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Ismail NZ, Khairuddean M, Abubakar S, Arsad H. Network pharmacology, molecular docking and molecular dynamics simulation of chalcone scaffold-based compounds targeting breast cancer receptors. J Biomol Struct Dyn 2025; 43:3242-3257. [PMID: 38149857 DOI: 10.1080/07391102.2023.2296606] [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: 08/01/2023] [Accepted: 12/12/2023] [Indexed: 12/28/2023]
Abstract
Compounds with a chalcone scaffold-based structure have demonstrated promising anticancer biological activity. However, the molecular interactions between chalcone scaffold-based compounds and breast cancer-associated proteins remain unclear. Through network pharmacology, molecular docking, and molecular dynamics (MD) simulation analyses, compounds with a chalcone scaffold-based structure were evaluated for their interaction with potential breast cancer targets. The compounds were retrieved from the ASINEX database, resulting in 575,302 compounds. A total of 342 compounds with chalcone scaffold-based structures were discovered. From the 342 compounds that was analysed, ten were chosen due to their adherence to Lipinski's rule, having an appropriate range of lipophilicity (LOGP), and topological polar surface area (TPSA), and absence of any toxicity. Based on target intersection, 50 target genes were found and subjected to protein-protein interaction (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Four target genes were found to be involved in the breast cancer pathway. Consequently, molecular docking was utilised to analyse the molecular interactions between the compounds and four target protein receptors. Compound 211 exhibited the highest binding affinities for the epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), oestrogen receptor (ESR1), and cyclin dependent kinase 6 (CDK6) with values of -8.95 kcal/mol, -8.60 kcal/mol, -10.33 kcal/mol, and -9.90 kcal/mol, respectively. During MD simulation, compound 211 and its respective proteins were stable, compact, and had minimal flexibility. The findings provide foundations for future studies into the interaction underlying the anti-breast cancer potential of compounds with chalcone-based scaffold structures.
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Affiliation(s)
| | - Melati Khairuddean
- School of Chemical Sciences, Universiti Sains Malaysia, Penang, Malaysia
| | - Sadiq Abubakar
- School of Chemical Sciences, Universiti Sains Malaysia, Penang, Malaysia
- Department of Pure and Industrial Chemistry, Bayero University Kano, Kano, Nigeria
| | - Hasni Arsad
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
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Pakhomova IG. Metabolic dysfunction-associated steatotic liver disease and drug-induced injuries: Pathogenetic aspects, treatment and prevention. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:70-78. [DOI: 10.21518/ms2024-343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Metabolic-associated fatty liver disease or metabolic dysfunction-associated steatotic liver disease is a common chronic disease characterized by increased fat accumulation in the liver and underlying metabolic dysfunction. In the occurrence of this disease, cardiometabolic factors are important: dyslipidemia, impaired carbohydrate metabolism, insulin resistance, which increase as metabolic dysfunction- associated steatotic liver progresses and most often contribute to the development of cardiovascular pathology. Currently, metabolic dysfunction-associated steatotic liver is a multisystem disease associated with obesity, type 2 diabetes, cardiovascular diseases, chronic kidney disease, oncology, etc. Metabolic dysfunction- associated steatotic liver most often affects comorbid patients who take a considerable number of medications. Over the past decades, many drugs have been identified that have the potential to cause steatohepatitis in susceptible individuals. The range of drugs that have hepatotoxicity is quite large. More than 300 drugs are known to cause drug-induced liver injury. However, the true prevalence of drug-induced liver injury remains unknown, since it is not always possible to determine the true cause of liver damage or a specific drug. In this regard, the issue of management tactics for patients with metabolic dysfunction-associated steatotic liver and drug-induced liver injury remains relevant, especially when it comes to the need to take medications that are vital for the patient. The article provides a review of the literature on the etiopathogenetic, clinical and diagnostic aspects of both metabolic dysfunction-associated steatotic liver and in combination with drug-induced liver injury, features of the management of comorbid patients with metabolic dysfunction-associated steatotic liver and drug-induced liver injury. Therapeutic approaches are reviewed with an emphasis on comprehensive management (non-pharmacological and pharmacotherapy). Prescribing essential phospholipids may be effective in the treatment of such patients.
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Huang CY, You YS, Lai JM, Lin CL, Hsu HY, Hsieh YW. The Association Between Antidepressant Use and Drug-Induced Liver Injury: A Nationwide, Population-Based Case-Control Study in Taiwan. Drugs Real World Outcomes 2024; 11:513-520. [PMID: 38837010 PMCID: PMC11365879 DOI: 10.1007/s40801-024-00419-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND AND OBJECTIVE The complex risk factors of liver injury have prevented the establishment of causal relationships. This study aimed to explore the effects of antidepressant class, cumulative days of medication exposure, presence of comorbidities, and the use of confounding drugs on the risk of antidepressant-induced liver injury. METHODS The population-based case-control study sample included individuals registered on the Taiwan National Health Insurance Database between 2000 and 2018. Hospitalized patients with suspected drug-induced liver injury were considered as cases, while control subjects were matched 1:1 by age, gender, and index date (the first observed diagnosis of liver injury). Multivariable regression models were performed to evaluate the association between antidepressants and liver injury. RESULTS The findings showed that antidepressant users exhibited a higher risk of liver injury (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.12-1.20), particularly those prescribed non-selective serotonin reuptake inhibitors (NSRIs; aOR 1.05; 95% CI 1.01-1.10), selective serotonin reuptake inhibitors (SSRIs; aOR 1.22; 95% CI 1.16-1.29), serotonin-norepinephrine reuptake inhibitors (SNRIs; aOR 1.18; 95% CI 1.13-1.24), and others (aOR 1.27; 95% CI 1.14-1.42). Moreover, cases exhibited a more significant proportion of antidepressant usage and longer durations of treatment compared with controls. The risk of liver injury was higher in the first 30 days of use across all classes of antidepressants (aOR 1.24; 95% CI 1.18-1.29). CONCLUSION SSRIs or SNRIs are commonly used to treat depression and other psychological disorders, and consideration of their potential effects on the liver is essential.
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Affiliation(s)
- Ching-Ya Huang
- Department of Pharmacy, Asia University Hospital, Taichung, Taiwan
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Ying-Shu You
- Department of Pharmacy, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404327, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Jian-Ming Lai
- Department of Pharmacy, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404327, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Hsing-Yu Hsu
- Department of Pharmacy, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404327, Taiwan
| | - Yow-Wen Hsieh
- School of Pharmacy, China Medical University, Taichung, Taiwan.
- Department of Pharmacy, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404327, Taiwan.
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Makunts T, Abagyan R. Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System. Front Psychiatry 2024; 15:1414622. [PMID: 38957734 PMCID: PMC11217510 DOI: 10.3389/fpsyt.2024.1414622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/29/2024] [Indexed: 07/04/2024] Open
Abstract
3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.
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Affiliation(s)
| | - Ruben Abagyan
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
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Khalil SM, MacKenzie KR, Maletic-Savatic M, Li F. Metabolic bioactivation of antidepressants: advance and underlying hepatotoxicity. Drug Metab Rev 2024; 56:97-126. [PMID: 38311829 PMCID: PMC11118075 DOI: 10.1080/03602532.2024.2313967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/30/2024] [Indexed: 02/06/2024]
Abstract
Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which toxicity is induced may be difficult to determine, identifying reactive metabolites that cause toxicity can offer valuable insights for decreasing the bioactivation potential of candidates during the drug discovery process. A comprehensive understanding of drug metabolic pathways can mitigate adverse drug-drug interactions that may be caused by elevated formation of reactive metabolites. This review provides a comprehensive overview of the current state of knowledge on antidepressant bioactivation, the metabolizing enzymes responsible for the formation of reactive metabolites, and their potential implication in hepatotoxicity. This information can be a valuable resource for medicinal chemists, toxicologists, and clinicians engaged in the fields of antidepressant development, toxicity, and depression treatment.
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Affiliation(s)
- Saleh M. Khalil
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kevin R. MacKenzie
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- NMR and Drug Metabolism Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mirjana Maletic-Savatic
- Department of Pediatrics, Baylor College of Medicine; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Feng Li
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- NMR and Drug Metabolism Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [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: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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Purwar S, Fatima A, Bhattacharyya H, Simhachalam Kutikuppala LV, Cozma MA, Srichawla BS, Komer L, Nurani KM, Găman MA. Toxicity of targeted anticancer treatments on the liver in myeloproliferative neoplasms. World J Hepatol 2023; 15:1021-1032. [PMID: 37900211 PMCID: PMC10600697 DOI: 10.4254/wjh.v15.i9.1021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/06/2023] [Accepted: 08/18/2023] [Indexed: 09/22/2023] Open
Abstract
The liver has a central role in metabolism, therefore, it is susceptible to harmful effects of ingested medications (drugs, herbs, and nutritional supplements). Drug-induced liver injury (DILI) comprises a range of unexpected reactions that occur after exposure to various classes of medication. Even though most cases consist of mild, temporary elevations in liver enzyme markers, DILI can also manifest as acute liver failure in some patients and can be associated with mortality. Herein, we briefly review available data on DILI induced by targeted anticancer agents in managing classical myeloproliferative neoplasms: Chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and myelofibrosis.
