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Sultana N, Izawa T, Kamei T, Fujiwara S, Ito Y, Takami Y, Kuwamura M. Application of humanized mice to toxicology studies: properties of chimeric mice with humanized liver (PXB-mice) for hepatotoxicity. J Toxicol Pathol 2025; 38:183-189. [PMID: 40190627 PMCID: PMC11966125 DOI: 10.1293/tox.2024-0092] [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: 11/18/2024] [Accepted: 01/23/2025] [Indexed: 04/09/2025] Open
Abstract
Chimeric mice with humanized liver are considered a useful tool to predict drug pharmacokinetics and in vivo toxicity in humans. The PXB-mouse is one of such chimeric (humanized) mouse models with more than 70% of human hepatocytes in their liver, which can produce human albumin with human-type bile secretion and express human xenobiotic metabolizing enzymes. However, data are limited regarding the properties of such humanized mice in hepatotoxicity studies. This study aimed to explore the distinctive characteristics of chimeric PXB-mice with humanized liver that can influence susceptibility to hepatotoxicity. Morphologically, the PXB-mice have a diffuse hepatic macrovesicular and microvesicular steatosis in the transplanted human hepatocytes, which can be suppressed after human growth hormone treatment. The humanized liver of the PXB-mice has a metabolic zonation of glutamine synthetase, cytochrome P450 2E1, and argininosuccinate synthase 1, similar to normal liver in rodents and humans. The transplanted human hepatocytes in the PXB liver have a markedly decreased N-cadherin expression compared with normal human liver. Scanning electron microscopy revealed formation of septum-like structures encircling the transplanted human hepatocytes in the PXB liver, which consists of an accumulation of fibers in the space of Disse under transmission electron microscopy and is immunolabeled for laminin. Overall, the present report demonstrated the morphological and immunohistochemical characteristics of the PXB-mice with humanized liver along with some abnormalities in the cell adhesion of the transplanted human hepatocytes. These findings would be useful for hepatotoxicity studies using humanized animal models.
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Affiliation(s)
- Nazneen Sultana
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Tomomi Kamei
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Sho Fujiwara
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Yuri Ito
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Yuki Takami
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
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Luo X, Linghu M, Zhou X, Ru Y, Huang Q, Liu D, Ji S, Ma Y, Luo Y, Huang Y. Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury. Free Radic Biol Med 2025; 229:68-81. [PMID: 39824447 DOI: 10.1016/j.freeradbiomed.2025.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/20/2025]
Abstract
The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases.
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Affiliation(s)
- Xianyu Luo
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Maoyuan Linghu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Xinru Zhou
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Yi Ru
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Qian Huang
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Didi Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Shurong Ji
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Yinchu Ma
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Yingli Luo
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
| | - Yi Huang
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
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Macasaet R, Payal F, Yagnik K, Rathod M, Aquino D, Shah S. A Rare Case of Drug-Induced Liver Injury (DILI) From Topiramate. Cureus 2025; 17:e81120. [PMID: 40276438 PMCID: PMC12018722 DOI: 10.7759/cureus.81120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
A 72-year-old male individual with a past medical history of seizures and ongoing management with topiramate for two months presented at the emergency department with jaundice. Ten days before the presentation, the patient started feeling fatigued and had intermittent generalized mild pain (grade 3/10) with dark-brown discoloration of urine. On physical examination, he was normotensive at 124/54 with a pulse rate of 72 beats per minute. His weight was 73.9 kg, with an average body mass index of 20.93 kg/m2. Physical examination revealed scleral icterus and diffuse jaundice all over his body, otherwise unremarkable. On laboratory work-up, the patient had elevations in alanine aminotransferase at 74.6 U/L and aspartate aminotransferase at 498 U/L. He also had extremely high alkaline phosphatase (ALP) at 1,353 U/L, total bilirubin was 10.9 mg/dL while his direct bilirubin was 8.1 mg/dL, lactate dehydrogenase (LDH) was mildly high at 300 U/L, Gamma-glutamyl transferase (GGT) was high at 1,274 U/L. Ammonia levels were found to be mildly high at 48 umol/L. His hemoglobin was 12.3 g/dL, at his baseline. Carbohydrate antigen 19-9 was slightly high at 71 U/mL, and alpha-fetoprotein was high at 10.9 ng/mL. An ultrasound of the abdomen showed no evidence of gallstone, gallbladder wall thickening, or common duct dilatation. Computed tomography (CT) scan with intravenous contrast of the abdomen and pelvis showed hepatic steatosis with borderline size liver (17 cm). A previous CT scan two months prior also showed normal liver and gallbladder. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) showed consistent results with CT scans. Topiramate was then tapered and then discontinued. During follow-up three months after discharge, his alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP, total bilirubin, and direct bilirubin all came back to normal. Drug-induced liver injury with topiramate is rare. Most previous studies and case reports have presented liver injury with topiramate only when combined with other antiepileptic drugs (AEDs), antipsychotics, or other hepatotoxic drugs. However, the case shows that topiramate can independently cause drug-induced liver injury. The timing of the onset of jaundice in our patient, coinciding with the initiation of topiramate, suggests a possible drug-induced liver injury, and so does discontinuation of the drug improved liver enzymes. Given that only a tiny percentage of patients on topiramate develop significant liver injury, this case highlights the need for vigilance in monitoring liver function in patients initiating this medication.
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Affiliation(s)
| | - Fnu Payal
- Internal Medicine, Monmouth Medical Center, Long Branch, USA
| | - Karan Yagnik
- Internal Medicine, Monmouth Medical Center, Long Branch, USA
| | - Malay Rathod
- Medicine, Rutgers Monmouth Hospital, New Jersey, USA
| | - David Aquino
- Internal Medicine, Monmouth Medical Center, Long Branch, USA
| | - Shilpan Shah
- Internal Medicine, Monmouth Medical Center, Long Branch, USA
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Han B, He Y, Zhu M, Zhang M, Lu L, Xu X, He X, Yi H, Tang S. Association of Gene Polymorphisms and Serum Levels of ALAS1 with the Risk of Anti-Tuberculosis Drug-Induced Liver Injury. J Clin Pharmacol 2025; 65:197-205. [PMID: 39297668 DOI: 10.1002/jcph.6137] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 09/08/2024] [Indexed: 01/28/2025]
Abstract
The accumulation of protoporphyrin IX in the liver caused by isoniazid and rifampicin through the disorder of heme biosynthesis was considered an important mechanism of anti-tuberculosis drug-induced liver injury (ATLI). Alanine synthase 1 (ALAS1) is a rate-limiting enzyme in the process of heme synthesis. This study aimed to investigate the association between ALAS1 gene polymorphism, serum ALAS1 level, and the risk of ATLI. This study was a case-control study including 58 ATLI cases and 192 controls. Four single nucleotide polymorphisms (SNPs) of the ALAS1 gene were selected for genotyping and serum ALAS1 concentrations were detected using ELISA kits. There was no significant difference in the genotype distribution of four SNPs between the ATLI cases and the controls under different genetic models. Patients carrying the GG genotype of SNP rs352163 in controls had higher baseline ALAS1 levels than those in ATLI cases (243.6 vs 290.2 ng/L, P = .034), and patients with baseline ALAS1 < 337.85 ng/L had a higher risk of ATLI than those with ALAS1 ≥ 337.85 ng/L (HR = 2.679, 95% CI: 1.360-5.278, P = .004). Our findings indicated that the serum ALAS1 concentrations in the ATLI cases were lower than those in the controls, and the lower baseline ALAS1 levels can be associated with higher ATLI risk.
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Affiliation(s)
- Bing Han
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yiwen He
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Min Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meiling Zhang
- Department of Infectious Disease, The Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Lihuan Lu
- Department of Tuberculosis, The Second People's Hospital of Changshu, Changshu, China
| | - Xiaoyan Xu
- Department of Tuberculosis, Changshu Center for Disease Control and Prevention, Suzhou, China
| | - Xiaomin He
- Department of Infectious Disease, The People's Hospital of Taixing, Taixing, China
| | - Honggang Yi
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shaowen Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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Shrestha A, Elliott S, Abasszade JH, Wu K, Worland T, Simpson I, Dev A. Drug-Induced Liver Injury Associated with Turmeric and Piperine: A Case and Review. Case Rep Gastroenterol 2025; 19:96-106. [PMID: 39995754 PMCID: PMC11850025 DOI: 10.1159/000543679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 01/03/2025] [Indexed: 02/26/2025] Open
Abstract
Introduction Turmeric is a common spice used in traditional Chinese and Ayurvedic medicine for a variety of purported health benefits. Recent concerns have arisen regarding turmeric-induced liver injury linked to formulations with enhanced bioavailability, often including piperine found in black pepper. Case Presentation We explore a case of a 40-year-old female with increasing fatigue, pruritus, and dark urine following consumption of turmeric and black pepper "wellness shots" leading to a significant drug-induced liver injury. Conclusion This case underscores the critical need to recognise herbal remedies, such as turmeric, as potential sources of hepatotoxicity. Despite a reputation of safety, limited regulation and testing of turmeric may mean potential adverse effects are under-recognised. Understanding the mechanisms behind turmeric and black pepper's hepatotoxicity, including the role of potential genetic predispositions, requires further investigation for its safe use.
