability of paediatric patients’ ADRs reported in a tertiary care hospital in Adana, Turkey. A retrospective study was conducted on all spontaneously reported ADRs between January 01, 2020, to July 30, 2021, in paediatric patients. The ADRs reports were evaluated in terms of gender, age, ADR characteristics, suspected drugs and reporting source. All included ADRs reports were characterized according to the Naranjo Algorithm/World Health Organization (WHO) causality scales, Hartwig/Siegel and Common Terminology Criteria for Adverse Events (CTCAE) severity scales, the modified Schoumock and Thornton preventability scale and hospital pharmacovigilance center criteria for seriousness. Therapeutic groups were also coded using the WHO-Anatomical Therapeutic and Chemical (ATC) classification. During the study period, 8,912 paediatric patients who were admitted had 16 ADRs with 1.7 ADRs/1,000 admissions. The majority of ADRs were found in infants (31.2%) and children (56.2%) as compared to adolescents (12.5%). ADRs were observed more in females (81.2%) than males. Skin (62.5%) was the most affected organ due to the ADRs, and maculopapular rash and erythema multiforme were the most commonly reported symptoms. Most ADRs were probable/likely (93.7%), severe (50%), preventable or probably preventable (43.7%) and serious (37.5%). Antibiotics (93.7%) were found to be the most common cause of ADRs in paediatric patients. The majority of ADRs were associated with vancomycin (68.7%). Most of the ADRs were reported by a medical doctor in this study. This small sample size study highlights significant problems of ADRs in paediatric patients, mainly caused by antibiotics and with a majority of ADRs manifest as skin reactions. Furthermore, a high proportion of the identified ADRs were found to be preventable. More focused efforts are needed at the national level to avoid preventable ADRs in hospitals. Monitoring and management of ADRs and future studies would be beneficial for better patient care and safety.
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Affiliation(s)
- Zakir Khan
- Department of Pharmacology, Institute of Health Sciences, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Yusuf Karataş
- Department of Pharmacology, Institute of Health Sciences, Faculty of Medicine, Cukurova University, Adana, Turkey.,Pharmacovigilance Specialist, Balcali Hospital, Faculty of Medicines, Cukurova University, Adana, Turkey
| | - Olcay Kıroğlu
- Department of Pharmacology, Institute of Health Sciences, Faculty of Medicine, Cukurova University, Adana, Turkey
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Choi JW, Yoo JJ, Kim SG, Kim YS, Chin S. Pazopanib-induced severe acute liver injury: A case report. Medicine (Baltimore) 2021; 100:e27731. [PMID: 34797298 PMCID: PMC8601284 DOI: 10.1097/md.0000000000027731] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/22/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Painkillers and fever antipyretics are the most common cause of DILI. Hepatic injury can be provoked by DILI as hepatocellular or cholestatic type. PATIENT CONCERNS A 48-year-old woman presented jaundice accompanied by nausea and vomiting. The patient was an inactive hepatitis B carrier with low viral titer and was diagnosed renal cell carcinoma (RCC) with hepatic metastasis requiring pazopanib treatment. Prior to administration of pazopanib, tenofovir administration was started to prevent exacerbation of hepatitis B. The patient was referred to clinic of gastroenterology department due to sudden elevation of bilirubin after 5 weeks of pazopanib treatment. DIAGNOSES Abdominal ultrasound and computed tomography showed non-specific finding other than metastatic nodule in the liver and liver cirrhosis. After then, the patient was performed liver biopsy, and the biopsy result was acute cholestatic hepatitis with centrilobular area necrosis and portal inflammation. Therefore, considering the clinical history and biopsy results, the patient was diagnosed as DILI due to pazopanib. INTERVENTIONS After the biopsy, empirical steroid therapy was initiated and after 7 weeks of pazopanib discontinuation. OUTCOMES The total bilirubin level returned to normal from peak level of 24.61 to 1.52 mg/dL. LESSONS In patients with renal cell carcinoma, pazopanib treatment requires clinical caution as it causes rare complications such as severe jaundice and acute cholestatic hepatitis.
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Affiliation(s)
- Jin-Wook Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
| | - Jeong-Ju Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
| | - Sang Gyune Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
| | - Young Seok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
| | - Susie Chin
- Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
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7
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Bassan A, Alves VM, Amberg A, Anger LT, Auerbach S, Beilke L, Bender A, Cronin MT, Cross KP, Hsieh JH, Greene N, Kemper R, Kim MT, Mumtaz M, Noeske T, Pavan M, Pletz J, Russo DP, Sabnis Y, Schaefer M, Szabo DT, Valentin JP, Wichard J, Williams D, Woolley D, Zwickl C, Myatt GJ. In silico approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity. COMPUTATIONAL TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 20:100187. [PMID: 35340402 PMCID: PMC8955833 DOI: 10.1016/j.comtox.2021.100187] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/15/2023]
Abstract
Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals.
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Affiliation(s)
- Arianna Bassan
- Innovatune srl, Via Giulio Zanon 130/D, 35129 Padova, Italy
| | - Vinicius M. Alves
- The National Institute of Environmental Health Sciences, Division of the National Toxicology, Program, Research Triangle Park, NC 27709, USA
| | - Alexander Amberg
- Sanofi, R&D Preclinical Safety Frankfurt, Industriepark Hoechst, D-65926 Frankfurt am Main, Germany
| | | | - Scott Auerbach
- The National Institute of Environmental Health Sciences, Division of the National Toxicology, Program, Research Triangle Park, NC 27709, USA
| | - Lisa Beilke
- Toxicology Solutions Inc., San Diego, CA, USA
| | - Andreas Bender
- AI and Data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW
| | - Mark T.D. Cronin
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK
| | | | - Jui-Hua Hsieh
- The National Institute of Environmental Health Sciences, Division of the National Toxicology, Program, Research Triangle Park, NC 27709, USA
| | - Nigel Greene
- Data Science and AI, DSM, IMED Biotech Unit, AstraZeneca, Boston, USA
| | - Raymond Kemper
- Nuvalent, One Broadway, 14th floor, Cambridge, MA, 02142, USA
| | - Marlene T. Kim
- US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, 20993, USA
| | - Moiz Mumtaz
- Office of the Associate Director for Science (OADS), Agency for Toxic Substances and Disease, Registry, US Department of Health and Human Services, Atlanta, GA, USA
| | - Tobias Noeske
- Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Manuela Pavan
- Innovatune srl, Via Giulio Zanon 130/D, 35129 Padova, Italy
| | - Julia Pletz
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK
| | - Daniel P. Russo
- Department of Chemistry, Rutgers University, Camden, NJ 08102, USA
- The Rutgers Center for Computational and Integrative Biology, Camden, NJ 08102, USA
| | - Yogesh Sabnis
- UCB Biopharma SRL, Chemin du Foriest – B-1420 Braine-l’Alleud, Belgium
| | - Markus Schaefer
- Sanofi, R&D Preclinical Safety Frankfurt, Industriepark Hoechst, D-65926 Frankfurt am Main, Germany
| | | | | | - Joerg Wichard
- Bayer AG, Genetic Toxicology, Müllerstr. 178, 13353 Berlin, Germany
| | - Dominic Williams
- Functional & Mechanistic Safety, Clinical Pharmacology & Safety Sciences, AstraZeneca, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge CB4 0FZ, UK
| | - David Woolley
- ForthTox Limited, PO Box 13550, Linlithgow, EH49 7YU, UK
| | - Craig Zwickl
- Transendix LLC, 1407 Moores Manor, Indianapolis, IN 46229, USA
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Kolaric TO, Nincevic V, Kuna L, Duspara K, Bojanic K, Vukadin S, Raguz-Lucic N, Wu GY, Smolic M. Drug-induced Fatty Liver Disease: Pathogenesis and Treatment. J Clin Transl Hepatol 2021; 9:731-737. [PMID: 34722188 PMCID: PMC8516847 DOI: 10.14218/jcth.2020.00091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 02/08/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (commonly known as MAFLD) impacts global health in epidemic proportions, and the resulting morbidity, mortality and economic burden is enormous. While much attention has been given to metabolic syndrome and obesity as offending factors, a growing incidence of polypharmacy, especially in the elderly, has greatly increased the risk of drug-induced liver injury (DILI) in general, and drug-induced fatty liver disease (DIFLD) in particular. This review focuses on the contribution of DIFLD to DILI in terms of epidemiology, pathophysiology, the most common drugs associated with DIFLD, and treatment strategies.
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Affiliation(s)
- Tea Omanovic Kolaric
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Vjera Nincevic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Lucija Kuna
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | | | - Kristina Bojanic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
- Health Center Osijek, Osijek, Croatia
| | - Sonja Vukadin
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Nikola Raguz-Lucic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Martina Smolic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
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9
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Lee HY, Lee AR, Yoo JJ, Chin S, Kim SG, Kim YS. Biopsy-confirmed fenofibrate-induced severe jaundice: A case report. World J Clin Cases 2021; 9:9295-9301. [PMID: 34786416 PMCID: PMC8567496 DOI: 10.12998/wjcc.v9.i30.9295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/05/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases.