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Affiliation(s)
- Shubhrat Purwar
- Department of Internal Medicine, Grant Government Medical College, Mumbai 400008, Maharashtra, India
| | - Anam Fatima
- Department of Internal Medicine, Pandit Jawaharlal Nehru Memorial Medical College, Raipur 492001, Chhattisgarh, India
| | | | | | - Matei-Alexandru Cozma
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology, Colentina Clinical Hospital, Bucharest 020125, Romania
| | - Bahadar Singh Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Leah Komer
- Department of Psychiatry, University of Toronto, Toronto M5G 1V7, Ontario, Canada
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania.
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Ma ZT, Shi Z, Xiao XH, Wang JB. New Insights into Herb-Induced Liver Injury. Antioxid Redox Signal 2023; 38:1138-1149. [PMID: 36401515 PMCID: PMC10259609 DOI: 10.1089/ars.2022.0134] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 11/21/2022]
Abstract
Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.
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Affiliation(s)
- Zhi-Tao Ma
- Department of Pharmaceutics of Chinese Materia Medica, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zhuo Shi
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-He Xiao
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jia-Bo Wang
- Department of Pharmaceutics of Chinese Materia Medica, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Steger-Hartmann T, Kreuchwig A, Wang K, Birzele F, Draganov D, Gaudio S, Rothfuss A. Perspectives of data science in preclinical safety assessment. Drug Discov Today 2023:103642. [PMID: 37244565 DOI: 10.1016/j.drudis.2023.103642] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 05/29/2023]
Abstract
The data landscape in preclinical safety assessment is fundamentally changing because of not only emerging new data types, such as human systems biology, or real-world data (RWD) from clinical trials, but also technological advancements in data-processing software and analytical tools based on deep learning approaches. The recent developments of data science are illustrated with use cases for the three factors: predictive safety (new in silico tools), insight generation (new data for outstanding questions); and reverse translation (extrapolating from clinical experience to resolve preclinical questions). Further advances in this field can be expected if companies focus on overcoming identified challenges related to a lack of platforms and data silos and assuring appropriate training of data scientists within the preclinical safety teams.
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Affiliation(s)
| | - Annika Kreuchwig
- Investigational Toxicology, Bayer AG, Pharmaceuticals, 13353 Berlin, Germany
| | - Ken Wang
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences F. Hoffmann-La-Roche AG, Basel, Switzerland
| | - Fabian Birzele
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences F. Hoffmann-La-Roche AG, Basel, Switzerland
| | - Dragomir Draganov
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences F. Hoffmann-La-Roche AG, Basel, Switzerland
| | - Stefano Gaudio
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences F. Hoffmann-La-Roche AG, Basel, Switzerland
| | - Andreas Rothfuss
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences F. Hoffmann-La-Roche AG, Basel, Switzerland
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Gupta V, Panigrahi B, De S, Nariya MB. Evaluation of the anti-arthritic activity of Rhuflex-F - A proprietary Ayurvedic herbomineral formulation in albino rats. Ayu 2023; 44:30-37. [PMID: 38505109 PMCID: PMC10946666 DOI: 10.4103/ayu.ayu_327_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/31/2023] [Accepted: 12/28/2023] [Indexed: 03/21/2024] Open
Abstract
Background Rhuflex-F is a proprietary Ayurvedic herbo-mineral formulation clinically used to combat and relieve stiffness in joints and muscles, reduce edema, restore mobility, and also effective in relieving the symptoms of other autoimmune illnesses that lead to rheumatism. Aims The aim and objective of the research study is to evaluate the efficacy of Rhuflex-F against in vitro protein denaturation and in vivo Freund's adjuvant-induced arthritis in albino rats. Materials and methods In vitro inhibition of protein denaturation activity was carried out using bovine serum albumin. For in vivo activity, arthritis was induced by complete Freund's adjuvant in albino rats. Rhuflex-F (135-270 mg/kg, po) was administered for 30th days in arthritic rats, and effects were assessed on primary and secondary paw edema, on pain response, hematological, serum biochemical parameters (serum transaminases, alkaline phosphatase, urea, uric acid, and orosomucoid), and serum anti-oxidant parameters and adrenal ascorbic acid. Results Aqueous extract of Rhuflex-F showed in vitro protein denaturation inhibitory activity in a dose-dependent manner. Rhuflex-F showed nonsignificant decrease in primary and secondary paw edema with reduced pain response, some reversal effects on hematological parameters such as white blood cell and red blood cell related parameters and serum orosomucoid and adrenal ascorbic acid in comparison to Fruend's adjuvant control group. Further, Rhuflex-F reversed Freund's adjuvant-induced adverse effects on oxidant status in the serum of albino rats. Conclusion Result of the present study suggested that Rhuflex-F formulation has anti-inflammatory activity, may be due to the inhibition of protein denaturation in vitro and in vivo anti-arthritic activity against complete Freund's adjuvant-induced arthritis in albino rats.
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Affiliation(s)
- Veerendra Gupta
- Department of Pharmacology, Institute of Teaching and Research in Ayurveda, Jamnagar, Gujarat, India
| | - Balaji Panigrahi
- Department of Pharmacology, Institute of Teaching and Research in Ayurveda, Jamnagar, Gujarat, India
| | - Subrata De
- Zoetic Ayurvedics Pvt., Ltd., Ahmedabad, Gujarat, India
| | - Mukeshkumar B. Nariya
- Department of Pharmacology, Institute of Teaching and Research in Ayurveda, Jamnagar, Gujarat, India
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Shen C, Liang D, Wang X, Shao W, Geng K, Wang X, Sun H, Xie H. Predictive performance and verification of physiologically based pharmacokinetic model of propylthiouracil. Front Pharmacol 2022; 13:1013432. [PMID: 36278167 PMCID: PMC9579312 DOI: 10.3389/fphar.2022.1013432] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations.Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations.Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations.Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments.Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.
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Affiliation(s)
- Chaozhuang Shen
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Dahu Liang
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Xiaohu Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Wenxin Shao
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Kuo Geng
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Xingwen Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Hua Sun
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Haitang Xie
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
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Hashmat Z, Channa IS, Safdar M, Ozaslan M, Saeed M, Siddique F, Junejo Y. Adrenergic blocker terazosin potentially suppresses acetaminophen induced-acute liver injury in animal models via CYP2E1 gene. Toxicol Res 2022; 38:323-330. [PMID: 35874506 PMCID: PMC9247125 DOI: 10.1007/s43188-021-00116-y] [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: 04/19/2021] [Revised: 11/17/2021] [Accepted: 11/20/2021] [Indexed: 10/19/2022] Open
Abstract
Drug induced liver injury (DILI) is a global issue and acetaminophen (APAP) is considered as the main cause of this. Due to increasing incidents of DILI, current study attempted to investigate an alternative but better role of terazosin (alpha-adrenergic blocker) in APAP-induced acute liver injury in an animal model using New Zealand rabbits. APAP (1 g/kg of body weight) was given to New Zealand rabbits either with or without terazosin (0.5 mg/kg) and serum was collected after 4 h. Serum alanine transaminase (ALT), alkaline phosphatase (ALP) and ferritin level were determined to analyze the liver functioning of treated rabbits. Furthermore, total cholesterol (TC), total lipids (TL), high-density lipoproteins (HDL), low-density lipoprotein (LDL) and triglycerides (TG) levels were estimated to find any change in lipid profile of the treated animals. Moreover, the urea and creatinine levels assayed the actual renal functionality. To identify any modification in gene expression, qPCR of cytochrome P2E1 (CYP2E1) was performed. Terazosin in combination with APAP enhanced liver functioning by reducing the levels of liver injury markers viz. ALP and ALT, while lipid profile was also lowered by down regulation of TC, TL, LDL and TG with enhanced HDL levels. It caused significant down regulation of expression level of CYP2E1. It is concluded that terazosin has better effects induced on the recovery of normal liver functioning, by improving the liver profile, lipid profile and renal functioning both at tissue and molecular levels.
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Affiliation(s)
- Zoya Hashmat
- Department of Molecular Biology, Virtual University of Pakistan, Karachi, Pakistan
| | - Iffat Saeed Channa
- Department of Molecular Biology, Virtual University of Pakistan, Karachi, Pakistan
- Health Education Officer, Shaheed Benazirabad, Government of Sindh, Nawabshah, Sindh, Pakistan
| | - Muhammad Safdar
- Division of Molecular Biology and Genetics, Deparment of Biology, Gaziantep University, Gaziantep, 27000 Turkey
- Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100 Pakistan
| | - Mehmet Ozaslan
- Division of Molecular Biology and Genetics, Deparment of Biology, Gaziantep University, Gaziantep, 27000 Turkey
| | - Muhammad Saeed
- Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100 Pakistan
| | - Faisal Siddique
- Derpartment of Microbiology, Cholistan University of Veterinary & Animal Sciences, Bahawalpur, 63100 Pakistan
| | - Yasmeen Junejo
- Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100 Pakistan
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13
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Averbukh LD, Turshudzhyan A, Wu DC, Wu GY. Statin-induced Liver Injury Patterns: A Clinical Review. J Clin Transl Hepatol 2022; 10:543-552. [PMID: 35836753 PMCID: PMC9240239 DOI: 10.14218/jcth.2021.00271] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/09/2021] [Accepted: 11/08/2021] [Indexed: 12/04/2022] Open
Abstract
Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.