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Affiliation(s)
- Atul Shrestha
- Department of Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia
| | - Sarah Elliott
- Department of Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia
| | | | - Kyle Wu
- Department of Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia
| | - Thomas Worland
- Department of Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia
| | - Ian Simpson
- Department of Anatomical Pathology, Monash Health, Clayton, VIC, Australia
| | - Anouk Dev
- Department of Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia
- School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
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Wang Q, Li M, Duan F, Xiao K, Sun QQ, Cheng JR, Ni L, Xu Z, Xu B, Xiao F, Kuai J, Wei W, Wang C. GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4. Cell Biol Toxicol 2024; 40:98. [PMID: 39546067 PMCID: PMC11567994 DOI: 10.1007/s10565-024-09940-y] [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: 06/04/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND The present study investigated the function of G protein-coupled receptor kinase 2 (GRK2) in acute liver injury (ALI) by cisplatin, and investigated the protective effect of pharmacological inhibition of GRK2. METHODS ALI models were generated in global adult hemizygous (ALI-Grk2±) mice and wild-type (WT) mice. Liver biochemistry parameters and histopathology were used to evaluate the severity of ALI and the protective effect of pharmacological inhibition of GRK2. GRK2-siRNA was used to knock down the expression of GRK2 in AML12 cells in vitro. RESULTS ALI model mice exhibited increased blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver pathology accompanied by imbalanced L-glutathione (GSH) levels. Cisplatin administration upregulated GKR2, p-GRK2 and NADPH oxidase 4 (NOX4) expression in the liver tissues of ALI model mice. Compared to WT mice injected with cisplatin, Grk2± mice that received cisplatin showed significant improvements in liver function and pathological performance, decreased NOX4 levels, reduced endoplasmic reticulum (ER) stress, and diminished liver cell apoptosis. In vitro, the transfection of AML12 cells with siRNA significantly reduced NOX4 expression and inhibited cisplatin-induced reactive oxygen species production, ER stress (increased levels of GRP94, GRP78, p-elF2α and CHOP) and apoptotic death. Moreover, pharmacological treatment with drugs that inhibit GRK2 (CP-25 or paroxetine) significantly ameliorated cisplatin-induced ALI by improving liver pathological manifestations, inhibiting oxidative stress and ER stress, and reducing liver cell apoptosis. Similar results were observed in vitro. CONCLUSIONS GRK2 mediates the development of cisplatin-induced ALI by modulating NOX4 and ER stress. Pharmacological inhibition of GRK2 with CP-25 or paroxetine effectively alleviated ALI. GRK2 can be used as a potential target for the prevention and treatment of liver injury.
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Affiliation(s)
- Qianlei Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Mengyang Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Fei Duan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Kangjun Xiao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Qing Qing Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Jiang Rui Cheng
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Lei Ni
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Zhengkun Xu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Bingfa Xu
- Department of Pharmacy, the Third Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Feng Xiao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Jiajie Kuai
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China.
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China.
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7
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Toofantabrizi M, Timshina A, Dongol RM. Cefepime-Induced Mixed Hepatocellular and Cholestatic Liver Injury: A Case Report. Cureus 2024; 16:e73393. [PMID: 39659312 PMCID: PMC11631161 DOI: 10.7759/cureus.73393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 12/12/2024] Open
Abstract
Drug-induced liver injury (DILI) presents significant diagnostic challenges, particularly in patients with multiple comorbidities. We report a case involving a 72-year-old female treated with cefepime for urosepsis, who developed markedly elevated liver enzymes after two weeks of therapy. After excluding other potential causes, including viral hepatitis, ischemia, and autoimmune hepatitis, cefepime-induced mixed pattern liver injury was determined to be the likely etiology of the elevated liver enzymes. This case underscores the importance of considering DILI in the differential diagnosis and emphasizes the necessity for vigilant monitoring and early recognition, particularly in elderly patients.
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Affiliation(s)
| | - Anuj Timshina
- Internal Medicine, MedStar Franklin Square Medical Center, Baltimore, USA
| | - Raj M Dongol
- Internal Medicine, MedStar Franklin Square Medical Center, Baltimore, USA
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8
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Ma C, Wolfinger RD. Toward an Explainable Large Language Model for the Automatic Identification of the Drug-Induced Liver Injury Literature. Chem Res Toxicol 2024; 37:1524-1534. [PMID: 39190012 DOI: 10.1021/acs.chemrestox.4c00134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
Drug-induced liver injury (DILI) stands as a significant concern in drug safety, representing the primary cause of acute liver failure. Identifying the scientific literature related to DILI is crucial for monitoring, investigating, and conducting meta-analyses of drug safety issues. Given the intricate and often obscure nature of drug interactions, simple keyword searching can be insufficient for the exhaustive retrieval of the DILI-relevant literature. Manual curation of DILI-related publications demands pharmaceutical expertise and is susceptible to errors, severely limiting throughput. Despite numerous efforts utilizing cutting-edge natural language processing and deep learning techniques to automatically identify the DILI-related literature, their performance remains suboptimal for real-world applications in clinical research and regulatory contexts. In the past year, large language models (LLMs) such as ChatGPT and its open-source counterpart LLaMA have achieved groundbreaking progress in natural language understanding and question answering, paving the way for the automated, high-throughput identification of the DILI-related literature and subsequent analysis. Leveraging a large-scale public dataset comprising 14 203 training publications from the CAMDA 2022 literature AI challenge, we have developed what we believe to be the first LLM specialized in DILI analysis based on LLaMA-2. In comparison with other smaller language models such as BERT, GPT, and their variants, LLaMA-2 exhibits an enhanced out-of-fold accuracy of 97.19% and area under the ROC curve of 0.9947 using 3-fold cross-validation on the training set. Despite LLMs' initial design for dialogue systems, our study illustrates their successful adaptation into accurate classifiers for automated identification of the DILI-related literature from vast collections of documents. This work is a step toward unleashing the potential of LLMs in the context of regulatory science and facilitating the regulatory review process.
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Affiliation(s)
- Chunwei Ma
- JMP Statistical Discovery, LLC, Cary, North Carolina 27513, United States
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9
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Gil-Pitarch C, Serrano-Maciá M, Simon J, Mosca L, Conter C, Rejano-Gordillo CM, Zapata-Pavas LE, Peña-Sanfélix P, Azkargorta M, Rodríguez-Agudo R, Lachiondo-Ortega S, Mercado-Gómez M, Delgado TC, Porcelli M, Aurrekoetxea I, Sutherland JD, Barrio R, Xirodimas D, Aspichueta P, Elortza F, Martínez-Cruz LA, Nogueiras R, Iruzubieta P, Crespo J, Masson S, McCain MV, Reeves HL, Andrade RJ, Lucena MI, Mayor U, Goikoetxea-Usandizaga N, González-Recio I, Martínez-Chantar ML. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway. Cell Rep Med 2024; 5:101653. [PMID: 39019009 PMCID: PMC11293357 DOI: 10.1016/j.xcrm.2024.101653] [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: 09/27/2023] [Revised: 02/28/2024] [Accepted: 06/19/2024] [Indexed: 07/19/2024]
Abstract
Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.
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Affiliation(s)
- Clàudia Gil-Pitarch
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Marina Serrano-Maciá
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Jorge Simon
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Laura Mosca
- Department of Life Sciences, Health and Health Professions, Link University, Via del Casale di San Pio V, 44 00165 Rome, Italy
| | - Carolina Conter
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Claudia M Rejano-Gordillo
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain
| | - L Estefanía Zapata-Pavas
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Patricia Peña-Sanfélix
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Mikel Azkargorta
- Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed-ISCIII, CIBERehd, Science and Technology Park of Bizkaia, 48160 Derio, Spain
| | - Rubén Rodríguez-Agudo
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Sofía Lachiondo-Ortega
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Maria Mercado-Gómez
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Teresa C Delgado
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Marina Porcelli
- Department of Life Sciences, Health and Health Professions, Link University, Via del Casale di San Pio V, 44 00165 Rome, Italy
| | - Igor Aurrekoetxea
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain; Biobizkaia Health Research Institute, 48903 Barakaldo, Spain
| | - James D Sutherland
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | - Rosa Barrio
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
| | | | - Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain; Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain
| | - Felix Elortza
- Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), ProteoRed-ISCIII, CIBERehd, Science and Technology Park of Bizkaia, 48160 Derio, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain
| | - Luis Alfonso Martínez-Cruz
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain
| | - Rubén Nogueiras
- Department of Physiology, School of Medicine-Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; Department of Physiology, CIMUS, 15782 University of Santiago de Compostela, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
| | - Paula Iruzubieta
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39011 Santander, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39011 Santander, Spain
| | - Steven Masson
- The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE7 7DN Newcastle upon Tyne, UK; Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK
| | - Misti Vanette McCain
- Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK
| | - Helen L Reeves
- The Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE7 7DN Newcastle upon Tyne, UK; Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, NE2 4HH Newcastle upon Tyne, UK
| | - Raul J Andrade
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain; Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29590 Málaga, Spain
| | - M Isabel Lucena
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, 29590 Málaga, Spain
| | - Ugo Mayor
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain
| | - Irene González-Recio
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain.
| | - María L Martínez-Chantar
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance, BRTA, Derio 48160 Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain.