CASE SUMMARY A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL.
CONCLUSION In patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.
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Affiliation(s)
- Hye Young Lee
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea
| | - Ae-Ra Lee
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea
| | - Susie Chin
- Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon 14584, South Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea
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10
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Mycophenolate Mofetil Hepatotoxicity Associated With Mitochondrial Abnormality in Liver Transplant Recipients and Mice. J Pediatr Gastroenterol Nutr 2021; 73:463-470. [PMID: 34016874 DOI: 10.1097/mpg.0000000000003171] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVES Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent. MMF hepatotoxicity has been reported in non-transplant and renal transplant patients with minimal histologic description. This is the first study describing detailed histology and ultrastructure of MMF hepatotoxicity. METHODS Four liver-transplant recipients (Cases 1-4) were suspected to have MMF hepatotoxicity. Cases 1-3 (two females and one male; 4-17 years) had multiple biopsies for liver function test (LFT) abnormalities. Case 4 (female; 16 years) had a surveillance biopsy. Electron-microscopic examination (EM) was requested on Cases 1-3 for unexplained, persistent LFT elevation and histologic abnormalities despite therapy and Case 4 for unexplained histologic abnormalities despite a stable clinical course. To confirm the pathologic changes in the human allografts, livers from MMF-treated and untreated mice were also reviewed. RESULTS While the allograft biopsies showed nonspecific histologic changes, EM revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders. In Cases 1 and 2, LFTs improved after stopping and reducing MMF, respectively. In Case 3, pre- and post-MMF treatment biopsies were performed and only the post-MMF biopsy demonstrated mitochondrial abnormalities. Mitochondrial abnormality in Case 4 was subclinical. The mouse study confirmed that MMF caused various stress changes in the mitochondria; number of mitochondria/cell (mean ± standard deviation; untreated group: 58.25 ± 8.426; MMF-treated group: 76.37 ± 18.66), number of lipid droplets/cell (untreated: 0.9691 ± 1.150; MMF-treated: 3.649 ± 4.143) and sizes of mitochondria (μm, untreated: 0.8550 ± 0.3409; MMF-treated: 0.9598 ± 0.5312) were significantly increased in hepatocytes in the MMF-treated mice compared with the untreated mice (P < 0.0001). CONCLUSIONS Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset. MMF hepatotoxicity should be considered for MMF-treated patients with unexplained, persistent LFT abnormalities and nonspecific histologic findings. EM should be requested for these cases.
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11
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Li J, Song D, Zhang B, Guo J, Li W, Zhang X, Zhao Q. Hepatoprotective Effects of Heracleum candicans Against Carbon Tetrachloride-Induced Acute Liver Injury in Rats. Dose Response 2021; 19:15593258211029510. [PMID: 34290575 PMCID: PMC8278464 DOI: 10.1177/15593258211029510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 01/08/2023] Open
Abstract
Purpose: To determine the hepatoprotective mechanisms of Heracleum candicans in rats with acute liver injury induced by carbon tetrachloride (CCl4). Methods: Rats were intragastrically administered H candicans twice a day for 14 consecutive days and were intraperitoneally challenged with CCl4. Alanine aminotransferase and aspartate aminotransferase were measured to indicate liver injury. Malondialdehyde antioxidant enzyme activity and tumor necrosis factor-alpha and interleukin 6 secretion were measured as liver injury indicators. Histopathological tests were conducted to determine whether H candicans ameliorated liver injury. Results: CCl4-induced liver injury led to significant increases in liver injury biochemical indicators transaminase and malondialdehyde activities. H candicans pretreatments inhibited these increases. Pathological sections in pretreated samples exhibited reduced vacuole formation, neutrophil infiltration, and necrosis. Conclusion: H candicans increases the antioxidant capacity of the liver and maintains hepatocyte function in the face of CCl4-induced injury.
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Affiliation(s)
- Jie Li
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Dan Song
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Bintao Zhang
- Xianyang Central Hospital, Xianyang, Shaanxi, China
| | - Jinwei Guo
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Wenping Li
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Xiaoying Zhang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Qin Zhao
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
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12
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Jahan A, Shams S, Ali S, Samrana S, Ali A, Adhikari A, Sajid M, Ali A, Ali H. Govaniadine Ameliorates Oxidative Stress, Inflammation, and Kupffer Cell Activation in Carbon Tetrachloride-Induced Hepatotoxicity in Rats. ACS OMEGA 2021; 6:2462-2472. [PMID: 33553864 PMCID: PMC7859953 DOI: 10.1021/acsomega.0c02261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 10/09/2020] [Indexed: 06/12/2023]
Abstract
Liver diseases such as hepatic carcinoma are one of the main health problems worldwide. Herbal drugs are largely used to treat liver injury in the indigenous system of medicine and may provide lead compounds for hepatoprotective drug discovery. The present study is investigated to test the Corydalis govaniana Wall. extract, fraction, and isolate therapeutically active constituents to explore their hepatoprotective, anti-inflammatory, and antioxidant activities. For this purpose, the antioxidant activity of govaniadine, caseadine, caseamine, and protopine was performed by assessing the scavenging events of the stable 2,2-diphenyl-1-picrylhydrazyl. Hepatoprotection of govaniadine was assessed in terms of reduction in serum enzymes (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase) caused by CCl4-induced liver injury in rats and by histopathological techniques. All the compounds showed significant antioxidant activity with a percentage inhibition of 92.2, 86.7, 85.3, and 79.7, respectively, compared to propyl gallate 90.3%. Treatment with govaniadine reduced the serum enzyme level down to normal levels in the CCl4-treated group while inhibiting the increase of malondialdehyde, and the induction of superoxide dismutase and the glutathione level was upregulated. Histopathology showed ∼47% damage to the liver cells in the CCl4-treated group; reduction in this damaged area was found to be better upon using govaniadine. Immunohistochemistry results showed that govaniadine as compared to silymarin has exceedingly decreased the inflammation by halting the CCl4-induced activation of hepatic macrophages. In carrageenan-induced paw edema assay, govaniadine significantly alleviated the edema after 1-5 h at a dose of 20 mg/kg (26.00 and 28.5%), 50 mg/kg (22.05 and 27.0%), and 100 mg/kg (20.02 and 25.30%), respectively. The results of our experiments suggest that govaniadine showed antioxidant and hepatoprotective activity in liver injury. The hepatoprotective function of govaniadine may be associated to the scavenging of the free radical and attenuation of oxidative stress as well as inflammatory responses in the liver. Hence, govaniadine may be a lead compound for the hepatoprotective drug discovery process and further research is needed to find out their molecular mechanism of protection.
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Affiliation(s)
- Azra Jahan
- Department
of Zoology, Abdul Wali Khan University, Mardan 23200, Khyber Pakhtunkhwa, Pakistan
| | - Sumaira Shams
- Department
of Zoology, Abdul Wali Khan University, Mardan 23200, Khyber Pakhtunkhwa, Pakistan
| | - Safdar Ali
- Department
of Physics, University of Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan
| | - Samrana Samrana
- College
of Agriculture and Biotechnology, Zhejiang
University, Hangzhou, Zhejiang 310058, China
| | - Amjad Ali
- Department
of Biochemistry, Quaid-i-Azam University, Islamabad 15320, Pakistan
| | - Achyut Adhikari
- H.
E. J. Research Institute of Chemistry, International Center for Chemical
and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
- Central Department
of Chemistry, Tribhuvan University, Kirtipur, Kathmandu 44618, Nepal
| | - Muhammad Sajid
- Department
of Biochemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan
| | - Abid Ali
- College
of Agriculture and Biotechnology, Zhejiang
University, Hangzhou, Zhejiang 310058, China
| | - Hamid Ali
- Department
of Biosciences, COMSATS University, Islamabad 44000, Pakistan
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13
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Mary YS, Mary YS. Utilization of doped/undoped graphene quantum dots for ultrasensitive detection of duphaston, a SERS platform. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 244:118865. [PMID: 32889339 DOI: 10.1016/j.saa.2020.118865] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 06/11/2023]
Abstract
Recently nanocluster based drug delivery systems have become the most skillful to study. Interaction mechanism of duphaston (DPH) over graphene (G), carboxyl substituted graphene (COG) and doped COG-X (X = O/S/N/B) were investigated. We studied different spectroscopic properties of adsorbed DPH with nanoclusters. To study effect adsorption of DPH with nanoclusters, the adsorption energies were measured. To track DPH, surface enhanced Raman scattering is used since it is an efficient approach to vibrational spectroscopy. The DPH detection was investigated using GQDs SERS property. For the adsorption of DPH with COG-B nanocluster maximum energy interaction is determined. DPH works on the electrophilic site of nanoclusters as donor of electrons and adsorbs. Charge transfer is higher for to COG-B nanocluster than for other nanoclusters. Variations in chemical descriptors are also noted to understand sensing property of DPH molecule-nanoclusters. The analysis of different properties demonstrates enhancement effect which makes it significant in detecting DPH in other products.