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Affiliation(s)
- Leon D. Averbukh
- Department of Medicine, Division of Gastroenterology-Hepatology, Allegheny Health Network, Pittsburgh, PA, USA
- Correspondence to: Leon D. Averbukh, Allegheny Health Network, 320 East North Avenue, 7th Floor, South Tower, Pittsburgh, PA 15212, USA. ORCID: https://orcid.org/0000-0002-7739-7689. Tel: +1-412-359-3846, Fax: +1-412-442-2139, E-mail:
| | - Alla Turshudzhyan
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - David C. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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14
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Sohal A, Alhankawi D, Sandhu S, Chintanaboina J. Turmeric-Induced Hepatotoxicity: Report of 2 Cases. Int Med Case Rep J 2021; 14:849-852. [PMID: 34992472 PMCID: PMC8711139 DOI: 10.2147/imcrj.s333342] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 12/08/2021] [Indexed: 12/29/2022] Open
Abstract
The use of herbal and dietary supplements is rising in the United States. Turmeric has been one of the most popular supplements recently, used widely for various conditions such as arthritis, digestive disorder, and liver conditions. Although rarely reported, hepatotoxicity can happen with turmeric use. Here, we present 2 cases of drug-induced liver injury due to turmeric use with the complete resolution after cessation.
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Affiliation(s)
- Aalam Sohal
- Department of Internal Medicine, UCSF Fresno, Fresno, CA, USA
| | - Dhuha Alhankawi
- Department of Gastroenterology and Hepatology, UCSF Fresno, Fresno, CA, USA
| | - Sunny Sandhu
- Department of Internal Medicine, UCSF Fresno, Fresno, CA, USA
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15
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Pata R, Dolkar T, Patel M, Nway N. Voriconazole-Induced Acute Liver Injury: A Case Report. Cureus 2021; 13:e20115. [PMID: 35003960 PMCID: PMC8723725 DOI: 10.7759/cureus.20115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2021] [Indexed: 11/05/2022] Open
Abstract
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Clinical presentation of drug-induced liver injury may vary from asymptomatic or subtle symptoms to encephalopathy with serious morbidity. Early discontinuation of the offending agent is important to prevent clinical deterioration. Occasionally, despite discontinuation, there may be worsening of liver failure with grim prognosis as we present in this case report. Here, we report a case of a 61-year-old lady with a past medical history of sarcoidosis, stage IV and severe pulmonary hypertension initially admitted for the management of COVID pneumonia. Her hospitalization was complicated by fungemia with Aspergillus for which voriconazole was initiated, and two weeks into the course, acute liver injury diagnosed was most probably related to voriconazole. Despite discontinuation, her condition deteriorated, eventually culminating in mortality.
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16
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17
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Li J, Zhang J, Xu X, Fang W, Qu S, Jin F, Zhou J, Han X, Raza HK, Li X, Mao Y. Hugan tablets for the treatment of RUCAM based drug-induced liver injury: a propensity score matching analysis using a nationwide database. Expert Rev Clin Pharmacol 2021; 14:1543-1550. [PMID: 34521298 DOI: 10.1080/17512433.2021.1981859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a major clinical challenge with no specific therapeutic drugs available. It is crucial to develop new agents to improve the clinical outcome of patients with DILI. This study evaluated the efficacy and safety of Hugan tablets in DILI patients using a nationwide database. RESEARCH DESIGN AND METHODS We analyzed the clinical data of DILI patients from a nationwide DILI database (www.hepatox.org). Patients who received oral Hugan tablets for DILI were defined as the Hugan group, and those who received no treatment for DILI were defined as the control group. RESULTS There were 111 cases in the Hugan group and 512 cases in the control group. One-to-one propensity score matching created 111 matched pairs. The normalization rates of alanine aminotransferase and aspartate aminotransferase in the Hugan group were significantly higher than those in the control group (50.45% vs. 26.13%, p ≤ .0002 and 67.57% vs. 41.75%, p ≤ .0001). There were no differences in the incidence of renal function impairment or blood abnormality between the two groups. CONCLUSIONS Hugan tablets are safe and effective in DILI treatment. Large-scale randomized controlled studies are needed to explore the effects of Hugan tablets on DILI induced by different offending drugs. TRIAL REGISTRATION The study protocol was posted on ClinicalTrials.gov with NCT number: NCT02407964.
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Affiliation(s)
- Jing Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianzhong Zhang
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Xiaorong Xu
- Department of Hepatology, Bozhou Huatuo Hospital of Traditional Chinese Medicine, Bozhou, China
| | - Weidong Fang
- Department of Infectious Diseases, Huangshan City People's Hospital, Huangshan, China
| | - Shilin Qu
- Department of Tuberculosis, Jingzhou Chest Hospital, Jingzhou, China
| | - Feng Jin
- Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, China
| | - Jie Zhou
- Department of Extrapulmonary Tuberculosis, Tianjin Tuberculosis Control Center, Tianjin, China
| | - Xian Han
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Hafiz Khuram Raza
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Xiaoyun Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yimin Mao
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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18
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Sernoskie SC, Jee A, Uetrecht JP. The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions. Pharmacol Rev 2021; 73:861-896. [PMID: 34016669 DOI: 10.1124/pharmrev.120.000090] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Idiosyncratic drug reactions (IDRs) range from relatively common, mild reactions to rarer, potentially life-threatening adverse effects that pose significant risks to both human health and successful drug discovery. Most frequently, IDRs target the liver, skin, and blood or bone marrow. Clinical data indicate that most IDRs are mediated by an adaptive immune response against drug-modified proteins, formed when chemically reactive species of a drug bind to self-proteins, making them appear foreign to the immune system. Although much emphasis has been placed on characterizing the clinical presentation of IDRs and noting implicated drugs, limited research has focused on the mechanisms preceding the manifestations of these severe responses. Therefore, we propose that to address the knowledge gap between drug administration and onset of a severe IDR, more research is required to understand IDR-initiating mechanisms; namely, the role of the innate immune response. In this review, we outline the immune processes involved from neoantigen formation to the result of the formation of the immunologic synapse and suggest that this framework be applied to IDR research. Using four drugs associated with severe IDRs as examples (amoxicillin, amodiaquine, clozapine, and nevirapine), we also summarize clinical and animal model data that are supportive of an early innate immune response. Finally, we discuss how understanding the early steps in innate immune activation in the development of an adaptive IDR will be fundamental in risk assessment during drug development. SIGNIFICANCE STATEMENT: Although there is some understanding that certain adaptive immune mechanisms are involved in the development of idiosyncratic drug reactions, the early phase of these immune responses remains largely uncharacterized. The presented framework refocuses the investigation of IDR pathogenesis from severe clinical manifestations to the initiating innate immune mechanisms that, in contrast, may be quite mild or clinically silent. A comprehensive understanding of these early influences on IDR onset is crucial for accurate risk prediction, IDR prevention, and therapeutic intervention.
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Affiliation(s)
- Samantha Christine Sernoskie
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
| | - Alison Jee
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
| | - Jack Paul Uetrecht
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.)
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19
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Panahi L, Surani SS, Udeani G, Patel NP, Sellers J. Hepatotoxicity Secondary to Levofloxacin Use. Cureus 2021; 13:e15973. [PMID: 34336465 PMCID: PMC8317250 DOI: 10.7759/cureus.15973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2021] [Indexed: 01/04/2023] Open
Abstract
Levofloxacin is a broad-spectrum antibiotic that is used in the treatment of many infections. A rare adverse drug reaction following the use of levofloxacin is drug-induced liver injury. The exact mechanism behind fluoroquinolone-induced liver injury is unknown, but many severe, sometimes fatal hepatotoxicity cases are reported. Current recommendations advise clinicians to discontinue levofloxacin immediately if the patient develops signs and symptoms of hepatitis. This case report presents a 79-year-old male who was prescribed levofloxacin 500 mg by mouth daily for seven days. The patient had a past medical history of dementia, seizures, cerebral vascular accident, pulmonary fibrosis, and chronic kidney disease. Upon admission, the patient began to show signs and symptoms of liver injury. We hereby present a case report and a review of significant literature on levofloxacin-induced liver injury.