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10
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Liu R, Jiang H, Yang W, Zheng Z, Wang X, Tian Z, Wang D, Kan D, Zhang D, Tang Z. Peroxynitrite imaging in ferroptosis-mediated drug-induced liver injury with a near-infrared fluorescence probe. Anal Chim Acta 2024; 1309:342673. [PMID: 38772656 DOI: 10.1016/j.aca.2024.342673] [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: 01/06/2024] [Revised: 04/18/2024] [Accepted: 05/01/2024] [Indexed: 05/23/2024]
Abstract
BACKGROUND Over-consumption of drugs can result in drug-induced liver damage (DILI), which can worsen liver failure. Numerous studies have shown the significant role ferroptosis plays in the pathophysiology of DILI, which is typified by a marked imbalance between the generation and breakdown of lipid reactive oxygen species (ROS). The content of peroxynitrite (ONOO-) rapidly increased during this process and was thought to be a significant marker of early liver injury. Therefore, the construction of fluorescence probe for the detection and imaging of ONOO- holds immense importance in the early diagnosis and treatment of ferroptosis-mediated DILI. RESULTS We designed a probe DILI-ONOO based on the ICT mechanism for the purpose of measuring and visualizing ONOO- in ferroptosis-mediated DILI processes and associated studies. This probe exhibited significant fluorescence changes with good sensitivity, selectivity, and can image exogenous and endogenous ONOO- in cells with low cytotoxicity. Using this probe, we were able to show changes in ONOO- content in ferroptosis-mediated DILI cells and mice models induced by the intervention of acetaminophen (APAP) and isoniazid (INH). By measuring the concentration of ferroptosis-related indicators in mice liver tissue, we were able to validate the role of ferroptosis in DILI. It is worth mentioning that compared to existing alanine transaminase (ALT) and aspartate aminotransferase (AST) detection methods, this probe can achieve early identification of DILI prior to serious liver injury. SIGNIFICANCE This work has significant reference value in researching the relationship between ferroptosis and DILI and visualizing research. The results indicate a strong correlation between the progression of DILI and ferroptosis. Additionally, the use of DILI-ONOO shows promise in investigating the DILI process and assessing the effectiveness of medications in treating DILI.
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Affiliation(s)
- Ruixin Liu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Haijing Jiang
- Wendeng Osteopathic Hospital of Shandong Province, Wendeng, 264400, China
| | - Wenjie Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Zhijuan Zheng
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xiaoming Wang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China; Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Zhenhua Tian
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China; Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Danyang Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Dongfang Kan
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Dan Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China; Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Zhixin Tang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China; Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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11
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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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12
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Mili A, Birangal S, Nandakumar K, Lobo R. A computational study to identify Sesamol derivatives as NRF2 activator for protection against drug-induced liver injury (DILI). Mol Divers 2024; 28:1709-1731. [PMID: 37392347 PMCID: PMC11269468 DOI: 10.1007/s11030-023-10686-8] [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: 01/07/2023] [Accepted: 06/23/2023] [Indexed: 07/03/2023]
Abstract
Drug-induced liver injury can be caused by any drugs, their metabolites, or natural products due to the inefficient functioning of drug-metabolizing enzymes, resulting in reactive oxygen species generation and leading to oxidative stress-induced cell death. For protection against oxidative stress, our cell has various defense mechanisms. One of the mechanisms is NRF2 pathway, when activated, protects the cell against oxidative stress. Natural antioxidants such as Sesamol have reported pharmacological activity (hepatoprotective & cardioprotective) and signaling pathways (NRF2 & CREM) altering potential. A Computational analysis was done using molecular docking, IFD, ADMET, MM-GBSA, and Molecular dynamic simulation of the Schrödinger suite. A total of 63,345 Sesamol derivatives were downloaded for the PubChem database. The protein structure of KEAP1-NRF2 (PDB: 4L7D) was downloaded from the RCSB protein database. The molecular docking technique was used to screen compounds that can form an interaction similar to the co-crystalized ligand (1VX). Based on MM-GBSA, docking score, and interactions, ten compounds were selected for ADMET profiling and IFD. After IFD, five compounds (66867225, 46148111, 12444939, 123892179, & 94817569) were selected for molecular dynamics simulation (MDS). Protein-ligand complex stability was assessed during MDS. The selected compounds (66867225, 46148111, 12444939, 123892179, & 94817569) complex with KEAP1 protein shows good stability and bond retentions. In our study, we observed that the selected compounds show good interaction, PCA, Rg, binding free energy, and ADMET profile. We can conclude that the selected compounds can act as NRF2 activators, which should be validated using proper in-vivo/in-vitro models.
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Affiliation(s)
- Ajay Mili
- Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Sumit Birangal
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Richard Lobo
- Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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13
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Alghzawi F, Jones R, Haas CJ. Turmeric-induced Liver Injury. J Community Hosp Intern Med Perspect 2024; 14:55-59. [PMID: 39036565 PMCID: PMC11259472 DOI: 10.55729/2000-9666.1332] [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: 08/31/2023] [Revised: 02/11/2024] [Accepted: 02/16/2024] [Indexed: 07/23/2024] Open
Abstract
The use of herbal and dietary supplements has gained an increasing foothold in the United States. While often touted as safer alternatives to more traditional "western" therapeutics, the pharmacology and pharmacokinetics of these substances, their interactions with other medications, their purity, and individual pharmacogenomics, remain unknown. Turmeric is a popular supplement that has been demonstrated to be safe, and even hepatoprotective. Recently, however, there have been several reports of turmeric-induced liver injury. We report a case of drug-induced liver injury due to turmeric that was complicated by acute liver failure and hepatorenal syndrome.
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Affiliation(s)
- Fadi Alghzawi
- MedStar Health Internal Medicine Residency Program, MedStar Union Memorial Hospital, Baltimore, MD,
USA
| | - Robert Jones
- Department of Pathology, MedStar Franklin Square Medical Center, Baltimore, MD,
USA
| | - Christopher J. Haas
- Department of Medicine, Georgetown University School of Medicine, Washington, DC,
USA
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14
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Abdelrazek FN, Shalaby RA, Fahim SA, Essam RM, Anis SE, Attia YM, Abd El Malak NS. Novel fast dissolving freeze dried sublingual baicalin tablets for enhanced hepatoprotective effect: in-vitro characterization, cell viability, and in-vivo evaluation. Pharm Dev Technol 2024; 29:371-382. [PMID: 38613468 DOI: 10.1080/10837450.2024.2341243] [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: 11/08/2023] [Accepted: 04/05/2024] [Indexed: 04/15/2024]
Abstract
Baicalin (BG), a natural product, has been used in the prevention and treatment of drug-induced liver injury (DILI); however, its poor solubility and extensive liver metabolism limit its pharmacological use. The aim of the present study was the formulation of fast-dissolving freeze-dried sublingual tablets (FFSTs) to increase BG dissolution, avoid first-pass metabolism, and overcome swallowing difficulties. FFSTs were prepared following a 23 factorial design. The effect of three independent variables namely matrix former, Maltodextrin, concentration (4%, and 6%), binder concentration (2%, and 3%), and binder type (Methocel E5, and Methocel E15) on the FFSTs' in-vitro disintegration time and percentage dissolution was studied along with other tablet characteristics. Differential scanning calorimetry, scanning electron microscopy, in-vitro HepG2 cell viability assay, and in-vivo characterization were also performed. F8 (6% Maltodextrin, 2% Mannitol, 2% Methocel E5), with desirability of 0.852, has been furtherly enhanced using 1%PEG (F10). F10 has achieved an in-vitro disintegration time of 41 secs, and 60.83% in-vitro dissolution after 2 min. Cell viability assay, in-vivo study in rats, and histopathological studies confirmed that pretreatment with F10 has achieved a significant hepatoprotective effect against acetaminophen-induced hepatotoxicity. The outcome of this study demonstrated that FFSTs may present a patient-friendly dosage form against DILI.
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Affiliation(s)
- Farida N Abdelrazek
- Pharmaceutics Department, School of Pharmacy, Newgiza University, Giza, Egypt
| | - Rodayna A Shalaby
- Pharmaceutics Department, School of Pharmacy, Newgiza University, Giza, Egypt
| | - Sally A Fahim
- Biochemistry Department, School of Pharmacy, Newgiza University, Giza, Egypt
| | - Reham M Essam
- Biology department, School of Pharmacy, Newgiza University, Giza, Egypt
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Shady E Anis
- Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yasmin M Attia
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nevine S Abd El Malak
- Pharmaceutics Department, School of Pharmacy, Newgiza University, Giza, Egypt
- Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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15
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Lee S, Yoo S. InterDILI: interpretable prediction of drug-induced liver injury through permutation feature importance and attention mechanism. J Cheminform 2024; 16:1. [PMID: 38173043 PMCID: PMC10765872 DOI: 10.1186/s13321-023-00796-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 12/17/2023] [Indexed: 01/05/2024] Open
Abstract
Safety is one of the important factors constraining the distribution of clinical drugs on the market. Drug-induced liver injury (DILI) is the leading cause of safety problems produced by drug side effects. Therefore, the DILI risk of approved drugs and potential drug candidates should be assessed. Currently, in vivo and in vitro methods are used to test DILI risk, but both methods are labor-intensive, time-consuming, and expensive. To overcome these problems, many in silico methods for DILI prediction have been suggested. Previous studies have shown that DILI prediction models can be utilized as prescreening tools, and they achieved a good performance. However, there are still limitations in interpreting the prediction results. Therefore, this study focused on interpreting the model prediction to analyze which features could potentially cause DILI. For this, five publicly available datasets were collected to train and test the model. Then, various machine learning methods were applied using substructure and physicochemical descriptors as inputs and the DILI label as the output. The interpretation of feature importance was analyzed by recognizing the following general-to-specific patterns: (i) identifying general important features of the overall DILI predictions, and (ii) highlighting specific molecular substructures which were highly related to the DILI prediction for each compound. The results indicated that the model not only captured the previously known properties to be related to DILI but also proposed a new DILI potential substructural of physicochemical properties. The models for the DILI prediction achieved an area under the receiver operating characteristic (AUROC) of 0.88-0.97 and an area under the Precision-Recall curve (AUPRC) of 0.81-0.95. From this, we hope the proposed models can help identify the potential DILI risk of drug candidates at an early stage and offer valuable insights for drug development.