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Affiliation(s)
- Y Sheena Mary
- Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India.
| | - Y Shyma Mary
- Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India
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14
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Guo X, Li W, An R, Huang M, Yu Z. Composite ammonium glycyrrhizin has hepatoprotective effects in chicken hepatocytes with lipopolysaccharide/enrofloxacin-induced injury. Exp Ther Med 2020; 20:52. [PMID: 32952642 PMCID: PMC7485299 DOI: 10.3892/etm.2020.9180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 05/17/2018] [Indexed: 11/06/2022] Open
Abstract
Composite ammonium glycyrrhizin (CAG) has anti-inflammatory activity. Lipopolysaccharide (LPS) and enrofloxacin (ENR) induce liver damage; however, the mechanism underlying LPS/ENR-induced hepatic injury remains to be elucidated. In the present study, the mechanism of LPS/ENR-induced liver injury was investigated in vitro and the protective effects of CAG were also evaluated. Primary chicken hepatocytes were isolated and a model of LPS/ENR-induced hepatocyte injury was established. mRNA and protein expression levels were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot, respectively. LPS/ENR exposure significantly increased supernatant aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In the LPS/ENR-treated group, glutathione (GSH) and the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were significantly increased. Flow cytometry results revealed that the apoptotic rate significantly increased in the LPS/ENR-treated group compared with the control, while treatment with CAG given 24 h prior to LPS/ENR caused a significant decrease in the apoptotic rate compared with the model group. Furthermore, CAG treatment reversed LPS/ENR-associated alterations in the mRNA and protein expression of Caspase-3, apoptosis regulator Bcl-2 (Bcl-2) and Bcl-2 associated X-protein. The mitochondrial membrane potential significantly decreased and the mitochondrial microstructure was notably altered following exposure to LPS/ENR compared with the control. In conclusion, these results suggested that LPS/ENR-treated hepatocytes were damaged via apoptotic signaling pathways and CAG prevented LPS/ENR-induced hepatocyte injury.
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Affiliation(s)
- Xuewen Guo
- Department of Veterinary Preventive Medicine, Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China
| | - Wenyang Li
- Department of Veterinary Preventive Medicine, Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China
| | - Ran An
- Department of Veterinary Preventive Medicine, Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China
| | - Mei Huang
- Department of Veterinary Preventive Medicine, Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China
| | - Zugong Yu
- Department of Veterinary Preventive Medicine, Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China
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15
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Smith B, Rowe J, Watkins PB, Ashina M, Woodhead JL, Sistare FD, Goadsby PJ. Mechanistic Investigations Support Liver Safety of Ubrogepant. Toxicol Sci 2020; 177:84-93. [PMID: 32579200 PMCID: PMC8312697 DOI: 10.1093/toxsci/kfaa093] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the approved clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.
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Affiliation(s)
| | | | - Paul B Watkins
- Eshelman School of Pharmacy and Institute for Drug Safety Sciences, University
of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Messoud Ashina
- Department of Neurology, Danish Headache Center, Faculty of Health and Medical
Sciences, University of Copenhagen, København, Denmark
| | | | | | - Peter J Goadsby
- NIHR-Wellcome Trust King’s Clinical Research Facility, SLaM Biomedical Research
Centre, King’s College London, London, UK
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16
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Zhang C, Crawford JJ, Landry ML, Chen H, Kenny JR, Khojasteh SC, Lee W, Ma S, Young WB. Strategies to Mitigate the Bioactivation of Aryl Amines. Chem Res Toxicol 2020; 33:1950-1959. [PMID: 32508087 DOI: 10.1021/acs.chemrestox.0c00138] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The bioactivation of xenobiotics to yield reactive metabolites can lead to tolerability and toxicity concerns within a drug discovery program. Development of strategies for mitigating the metabolic liability of commonly encountered toxicophores, such as anilines, relies on an understanding of the relative tendency of these functionalities to undergo bioactivation. In this report, we present the first systematic study of the structure-activity relationships of the bioactivation of aryl amine fragments (molecular weight < 250 Da) using a glutathione (GSH) trapping assay in the presence of human liver microsomes and the reduced form of nicotinamide adenine dinucleotide phosphate. This study demonstrates that conversion of anilines to nitrogen-containing heteroarylamines results in a lower abundance of GSH conjugates in the order phenyl > pyrimidine ≈ pyridine > pyridazine. Introduction of electron-withdrawing functionality on the aromatic ring had a less pronounced effect on the extent of GSH conjugation. Examination of more drug-like compounds sourced from in-house drug discovery programs revealed similar trends in bioactivation between matched pairs containing (hetero)aryl amines. This study provides medicinal chemists with insights and qualitative guidance for the minimization of risks related to aryl amine metabolism.
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Affiliation(s)
- Chenghong Zhang
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - James J Crawford
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Matthew L Landry
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Huifen Chen
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Jane R Kenny
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - S Cyrus Khojasteh
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Wendy Lee
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Shuguang Ma
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Wendy B Young
- Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States
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17
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Sandhu N, Navarro V. Drug-Induced Liver Injury in GI Practice. Hepatol Commun 2020; 4:631-645. [PMID: 32363315 PMCID: PMC7193133 DOI: 10.1002/hep4.1503] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/18/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although drug-induced liver injury (DILI) is a rare clinical event, it carries significant morbidity and mortality, leaving it as the leading cause of acute liver failure in the United States. It is one of the most challenging diagnoses encountered by gastroenterologists. The development of various drug injury networks has played a vital role in expanding our knowledge regarding drug-related and herbal and dietary supplement-related liver injury. In this review, we discuss what defines liver injury, epidemiology of DILI, its biochemical and pathologic patterns, and management.
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Affiliation(s)
- Naemat Sandhu
- Division of Digestive Diseases and TransplantationAlbert Einstein Healthcare NetworkPhiladelphiaPA
| | - Victor Navarro
- Division of Digestive Diseases and TransplantationAlbert Einstein Healthcare NetworkPhiladelphiaPA
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18
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Zhou Z, Qi J, Kim JW, You MJ, Lim CW, Kim B. AK-1, a Sirt2 inhibitor, alleviates carbon tetrachloride-induced hepatotoxicity in vivo and in vitro. Toxicol Mech Methods 2020; 30:324-335. [PMID: 32063085 DOI: 10.1080/15376516.2020.1729915] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background/Aim: Acute liver injury (ALI) is a life-threatening clinical syndrome that is usually caused by toxic chemicals, drugs, or pathogen infections. Sirtuin2 (Sirt2), an NAD+-dependent deacetylase, appears to play detrimental roles in liver injury. Here, we evaluated the therapeutic application targeting Sirt2 in carbon tetrachloride (CCl4)-induced ALI, by using AK-1 (a Sirt2 inhibitor).Methods: For in vivo experiments, a single injection of CCl4 was used to induce ALI. One hour later, mice were intraperitoneally injected with AK-1 and were sacrificed 24 h after CCl4 administration. For in vitro experiments, primary mouse hepatocytes were used to determine the effects of AK-1 on oxidative stress and hepatocellular death induced by CCl4.Results: AK-1 alleviated CCl4-induced ALI as confirmed by histopathologic analysis, and decreased levels of serum biochemicals and inflammatory cytokines. Although it barely affected the expression of hepatic cytochrome P450 enzymes, AK-1 attenuated CCl4-induced oxidative stress and its related cell death. Mechanistically, Sirt2 inhibition significantly increased the nuclear protein level of nuclear factor erythroid 2-related factor 2 (Nrf2), and meanwhile decreased phosphorylation of c-Jun N-terminal kinases (JNK), in normal and injured livers. Similar results were observed in vitro. AK-1 significantly attenuated CCl4-induced cytotoxicity and oxidative stress by up-regulating the activity of Nrf2, and down-regulating JNK signaling in hepatocytes.Conclusions: Our results suggest that AK-1 treatment attenuated oxidative stress and cell death in the ALI model, at least partially, via activating Nrf2 and inhibiting JNK signaling, and that Sirt2 inhibition might be a potential approach to cure ALI.
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Affiliation(s)
- Zixiong Zhou
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Jing Qi
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Jong-Won Kim
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Myung-Jo You
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Chae Woong Lim
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Bumseok Kim
- Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea
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19
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Garzel B, Zhang L, Huang SM, Wang H. A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis. Curr Drug Metab 2020; 20:621-632. [PMID: 31288715 DOI: 10.2174/1389200220666190709170256] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/22/2019] [Accepted: 06/12/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms. METHODS We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so. RESULTS We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC. CONCLUSION Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.