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Affiliation(s)
- Ladan Panahi
- College of Pharmacy, Texas Agricultural and Mechanical University, Kingsville, USA
| | - Salim Surani Surani
- College of Medicine, Texas Agricultural and Mechanical University, College Station, USA.,College of Pharmacy, Texas Agricultural and Mechanical University, Kingsville, USA.,Section of Pulmonary - Critical Care & Fellowship Program, Corpus Christi Medical Center, Corpus Christi, USA
| | - George Udeani
- College of Pharmacy, Texas Agricultural and Mechanical University, Kingsville, USA
| | - Niraj P Patel
- College of Pharmacy, Texas Agricultural and Mechanical University, Kingsville, USA
| | - Jacob Sellers
- College of Pharmacy, Texas Agricultural and Mechanical University, Kingsville, USA
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20
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The potential effect of phytochemicals and herbal plant remedies for treating drug-induced hepatotoxicity: a review. Mol Biol Rep 2021; 48:4767-4788. [PMID: 34075538 DOI: 10.1007/s11033-021-06444-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/27/2021] [Indexed: 02/08/2023]
Abstract
Drug-induced liver injury significantly caused by synthetic drugs, and other xenobiotics contribute to clinical hepatic dysfunction, which has been a substantial challenge for both patients and physicians. Traditional medicines used as an alternative therapy because of their pharmacological benefits, less or no side effects, and enormous availability in nature. Phytochemicals are essential ingredients of plants that reduce necrotic cell death, restore the antioxidant defence mechanism, limit oxidative stress, and prevent the inflammation of tissue and dysfunction of the mitochondria. In this review, we principally focused on the potential effect of the herbal plants and their phytochemicals in treating drug-induced hepatotoxicity.
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21
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Dobreva I, Karagyozov P. Drug-induced Bile Duct Injury - A Short Review. Curr Drug Metab 2021; 21:256-259. [PMID: 32310045 DOI: 10.2174/1389200221666200420100129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/03/2020] [Accepted: 01/29/2020] [Indexed: 01/23/2023]
Abstract
The liver represents the major site of drug metabolism, i.e. the key organ in the processes of detoxification and elimination of drugs from the organism. It is therefore often affected by toxic metabolites and suffers sometimes fatal consequences. The spectrum of pathologies differs by the cell type primarily damaged and the group of the cholangiopathies includes those conditions affecting the bile duct epithelium or the cholangiocytes. They can range from transient cholestasis to vanishing bile duct syndrome and sclerosing cholangitis, both leading eventually to the development of biliary fibrosis and cirrhosis. In this review article, we focus on the etiology, predisposing factors, clinical manifestations, and histopathological characteristics of bile duct injury as a consequence of drug treatment and discuss separately the different bile duct pathologies.
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Affiliation(s)
- Inna Dobreva
- Interventional Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria
| | - Petko Karagyozov
- Interventional Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria
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22
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Bakhati B, Sibi VM, Mekala AP, Ronen JA, Mungara S. What Is Uncommon Can Be Critical: A Case of Quinolone-Induced Acute Liver Failure. Cureus 2021; 13:e14780. [PMID: 34094745 PMCID: PMC8169093 DOI: 10.7759/cureus.14780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Many drugs are known to potentially cause liver injury; however, only a few reports investigate the association between levofloxacin and acute liver failure (ALF). The case describes a 65-year-old man who was admitted with primary diagnoses of cerebrovascular accident (CVA) and acute coronary syndrome (ACS) who developed an upper respiratory tract infection for which he was started on levofloxacin. Following its administration, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased more than 100-fold above the upper limit of normal. Over the next 24 hours, AST peaked at 9334 U/L, ALT at 4525 U/L, prothrombin time to 24.6 seconds, international normalized ratio (INR) to 2.22, and serum ammonia to 157 µmol/L. The patient developed signs and symptoms of decompensated liver disease, namely hepatic encephalopathy (HE). Levofloxacin was discontinued immediately, and evidence-based treatment per society guidelines from The American Association for the Study of Liver Diseases consisting of IV n-acetylcysteine as well as lactulose and rifaximin was initiated. Such medical management resulted in clinical resolution of his ALF, but he had a poor overall prognosis and eventually succumbed to critical illness.
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Affiliation(s)
- Bibek Bakhati
- Internal Medicine, Texas Tech University Health Sciences Center School of Medicine at the Permian Basin, Odessa, USA
| | - Victoria M Sibi
- Medicine, North-Western State Medical University, St. Petersburg, RUS
| | - Armugam P Mekala
- Internal Medicine, Texas Tech University Health Sciences Center School of Medicine at the Permian Basin, Odessa, USA
| | - Joshua A Ronen
- Internal Medicine, Texas Tech University Health Sciences Center School of Medicine at the Permian Basin, Odessa, USA
| | - Sai Mungara
- Internal Medicine, Texas Tech University Health Sciences Center School of Medicine at the Permian Basin, Odessa, USA
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23
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Qin N, Xu G, Wang Y, Zhan X, Gao Y, Wang Z, Fu S, Shi W, Hou X, Wang C, Li R, Liu Y, Wang J, Zhao H, Xiao X, Bai Z. Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity. Front Med 2021; 15:594-607. [PMID: 33909257 DOI: 10.1007/s11684-020-0809-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 06/03/2020] [Indexed: 12/31/2022]
Abstract
Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.
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Affiliation(s)
- Nan Qin
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.,Department of Pharmacy, Nantong Hospital of Traditional Chinese Medicine, Nantong, 226300, China
| | - Guang Xu
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Yan Wang
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.,School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xiaoyan Zhan
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Yuan Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Zhilei Wang
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Shubin Fu
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Wei Shi
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiaorong Hou
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Chunyu Wang
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Ruisheng Li
- Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Yan Liu
- Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Jiabo Wang
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Haiping Zhao
- School of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
| | - Xiaohe Xiao
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China. .,Integrative Medical Centre, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.
| | - Zhaofang Bai
- China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.
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24
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Ahn JH, Jegal H, Choi MS, Kim S, Park SM, Ahn J, Han HY, Cho HS, Yoon S, Oh JH. TNFα enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett 2021; 342:73-84. [PMID: 33609687 DOI: 10.1016/j.toxlet.2021.02.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022]
Abstract
Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress.
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Affiliation(s)
- Jun-Ho Ahn
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Bio Medical Research Center, Bio Medical & Health Division, Korea Testing Laboratory (KTL), Seoul, 08389, Republic of Korea
| | - Hyun Jegal
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea
| | - Mi-Sun Choi
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Soojin Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Se-Myo Park
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Jaehwan Ahn
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Hyoung-Yun Han
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
| | - Hyun-Soo Cho
- Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Seokjoo Yoon
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
| | - Jung-Hwa Oh
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
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Greca RD, Cunha-Silva M, Costa LBE, Costa JGF, Mazo DFC, Sevá-Pereira T, Nascimento MMC, Pereira IE, Oliveira FC, Faria GAS, Neto FLP, Almeida JRS. Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case. Ann Hepatol 2021; 19:107-112. [PMID: 31537508 DOI: 10.1016/j.aohep.2019.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/03/2019] [Accepted: 06/10/2019] [Indexed: 02/04/2023]
Abstract
Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.
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Affiliation(s)
- Raquel D Greca
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil.
| | - Marlone Cunha-Silva
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Larissa B E Costa
- Department of Pathology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Júlia G F Costa
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Daniel F C Mazo
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil; Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Tiago Sevá-Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marlla M C Nascimento
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isadora E Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Flávia C Oliveira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Guilherme A S Faria
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Fernando L P Neto
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Jazon R S Almeida
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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26
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MacKenzie KR, Zhao M, Barzi M, Wang J, Bissig KD, Maletic-Savatic M, Jung SY, Li F. Metabolic profiling of norepinephrine reuptake inhibitor atomoxetine. Eur J Pharm Sci 2020; 153:105488. [PMID: 32712217 PMCID: PMC7506503 DOI: 10.1016/j.ejps.2020.105488] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/25/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
Atomoxetine (ATX), a selective and potent inhibitor of the presynaptic norepinephrine transporter, is used mainly to treat attention-deficit hyperactivity disorder. Although multiple adverse effects associated with ATX have been reported including severe liver injuries, the mechanisms of ATX-related toxicity remain largely unknown. Metabolism frequently contributes to adverse effects of a drug through reactive metabolites, and the bioactivation status of ATX is still not investigated yet. Here, we systematically investigated ATX metabolism, bioactivation, species difference in human, mouse, and rat liver microsomes (HLM, MLM, and RLM) and in mice using metabolomic approaches as mice and rats are commonly used animal models for the studies of drug toxicity. We identified thirty one ATX metabolites and adducts in LMs and mice, 16 of which are novel. In LMs, we uncovered two methoxyamine-trapped aldehydes, two cyclization metabolites, detoluene-ATX, and ATX-N-hydroxylation for the first time. Detoluene-ATX and one cyclization metabolite were also observed in mice. Using chemical inhibitors and recombinant CYP enzymes, we demonstrated that CYP2C8 and CYP2B6 mainly contribute to the formation of aldehyde; CYP2D6 is the dominant enzyme for the formation of ATX cyclization and detoluene-ATX; CYP3A4 is major enzyme responsible for the hydroxylamine formation. The findings concerning aldehydes should be very useful to further elucidate the mechanistic aspects of adverse effects associated with ATX from metabolic angles. Additionally, the species differences for each metabolite should be helpful to investigate the contribution of specific metabolites to ATX toxicity and possible drug-drug interactions in suitable models.