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Affiliation(s)
- Soyeon Lee
- Department of ICT Convergence System Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Division of Bioresources Bank, Honam National Institute of Biological Resources, Mokpo, 58762, Republic of Korea
| | - Sunyong Yoo
- Department of ICT Convergence System Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea.
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16
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Alatawi FS, Omran AME, Alatawi MS, Rashad E, Yasin NAE, Soliman AF. Network Pharmacology Prediction and Experimental Validation of Ferulic Acid’s Protective Effects against Diclofenac‐Induced Liver Injury. J Food Biochem 2024; 2024. [DOI: 10.1155/2024/5592390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/04/2024] [Indexed: 07/31/2024]
Abstract
Despite being one of the most consumed analgesics worldwide, liver injury is an adverse effect of diclofenac (DF). In pursuit of reliable hepatoprotective natural remedies, this study aimed to investigate the potential protective effect of ferulic acid (FA) and its mechanism against DF‐induced liver injury. Various network databases and datasets were used to collect targets corresponding to FA and DF‐induced liver injury. Enrichment analyses of common targets were performed, a protein‐protein interaction (PPI) network was constructed, the hub genes were identified, and the upstream miRNA interacting with the top hub gene was later predicted. A DF‐induced liver injury rat model was established to verify FA’s protective effects, and the selected hub gene expression level with its upstream regulatory miRNA and a downstream set of targets was examined to elucidate the underlying mechanism. A total of 18 genes were identified as potential targets of FA to protect against DF‐induced liver injury. Data from the enrichment and PPI analyses and the prediction of the upstream miRNAs indicated that the most worthwhile pair to study was miR‐296‐5p/Jun. In vivo findings showed that coadministration of FA significantly reduced the DF‐induced alterations in the liver function indices, oxidative stress, and liver histology. Mechanistically, FA downregulated the expression of Jun, Bim, Bax, Casp3, IL‐1β, IL‐6, and TNF‐α, whereas it upregulated the expression of rno‐miR‐296‐5p and Bcl2. In conclusion, combining network pharmacology and an in vivo study revealed that miR‐296‐5p/Jun axis could mediate the mitigative effect of FA against DF‐induced liver injury.
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17
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Wang J, Zhang L, Sun J, Yang X, Wu W, Chen W, Zhao Q. Predicting drug-induced liver injury using graph attention mechanism and molecular fingerprints. Methods 2024; 221:18-26. [PMID: 38040204 DOI: 10.1016/j.ymeth.2023.11.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/14/2023] [Accepted: 11/25/2023] [Indexed: 12/03/2023] Open
Abstract
Drug-induced liver injury (DILI) is a significant issue in drug development and clinical treatment due to its potential to cause liver dysfunction or damage, which, in severe cases, can lead to liver failure or even fatality. DILI has numerous pathogenic factors, many of which remain incompletely understood. Consequently, it is imperative to devise methodologies and tools for anticipatory assessment of DILI risk in the initial phases of drug development. In this study, we present DMFPGA, a novel deep learning predictive model designed to predict DILI. To provide a comprehensive description of molecular properties, we employ a multi-head graph attention mechanism to extract features from the molecular graphs, representing characteristics at the level of compound nodes. Additionally, we combine multiple fingerprints of molecules to capture features at the molecular level of compounds. The fusion of molecular fingerprints and graph features can more fully express the properties of compounds. Subsequently, we employ a fully connected neural network to classify compounds as either DILI-positive or DILI-negative. To rigorously evaluate DMFPGA's performance, we conduct a 5-fold cross-validation experiment. The obtained results demonstrate the superiority of our method over four existing state-of-the-art computational approaches, exhibiting an average AUC of 0.935 and an average ACC of 0.934. We believe that DMFPGA is helpful for early-stage DILI prediction and assessment in drug development.
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Affiliation(s)
- Jifeng Wang
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan 114051, China
| | - Li Zhang
- School of Life Science, Liaoning University, Shenyang 110036, China
| | - Jianqiang Sun
- School of Information Science and Engineering, Linyi University, Linyi 276000, China
| | - Xin Yang
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan 114051, China
| | - Wei Wu
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan 114051, China
| | - Wei Chen
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Qi Zhao
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan 114051, China.
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18
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Marín-Romero A, Regele V, Kolanovic D, Hofner M, Díaz-Mochón JJ, Nöhammer C, Pernagallo S. MAGPIX and FLEXMAP 3D Luminex platforms for direct detection of miR-122-5p through dynamic chemical labelling. Analyst 2023; 148:5658-5666. [PMID: 37807710 DOI: 10.1039/d3an01250f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
MicroRNAs (miRs) have emerged as promising biomarkers for diagnosing and predicting the prognosis of liver injury. This study aimed to compare the performance of two Luminex platforms, MAGPIX and FLEXMAP 3D, utilizing the innovative Dynamic Chemical Labelling (DCL) technology for direct detection and analysis of miR-122-5p in serum samples from patients with liver injury. Serum samples were collected from four patients with liver injury and four healthy controls. The levels of miR-122-5p were measured using the DCL method on both MAGPIX and FLEXMAP 3D platforms. The performance evaluation included the limit of detection (LOD), intra-assay and inter-assay precision, as well as accuracy. The results demonstrated that both platforms exhibited high sensitivity and specificity in detecting miR-122-5p in serum samples from patients with liver injury. However, FLEXMAP 3D indicated a lower LOD compared to MAGPIX. The precision of miR-122-5p detection was similar between the two platforms. In conclusion, both MAGPIX and FLEXMAP 3D Luminex platforms, in conjunction with DCL reagents, proved to be reliable and sensitive tools for detecting miR-122-5p in serum samples from patients with liver injury. Although both platforms were effective, FLEXMAP 3D exhibited slightly better performance, suggesting its preference for miR detection in clinical settings. These findings offer valuable insights for selecting the appropriate Luminex platform for miR detection in patients with liver injury and beyond.
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Affiliation(s)
- Antonio Marín-Romero
- DESTINA Genomica S.L. Parque Tecnológico Ciencias de la Salud (PTS), Edificio BIC, Avenida de la Innovación 1, Granada 18016, Spain.
| | - Valerie Regele
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Dajana Kolanovic
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Manuela Hofner
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Juan José Díaz-Mochón
- Department of Medicinal & Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada, Spain
- GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government., PTS Granada - Avenida de la Ilustración, 114, 18016, Granada, Spain
- Unit of Excellence in Chemistry Applied to Biomedicine and the Environment of the University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
| | - Christa Nöhammer
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Salvatore Pernagallo
- DESTINA Genomica S.L. Parque Tecnológico Ciencias de la Salud (PTS), Edificio BIC, Avenida de la Innovación 1, Granada 18016, Spain.
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Shi M, Zhang J, Li M, Zhao Y, Guo Y, Xu J, Liu R, Li Z, Ren D, Liu P. Liquiritigenin Confers Liver Protection by Enhancing NRF2 Signaling through Both Canonical and Non-canonical Signaling Pathways. J Med Chem 2023; 66:11324-11334. [PMID: 37534604 DOI: 10.1021/acs.jmedchem.3c00815] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Abstract
Oxidative stress plays a critical role in drug-induced liver injury. In recent years, liquiritigenin (LQ), a natural flavonoid distributed in Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effects against oxidative hepatotoxicity. However, the underlying mechanism remains unclear. In this study, we mainly investigated the role of NRF2, a core transcription factor in oxidative stress, in LQ-induced hepatoprotection. Our results indicated that the function of LQ to eliminate reactive oxygen species in liver cells was dependent on NRF2 activation. Both a canonical signaling pathway and a non-canonical signaling pathway are involved in LQ-induced NRF2 activation. LQ induced NRF2 activation in a KEAP1-C151-dependent manner partially. Meanwhile, LQ led to the blockage of autophagic flux and upregulation of p62, which competitively bound with KEAP1 and conferred NRF2 activation in a KEAP1-C151-independent manner. Totally, our study reveals a novel molecular mechanism underlying the hepatoprotection of LQ, providing a new insight into the pathogenesis and therapeutic strategy of oxidative liver injury.
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Affiliation(s)
- Mengjiao Shi
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Jian Zhang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Miaomiao Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun 130021, China
| | - Yaping Zhao
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Ying Guo
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Jiayi Xu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Rongrong Liu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
| | - Pengfei Liu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Key Laboratory of Environment and Genes Related To Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an 710061, China
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20
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Abstract
Aminopeptidase N (APN), a transmembrane ectoenzyme, plays multifunctional roles in cell survival and migration, angiogenesis, blood pressure regulation, and viral uptake. Abnormally high levels of the enzyme can be found in some tumors and injured liver and kidney. Therefore, noninvasive detection methods for APN are in demand for diagnosing and studying the associated diseases, leading to two dozen activatable small-molecule probes reported up to date. All of the known probes, however, analyze the enzyme activity by monitoring fluorescent molecules inside cells, despite the enzymatic reaction taking place on the outer cell membrane. In this case, different cell permeability and enzyme kinetics can cause false signal data. To address this critical issue, we have developed two cell-membrane-localizing APN probes whose enzymatic products also localize the outer cell membrane. The probes selectively respond to APN with ratiometric fluorescence signal changes. A selected probe, which has two-photon imaging capability, allowed us to determine the relative APN levels in various organ tissues for the first time: 4.3 (intestine), 2.1 (kidney), 2.7 (liver), 3.2 (lung), and 1.0 (stomach). Also, a higher APN level was observed from a HepG2-xenograft mouse tissue in comparison with the normal tissue. Furthermore, we observed a significant APN level increase in the mouse liver of a drug (acetaminophen)-induced liver injury model. The probe thus offers a reliable means for studying APN-associated biology including drug-induced hepatotoxicity simply by ratiometric imaging.