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Affiliation(s)
- Brandy Garzel
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.,Becton Dickinson, 54 Loveton Circle, Sparks, MD 21152, United States
| | - Lei Zhang
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.,Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, United States
| | - Shiew-Mei Huang
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States
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20
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Sharma B, Antoine M, Shah M, John S. Idiosyncratic Drug-Induced Liver Injury Secondary to Trimethoprim-Sulfamethoxazole. Am J Ther 2020; 27:e664-e667. [PMID: 31425162 DOI: 10.1097/mjt.0000000000001032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | | | - Mili Shah
- Internal Medicine, SUNY Upstate, Syracuse, NY
| | - Savio John
- Gastroenterology, SUNY Upstate, Syracuse, NY
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21
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Susilo RJK, Winarni D, Husen SA, Hayaza S, Punnapayak H, Wahyuningsih SPA, Sajidah ES, Darmanto W. Hepatoprotective effect of crude polysaccharides extracted from Ganoderma lucidum against carbon tetrachloride-induced liver injury in mice. Vet World 2019; 12:1987-1991. [PMID: 32095051 PMCID: PMC6989327 DOI: 10.14202/vetworld.2019.1987-1991] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/08/2019] [Indexed: 12/17/2022] Open
Abstract
Background and Aim Natural products are currently widely used as alternative treatments for liver disease. The study aimed to determine the hepatoprotective effect of crude polysaccharides extracted from Ganoderma lucidum against liver injury induced by carbon tetrachloride (CCl4). Materials and Methods Twenty-four male BALB/C mice were randomly divided into six groups. Serum and liver samples were taken on day 10 after G. lucidum administration. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured using enzyme-linked immunosorbent assays, and the histology of the liver was evaluated using light microscopy. Results G. lucidum extract significantly decreased the levels of ALT, AST, and MDA and significantly increased the levels of SOD and CAT. In the histological evaluation, the liver tissue of CCl4-treated mice exhibited hydropic degeneration, necrosis, and sinusoidal dilatation. G. lucidum extract administration improved this liver tissue histopathology. Conclusion Crude polysaccharides extracted from G. lucidum showed a hepatoprotective effect, regenerating damaged liver tissue.
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Affiliation(s)
| | - Dwi Winarni
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Saikhu Akhmad Husen
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Suhailah Hayaza
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Hunsa Punnapayak
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia.,Plant Biomass Utilization Research Unit, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | | | - Elma Sakinatus Sajidah
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Win Darmanto
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
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Kakisaka K, Suzuki Y, Jinnouchi Y, Kanazawa J, Sasaki T, Yonezawa T, Yoshida Y, Kuroda H, Takikawa Y. Unfavorable prognosis of patients with acute liver injury due to drug-induced liver injury and acute exacerbation of hepatitis B virus infection. Hepatol Res 2019; 49:1286-1293. [PMID: 31251432 DOI: 10.1111/hepr.13397] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/05/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023]
Abstract
AIM Acute liver injury (ALI) has a favorable prognosis, whereas acute liver failure (ALF) leads to organ failure and thus has an unfavorable prognosis. The effect of each etiology on the clinical course of ALI remains unclear. This study aimed to determine how each etiology and glucocorticoid on the unfavorable etiology affects the clinical course of ALI. METHODS This prospective observational study enrolled 522 patients with ALI/ALF from 2004 and 2017. To evaluate the influence of etiology on prognosis, decision tree analysis was carried out using age, disease type, etiology, and the presence of hepatic encephalopathy. RESULTS Of 522 patients, 398 patients satisfied the ALI criteria at registration in this study. The ALI etiologies were as follows: viral hepatitis through oral infection (n = 54), acute hepatitis B virus (HBV) infection (n = 24), acute exacerbation of HBV infection (n = 30), de novo hepatitis due to HBV (n = 5), autoimmune hepatitis (n = 59), drug-induced liver injury (DILI; n = 85), other viruses (n = 12), and undetermined (n = 129). ALI in 46 patients progressed to ALF after registration. Of 11 patients (age >52 years) with ALF due to acute exacerbation of HBV infection or DILI, seven patients (63.6%) died. Whether glucocorticoid affected the clinical course of ALI due to acute exacerbation of HBV infection or DILI was evaluated using propensity score matching (age, sex, alanine aminotransferase, total bilirubin, and prothrombin time-international normalized ratio). Glucocorticoid did not improve the prognosis of ALI patients due to the two etiologies. CONCLUSIONS Progression of ALI due to DILI or acute exacerbation of HBV infection to ALF showed a poor prognosis.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Yukina Jinnouchi
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Jo Kanazawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Tokio Sasaki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Takehiro Yonezawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Iwate, Japan
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Urrutia-Maldonado E, Abril-Molina A, Alés-Palmer M, Gómez-Luque JM, Muñoz de Rueda P, Ocete-Hita E. Lesión hepática inducida por quimioterapia en niños. An Pediatr (Barc) 2019; 91:256-263. [DOI: 10.1016/j.anpedi.2019.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 01/19/2023] Open
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24
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Urrutia-Maldonado E, Abril-Molina A, Alés-Palmer M, Gómez-Luque JM, Muñoz de Rueda P, Ocete-Hita E. Chemotherapy-induced liver injury in children. An Pediatr (Barc) 2019. [DOI: 10.1016/j.anpede.2019.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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25
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Aleo MD, Shah F, Allen S, Barton HA, Costales C, Lazzaro S, Leung L, Nilson A, Obach RS, Rodrigues AD, Will Y. Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential. Chem Res Toxicol 2019; 33:223-238. [DOI: 10.1021/acs.chemrestox.9b00262] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
| | | | - Scott Allen
- Drug Safety Research and Development, Investigative Toxicology, Pfizer Worldwide Research & Development, One Burtt Road, Andover, Massachusetts 01810, United States
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26
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Lee DH, Lee B, Park JS, Lee YS, Kim JH, Cho Y, Jo Y, Kim HS, Lee YH, Nam KT, Bae SH. Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation. BMB Rep 2019. [PMID: 30021675 PMCID: PMC6476489 DOI: 10.5483/bmbrep.2019.52.3.083] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD+-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirt2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP-mediated endoplasmic reticulum (ER) stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries.
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Affiliation(s)
- Da Hyun Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Buhyun Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jeong Su Park
- Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yu Seol Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jin Hee Kim
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yoonjung Jo
- Department of Bioinspired Science, Ewha Womans University, Seoul 03760, Korea
| | - Hyun-Seok Kim
- Department of Bioinspired Science, Ewha Womans University, Seoul 03760, Korea
| | - Yong-Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Ki Taek Nam
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo Han Bae
- Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
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Acute and Subchronic (28-day) Oral Toxicity Studies on the Film Formulation of k-Carrageenan and Konjac Glucomannan for Soft Capsule Application. Sci Pharm 2019. [DOI: 10.3390/scipharm87020009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The aim of this study was to investigate the acute and subchronic toxicity of a film formulation that combines κ-Carrageenan and konjac glucomannan for soft capsule application. For the acute toxicity study, a dose of 2000 mg/kg body weight (bw) of the film suspension was administered orally to rats. The animals were observed for toxic symptoms and mortality daily for 14 days. In a subchronic toxicity study, the film suspension, at doses of 10, 30 and 75 mg/kg bw for 28 days, were orally administered to rats. After 28 days, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity study, neither signs of toxicity nor death among the rats were observed for up to 14 days of the experimental period. The results of the subchronic toxicity study show that there were no significant changes observed in the hematology and organ histology. Some alterations to the relative organ weight and blood biochemistry were observed, but they were considered to be temporary effects and not an indication of toxic effects. The overall findings of this study indicate that the film formulation of κ-Carrageenan and konjac glucomannan is non-toxic up to a dose of 75 mg/kg bw, which could be considered a safe dose for soft capsule application.
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Acute Liver Failure in Children. PEDIATRIC HEPATOLOGY AND LIVER TRANSPLANTATION 2019. [PMCID: PMC7122201 DOI: 10.1007/978-3-319-96400-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
“Acute liver failure” (ALF) and “fulminant liver failure” are terms used interchangeably to describe severe and sudden onset of liver cell dysfunction leading on to synthetic and detoxification failure across all age groups. Considerable variations exist between ALF in children and adults, in terms of aetiology and prognosis. Encephalopathy is not essential to make a diagnosis of ALF in children but when present has a bad prognosis. Early recognition of ALF and initiation of supportive management improve the outcome. Liver transplantation remains the only definitive treatment when supportive medical management fails.