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Affiliation(s)
- Kevin R MacKenzie
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; NMR and Drug Metabolism Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mingkun Zhao
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mercedes Barzi
- Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jin Wang
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Karl-Dimiter Bissig
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mirjana Maletic-Savatic
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA
| | - Sung Yun Jung
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Feng Li
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; NMR and Drug Metabolism Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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27
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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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Abouelghar GE, El-Bermawy ZA, Salman HMS. Oxidative stress, hematological and biochemical alterations induced by sub-acute exposure to fipronil (COACH ®) in albino mice and ameliorative effect of selenium plus vitamin E. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:7886-7900. [PMID: 31889272 DOI: 10.1007/s11356-019-06579-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/23/2019] [Indexed: 06/10/2023]
Abstract
Fipronil (FIP) is a highly effective, broad-use insecticide that belongs to the phenylpyrazole chemical group. It is extensively used in the agriculture and veterinary medicine for controlling a wide variety of pests. Though FIP showed lower toxicity in vertebrates than in insects, it was recognized to have a variety of toxic effects in mammals. The present study was undertaken to evaluate FIP-induced alterations in the blood biochemical markers and oxidative stress parameters in male albino mice via oral sub-acute toxicity exposure. The possible ameliorative effect of the pretreatment with selenium plus α-tocopherol (vitamin E) against the harmful effects of FIP was also investigated. Mice in FIP-test groups were exposed to different sublethal doses, i.e., 1.43, 2.87, and 4.78 mg active ingredient (AI)/kg body weight (b.w.), equal to 1/100, 1/50, and 1/30 LD50 of FIP, respectively, for 28 days. Mice in the amelioration groups were orally administered with selenium + vitamin E (0.3 mg + 22.5 mg/kg b.w., respectively) 14 days prior to exposure to the higher dose (4.78 mg/kg) of FIP for another 14 days. Fipronil exposure at medium and high doses showed lowered values of red blood cell count (RBC), hematocrit (HCT), hemoglobin (HGB), white blood cell (WBC), and platelet (PLT) counts after 28-day exposure, compared to the control. All three doses caused significant increases in levels of liver-function biomarkers, i.e., aspartate amino transaminase (AST), alanine amino transaminase (ALT), alkaline phosphatase (ALP), cholesterol, and bilirubin levels compared to the control. Levels of biomarkers related to kidney functions, i.e., urea, uric acid, and creatinine, increased significantly than these of the control. Likewise, the oxidative stress indices, i.e., hydrogen peroxide (H2O2) and malondialdehyde (MDA), significantly increased at the higher and medium doses, while antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), decreased significantly. On the other hand, prior administration of selenium + vitamin E in the FIP-exposed mice led to restore values of most hematological parameters nearly to these of the control. Also, the levels of AST, total protein, and creatinine seemed to be restored to the control values. Interestingly, pretreatment with selenium + vitamin E restored the levels of antioxidant enzymes, CAT and SOD, to the control values, whereas, oxidative stress indices, H2O2 and MDA, remained significantly high. It is our thought that the sublethal dose less than 1.43 mg/kg b.w. of commercial formulation of FIP (COACH® 200 SC) could be considered as no-observed-adverse-effect-level(NOAEL) under our present experimental conditions at short-term toxicity study. On the other hand, the higher sublethal doses, 4.78 and 2.87 mg/kg b.w., induced significant adverse effects in biomarkers and may be deleterious to human health following long-term exposure.
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Affiliation(s)
- Gamal E Abouelghar
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt.
| | - Zeinab A El-Bermawy
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt
| | - Hagar M S Salman
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt
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29
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Alshabeeb MA, Aithal GP, Daly AK. Investigation of Oxidative Stress-Related Candidate Genes as Risk Factors for Drug-Induced Liver Injury due to Co-Amoxiclav. DNA Cell Biol 2020; 39:349-354. [PMID: 31905014 DOI: 10.1089/dna.2019.4982] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The liver is susceptible to drug toxicity due to its vital role in xenobiotic metabolism and elimination. In addition to human leukocyte antigen (HLA) variants, which were previously determined as risk factors for drug-induced liver injury (DILI) due to co-amoxiclav, other non-HLA genes may contribute to hepatotoxicity risk. In this study, the association between DILI due to co-amoxiclav and several non-HLA genes was investigated. Association of variants in candidate genes (SOD2, GPX1, GSTM1, and GSTT1) with DILI due to various drugs was reported previously in other DILI cohorts. This study examined relevance in a co-amoxiclav-DILI cohort. One hundred sixty-five co-amoxiclav DILI cases were recruited from several European countries by two different studies (DILIGEN and iDILIC). A North-East England population group (n = 334) was used as the control group. PCR assays were used to genotype for the GSTM1 and GSTT1 null alleles with TaqMan SNP genotyping assays used for SOD2 (rs4880) and GPX1 (rs1050450). Fisher's exact test was used to assess differences in significance between cases and controls. None of the studied variants (SOD2 rs4880, GPX1 rs1050450, GSTM1 null allele, and GSTT1 null allele) was significantly associated with co-amoxiclav DILI compared with the control group. No significant differences between cases and controls were seen when combined SOD2/GPX1 genotypes and GST genotypes were considered. Despite the possible functional relevance and the previously reported contribution of the selected genes to DILI, our study failed to confirm associations between the selected genes and liver injury induced by co-amoxiclav.
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Affiliation(s)
- Mohammad A Alshabeeb
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.,Department of Developmental Medicine, King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, United Kingdom.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Ann K Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
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30
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Tesfa E, Siefu D, Belayneh Y, Mekonnen Z. Liver enzyme elevation in patients taking HAART compared with treatment naïve controls at Debre Berhan Referral Hospital: a comparative cross-sectional study, Northeast Ethiopia. BMC Res Notes 2019; 12:714. [PMID: 31666123 PMCID: PMC6822479 DOI: 10.1186/s13104-019-4748-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 10/18/2019] [Indexed: 01/08/2023] Open
Abstract
Objective HAART had significantly improved the quality of life of HIV patients. However, it results different adverse effects such as: hepatotoxicity, nephrotoxicity, lipodystrophy, anemia, diarrhea, psychiatric disorder and others. Therefore, this comparative cross sectional study was designed to investigate liver enzyme elevation in patients taking HAART compared with treatment naïve controls at Debre Berhan Referral Hospital. Result A total of 152 individuals (76 cases and 76 controls) were included in this study. The mean ages of treatment and control groups were 37.37 and 36.38 respectively. The mean values of liver enzymes (ALT, AST and ALP), total bilirubin and direct bilirubin were significantly higher (p < 0.05) while, total protein and creatinine were significantly lower in patients taking HAART compared with treatment naïve controls. In this study, about 19 (25%) of clients in HAART treated groups and 7 (9.2%) of treatment naïve controls had showed liver enzyme changes. Moreover, 23.7% and 1.3% of the HAART treated groups developed mild and moderate liver enzyme elevation or hepatotoxicity, respectively. In this study, significant difference was observed in liver enzyme elevation between ART and pre-ART patients. As a result, regular clinical and laboratory monitoring of liver function will be necessary to prevent severe form of liver injury.
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Affiliation(s)
- Endalamaw Tesfa
- Department of Biochemistry, College of Medicine and Health Sciences, Bahir Dar University, P.O. Box 79, Bahir Dar, Ethiopia.
| | - Daniel Siefu
- Department of Biochemistry, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yididya Belayneh
- Department of Biochemistry, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Zewdie Mekonnen
- Department of Biochemistry, College of Medicine and Health Sciences, Bahir Dar University, P.O. Box 79, Bahir Dar, Ethiopia
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31
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Douros A, Azoulay L, Yin H, Suissa S, Renoux C. Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury. J Am Coll Cardiol 2019. [PMID: 29519351 DOI: 10.1016/j.jacc.2018.01.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Non-vitamin K antagonist oral anticoagulants (NOACs) are relatively new drugs used for stroke prevention in nonvalvular atrial fibrillation (NVAF). However, there are concerns that their use may be associated with hepatotoxic effects. OBJECTIVES The purpose of this study was to determine whether the use of NOACs is associated with an increased risk of serious liver injury compared with the use of vitamin K antagonists (VKAs) in NVAF patients with and without prior liver disease. METHODS Using the administrative databases of the Canadian province of Quebec's health insurances, the authors conducted a cohort study among patients newly diagnosed with NVAF between January 2011 and December 2014. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious liver injury (defined as either a hospitalization or related death) were estimated using time-dependent Cox proportional hazards models, comparing current use of NOACs to current use of VKAs separately among patients with or without prior liver disease. RESULTS The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person-years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively). CONCLUSIONS Compared with VKAs, NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status. Overall, these results provide reassurance regarding the hepatic safety of NOACs.