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Affiliation(s)
- Yun Jae Yang
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Mingchong Dai
- CEDAR, Knight Cancer Institute, School of Medicine, Oregon Health and Science University, Portland, Oregon 97201, United States
| | - Kyo Han Ahn
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, South Korea
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21
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Kosuta I, Ostojic A, Vujaklija Brajkovic A, Babel J, Simunov B, Sremac M, Mrzljak A. Shifting perspectives in liver diseases after kidney transplantation. World J Hepatol 2023; 15:883-896. [PMID: 37547033 PMCID: PMC10401415 DOI: 10.4254/wjh.v15.i7.883] [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: 03/26/2023] [Revised: 05/15/2023] [Accepted: 06/06/2023] [Indexed: 07/21/2023] Open
Abstract
Liver diseases after kidney transplantation range from mild biochemical abnormalities to severe hepatitis or cirrhosis. The causes are diverse and mainly associated with hepatotropic viruses, drug toxicity and metabolic disorders. Over the past decade, the aetiology of liver disease in kidney recipients has changed significantly. These relates to the use of direct-acting antiviral agents against hepatitis C virus, the increasing availability of vaccination against hepatitis B and a better understanding of drug-induced hepatotoxicity. In addition, the emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has brought new challenges to kidney recipients. This review aims to provide healthcare professionals with a comprehensive understanding of recent advances in the management of liver complications in kidney recipients and to enable them to make informed decisions regarding the risks and impact of liver disease in this population.
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Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia.
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ana Vujaklija Brajkovic
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Jaksa Babel
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Bojana Simunov
- Department of Nephrology, University Hospital Merkur, Zagreb 10000, Croatia
| | - Maja Sremac
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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22
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Cho KH, Kim JE, Komatsu T, Uehara Y. Protection of Liver Functions and Improvement of Kidney Functions by Twelve Weeks Consumption of Cuban Policosanol (Raydel ®) with a Decrease of Glycated Hemoglobin and Blood Pressure from a Randomized, Placebo-Controlled, and Double-Blinded Study with Healthy and Middle-Aged Japanese Participants. Life (Basel) 2023; 13:1319. [PMID: 37374102 DOI: 10.3390/life13061319] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Policosanol consumption has been associated with treating blood pressure and dyslipidemia by increasing the level of high-density lipoproteins-cholesterol (HDL-C) and HDL functionality. Although policosanol supplementation also ameliorated liver function in animal models, it has not been reported in a human clinical study, particularly with a 20 mg doage of policosanol. In the current study, twelve-week consumption of Cuban policosanol (Raydel®) significantly enhanced the hepatic functions, showing remarkable decreases in hepatic enzymes, blood urea nitrogen, and glycated hemoglobin. From the human trial with Japanese participants, the policosanol group (n = 26, male 13/female 13) showed a remarkable decrease in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline up to 21% (p = 0.041) and 8.7% (p = 0.017), respectively. In contrast, the placebo group (n = 26, male 13/female 13) showed almost no change or slight elevation. The policosanol group showed a 16% decrease in γ-glutamyl transferase (γ-GTP) at week 12 from the baseline (p = 0.015), while the placebo group showed a 1.2% increase. The policosanol group exhibited significantly lower serum alkaline phosphatase (ALP) levels at week 8 (p = 0.012), week 12 (p = 0.012), and after 4-weeks (p = 0.006) compared to those of the placebo group. After 12 weeks of policosanol consumption, the ferric ion reduction ability and paraoxonase of serum were elevated by 37% (p < 0.001) and 29% (p = 0.004) higher than week 0, while placebo consumption showed no notable changes. Interestingly, glycated hemoglobin (HbA1c) in serum was lowered significantly in the policosanol group 4 weeks after consumption, which was approximately 2.1% (p = 0.004) lower than the placebo group. In addition, blood urea nitrogen (BUN) and uric acid levels were significantly lower in the policosanol group after 4 weeks: 14% lower (p = 0.002) and 4% lower (p = 0.048) than those of the placebo group, respectively. Repeated measures of ANOVA showed that the policosanol group had remarkable decreases in AST (p = 0.041), ALT (p = 0.008), γ-GTP (p = 0.016), ALP (p = 0.003), HbA1c (p = 0.010), BUN (p = 0.030), and SBP (p = 0.011) from the changes in the placebo group in point of time and group interaction. In conclusion, 12 weeks of 20 mg consumption of policosanol significantly enhanced hepatic protection by lowering the serum AST, ALT, ALP, and γ-GTP via a decrease in glycated hemoglobin, uric acid, and BUN with an elevation of serum antioxidant abilities. These results suggest that improvements in blood pressure by consumption of 20 mg of policosanol (Raydel®) were accompanied by protection of liver function and enhanced kidney function.
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Affiliation(s)
- Kyung-Hyun Cho
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Ji-Eun Kim
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Tomohiro Komatsu
- Center for Preventive, Anti-Aging and Regenerative Medicine, Fukuoka University Hospital, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Faculty of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Yoshinari Uehara
- Center for Preventive, Anti-Aging and Regenerative Medicine, Fukuoka University Hospital, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Faculty of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
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23
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Singh S, Kumar PVSNK, Kumar JP, Tomo S, Yadav D, Sharma P, Rao M, Banerjee M. Genetic and Epigenetic Basis of Drug-Induced Liver Injury. Semin Liver Dis 2023; 43:163-175. [PMID: 37225145 DOI: 10.1055/a-2097-0531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Drug-induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of postmarketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors, can contribute to development and progression of DILI. Studies on microRNA, histone modification, DNA methylation, and single nucleotide polymorphisms related to DILI were retrieved from databases and were analyzed for the current research and updated to develop this narrative review. We have compiled some of the major genetic, epigenetic, and pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolizing enzymes, HLA alleles, and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and on implementation of personalized medicine.
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Affiliation(s)
- Snigdha Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - P V S N Kiran Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - J Pradeep Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Dharamveer Yadav
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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24
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Molecular Mechanisms of Hepatotoxicity. Int J Mol Sci 2023; 24:ijms24043791. [PMID: 36835204 PMCID: PMC9961832 DOI: 10.3390/ijms24043791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
Drug-induced liver injury, also known as drug-induced hepatotoxicity (DILI), is a major cause of medicine withdrawal (prescription or over-the-counter) from the market [...].
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25
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Muacevic A, Adler JR, Coombes K, Moin K, Joseph BM, Funk CM. Remdesivir-Associated Acute Liver Failure in a COVID-19 Patient: A Case Report and Literature Review. Cureus 2023; 15:e34221. [PMID: 36852363 PMCID: PMC9960027 DOI: 10.7759/cureus.34221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2023] [Indexed: 01/27/2023] Open
Abstract
There is a broad classification of the causes of acute liver failure (ALF) that include drug-induced liver injury (DILI). In this report, we aim to discuss the association between remdesivir, a novel therapeutic drug for hypoxic coronavirus disease 2019 (COVID-19) pneumonia, and DILI with subsequent ALF in a patient who was recently treated with the drug in question. Remdesivir, which is a direct-acting nucleoside RNA polymerase inhibitor, is one of the only FDA-approved drugs on the market for COVID-19 pneumonia associated with hypoxia. Our case describes a patient with an extensive past medical history who was treated for COVID-19 pneumonia with remdesivir and subsequently developed ALF in the absence of all other possible etiologies. This association has only been highlighted in anecdotal case reports in the past and to a lesser degree in the safety documentation of remdesivir.
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26
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Wang N, Chen X, Hao Z, Guo J, Wang X, Zhu X, Yi H, Wang Q, Tang S. Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis. J Trop Med 2022; 2022:8266878. [PMID: 36249736 PMCID: PMC9553535 DOI: 10.1155/2022/8266878] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/30/2022] [Accepted: 07/28/2022] [Indexed: 11/25/2022] Open
Abstract
Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed, and the protocol was registered in PROSPERO (CRD42020200077). Five electronic databases were searched to identify eligible studies published between 1990 and 2022. Search terms included anti-TB treatment and drug-induced liver injury. Studies that reported the incidence of ATLI or provided sufficient data to calculate the incidence of ATLI were included, and duplicate studies were excluded. Meta-analysis was conducted on the basis of logit-transformed metrics for the incidence of ATLI with 95% confidence intervals (CIs), followed by a predefined subgroup meta-analysis. Temporal trend analyses were performed to describe the change in pooled incidence over time. A random effects metaregression was conducted to explore the source of heterogeneity. All statistical analyses were carried out using R 4.0.1. Results A total of 160 studies from 156 records with 116147 patients were included in the meta-analysis. Based on the random effects model, the pooled incidence of ATLI was 11.50% (95% CI: 10.10%-12.97%) and showed an upward trend over time (P < 0.001). Patients who received first-line anti-TB drugs, patients in South America, and patients with hepatitis B and C virus coinfection had a higher incidence of ATLI (13.66%, 18.16%, and 39.19%, respectively). Sensitivity analyses also confirmed this robust incidence after the exclusion of some studies. The metaregression showed that different anti-TB regimens and geographical regions were important explanatory factors of the heterogeneity between studies. Conclusions The present systematic review provided a basis for estimating the incidence of ATLI worldwide, which varied among patients with different anti-TB regimens in different geographical regions and with different coinfections and had an upward trend. Regular liver function monitoring is imperative for patient safety during the anti-TB treatment course.