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Narciso-Schiavon JL, Delziovo HA, Santos LEB, Shiozawa MBC, Schiavon LL. Recurrent albendazole-induced acute hepatitis. REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2018; 33:473. [DOI: 10.22516/25007440.206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
El albendazol es un medicamento usado para tratar infecciones por helmintos y usualmente presenta pocos o ningún efecto secundario. A pesar de que hay un incremento transitorio de enzimas hepáticas luego de su uso, existe poca evidencia en la literatura en la que se reporte lesión hepática luego de automedicación con albendazol. En este informe, el paciente se presentó con hepatitis aguda luego de automedicarse con albendazol. El paciente cuenta además con una historia de episodios similares después de haber usado el fármaco. Se evaluada la causalidad con el método de evaluación de causalidad de Roussel Uclaf del Concejo para Organizaciones Internacionales de Ciencias Médicas, cuyo resultado fue un puntaje de 10, lo que indicó una alta probabilidad de lesión hepática inducida por albendazol al cabo de realizarse una investigación rigurosa y de excluir otras posibles causas de la condición física del paciente. En conclusión, aunque es ideal agilizar el proceso para combatir a los helmintos, es necesario intensificar la necesidad de monitorizaciones de calidad para evitar reacciones adversas como la hepatitis inducida por medicamentos. Asimismo, la automedicación de cualquier medicamento debe ser siempre evitada.
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Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online 2018; 38:249-259. [PMID: 30595525 DOI: 10.1016/j.rbmo.2018.11.017] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/15/2018] [Accepted: 11/07/2018] [Indexed: 12/29/2022]
Abstract
The pharmacological and physiological profiles of progestogens used for luteal phase support during assisted reproductive technology are likely to be important in guiding clinical choice towards the most appropriate treatment option. Various micronized progesterone formulations with differing pharmacological profiles have been investigated for several purposes. Dydrogesterone, a stereoisomer of progesterone, is available in an oral form with high oral bioavailability; it has been used to treat a variety of conditions related to progesterone deficiency since the 1960s and has recently been approved for luteal phase support as part of an assisted reproductive technology treatment. The primary objective of this review is to critically analyse the clinical implications of the pharmacological and physiological properties of dydrogesterone for its uses in luteal phase support and in early pregnancy.
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31
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di Bello G, Vendemiale G, Bellanti F. Redox cell signaling and hepatic progenitor cells. Eur J Cell Biol 2018; 97:546-556. [PMID: 30278988 DOI: 10.1016/j.ejcb.2018.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 09/20/2018] [Accepted: 09/20/2018] [Indexed: 02/08/2023] Open
Abstract
Hepatic diseases are widespread in the world and organ transplantation is currently the only treatment for liver failure. New cell-based approaches have been considered, since stem cells may represent a possible source to treat liver diseases. Acute and chronic liver diseases are characterized by high production of reactive oxygen and nitrogen species, with consequent oxidative modifications of cellular macromolecules and alteration of signaling pathways, metabolism and cell cycle. Although considered harmful molecules, reactive species are involved in cell growth and differentiation processes, modulating the activity of transcription factors, which take part in stemness/proliferation. It is conceivable that redox balance may regulate the development of hepatic progenitor cells, function and survival in synchrony with metabolism during chronic liver diseases. This review aims to summarize diverse redox-sensitive signaling pathways involved in stem cell fate, highlighting the important role of hepatic progenitor cells as a possible source to treat end-stage liver disease for organ regeneration.
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Affiliation(s)
- Giorgia di Bello
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Gianluigi Vendemiale
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Francesco Bellanti
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy.
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Montrief T, Koyfman A, Long B. Acute liver failure: A review for emergency physicians. Am J Emerg Med 2018; 37:329-337. [PMID: 30414744 DOI: 10.1016/j.ajem.2018.10.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization. OBJECTIVE This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF. DISCUSSION While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes neurologic dysfunction, an international normalized ratio ≥ 1.5, no prior evidence of liver disease, and a disease course of ≤26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care. CONCLUSIONS ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the underlying etiology and initiating symptomatic care.
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Affiliation(s)
- Tim Montrief
- University of Miami, Jackson Memorial Hospital/Miller School of Medicine, Department of Emergency Medicine, 1611 N.W. 12th Avenue, Miami, FL 33136, United States
| | - Alex Koyfman
- The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States
| | - Brit Long
- Brooke Army Medical Center, Department of Emergency Medicine, 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.
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Wang W, Chen K, Xia Y, Mo W, Wang F, Dai W, Niu P. The Hepatoprotection by Oleanolic Acid Preconditioning: Focusing on PPAR α Activation. PPAR Res 2018; 2018:3180396. [PMID: 29805439 PMCID: PMC5901823 DOI: 10.1155/2018/3180396] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 02/08/2018] [Accepted: 02/19/2018] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Previous studies have characterized the hepatoprotective and anti-inflammatory properties of oleanolic acid (OA). This study aimed to investigate the molecular mechanisms of OA hepatoprotection in concanavalin A- (ConA-) induced acute liver injury. MATERIALS AND METHODS ConA (20 mg/kg) was intravenously injected to induce acute liver injury in Balb/C mice. OA pretreatment (20, 40, and 80 mg/kg) was administered subcutaneously once daily for 3 consecutive days prior to treatment with ConA; 2, 8, and 24 h after ConA injection, the levels of serum liver enzymes and the histopathology of major factors and inflammatory cytokines were determined. RESULTS OA reduced the release of serum liver enzymes and inflammatory factors and prevented ConA mediated damage to the liver. OA elevated the expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and decreased the phosphorylation of c-Jun NH2-terminal kinase (JNK). CONCLUSION OA exhibits anti-inflammatory properties during ConA-induced acute liver injury by attenuating apoptosis and autophagy through activation of PPARα and downregulation of JNK signaling.
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Affiliation(s)
- Wenwen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Wenhui Mo
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Weiqi Dai
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Peiqin Niu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Shanghai Tenth People's Hospital Chongming Branch, Tongji University School of Medicine, Shanghai 202157, China
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Ahmad A, Al-Abbasi FA, Sadath S, Ali SS, Abuzinadah MF, Alhadrami HA, Mohammad Alghamdi AA, Aseeri AH, Khan SA, Husain A. Ameliorative Effect of Camel's Milk and Nigella Sativa Oil against Thioacetamide-induced Hepatorenal Damage in Rats. Pharmacogn Mag 2018; 14:27-35. [PMID: 29576698 PMCID: PMC5858237 DOI: 10.4103/pm.pm_132_17] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 04/28/2017] [Indexed: 01/18/2023] Open
Abstract
Background: Camel milk (CM) and Nigella sativa (NS) have been traditionally claimed to cure wide range of diseases and used as medicine in different part of world, particularly in Saudi Arabia. Several research studies have been published that proved beneficial effects of CM and NS. Objective: This study was undertaken to investigate the antihepatotxic potential of CM and NS oil (NSO) against thioacetamide (TAA)-induced hepato and nephrotoxicity in rats. Materials and Methods: Thirty female Albino Wistar rats were randomly divided in to six groups having five rats in each group. A single subcutaneous injection of TAA (100 mg/kg b. w.) was administered to all the rats in Group-II to VI on 1st day to induce hepatorenal damage. Group I served as a normal control while Group II served as toxic control for comparison purpose. Experimental animals in Group III, IV, and V were supplemented with fresh CM, (250 mL/24 h/cage), NSO (2 mL/kg/day p. o.), and NSO + fresh CM, respectively. Group VI was treated with a polyherbal hepatoprotective Unani medicine Jigreen (2 mL/kg/day p. o.) for 21 days. TAA-induced hepatorenal damage and protective effects of CM and NSO were assessed by analyzing liver and kidney function tests in the serum. Histopathology of liver and kidney tissues was also carried out to corroborate the findings of biochemical investigation. Results: The results indicated that the TAA intoxicated rats showed significant increase in the alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lipid profile, urea, creatinine, uric acid, sodium, and potassium levels in serum. Treatment of rats with CM, NSO, and CM plus NSO combination and Jigreen significantly reversed the damage and brought down the serum biochemical parameters and lipid profile toward the normal levels. The histopathological studies also support the hepato and nephroprotective effects of CM and NSO. Conclusion: This study demonstrated the ameliorative effects of CM, NSO, and CM plus NSO combination against TAA-induced hepatorenal toxicity in rats. SUMMARY
The antihepatotxic potential of Camel's Milk (CM) and Nigella sativa oil (NSO) against thioacetamide (TAA) induced hepatorenal toxicity was evaluated in rats The oral administration of fresh CM (250 mL/24h/cage), NSO (2 mL/kg/day) and NSO+fresh CM and Jigreen (2 mL/kg/day) for 21 days significantly decreased the hepatorenal toxicity as evidenced from analyzed biochemical parameters in serum and histopathological studies of liver and kidney tissues This study demonstrated the ameliorative effects of CM and NSO against TAA induced hepatorenal toxicity. Abbreviations used: CM: Camel milk; NS: Nigella sativa; NSO: Nigella sativa Oil; TAA: Thioacetamide; S.C.: Subcutaneous; Jig: Jigreen; b.w.: Body Weight; mL: Milli liter; mg: Milli gram; g: Gram; Kg: Kilo gram; ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: Gamma-Glutamyl Transpeptidase; ALP: Alkaline Phosphatase; TC: Total Cholesterol; HDL-C: High Density Lipoprotein Cholesterol; LDL-C: Low Density Lipoprotein Cholesterol; TG: Triglyceride; TB: Total bilirubin; K+: Potassium; Na+: Sodium; CCl4: Carbon Tetrachloride; °C: Degree Celsius; p.o.: Per Oral; RPM: Revolutions per minute; H&E: Hematoxylin and Eosin; SEM: Standard Error of Mean; ANOVA: The one-way analysis of variance.