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Affiliation(s)
- Antonios Douros
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Laurent Azoulay
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Hui Yin
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Samy Suissa
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Christel Renoux
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
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Wu L, Ingle T, Liu Z, Zhao-Wong A, Harris S, Thakkar S, Zhou G, Yang J, Xu J, Mehta D, Ge W, Tong W, Fang H. Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA. BMC Bioinformatics 2019; 20:97. [PMID: 30871458 PMCID: PMC6419320 DOI: 10.1186/s12859-019-2628-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Adverse Drug Reactions (ADRs) are of great public health concern. FDA-approved drug labeling summarizes ADRs of a drug product mainly in three sections, i.e., Boxed Warning (BW), Warnings and Precautions (WP), and Adverse Reactions (AR), where the severity of ADRs are intended to decrease in the order of BW > WP > AR. Several reported studies have extracted ADRs from labeling documents, but most, if not all, did not discriminate the severity of the ADRs by the different labeling sections. Such a practice could overstate or underestimate the impact of certain ADRs to the public health. In this study, we applied the Medical Dictionary for Regulatory Activities (MedDRA) to drug labeling and systematically analyzed and compared the ADRs from the three labeling sections with a specific emphasis on analyzing serious ADRs presented in BW, which is of most drug safety concern. RESULTS This study investigated New Drug Application (NDA) labeling documents for 1164 single-ingredient drugs using Oracle Text search to extract MedDRA terms. We found that only a small portion of MedDRA Preferred Terms (PTs), 3819 out of 21,920 or 17.42%, were observed in a whole set of documents. In detail, 466/3819 (12.0%) PTs were in BW, 2023/3819 (53.0%) were in WP, and 2961/3819 (77.5%) were in AR sections. We also found a higher overlap of top 20 occurring BW PTs with WP sections compared to AR sections. Within the MedDRA System Organ Class levels, serious ADRs (sADRs) from BW were prevalent in Nervous System disorders and Vascular disorders. A Hierarchical Cluster Analysis (HCA) revealed that drugs within the same therapeutic category shared the same ADR patterns in BW (e.g., nervous system drug class is highly associated with drug abuse terms such as dependence, substance abuse, and respiratory depression). CONCLUSIONS This study demonstrated that combining MedDRA standard terminologies with data mining techniques facilitated computer-aided ADR analysis of drug labeling. We also highlighted the importance of labeling sections that differ in seriousness and application in drug safety. Using sADRs primarily related to BW sections, we illustrated a prototype approach for computer-aided ADR monitoring and studies which can be applied to other public health documents.
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Affiliation(s)
- Leihong Wu
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Taylor Ingle
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Zhichao Liu
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Anna Zhao-Wong
- MedDRA Maintenance and Support Services Organization, 7575 Colshire Dr., McLean, VA, 22102, USA
| | - Stephen Harris
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Shraddha Thakkar
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Guangxu Zhou
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Junshuang Yang
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Joshua Xu
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Darshan Mehta
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Weigong Ge
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Weida Tong
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
| | - Hong Fang
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
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Abstract
The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration. Because the adverse effects seem unrelated to the mode of action, it is likely, that both drugs that occupied important therapeutic niches, could be replaced. Reasons for the clinically relevant toxicity will be clarified and future substitutes for these drugs presented in this review.
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Kwon J, Kim S, Yoo H, Lee E. Nimesulide-induced hepatotoxicity: A systematic review and meta-analysis. PLoS One 2019; 14:e0209264. [PMID: 30677025 PMCID: PMC6345488 DOI: 10.1371/journal.pone.0209264] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 12/03/2018] [Indexed: 01/10/2023] Open
Abstract
Objective This study aimed to evaluate the risk for hepatotoxicity with nimesulide, a non-steroidal anti-inflammatory drug (NSAID) available in Republic of Korea but withdrawn from the market in several countries. Methods A systematic review and meta-analysis were conducted of studies retrieved from PubMed, EMBASE, Cochrane, the Research Information Sharing Service and ClinicalTrials.gov up to September 2017. All studies reporting nimesulide-associated hepatotoxicity in patients as compared with the unexposed or the exposed to other NSAIDs were included. Studies using spontaneous reporting databases were included to estimate reporting odds ratio (ROR) of hepatotoxicity associated with nimesulide exposure. The association between nimesulide use and hepatotoxicity was estimated using relative risk (RR) and ROR with 95% confidence interval (CI). Results A total of 25 observational studies were eligible for review. In a meta-analysis of five observational studies, nimesulide was significantly associated with hepatotoxicity [RR 2.21, 95% CI 1.72–2.83]. From studies using spontaneous reporting databases (n = 6), rates of reported hepatotoxicity were significantly higher in patients using nimesulide, compared with those treated with other NSAIDs [pooled ROR 3.99, 95% CI 2.86–5.57]. Of a total of 33 patients from case studies and series, the majority (n = 28, 84.8%) were female, and the mean age (± standard deviation) was 56.8 (± 15.6) years. Almost half of the patients on nimesulide (45.5%) either required liver transplantation or died due to fulminant hepatic failure, of whom a third developed hepatotoxicity within less than 15 days of nimesulide administration. Conclusions Our study findings support previous reports of an increased risk for hepatotoxicity with nimesulide use and add to existing literature by providing risk estimates for nimesulide-associated hepatotoxicity. As the limited number of studies with primarily observational study designs were included in the analysis, more studies are needed to further describe the effects of dose and length of treatment on the risk for hepatotoxicity.
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Affiliation(s)
- Jeongyoon Kwon
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seungyeon Kim
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Hyejin Yoo
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Euni Lee
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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Kuna L, Bozic I, Kizivat T, Bojanic K, Mrso M, Kralj E, Smolic R, Wu GY, Smolic M. Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives. Curr Drug Metab 2018; 19:830-838. [PMID: 29788883 PMCID: PMC6174638 DOI: 10.2174/1389200219666180523095355] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/20/2018] [Accepted: 03/28/2018] [Indexed: 12/13/2022]
Abstract
Background: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases. Methods: A structured search of bibliographic databases – Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described. Results: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described. Conclusion: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.
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Affiliation(s)
- Lucija Kuna
- Department of Chemistry and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ivana Bozic
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Tomislav Kizivat
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Kristina Bojanic
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Margareta Mrso
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Edgar Kralj
- Inspecto, LLC, Martina Divalta 193, 31000 Osijek, Croatia
| | - Robert Smolic
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, United States
| | - Martina Smolic
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia.,Department of Pharmacology, Faculty Of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia
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Gündüz N, Turgut C. Risperidon Kullanımına Bağlı Ortaya Çıkan Akut Toksik Hepatit: Olgu Sunumu. KOCAELI ÜNIVERSITESI SAĞLIK BILIMLERI DERGISI 2018. [DOI: 10.30934/kusbed.366173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Assessment of fipronil toxicity on wistar rats: A hepatotoxic perspective. Toxicol Rep 2018; 5:448-456. [PMID: 29854616 PMCID: PMC5978010 DOI: 10.1016/j.toxrep.2018.02.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 02/28/2018] [Accepted: 02/28/2018] [Indexed: 02/06/2023] Open
Abstract
Fipronil was found to induce oxidative stress. Exposure to fipronil resulted in histopathology of hepatic tissue. Peak absorption changes in FT-IR was evident in liver of rats on Fipronil exposure. Fipronil modulated the enzymatic threshold of hepatic enzymes. Extensive pesticide application has contributed to environmental contamination globally, imposing adverse health effects on non-target organisms. Need for an understanding of cellular response following pesticide exposure is, therefore, paradigmatic for elucidating perturbations occurring within biological systems. The present investigation was aimed to examine safe and toxic dose level of a persistent, synthetic, phenylpyrazole based insecticide, Fipronil (FPN) on rat liver. Experimental animals were divided into four groups and gavaged with 0.0 (control), 32.33 (high), 12.12 (medium) and 6.46 mg/kg body weight/day (low dose) of FPN for 90 days. While results for liver catalase and glutathione S-transferase indicated significant changes in high and medium dose groups, the superoxide dismutase and glutathione peroxidase activity suggested significant changes in all exposed groups as compared to control. Elevated levels of liver malondialdehyde reflected oxidative damage potential under the exposed groups but remained insignificant for low dose. Histologically, structural irregularities with findings like impaired portal vein and hypertrophy of hepatocytes were prominent under all the exposed groups. The FT-IR based spectral investigation further revealed changes in absorption patterns and peak intensities in rats exposed to FPN. Significant elevation was also noticed in liver enzymes; alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in rat serum suggesting the toxicity in dose -dependent pattern. Based on the outcome, it could be ascertained that the toxicity of FPN is certain at high and medium dose levels but remains ambiguous at a low dose of 6.46 mg/kg body weight/day. The current upshots serve as a preliminary report thereby advising the farming community against the usage of FPN insecticide.
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Karahalil B, Hare E, Koç G, Uslu İ, Şentürk K, Özkan Y. Hepatotoxicity associated with statins. Arh Hig Rada Toksikol 2018; 68:254-260. [DOI: 10.1515/aiht-2017-68-2994] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 10/01/2017] [Indexed: 12/13/2022] Open
Abstract
Abstract
Treatment with statins is known all over the world. They are generally considered safe at therapeutic doses. Nevertheless, clinical trials are not enough to assess their scarce adverse effects such as idiosyncratic drug induced liver injury (DILI). Due to some conditions, such as concomitant usage (drug-drug interaction using an identical metabolising enzyme) and genetic polymorphisms, there is an increasing concern about their safety. Hepatotoxicity and rhabdomyolysis have begun to appear in published studies. Most of investigations have focused on both these adverse effects and mechanisms of drug induced toxicity. The present review has attempted to compile almost all of the existing studies on the hepatotoxicity of statins but not rhabdomyolysis. The aim of our study is to provide an overview of the studies on the statin-associated hepatotoxicity and to discuss the published studies. The researchers are of the opinion that the research on this topic is incomplete but extremely necessary.