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Affiliation(s)
- Nannan Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinyu Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhuolu Hao
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jia Guo
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xuwen Wang
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Xijing Zhu
- First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Honggang Yi
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qingliang Wang
- Department of Medical Affairs, Qilu Hospital of Shandong University, Jinan, China
| | - Shaowen Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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27
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Aquino-Matus J, Uribe M, Chavez-Tapia N. COVID-19: Current Status in Gastrointestinal, Hepatic, and Pancreatic Diseases—A Concise Review. Trop Med Infect Dis 2022; 7:tropicalmed7080187. [PMID: 36006279 PMCID: PMC9415805 DOI: 10.3390/tropicalmed7080187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/09/2022] [Accepted: 08/09/2022] [Indexed: 01/08/2023] Open
Abstract
The gastrointestinal tract plays an important role in the pathogenesis of COVID-19. The angiotensin-converting enzyme 2 receptor and the transmembrane protease serine 2 receptor bind and activate SARS-CoV-2 and are present in high concentrations throughout the gastrointestinal tract. Most patients present with gastrointestinal symptoms and/or abnormal liver function tests, both of which have been associated with adverse outcomes. The mechanisms of liver damage are currently under investigation, but the damage is usually transient and nonsevere. Liver transplantation is the only definitive treatment for acute liver failure and end-stage liver disease, and unfortunately, because of the need for ventilators during the COVID-19 pandemic, most liver transplant programs have been suspended. Patients with gastrointestinal autoimmune diseases require close follow-up and may need modification in immunosuppression. Acute pancreatitis is a rare manifestation of COVID-19, but it must be considered in patients with abdominal pain. The gastrointestinal tract, including the liver and the pancreas, has an intimate relationship with COVID-19 that is currently under active investigation.
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28
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Liu W, Wang N, Zhu J, Zhang M, Lu L, Pan H, He X, Yi H, Tang S. The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study. Therapie 2022; 78:259-266. [DOI: 10.1016/j.therap.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/06/2022] [Accepted: 05/23/2022] [Indexed: 10/18/2022]
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29
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Zhang M, Zhu J, Wang N, Liu W, Lu L, Pan H, He X, Yi H, Tang S. The role of the genetic variant FECH rs11660001 in the occurrence of anti-tuberculosis drug-induced liver injury. J Clin Pharm Ther 2022; 47:1276-1283. [PMID: 35470464 DOI: 10.1111/jcpt.13672] [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: 03/25/2022] [Accepted: 03/31/2022] [Indexed: 11/30/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE The pathogenic mechanism of anti-tuberculosis drug-induced liver injury (AT-DILI) is still largely unknown. Recent studies have indicated that rifampicin and isoniazid cotreatment causes the accumulation of endogenous protoporphyrin IX in the liver through the haem biosynthesis pathway. Alanine synthase 1 (ALAS1) and ferrochelatase (FECH) are the rate-limiting enzymes in the production of haem. The present study aimed to investigate the genetic contribution of the ALAS1 and FECH genes to the risk of AT-DILI in an Eastern Chinese Han population. METHODS A 1:4 matched case-control study was conducted, and eight SNPs in the ALAS1 and FECH genes were detected and assessed. A multivariate conditional logistic regression model was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking and drinking history as covariates. RESULTS AND DISCUSSION Overall, 202 AT-DILI cases and 808 controls were included in this study. The female patients carrying polymorphisms of rs11660001 in FECH had an increased risk of AT-DILI under the dominant and additive models (OR = 1.831, 95% CI: 1.014-3.307, p = 0.045; OR = 1.673, 95% CI: 1.015-2.760, p = 0.044, respectively). The peak aspartate transaminase level was significantly higher in female patients carrying the GA+AA genotype of rs11660001 than in those with the GG genotype during anti-TB treatment (p = 0.032). WHAT IS NEW AND CONCLUSION Based on this 1:4 individual matched case-control study, SNP rs11660001 in the FECH gene may be associated with susceptibility to AT-DILI in Chinese female anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.
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Affiliation(s)
- Meiling Zhang
- Department of Infectious Disease, The Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Jia Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Nannan Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wenpei Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lihuan Lu
- Department of Tuberculosis, The Second People's Hospital of Changshu, Changshu, China
| | - Hongqiu Pan
- Department of Tuberculosis, The Third People's Hospital of Zhenjiang Affiliated to Jiangsu University, Zhenjiang, China
| | - Xiaomin He
- Department of Infectious Disease, The People's Hospital of Taixing, Taixing, China
| | - Honggang Yi
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shaowen Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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30
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Kim C, Zhu S, Kouros-Mehr H, Khaldoyanidi S. Incidence of Elevated Aminotransferases With or Without Bilirubin Elevation During Treatment With Immune Checkpoint Inhibitors: A Retrospective Study of Patients From Community Oncology Clinics in the United States. Cureus 2022; 14:e24053. [PMID: 35573501 PMCID: PMC9095812 DOI: 10.7759/cureus.24053] [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] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction The elevation of aminotransferase levels is regarded as an indicator of hepatocellular injury. The objective of this study was to describe real-world incidence of elevated aminotransferase levels with or without bilirubin elevation among patients treated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods This retrospective cohort study used an electronic health record database representing > 1.5 million active United States (US) cancer patients and included patients diagnosed with any cancer between January 1, 2014 and March 31, 2019, and treated with one or more ICIs such as ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The frequency, onset, duration, management of grade ≥ 3 elevation of aminotransferase levels with or without bilirubin elevation events, progression rate from isolated elevation of aminotransferase levels (IAT) to elevated aminotransferase levels with elevated bilirubin (ATWB), and mortality were described. Results Overall, 69,140 patients received 85,433 treatment courses. A total of 1,799 (2.11%) IAT and 441 (0.52%) ATWB events were observed during treatment courses. The median onset was 51 and 42 days for IAT and ATWB, respectively, across treatment courses, and the median duration of both was approximately seven days. Approximately 5% (n=96) of IAT events progressed to ATWB in a median time of 11 days. The proportion of patients who received corticosteroids after elevated aminotransferase levels with or without bilirubin was ~37% (n=671/1,799 of IAT and n=147/441 of ATWB) and ~8% discontinued ICI treatment (n=118/1,799 of IAT and n=43/441 of ATWB). About 46% (n=68/147) of ATWB and and 25% (n=172/671) of IAT events treated with steroids led to death within 45 days. Similarly, 49% (n=21/43) of ATWB and 35% (n=42/118) of IAT events leading to treatment discontinuation led to death within 45 days. Conclusions Real-world data from oncology clinics in US suggest low incidence of grade ≥ 3 elevated aminotransferase levels with or without bilirubin elevation following treatment with ICIs. In most cases, ICI treatment was not discontinued and management of elevated aminotransferases consisted of corticosteroid treatment in one-third of cases.
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Affiliation(s)
- Christopher Kim
- Center for Observational Research, Amgen Inc., Thousand Oaks, USA
| | - Shao Zhu
- Biostatistics, Simulstat Inc., San Diego, USA
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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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Akimoto H, Nagashima T, Minagawa K, Hayakawa T, Takahashi Y, Asai S. Signal Detection of Potential Hepatotoxic Drugs: Case-Control Study Using Both a Spontaneous Reporting System and Electronic Medical Records. Biol Pharm Bull 2021; 44:1514-1523. [PMID: 34602560 DOI: 10.1248/bpb.b21-00407] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.
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Affiliation(s)
- Hayato Akimoto
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Takuya Nagashima
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Kimino Minagawa
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine
| | - Takashi Hayakawa
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Yasuo Takahashi
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine
| | - Satoshi Asai
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
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Akhilraj AR, Bhat S, Priyalatha B, Vimala KS. Comparative hepatoprotective activity of detoxified roots of Plumbago zeylanica L. and Plumbago rosea L. in Wistar rats. J Ayurveda Integr Med 2021; 12:452-457. [PMID: 34366166 PMCID: PMC8377173 DOI: 10.1016/j.jaim.2021.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/23/2020] [Accepted: 04/03/2021] [Indexed: 11/17/2022] Open
Abstract
Background Paracetamol (acetaminophen) toxicity is considered to be one of the major causes of drug-induced hepatic failure. Citraka (Plumbago rosea L. and Plumbago zeylanica L.) was mentioned in Ayurveda classics as a remedy in liver disorders. Objective(s) The aim of the study was to experimentally evaluate the comparative effect of hepatoprotective activity of detoxified root decoction of the two species of Citraka against paracetamol-induced hepatotoxicity in male Wistar albino rats. Materials and methods The hepatoprotective effect of Citraka decoction of two species was evaluated by the assessment of biochemical parameters such as SGOT, SGPT, alkaline phosphatase, total bilirubin, direct bilirubin, and serum creatinine. The study was also supported by histopathological assessment of liver sections. Results The results showed the elevated concentration of biochemical markers and histopathological degenerative changes in animals treated with paracetamol indicating severe hepatic damage; whereas, the treatment with decoction of both the species of Citraka showed significant reduction in the serum markers and regenerative changes in the histopathological specimens pointing towards its effectiveness as a hepatoprotective drug. Conclusion The present study showed Citraka’s effectiveness as a hepatoprotective drug and proved that the detoxified root decoction of P. rosea L. has a significant protective activity against paracetamol-induced hepatotoxicity than P. zeylanica L.