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Affiliation(s)
- Aftab Ahmad
- Department of Health Information Technology, Jeddah Community College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Saida Sadath
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Soad Shaker Ali
- Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Scientific Chair of Yousef Abdullatif Jameel of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammed F Abuzinadah
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Saudi Arabia
| | - Hani A Alhadrami
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Saudi Arabia
| | - Anwar Ali Mohammad Alghamdi
- Department of Health Information Technology, Jeddah Community College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ali H Aseeri
- Jeddah Regional Lab, Ministry of Health, Jeddah, Kingdom of Saudi Arabia
| | - Shah Alam Khan
- Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman
| | - Asif Husain
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi, India
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Cho JH, Oh DS, Hong SH, Ko H, Lee NH, Park SE, Han CW, Kim SM, Kim YC, Kim KS, Choi CW, Shin SM, Kim KT, Choi HS, Lee JH, Kim JY, Kang JY, Lee DS, Ahn YC, Son CG. A nationwide study of the incidence rate of herb-induced liver injury in Korea. Arch Toxicol 2017; 91:4009-4015. [PMID: 28634823 PMCID: PMC5719126 DOI: 10.1007/s00204-017-2007-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 06/01/2017] [Indexed: 02/08/2023]
Abstract
Discrepant incidence has been reported regarding the incidence of herb-induced liver injury (HILI). To address the growing worldwide concern of HILI, we evaluated the risk of HILI in a nationwide prospective study. Between April 2013 and January 2016, 1001 inpatients (360 males and 641 females) from 10 tertiary hospitals throughout South Korea were treated with herbal drugs and had their liver enzymes periodically measured. A total of six patients met the criteria for HILI with RUCAM scores ranging from 4 to 7. All these participants were women and developed the hepatocellular type of HILI. One HILI participant met the criteria for Hy's law; however, none of six cases presented clinical symptoms related to liver injury. This is the first nationwide prospective study that estimated the extent of the incidence of HILI [total: 0.60%, 95% confidence interval (CI) 0.12-1.08; women: 0.95%, 95% CI 0.19-1.68] and described its features in hospitalized participants.
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Affiliation(s)
- Jung-Hyo Cho
- Hepatology Department, Daejeon Oriental Hospital of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon, 34929, South Korea
| | - Dal-Seok Oh
- The K-herb Research Centre, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Sang-Hoon Hong
- Department of Internal Medicine, Dongeui Oriental Hospital of Dongeui University, Busan, South Korea
| | - Heung Ko
- Department of Internal Medicine, Oriental Hospital of Semyung University, Jecheon, South Korea
| | - Nam-Hun Lee
- Department of Internal Medicine, Cheonan Oriental Hospital of Daejeon University, Cheonan, South Korea
| | - Sang-Eun Park
- Department of Internal Medicine, Ulsan Oriental Hospital of Dongeui University, Ulsan, South Korea
| | - Chang-Woo Han
- School of Korean Medicine, Pusan National University, Busan, South Korea
| | - Seung-Mo Kim
- Department of Internal Medicine, Oriental Hospital of Daegu Haany University, Daegu, South Korea
| | - Young-Chul Kim
- Department of Internal Medicine, Kyung Hee University Oriental Medical Hospital, Seoul, South Korea
| | - Kang-San Kim
- Department of Internal Medicine, Oriental Hospital of Wonkwang University, Iksan, South Korea
| | - Chang-Won Choi
- Department of Internal Medicine, Oriental Hospital of Dongshin University, Suncheon, South Korea
| | - Seon-My Shin
- Department of Internal Medicine, Oriental Hospital of Semyung University, Jecheon, South Korea
| | - Ki-Tae Kim
- Department of Internal Medicine, Oriental Hospital of Semyung University, Jecheon, South Korea
| | - Hong-Sik Choi
- Department of Internal Medicine, Oriental Hospital of Daegu Haany University, Daegu, South Korea
| | - Jang-Hoon Lee
- Department of Internal Medicine, Kyung Hee University Oriental Medical Hospital, Seoul, South Korea
| | - Jun-Young Kim
- Hepatology Department, Daejeon Oriental Hospital of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon, 34929, South Korea
| | - Ji-Young Kang
- Hepatology Department, Daejeon Oriental Hospital of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon, 34929, South Korea
| | - Dong-Soo Lee
- Department of Internal Medicine, Daejeon St. Mary's Hospital of Catholic University, Daejeon, South Korea
| | - Yo-Chan Ahn
- Department of Health Service Management, Daejeon University, Daejeon, South Korea
| | - Chang-Gue Son
- Hepatology Department, Daejeon Oriental Hospital of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon, 34929, South Korea.
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Slim R, Asmar N, Yaghi C, Honein K, Sayegh R, Chelala D. Trimethoprim-Sulfamethoxazole-induced Hepatotoxicity in a Renal Transplant Patient. Indian J Nephrol 2017; 27:482-483. [PMID: 29217891 PMCID: PMC5704419 DOI: 10.4103/ijn.ijn_339_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Drug-induced liver injury (DILI) represents liver damage from various therapeutic drugs. Antimicrobials are among the most common causes of DILI. We report a case of hepatic toxicity due to Trimethoprim-sulfamethoxazole (TMP-SMX) in a patient who underwent renal transplantation. Diagnosis has been made after a careful history taking, exclusion of competing etiologies and reversal of biochemical abnormalities after withdrawal of the antibiotic. TMP-SMX liver toxicity is well known but remains unpredictable and is rarely reported.
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Affiliation(s)
- R. Slim
- Department of Gastroenterology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - N. Asmar
- Department of Gastroenterology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - C. Yaghi
- Department of Gastroenterology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - K. Honein
- Department of Gastroenterology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - R. Sayegh
- Department of Gastroenterology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
| | - D. Chelala
- Department of Nephrology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon
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Sundaram V, Björnsson ES. Drug-induced cholestasis. Hepatol Commun 2017; 1:726-735. [PMID: 29404489 PMCID: PMC5678916 DOI: 10.1002/hep4.1088] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 06/25/2017] [Accepted: 08/07/2017] [Indexed: 12/14/2022] Open
Abstract
Cholestatic drug-induced liver injury (DILI) can be a diagnostic challenge due to a large differential diagnosis, variability in clinical presentation, and lack of serologic biomarkers associated with this condition. The clinical presentation of drug-induced cholestasis includes bland cholestasis, cholestatic hepatitis, secondary sclerosing cholangitis, and vanishing bile duct syndrome. The associate mortality of cholestatic DILI can be as high as 10%, and thus prompt recognition and removal of the offending agent is of critical importance. Several risk factors have been identified for drug-induced cholestasis, including older age, genetic determinants, and properties of certain medications. Antibiotics, particularly amoxicillin/clavulanate, remain the predominant cause of cholestatic DILI, although a variety of other medications associated with this condition have been identified. In this review, we summarize the presentation, clinical approach, risk factors, implicated medications, and management of drug-induced cholestatic liver injury. (Hepatology Communications 2017;1:726-735).
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Affiliation(s)
- Vinay Sundaram
- Department of Medicine and Comprehensive Transplant CenterCedars‐Sinai Medical CenterLos AngelesCA
| | - Einar S. Björnsson
- Section of Gastroenterology and Hepatology, Department of Internal MedicineNational University Hospital of IcelandReykjavíkIceland
- Faculty of Medicine and School of EducationUniversity of IcelandReykjavíkIceland
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38
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Clinical Epidemiology of Single Versus Multiple Substance Use Disorders. Med Care 2017; 55 Suppl 9 Suppl 2:S24-S32. [DOI: 10.1097/mlr.0000000000000731] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kotsampasakou E, Montanari F, Ecker GF. Predicting drug-induced liver injury: The importance of data curation. Toxicology 2017; 389:139-145. [PMID: 28652195 PMCID: PMC6422282 DOI: 10.1016/j.tox.2017.06.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/10/2017] [Accepted: 06/15/2017] [Indexed: 12/12/2022]
Abstract
Drug-induced liver injury (DILI) is a major issue for both patients and pharmaceutical industry due to insufficient means of prevention/prediction. In the current work we present a 2-class classification model for DILI, generated with Random Forest and 2D molecular descriptors on a dataset of 966 compounds. In addition, predicted transporter inhibition profiles were also included into the models. The initially compiled dataset of 1773 compounds was reduced via a 2-step approach to 966 compounds, resulting in a significant increase (p-value < 0.05) in model performance. The models have been validated via 10-fold cross-validation and against three external test sets of 921, 341 and 96 compounds, respectively. The final model showed an accuracy of 64% (AUC 68%) for 10-fold cross-validation (average of 50 iterations) and comparable values for two test sets (AUC 59%, 71% and 66%, respectively). In the study we also examined whether the predictions of our in-house transporter inhibition models for BSEP, BCRP, P-glycoprotein, and OATP1B1 and 1B3 contributed in improvement of the DILI mode. Finally, the model was implemented with open-source 2D RDKit descriptors in order to be provided to the community as a Python script.