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Affiliation(s)
- Bensu Karahalil
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
| | - Emine Hare
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
| | - Göksel Koç
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
| | - İrem Uslu
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
| | - Kerem Şentürk
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
| | - Yağmur Özkan
- Toxicology Department, Faculty of Pharmacy, Gazi University Ankara, Ankara , Turkey
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Joseph P. Transcriptomics in toxicology. Food Chem Toxicol 2017; 109:650-662. [PMID: 28720289 PMCID: PMC6419952 DOI: 10.1016/j.fct.2017.07.031] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/12/2017] [Accepted: 07/14/2017] [Indexed: 12/11/2022]
Abstract
Xenobiotics, of which many are toxic, may enter the human body through multiple routes. Excessive human exposure to xenobiotics may exceed the body's capacity to defend against the xenobiotic-induced toxicity and result in potentially fatal adverse health effects. Prevention of the adverse health effects, potentially associated with human exposure to the xenobiotics, may be achieved by detecting the toxic effects at an early, reversible and, therefore, preventable stage. Additionally, an understanding of the molecular mechanisms underlying the toxicity may be helpful in preventing and/or managing the ensuing adverse health effects. Human exposures to a large number of xenobiotics are associated with hepatotoxicity or pulmonary toxicity. Global gene expression changes taking place in biological systems, in response to exposure to xenobiotics, may represent the early and mechanistically relevant cellular events contributing to the onset and progression of xenobiotic-induced adverse health outcomes. Hepatotoxicity and pulmonary toxicity resulting from exposure to xenobiotics are discussed as specific examples to demonstrate the potential application of transcriptomics or global gene expression analysis in the prevention of adverse health effects associated with exposure to xenobiotics.
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Affiliation(s)
- Pius Joseph
- Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health (NIOSH), Morgantown, WV, USA.
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Cheng Y, Chen S, Freeden C, Chen W, Zhang Y, Abraham P, Nelson DM, Humphreys WG, Gan J, Lai Y. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone. J Pharmacol Exp Ther 2017; 362:385-394. [PMID: 28645914 DOI: 10.1124/jpet.117.242370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 06/22/2017] [Indexed: 12/17/2022] Open
Abstract
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats.
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Affiliation(s)
- Yaofeng Cheng
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Shenjue Chen
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Chris Freeden
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Weiqi Chen
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Yueping Zhang
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Pamela Abraham
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - David M Nelson
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - W Griffith Humphreys
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Jinping Gan
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Yurong Lai
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
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The Effects of Melatonin on Elevated Liver Enzymes during Statin Treatment. BIOMED RESEARCH INTERNATIONAL 2017. [PMID: 28630863 PMCID: PMC5467275 DOI: 10.1155/2017/3204504] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Taking statins can cause increase in the level of aspartate and alanine aminotransferase. The aim of this study was to assess the usefulness of melatonin in counteracting the adverse hepatic events from statins. Methods. The research program included 60 patients (aged 47–65 years, 41 women and 19 men) with hyperlipidemia taking atorvastatin or rosuvastatin at a dose of 20–40 mg daily. The patients were randomly allocated in two groups. Group I (n = 30) was recommended to take the same statin at a standardized daily dose of 20 mg together with melatonin at a dose of 2 × 5 mg. Group II (n = 30) patients took statin with placebo at the same dose and time of the day. Follow-up laboratory tests (AST, ALT, GGT, and ALP) were evaluated after 2, 4, and 6 months of treatment. Results. In Group I the levels of all enzymes decreased after 6 months, particularly AST, 97,2 ± 19,1 U/L versus 52,8 ± 12,3 U/L (p < 0,001); ALT, 87,4 ± 15,6 U/L versus 49,8 ± 14,5 U/L (p < 0,001); and GGT, 84,1 ± 14,8 U/L versus 59,6 U/L (p < 0,001). Conclusion. Melatonin exerts a hepatoprotective effect in patients taking statins.
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Riede J, Poller B, Huwyler J, Camenisch G. Assessing the Risk of Drug-Induced Cholestasis Using Unbound Intrahepatic Concentrations. Drug Metab Dispos 2017; 45:523-531. [PMID: 28254950 DOI: 10.1124/dmd.116.074179] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 03/01/2017] [Indexed: 02/13/2025] Open
Abstract
Inhibition of the bile salt export pump (BSEP) has been recognized as a key factor in the development of drug-induced cholestasis (DIC). The risk of DIC in humans has been previously assessed using in vitro BSEP inhibition data (IC50) and unbound systemic drug exposure under assumption of the "free drug hypothesis." This concept, however, is unlikely valid, as unbound intrahepatic drug concentrations are affected by active transport and metabolism. To investigate this hypothesis, we experimentally determined the in vitro liver-to-blood partition coefficients (Kpuu) for 18 drug compounds using the hepatic extended clearance model (ECM). In vitro-in vivo translatability of Kpuu values was verified for a subset of compounds in rat. Consequently, unbound intrahepatic concentrations were calculated from clinical exposure (systemic and hepatic inlet) and measured Kpuu data. Using these values, corresponding safety margins against BSEP IC50 values were determined and compared with the clinical incidence of DIC. Depending on the ECM class of a drug, in vitro Kpuu values deviated up to 14-fold from unity, and unbound intrahepatic concentrations were affected accordingly. The use of in vitro Kpuu-based safety margins allowed separation of clinical cholestasis frequency into three classes (no cholestasis, cholestasis in ≤2%, and cholestasis in >2% of subjects) for 17 out of 18 compounds. This assessment was significantly superior compared with using unbound extracellular concentrations as a surrogate for intrahepatic concentrations. Furthermore, the assessment of Kpuu according to ECM provides useful guidance for the quantitative evaluation of genetic and physiologic risk factors for the development of cholestasis.
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Affiliation(s)
- Julia Riede
- Division of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.R., B.P., G.C.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (J.R., J.H.)
| | - Birk Poller
- Division of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.R., B.P., G.C.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (J.R., J.H.)
| | - Jörg Huwyler
- Division of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.R., B.P., G.C.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (J.R., J.H.)
| | - Gian Camenisch
- Division of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.R., B.P., G.C.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (J.R., J.H.)
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Araújo AM, Carvalho M, Carvalho F, Bastos MDL, Guedes de Pinho P. Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI). Crit Rev Toxicol 2017; 47:633-649. [PMID: 28436314 DOI: 10.1080/10408444.2017.1309638] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.
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Affiliation(s)
- Ana Margarida Araújo
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Márcia Carvalho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal.,b UFP Energy, Environment and Health Research Unit (FP-ENAS) , University Fernando Pessoa , Porto , Portugal
| | - Félix Carvalho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Maria de Lourdes Bastos
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Paula Guedes de Pinho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
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Tang N, Liu J, Chen B, Zhang Y, Yu M, Cai Z, Chen H. Effects of gap junction intercellular communication on the docetaxel-induced cytotoxicity in rat hepatocytes. Mol Med Rep 2017; 15:2689-2694. [PMID: 28447724 DOI: 10.3892/mmr.2017.6295] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 01/24/2017] [Indexed: 11/06/2022] Open
Abstract
The effect of gap junction intercellular communication (GJIC) on docetaxel-induced hepatotoxicity and its underlying mechanisms are largely unknown. The present study involved investigating the effect of downregulating GJs derived from connexin (Cx) 32 in BRL-3A cells by three different mechanisms: Using a low-density culture; suppression of Cx32 using small interfering RNA; and use of the chemical inhibitor 2‑aminoethoxydiphenyl borate (2‑APB), all of which led to attenuated docetaxel hepatotoxicity. In order to investigate the relevant mechanisms involved, apoptosis and caspase activities of BRL‑3A cells were determined. The increase of apoptosis and the activation of caspase‑3 and caspase‑9, but not caspase-8, were detected following cell exposure with docetaxel, demonstrating that the mitochondrial‑mediated apoptosis pathway is largely responsible for docetaxel hepatotoxicity. However, reduced apoptosis and caspase‑3, and ‑9 activities were observed following docetaxel application when BRL‑3A GJIC was deficient from the knockdown of Cx32 expression or pretreatment with 2‑APB. These observations illustrate that GJs are important in docetaxel-induced hepatotoxicity. Furthermore, inhibition of GJIC could prevent amplification of toxicity to docetaxel. Due to GJIC blockage, this hepatoprotection was associated, in part, with decreasing apoptosis of BRL‑3A cells through the mitochondrial pathway. The present study provides evidence for potential therapeutic targets for the treatment of docetaxel-induced liver injury.