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Affiliation(s)
- A R Akhilraj
- Department of Dravyaguna (Ayurvedic Pharmacology), Amrita School of Ayurveda, Amritapuri, Amrita Vishwa Vidyapeetham, India.
| | - Sudhakar Bhat
- Department of Pharmacology, Sri Dharmasthala Manjunatheshwara Centre for Research in Ayurveda and Allied Science, Udupi, India
| | - B Priyalatha
- Department of Dravyaguna (Ayurvedic Pharmacology), Amrita School of Ayurveda, Amritapuri, Amrita Vishwa Vidyapeetham, India
| | - K S Vimala
- Department of Dravyaguna (Ayurvedic Pharmacology), Amrita School of Ayurveda, Amritapuri, Amrita Vishwa Vidyapeetham, India
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Ballotin VR, Bigarella LG, Brandão ABDM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases 2021; 9:5490-5513. [PMID: 34307603 PMCID: PMC8281430 DOI: 10.12998/wjcc.v9.i20.5490] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/03/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI). AIM To identify herbal products associated with HILI and describe the type of lesion associated with each product. METHODS Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results. RESULTS The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively. CONCLUSION HILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.
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Affiliation(s)
| | | | - Ajacio Bandeira de Mello Brandão
- Post-Graduate Program in Medicine, Division of Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-110, RS, Brazil
| | - Raul Angelo Balbinot
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
| | - Silvana Sartori Balbinot
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
| | - Jonathan Soldera
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
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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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36
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Sonn BJ, Heard KJ, Heard SM, D'Alessandro A, Reynolds KM, Dart RC, Rumack BH, Monte AA. Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen. Clin Toxicol (Phila) 2021; 60:221-230. [PMID: 34047639 DOI: 10.1080/15563650.2021.1925686] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.
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Affiliation(s)
- Brandon J Sonn
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Center for Bioinformatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Kennon J Heard
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
| | - Susan M Heard
- Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
| | - Angelo D'Alessandro
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.,Department of Structural Biology and Biochemistry, Metabolomics Core, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kate M Reynolds
- Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
| | - Richard C Dart
- Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
| | - Barry H Rumack
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
| | - Andrew A Monte
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Center for Bioinformatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA.,Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.,Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority, Denver, CO, USA
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Mega A, Marzi L, Kob M, Piccin A, Floreani A. Food and Nutrition in the Pathogenesis of Liver Damage. Nutrients 2021; 13:nu13041326. [PMID: 33923822 PMCID: PMC8073814 DOI: 10.3390/nu13041326] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 11/19/2022] Open
Abstract
The liver is an important organ and plays a key role in the regulation of metabolism and in the secretion, storage, and detoxification of endogenous and exogenous substances. The impact of food and nutrition on the pathophysiological mechanisms of liver injury represents a great controversy. Several environmental factors including food and micronutrients are involved in the pathogenesis of liver damage. Conversely, some xenobiotics and micronutrients have been recognized to have a protective effect in several liver diseases. This paper offers an overview of the current knowledge on the role of xenobiotics and micronutrients in liver damage.
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Affiliation(s)
- Andrea Mega
- Gastroenterology Department, Bolzano Regional Hospital, 39100 Bolzano, Italy;
- Correspondence:
| | - Luca Marzi
- Gastroenterology Department, Bolzano Regional Hospital, 39100 Bolzano, Italy;
| | - Michael Kob
- Dietetics and Clinical Nutrition Unit, Bolzano Regional Hospital, 39100 Bolzano, Italy;
| | - Andrea Piccin
- Northern Ireland Blood Transfusion Service, Belfast BT9 7TS, UK;
- Department of Internal Medicine V, Medical University of Innsbruck, A-6020 Innsbruck, Austria
- Department of Industrial Engineering, University of Trento, 38100 Trento, Italy
| | - Annarosa Floreani
- Scientific Institute for Research, Hospitalization and Healthcare, 37024 Negrar-Verona, Italy;
- Department Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
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Aguirre-Plans J, Piñero J, Souza T, Callegaro G, Kunnen SJ, Sanz F, Fernandez-Fuentes N, Furlong LI, Guney E, Oliva B. An ensemble learning approach for modeling the systems biology of drug-induced injury. Biol Direct 2021; 16:5. [PMID: 33435983 PMCID: PMC7805064 DOI: 10.1186/s13062-020-00288-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 12/09/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) is an adverse reaction caused by the intake of drugs of common use that produces liver damage. The impact of DILI is estimated to affect around 20 in 100,000 inhabitants worldwide each year. Despite being one of the main causes of liver failure, the pathophysiology and mechanisms of DILI are poorly understood. In the present study, we developed an ensemble learning approach based on different features (CMap gene expression, chemical structures, drug targets) to predict drugs that might cause DILI and gain a better understanding of the mechanisms linked to the adverse reaction. RESULTS We searched for gene signatures in CMap gene expression data by using two approaches: phenotype-gene associations data from DisGeNET, and a non-parametric test comparing gene expression of DILI-Concern and No-DILI-Concern drugs (as per DILIrank definitions). The average accuracy of the classifiers in both approaches was 69%. We used chemical structures as features, obtaining an accuracy of 65%. The combination of both types of features produced an accuracy around 63%, but improved the independent hold-out test up to 67%. The use of drug-target associations as feature obtained the best accuracy (70%) in the independent hold-out test. CONCLUSIONS When using CMap gene expression data, searching for a specific gene signature among the landmark genes improves the quality of the classifiers, but it is still limited by the intrinsic noise of the dataset. When using chemical structures as a feature, the structural diversity of the known DILI-causing drugs hampers the prediction, which is a similar problem as for the use of gene expression information. The combination of both features did not improve the quality of the classifiers but increased the robustness as shown on independent hold-out tests. The use of drug-target associations as feature improved the prediction, specially the specificity, and the results were comparable to previous research studies.
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Affiliation(s)
- Joaquim Aguirre-Plans
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
| | - Janet Piñero
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
| | - Terezinha Souza
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Giulia Callegaro
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Steven J. Kunnen
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Ferran Sanz
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
| | - Narcis Fernandez-Fuentes
- Department of Biosciences, U Science Tech, Universitat de Vic-Universitat Central de Catalunya, Vic, Spain
- Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, UK
| | - Laura I. Furlong
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
| | - Emre Guney
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
| | - Baldo Oliva
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF), Barcelona, Spain
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Ameliorative effect of extract of Tecoma stans (L.) Juss. ex kunth leaves against CCl4 - and acetaminophen—induced liver damage in rats. ADVANCES IN TRADITIONAL MEDICINE 2020. [DOI: 10.1007/s13596-020-00465-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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40
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Elaziz MA, Moemen YS, Hassanien AE, Xiong S. Toxicity risks evaluation of unknown FDA biotransformed drugs based on a multi-objective feature selection approach. Appl Soft Comput 2020. [DOI: 10.1016/j.asoc.2019.105509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Lee FY, Wong HS, Chan HK, Mohamed Ali N, Abu Hassan MR, Omar H, Abdul Mutalib NA. Hepatic adverse drug reactions in Malaysia: An 18-year review of the national centralized reporting system. Pharmacoepidemiol Drug Saf 2020; 29:1669-1679. [PMID: 33064335 DOI: 10.1002/pds.5153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE To determine the incidence, demographic profile, background of reporters, causative agents, severity and clinical outcomes of hepatic adverse drug reaction (ADR) reports in Malaysia using the national ADR reporting database. METHODS The ADR reports recorded between 2000 and 2017 were retrospectively analysed to identify hepatic ADR reports. The trend and characteristics of hepatic ADR cases were described. Multivariate disproportionality analysis of the causative agents was performed to generate signals of hepatic ADRs. RESULTS A total of 2090 hepatic ADRs (1.77% of all ADRs) were reported with mortality rate of 12.7% among cases with known clinical outcomes. The incidence of hepatic ADR reporting in Malaysia increased significantly over 18 years from 0.26 to 9.45 per million population (P < .001). Antituberculosis drugs (n = 268, 12.82%) was the most common suspected class of causative agents with a reporting odds ratio (ROR) and 95% CI of 8.39 (7.26-9.70), followed by traditional/complementary medicines or herbal/dietary supplements (TCM/HDS) (n = 235, 11.24%, ROR 3.26 [2.84-3.75]), systemic antibacterials (n = 159, 7.61%, ROR 2.65 [2.25-3.13]), lipid modifying agents (n = 142, 6.79%, ROR 2.21 [1.86-2.63]) and amiodarone (n = 137, 6.56%, ROR 35.25 [28.40-43.75]). Most (72.9%) of the TCM/HDS were not registered with the authorities. CONCLUSIONS Hepatic ADR cases have increased significantly in Malaysia, with antituberculosis drugs, systemic antibacterials, and TCM/HDS being the most common causative agents reported. Most TCM/HDS reported to be associated with hepatic ADR were not registered with the authorities.