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Affiliation(s)
- Eleni Kotsampasakou
- University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria
| | - Floriane Montanari
- University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria
| | - Gerhard F Ecker
- University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
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Yu Z, Wu F, Tian J, Guo X, An R, Guo Y. Ammonium glycyrrhizin counteracts liver injury caused by lipopolysaccharide/amoxicillin-clavulanate potassium. Oncotarget 2017; 8:96837-96851. [PMID: 29228575 PMCID: PMC5722527 DOI: 10.18632/oncotarget.18291] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 05/07/2017] [Indexed: 12/31/2022] Open
Abstract
We treated isolated chicken primary hepatocytes with lipopolysaccharide/amoxicillin clavulanate potassium (LPS/AC) to model liver injury and investigate its underlying mechanisms. We also used this model to assess the cytoprotective effects of compound ammonium glycyrrhizin (CAG) in vitro. LPS/AC-induced injury decreased cell viability and increased the activity of serum aspartate transaminase and alanine transaminase. Levels of superoxide dismutase, glutathione, and glutathione peroxidase were lower than control, while levels of the oxidative product malondialdehyde and reactive oxygen species were higher. Treatment with CAG for 24 h ameliorated these changes. Caspase-3 activity assays and flow cytometry revealed increased apoptosis in the model group. However, apoptosis decreased after CAG treatment, as confirmed by Hoechst 33342 staining. We also observed changes in mitochondrial ultrastructure. Real-time PCR and western blot analyses showed that CAG treatment downregulated LPS/AC-induced RNA expression of caspase-3, caspase-9, bax, cytochrome c, and fas, and upregulated the expression of bcl-2. Mitochondrial cytochrome c was released into the cytosol and the inner mitochondrial membrane potential (ΔΨm) was decreased. Our results highlight CAG as a potential therapeutic agent to counteract LPS/AC-induced liver injury.
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Affiliation(s)
- Zugong Yu
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Feng Wu
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Jing Tian
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Xuewen Guo
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Ran An
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Yangyang Guo
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
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Nägele V, Kratzer A, Zugmaier G, Holland C, Hijazi Y, Topp MS, Gökbuget N, Baeuerle PA, Kufer P, Wolf A, Klinger M. Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL. Exp Hematol Oncol 2017; 6:14. [PMID: 28533941 PMCID: PMC5437652 DOI: 10.1186/s40164-017-0074-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/02/2017] [Indexed: 12/24/2022] Open
Abstract
Background Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study. Methods Data from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release. Associations with clinical response were evaluated. Results Liver enzymes and inflammatory parameters transiently increased primarily during the first treatment week without clinical symptoms and reversed to baseline levels thereafter. B and T cells showed expected depletion and redistribution kinetics, respectively. Similarly, thrombocytes and T cells displayed an initial decline in cell counts, whereas neutrophils peaked during the first days after infusion start. T-cell redistribution coincided with upregulation of LFA-1 and CD69. Patients who responded to blinatumomab had more pronounced T-cell expansion, which was associated with proliferation of CD4+ and CD8+ T cells and memory subsets. Release of cytokines and granzyme B primarily occurred during the first week of cycle 1, except for IL-10, which was released in subsequent cycles. Blinatumomab step-dosing was associated with lower cytokine release and lower body temperature. Conclusions In this study of relapsed/refractory ALL, blinatumomab-induced changes in laboratory parameters were transient and reversible. The evaluated PD markers demonstrated blinatumomab activity, and the analysis of cytokines supported the rationale for stepwise dosing. (ClinicalTrials.gov Identifier NCT01209286.) Electronic supplementary material The online version of this article (doi:10.1186/s40164-017-0074-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Virginie Nägele
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Andrea Kratzer
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Gerhard Zugmaier
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | | | - Youssef Hijazi
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Max S Topp
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Nicola Gökbuget
- Department of Medicine II, Goethe University, Frankfurt, Germany
| | - Patrick A Baeuerle
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Peter Kufer
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Andreas Wolf
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
| | - Matthias Klinger
- Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany
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Qu X, Xu K, Zhao C, Song X, Li J, Li L, Nie W, Bao H, Wang J, Niu F, Li J. Genotoxicity and acute and subchronic toxicity studies of a bioactive polyoxometalate in Wistar rats. BMC Pharmacol Toxicol 2017; 18:26. [PMID: 28381296 PMCID: PMC5382445 DOI: 10.1186/s40360-017-0133-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/29/2017] [Indexed: 01/05/2023] Open
Abstract
Background Cs2K4Na [SiW9Nb3O40] (POM93) is a novel broad-spectrum antiviral agent with high activity, high stability, and low toxicity in vitro. Most toxicity studies for POM93 have been performed in cultured cell lines rather than in animals. Like other POMs, there is a lack of evidence for in vivo toxicity limits, oral bioavailability, and therapeutic applications. Methods The toxic properties of POM93 were evaluated comprehensively in vivo, including the acute and subchronic oral toxicity studies and genotoxicity tests. Results The acute toxicity study showed no abnormal changes or mortality in rats treated with POM93 even at the single high dose of 5000 mg/kg body weight. In the subchronic toxicity study, regardless of the body weight, the organ weight, and the hematological parameters, similar results were observed between the control group and the experimental groups. POM93 produced mild changes in rare hematological parameters in the liver and kidneys, but did not induce the clinical symptoms of liver or kidneys injury in rats as confirmed by histopathological analysis. Moreover, neither mutagenicity nor clastogenicity was caused by POM93 treatment in vitro and in vivo. Conclusions The present study demonstrates that the oral administration of POM93 is presumed safe and poses a low risk of potential health risks. Electronic supplementary material The online version of this article (doi:10.1186/s40360-017-0133-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaofeng Qu
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Kun Xu
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Chao Zhao
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Xiuling Song
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Jinhua Li
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Li Li
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Wei Nie
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Hao Bao
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Juan Wang
- School of Public Health, Jilin University, Changchun, Jilin, China.
| | - Fenglan Niu
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Juan Li
- School of Public Health, Jilin University, Changchun, Jilin, China
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Yucha RW, He K, Shi Q, Cai L, Nakashita Y, Xia CQ, Liao M. In Vitro Drug-Induced Liver Injury Prediction: Criteria Optimization of Efflux Transporter IC50 and Physicochemical Properties. Toxicol Sci 2017; 157:487-499. [DOI: 10.1093/toxsci/kfx060] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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Jan NU, Ahmad B, Ali S, Adhikari A, Ali A, Jahan A, Ali A, Ali H. Steroidal Alkaloids as an Emerging Therapeutic Alternative for Investigation of Their Immunosuppressive and Hepatoprotective Potential. Front Pharmacol 2017; 8:114. [PMID: 28377714 PMCID: PMC5359222 DOI: 10.3389/fphar.2017.00114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 02/23/2017] [Indexed: 12/17/2022] Open
Abstract
The compounds, sarcovagine-D, alkaloid-C, and holaphylline isolated from Sarcococca saligna were found to possess immunosuppressive activities. These compounds were characterized for in vitro inhibition on human T-cells proliferation and IL-2 production. The compounds showed significant immunosuppressive effect on IL-2 production as well as on phytohemagglutinin stimulated T-cell proliferation in a dose dependent manner. Of all the tested compounds holaphylline was found to be less toxic and safe. These compounds were then evaluated for their in vivo hepatoprotective potential against CCl4, in which alkaloid-C and holaphylline showed markedly reduced liver inflammation and biochemical parameter (ALT, AST, and ALP) of liver injury. The decrease in the activity of hepatic antioxidant enzyme (SOD) was significantly prevented by holaphylline, likewise gradually the levels of MDA and GSH were also normalized compared to silymarin. The CCl4 induced inflammation and necrosis around the central vein of liver was reduced by sarcovagine-D, alkaloid-C and holaphylline, to 8%, 4% to 1% respectively as assessed by histopathology, thus having better hepatoprotective effect compared to positive control. Steroidal alkaloids attenuated the inflammation of liver around the injured central vein region by down regulating the CCl4 induced activation of hepatic macrophages as well as their number respectively. Therefore, the in vitro and in vivo results suggest that steroidal alkaloids from S. saligna could be excellent immunosuppressive and hepatoprotective agents.