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Affiliation(s)
- Nan Tang
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Jinghua Liu
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Bo Chen
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Yuan Zhang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Meiling Yu
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Ziqing Cai
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Hongpeng Chen
- School of Information Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Brown DL. Immunopathology of the Hepatobiliary System. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2017:329-417. [DOI: 10.1007/978-3-319-47385-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang D, Yang J, Du Q, Li H, Wang S. The total alkaloid fraction of bulbs of Fritillaria cirrhosa displays anti-inflammatory activity and attenuates acute lung injury. JOURNAL OF ETHNOPHARMACOLOGY 2016; 193:150-158. [PMID: 27497638 DOI: 10.1016/j.jep.2016.08.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 06/01/2016] [Accepted: 08/03/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bulb of Fritillaria cirrhosa D.Don (BFC) has been wildly used in China for a long time for folk medicine since its significant therapeutic effects on respiratory diseases, such as cough, expectoration, pneumonia and bronchial inflammation, which are related to respiratory inflammatory response. However, there is a lack of investigation on the in vivo anti-inflammatory properties of BFC. AIM OF THE STUDY The aim of this study was to evaluate the in vivo anti-inflammatory activity of the purified total alkaloid fraction of BFC (TAF) by using different animal models of inflammation to provide scientific evidence for its traditional use. MATERIALS AND METHODS The total alkaloid fraction from BFC was prepared by using H-103 resin column. Anti-inflammatory effect of TAF was evaluated by models of acetic acid-induced capillary permeability accentuation, carrageenan-induced rat paw edema, cotton pellet-induced granuloma formation and LPS-induced acute lung injury (ALI). The level of cytokines (TNF, IL-6, IL-4 and IL-10) was measured by ELISA. Histopathological analyses were performed by using hematoxylin and eosin staining. RESULTS TAF can inhibit acetic acid-induced capillary permeability accentuation, carrageenan-induced paw edema, cotton pellet-induced granuloma formation, suppress inflammatory cells recruitment and cytokine production in the bronchoalveolar lavage fluid from LPS-induced ALI mice, and attenuate pathological changes in the lung tissues of ALI mice. CONCLUSION This study provides scientific evidence for bulb of F. cirrhosa to treat respiratory inflammation.
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Affiliation(s)
- Dongdong Wang
- Department of Pharmacognosy, West China College of Pharmacy, Sichuan University, No. 17, RenMin NanLu 3 Duan, Chengdu 610041, PR China; Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, Vienna A-1090, Austria.
| | - Jie Yang
- Department of Urology, Chengdu First People's Hospital, GaoXinQu WanXiang BeiLu 18 Hao, Chengdu 610041, PR China
| | - Qingdan Du
- Department of Pharmacognosy, West China College of Pharmacy, Sichuan University, No. 17, RenMin NanLu 3 Duan, Chengdu 610041, PR China
| | - Houcong Li
- Department of Pharmacognosy, West China College of Pharmacy, Sichuan University, No. 17, RenMin NanLu 3 Duan, Chengdu 610041, PR China
| | - Shu Wang
- Department of Pharmacognosy, West China College of Pharmacy, Sichuan University, No. 17, RenMin NanLu 3 Duan, Chengdu 610041, PR China.
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Metformin as a Rare Cause of Drug-Induced Liver Injury, a Case Report and Literature Review. Am J Ther 2016; 23:e315-7. [PMID: 24263160 DOI: 10.1097/mjt.0000000000000007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. Although metformin-associated gastrointestinal upset and metabolic acidosis is widely recognized side effect of this drug, metformin-induced liver injury has been rarely reported in the literature. In most cases reported, metformin-induced liver injury was associated with concomitant intake of other hepatotoxic drugs. Here, we report a case of a 70-year-old white woman who suffered metformin-induced liver injury 5 weeks after starting on this medication, and she was not on any other hepatotoxic agent. With increasing prescription of metformin, this case deserves particular attention for this rare but important side effect.
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Kuijper IA, Yang H, Van De Water B, Beltman JB. Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling. Expert Opin Drug Metab Toxicol 2016; 13:5-17. [PMID: 27609146 DOI: 10.1080/17425255.2017.1234607] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.
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Affiliation(s)
- Isoude A Kuijper
- a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands
| | - Huan Yang
- a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands
| | - Bob Van De Water
- a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands
| | - Joost B Beltman
- a Division of Toxicology, Leiden Academic Centre for Drug Research , Leiden University , Leiden , The Netherlands
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Soleimanpour M, Imani F, Safari S, Sanaie S, Soleimanpour H, Ameli H, Alavian SM. The Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in the Treatment of Patients With Hepatic Disease: A Review Article. Anesth Pain Med 2016; 6:e37822. [PMID: 27843779 PMCID: PMC5100664 DOI: 10.5812/aapm.37822] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/11/2016] [Accepted: 06/27/2016] [Indexed: 12/29/2022] Open
Abstract
CONTEXT Patients with hepatic dysfunction suffer from many problems and associated complications in organs other than the liver. Therefore, it is very important to investigate the effects of different drugs in the treatment of these patients. Due to the high consumption of non-steroidal anti-inflammatory drugs (NSAIDs), studying the effects of these drugs in patients with hepatic dysfunction is particularly important. EVIDENCE ACQUISITION Research studies published from 1958 to 2014 were investigated in the present study. The literature search was conducted based on the following keywords: non-steroidal anti-inflammatory drugs (NSAIDs), liver dysfunction, cirrhosis, pharmaceutical complications, drug-induced liver injury (DILI), and similar words from reliable resources. In total, 63 articles and two books (out of 179 initially identified resources) were included in the study. RESULTS In addition to significant hemostatic disorders and cardiovascular disorders, disorders of the renal, respiratory, and gastrointestinal systems, as well as disorders of the central nervous system, occur in patients with hepatic dysfunction. The various NSAIDs have different effects on different bodily systems. Therefore, the appropriate drug should be chosen based on both the condition of the disease and the severity of the dysfunction. CONCLUSIONS Due to the potential adverse effects of NSAIDs in patients with hepatic disease, their impact on all bodily systems should be emphasized when determining whether their use is necessary. Further, the appropriate medication should be selected after a careful assessment of the severity of the disease and any associated complications. It is logical that medicines should only be prescribed by a qualified physician.
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Affiliation(s)
- Maryam Soleimanpour
- Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farnad Imani
- Pain Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeid Safari
- Pain Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sarvin Sanaie
- Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Soleimanpour
- Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hoorolnesa Ameli
- Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Tehran Hepatitis Center, Tehran, Iran
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Chen SS, Yu KK, Huang C, Li N, Zheng JM, Bao SX, Chen MQ, Zhang WH. The characteristics and clinical outcome of drug-induced liver injury in a Chinese hospital: A retrospective cohort study. Medicine (Baltimore) 2016; 95:e4683. [PMID: 27559976 PMCID: PMC5400343 DOI: 10.1097/md.0000000000004683] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The aim of this cohort study was to determine the characteristics and clinical outcome of 287 patients with drug-induced liver injury (DILI) in a Chinese hospital.Between January 2008 and January 2013, individuals who were diagnosed with DILI were selected. The complete medical records of each case were reviewed, and factors for the outcome of patients with DILI were extracted and analyzed using univariate and multivariate analysis.Two hundred eighty-seven cases identified as DILI were included in the study. A total of 105 different drugs were considered to be related to the hepatotoxicity. The main causative group of drugs was Chinese herb (n = 111). Liver failure developed in 9 (3.1%) patients, and 2 died (0.7%). Overall, complete recovery occurred in 92 (32.1%) patients. Univariate analysis and binary logistic regression analysis identified the digestive symptoms, jaundice, total bilirubin (TBIL), and direct bilirubin (DBIL) as independent factors for the non-recovery of DILI. Then the prediction model, including digestive symptoms, jaundice, TBIL, and DBIL, was built by using binary logistic regression analysis again. Receiver operating characteristic curve validated the strong power (area under the curve (AUC) = 0.907) of prediction model for predicting the DILI non-recovery.DILI is an important cause of liver test abnormalities, and Chinese herb represented the most common drug group. The factors such as digestive symptoms, jaundice, TBIL, and DBIL have effect on DILI outcomes. The prediction model, including digestive symptoms, jaundice, TBIL, and DBIL, established in this study is really an excellent predictive tool for non-recovery of DILI patients.
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Affiliation(s)
| | | | | | | | | | | | - Ming-Quan Chen
- Department of Infectious Diseases and Hepatology, Huashan Hospital, Fudan University, Shanghai, China
- Correspondence: Ming-Quan Chen, Department of Infectious Diseases and Hepatology of Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China (e-mail: ), Wen-Hong Zhang, Department of Infectious Diseases and Hepatology of Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China (e-mail: )
| | - Wen-Hong Zhang
- Department of Infectious Diseases and Hepatology, Huashan Hospital, Fudan University, Shanghai, China
- Correspondence: Ming-Quan Chen, Department of Infectious Diseases and Hepatology of Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China (e-mail: ), Wen-Hong Zhang, Department of Infectious Diseases and Hepatology of Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China (e-mail: )
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