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Affiliation(s)
- Naeem U Jan
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar Pakistan
| | - Bashir Ahmad
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar Pakistan
| | - Safdar Ali
- Pakistan Institute of Engineering and Applied Sciences, Islamabad Pakistan
| | - Achyut Adhikari
- Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi Pakistan
| | - Amjad Ali
- Faculty of Biological Sciences, Department of Biochemistry, Quaid-i-Azam University, Islamabad Pakistan
| | - Azra Jahan
- Department of Zoology, Abdul Wali Khan University, Mardan Pakistan
| | - Abid Ali
- Laboratory of Germplasm Innovation and Molecular Breeding, Department of Vegetable Sciences, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou China
| | - Hamid Ali
- Department of Biosciences, COMSATS Institute of Information Technology, IslamabadPakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, KarachiPakistan
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Hepatoprotective Effects of Nicotiflorin from Nymphaea candida against Concanavalin A-Induced and D-Galactosamine-Induced Liver Injury in Mice. Int J Mol Sci 2017; 18:ijms18030587. [PMID: 28282879 PMCID: PMC5372603 DOI: 10.3390/ijms18030587] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 03/02/2017] [Indexed: 12/18/2022] Open
Abstract
Nymphaea candida was used to treat hepatitis in Ugyhur medicine, and nicotiflorin (kaempferol 3-O-β-rutinoside) is the main characteristic component in this plant. In this study, The the hepatoprotective activities of nicotiflorin from N. candida were investigated by Concanavalin A (Con A, 20 mg/kg bw)- and d-Galactosamine (d-GalN, 800 mg/kg bw)-induced acute liver injury in mice. Pretreatment with nicotiflorin (25, 50, 100 mg/kg bw/day, p.o.) for ten days significantly reduced the impact of Con A toxicity (20 mg/kg bw) on the serum markers of liver injury, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The hepatic anti-oxidant parameters (malondialdehyde, MDA; superoxide dismutase, SOD; glutathione, GSH; and nitric oxide, NO) in mice with nicotiflorin treatment were significantly antagonized for the pro-oxidant effects of Con A. Moreover, pretreatment with nicotiflorin (100 mg/kg bw) significantly decreased Con A-induced elevation in the serum levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) (p < 0.05). A protective effect was reconfirmed against d-GalN-induced chemical liver injury, elevated serum enzymatic and cytokines levels were significantly decreased by nicotiflorin, and liver homogenate antioxidant indicators were significantly restored toward normal levels. Both histopathological studies also supported the protective effects of nicotiflorin. Therefore, the presented results suggest that nicotiflorin is the potent hepatoprotective agent that could protect the liver against acute immunological and chemical injury; this ability might be attributed to its antioxidant and immunoregulation potential.
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Diphenhydramine as a Cause of Drug-Induced Liver Injury. Case Reports Hepatol 2017; 2017:3864236. [PMID: 28246565 PMCID: PMC5299161 DOI: 10.1155/2017/3864236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/10/2017] [Indexed: 01/13/2023] Open
Abstract
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E), autoimmune, toxic, ischemic, and metabolic etiologies including Wilson's disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.
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Ali H, Kabir N, Shah MR, Muhammad A, Ali S, Mehmood S, Ali A, Ali A, Jahan A. Hepatoprotective activity of viscosine is mediated by attenuation of hepatic macrophages and iNOS expression in CCl 4-intoxicated rats. Toxicol Res (Camb) 2016; 5:1688-1698. [PMID: 30090468 DOI: 10.1039/c6tx00165c] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
This study investigated the molecular mechanism(s) of the protective effects of a C-alkylated flavonoid, viscosine on an animal model of CCl4-induced hepatotoxicity. Viscosine at 20, 50 and 100 mg kg-1 was orally administered in a dose dependent manner per day for 3 days before the CCl4 (1 : 1 v/v in olive oil, 1 ml kg-1) treatment and 2 days after the treatment. Hepatoprotection was assessed in terms of reduction in serum enzyme activities (ALT, AST, and ALP) that occur after CCl4 injury, and by histopathology and immunohistochemistry. The rise in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in CCl4-intoxicated rats was markedly suppressed by viscosine in a concentration dependent manner. The decrease in the activity of hepatic antioxidant enzyme, SOD, was significantly prevented by viscosine, likewise gradually the levels of MDA and GSH were also normalized compared to silymarin. Viscosine also reduced the CCl4-induced damaged area from 2% to 0% as assessed by histopathology and prevented the mixed inflammatory infiltrate. Viscosine attenuated the inflammation in the liver around the injured central vein region by downregulating the CCl4 induced activation of hepatic CD68+ macrophages, thereby reducing their number as well. The expression of inducible nitric oxide synthase (iNOS) was more potentially suppressed by viscosine compared to the FDA approved positive control silymarin. The results of this study indicate that viscosine could be effective in protecting the liver from acute CCl4-induced injury. The hepatoprotective mechanisms of viscosine may be related to the free radical scavenging and attenuation of oxidative stress, as well as to the inhibition of inflammatory response in the liver. Here, we are proposing a novel mechanism of action of viscosine and suggesting that it may be a safe and better in vivo antioxidant.
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Affiliation(s)
- Hamid Ali
- Department of Biosciences , COMSATS Institute of Information Technology , Park road , Chack Shehzad , Islamabad-44000 , Pakistan . ; ; ; Tel: +3329408516 ; Tel: +(03) 7967-4213.,Dr. Panjwani Center for Molecular Medicine and Drug Research , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Nurul Kabir
- Institute of Biological Sciences , Faculty of Science , University of Malaya , 50603 Kuala Lumpur , Malaysia
| | - Muhammad Raza Shah
- HEJ , Research Institute of Chemistry , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Akhtar Muhammad
- Department of Chemistry , Faculty of Sciences , Mugla Sitki Kocman University , Kotekli-48121 , Mugla , Turkey.,HEJ , Research Institute of Chemistry , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Safdar Ali
- Pakistan Institute of Engineering and Applied Sciences , Nilore , 45650 , Islamabad , Pakistan
| | - Shahab Mehmood
- Department of Biosciences , Shaheed Zulfikar Ali Bhutto Institute of Science and Technology , Karachi-75600 , Pakistan
| | - Amjad Ali
- Department of Biochemistry , Quaid-e-azam University , Islamabad , Pakistan
| | - Abid Ali
- Laboratory of Germplasm and Molecular Genetics , Department of Vegetable Sciences , College of Agriculture and Biotechnology , Zhejiang University , Hangzhou 310029 , PR-China
| | - Azra Jahan
- Department of Zoology , Hazara University , Mansehra , Khyber Pakhtunkhwa , Pakistan
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El-Hosseiny LS, Alqurashy NN, Sheweita SA. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats. INTERNATIONAL JOURNAL OF BIOMEDICAL SCIENCE : IJBS 2016; 12:71-8. [PMID: 27493593 PMCID: PMC4947092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 06/12/2016] [Indexed: 11/06/2022]
Abstract
Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.
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Affiliation(s)
- L S El-Hosseiny
- Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Egypt
| | - N N Alqurashy
- Department of Biology, College of Science, Wasit University, Iraq
| | - S A Sheweita
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, 163 El Horreya Avenue, P.O. box 832 El-Shatby, Alexandria 21526, Egypt
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Qiu W, Lv GY, Jiang C, Zhang P, Sun XD, Shi XJ, Liu XY, Wang GY. Successful salvage treatment of acute graft-versus-host disease after liver transplantation by withdrawal of immunosuppression: a case report. KOREAN JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2016; 20:38-43. [PMID: 26925149 PMCID: PMC4767263 DOI: 10.14701/kjhbps.2016.20.1.38] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 11/24/2015] [Accepted: 11/30/2015] [Indexed: 11/17/2022]
Abstract
Acute graft-versus-host disease (GVHD) following liver transplantation is a rare but fatal complication. The correct diagnosis and management of GVHD after liver transplantation are still major challenges. Herein, we reported successful salvage treatment of acute GVHD by withdrawal of immunosuppression in a patient who presented with fever, skin rashes, and decreased blood cell counts after liver transplantation. This case highlights the need for awareness of drug-induced liver injury if liver function tests are elevated during treatment, especially in patients taking multiple potentially hepatotoxic drugs, such as broad-spectrum antibiotics. When occurs, an artificial liver support system is a useful tool to provide temporary support of liver function for the patient in the event of drug-induced liver injury.
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Affiliation(s)
- Wei Qiu
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Guo-Yue Lv
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Chao Jiang
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Ping Zhang
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Xiao-Dong Sun
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Xiao-Ju Shi
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Xue-Yan Liu
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Guang-Yi Wang
- Department of Hepato-biliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
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Abstract
Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin-clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.
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Affiliation(s)
- Anna Licata
- Sezione di Gastroenterologia & Epatologia, Dipartimento di Medicina Interna e Specialistica, DiBiMIS, Università di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
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