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Affiliation(s)
- Fei Yee Lee
- Clinical Research Centre, Selayang Hospital, Ministry of Health Malaysia, Batu Caves, Selangor, Malaysia
| | - Hin-Seng Wong
- Clinical Research Centre, Selayang Hospital, Ministry of Health Malaysia, Batu Caves, Selangor, Malaysia
| | - Huan-Keat Chan
- Clinical Research Centre, Sultanah Bahiyah Hospital, Ministry of Health Malaysia, Alor Setar, Kedah, Malaysia
| | - Norleen Mohamed Ali
- Pharmacovigilance Section, Center For Post-Registration and Cosmetic Control, National Pharmaceutical Regulatory Agency (NPRA), Petaling Jaya, Selangor, Malaysia
| | - Muhammad Radzi Abu Hassan
- Clinical Research Centre, Sultanah Bahiyah Hospital, Ministry of Health Malaysia, Alor Setar, Kedah, Malaysia.,Gastroenterology Unit, Department of Medicine, Sultanah Bahiyah Hospital, Ministry of Health Malaysia, Alor Setar, Kedah, Malaysia
| | - Haniza Omar
- Hepatology Department, Selayang Hospital, Ministry of Health Malaysia, Batu Caves, Selangor, Malaysia
| | - Noor Aliza Abdul Mutalib
- Hepatology Department, Selayang Hospital, Ministry of Health Malaysia, Batu Caves, Selangor, Malaysia
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Krajnc E, Visentin M, Gai Z, Stieger B, Samodelov SL, Häusler S, Kullak-Ublick GA. Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone. J Pharmacol Exp Ther 2020; 375:239-246. [PMID: 32848075 DOI: 10.1124/jpet.120.000120] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/10/2020] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult. To uncover novel pathways potentially involved in DILI, we investigated in vitro the metabolic perturbations associated with nefazodone, an antidepressant associated with acute liver failure. Several pathways associated with ATP production, including gluconeogenesis, anaerobic glycolysis, and oxidative phosphorylation, were altered in human hepatocellular carcinoma-derived (Huh7) cells after 2-hour exposure to a 50 μM extracellular concentration of nefazodone. In the presence or absence of glucose, ATP production of Huh7 cells was glycolysis- and oxidative phosphorylation-dependent, respectively. In glucose-containing medium, nefazodone-induced ATP depletion from Huh7 cells was biphasic. Huh7 cells in glucose-free medium were more sensitive to nefazodone than those in glucose-containing medium, losing the biphasic inhibition. Nefazodone-induced ATP depletion in primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, was monophasic. At lower extracellular concentrations, nefazodone inhibited the oxygen consumption of Huh7 cells, whereas at higher extracellular concentrations, it also inhibited the extracellular acidification. ATP content was rescued by increasing the extracellular concentration of glucose. In conclusion, nefazodone has a dual inhibitory effect on mitochondrial-dependent and mitochondrial-independent ATP production. SIGNIFICANCE STATEMENT: Mitochondrial damage is a hallmark of drug-induced liver injury, yet other collateral alterations might contribute to the severity and evolution of the injury. Our in vitro study supports previous results arguing that a deficit in hepatic glucose metabolism, concomitant to the mitochondrial injury, might be cardinal in the prognosis of the initial insult to the liver. From a drug development standpoint, coupling anaerobic glycolysis and mitochondrial function assessment might increase the drug-induced liver injury preclinical screening performance.
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Affiliation(s)
- Evelin Krajnc
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Sophia L Samodelov
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Stephanie Häusler
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Association Between Nonvitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study. Am J Gastroenterol 2020; 115:1513-1524. [PMID: 32467502 DOI: 10.14309/ajg.0000000000000678] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests. METHODS Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression. RESULTS After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury. DISCUSSION Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.
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Alrashood ST, Al-Asmari AK, Alotaibi AK, Manthiri RA, Rafatullah S, Hasanato RM, Khan HA, Ibrahim KE, Wali AF. Protective effect of lyophilized sapodilla ( Manilkara zapota) fruit extract against CCl 4-induced liver damage in rats. Saudi J Biol Sci 2020; 27:2373-2379. [PMID: 32884419 PMCID: PMC7451601 DOI: 10.1016/j.sjbs.2020.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/10/2020] [Accepted: 05/03/2020] [Indexed: 02/08/2023] Open
Abstract
The tropical fruit sapodilla (Manilkara zapota syn. Achras zapota) is a rich source of nutrients, minerals and a myriad of bioactive phytochemicals such as flavonoids and catechins. Pharmacologically, sapodilla has been shown to exhibit anti-bacterial, anti-parasitic, anti-fungal, antiglycative, hypocholesterolemic and anti-cancer effects. However, its influence on hepatic tissue and serum lipids remains obscure. To address this, we used an in vivo model of liver damage to elucidate the effect of lyophilized sapodilla extract (LSE) treatment in carbon tetra chloride (CCl4) intoxicated rats. Exposure of CCl4 resulted in elevation of serum biomarkers of liver damage (aspartate transaminase, alanine aminotransferase, γ-glutamyl transferase and alkaline phosphatase), bilirubin and dysregulation of serum lipid profile (cholesterol and triglycerides). These effects were significantly and dose-dependently reversed by LSE treatment (250 and 500 mg/kg). Administration of LSE also reduced the structural damage caused by CCl4 in the liver. Furthermore, determination of oxidative stress parameters (malondialdehyde and non-protein sulfhydryls) revealed that LSE treatment mitigated CCl4-triggered modulation of both molecules. LSE also showed a strong antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and β-carotene-linoleic acid assays. In conclusion, the present study discloses the hepatoprotective and lipid-lowering effects of lyophilized sapodilla extract against CCl4-induced liver damage, an effect, at least in part, mediated by its antioxidant activity.
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Affiliation(s)
- Sara T. Alrashood
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdulrahman K. Al-Asmari
- Scientific Research Center, Medical Service Department (MSD), Ministry of Defence, Riyadh, Saudi Arabia
| | - Abdullah K. Alotaibi
- Scientific Research Center, Medical Service Department (MSD), Ministry of Defence, Riyadh, Saudi Arabia
| | - Rajamohamed A. Manthiri
- Scientific Research Center, Medical Service Department (MSD), Ministry of Defence, Riyadh, Saudi Arabia
| | - Syed Rafatullah
- Scientific Research Center, Medical Service Department (MSD), Ministry of Defence, Riyadh, Saudi Arabia
| | - Rana M. Hasanato
- Department of Pathology, College of Medicine, King Saud University Medical City, Riyadh 11472, Saudi Arabia
| | - Haseeb A. Khan
- Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid E. Ibrahim
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Adil F. Wali
- Department of Pharmaceutical Chemistry, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
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Agarwal T, Borrelli MR, Makvandi P, Ashrafizadeh M, Maiti TK. Paper-Based Cell Culture: Paving the Pathway for Liver Tissue Model Development on a Cellulose Paper Chip. ACS APPLIED BIO MATERIALS 2020; 3:3956-3974. [DOI: 10.1021/acsabm.0c00558] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Tarun Agarwal
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
| | - Mimi R. Borrelli
- Department of Surgery, Stanford University School of Medicine, Stanford, California 94305, United States
| | - Pooyan Makvandi
- Institute for Polymers, Composites and Biomaterials (IPCB), National Research Council (CNR), Naples 80078, Italy
| | - Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 51666-16471, Iran
| | - Tapas Kumar Maiti
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
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Zhou J, Zhang Y, Li S, Zhou Q, Lu Y, Shi J, Liu J, Wu Q, Zhou S. Dendrobium nobile Lindl. alkaloids-mediated protection against CCl 4-induced liver mitochondrial oxidative damage is dependent on the activation of Nrf2 signaling pathway. Biomed Pharmacother 2020; 129:110351. [PMID: 32535387 DOI: 10.1016/j.biopha.2020.110351] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/25/2020] [Accepted: 06/01/2020] [Indexed: 12/12/2022] Open
Abstract
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway has been involved in the mechanisms of a variety of protective agents against cellular oxidative stress. We recently demonstrated that Dendrobium nobile Lindl. alkaloids (DNLA), the active ingredients of Dendrobium, protects mice from CCl4-induced liver injury, dependent on the Nrf2 signaling pathway. The present study was aimed to determine whether the protection against mitochondrial oxidative damage plays a role in the mode of action of DNLA on CCl4-induced liver injury, and to further investigate whether the DNLA-conferred mitochondrial beneficial effects is dependent on the activation of Nrf2 signaling. The CCl4-induced acute liver injury model was employed in both wild-type (WT) and Nrf2-knockout (Nrf2-/-) mice. The results showed that in WT mice DNLA reduced CCl4-induced liver injury, accompanied by a significant reduction in CCl4-induced mitochondrial oxidative stress as evidenced by a decrease in mitochondrial H2O2 content and MDA production, and a marked increase in GSH level and Mn-SOD activity. However, these protective effects were significantly attenuated in Nrf2-/- mice. Furthermore, the administration of DNLA improved mitochondrial oxygen consumption, elevated ATP production, and decreased CCl4-induced apoptosis in the WT mice, whereas the DNLA-mediated protections on mitochondrial function were diminished in the Nrf2 null mice. These results demonstrate that the improvement of mitochondrial oxidative stress and mitochondrial dysfunction is implicated in the mechanism of DNLA-mediated protection on CCl4-induced liver injury, and this DNLA-modulated mode of action is dependent on the activation of Nrf2 signaling pathway.
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Affiliation(s)
- Jinxin Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Ya Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Shiyue Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Qian Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Yuanfu Lu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jingshan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Qin Wu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China.
| | - Shaoyu Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China.
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Ke L, Lu C, Shen R, Lu T, Ma B, Hua Y. Knowledge Mapping of Drug-Induced Liver Injury: A Scientometric Investigation (2010-2019). Front Pharmacol 2020; 11:842. [PMID: 32581801 PMCID: PMC7291871 DOI: 10.3389/fphar.2020.00842] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
Background Drug-induced liver injury (DILI) is a common adverse event, which compromises the safety of numerous drugs, poses a significant risk to patient health, and enhances healthcare expenditures. Many articles have been recently published on DILI related research, though no relevant scientometric study has been published yet. This scientometric study was aimed at comprehensively analyzing the knowledge base and emerging topics on DILI. Methods The articles and reviews related to DILI, published from 2010 to 2019 in the Web of Science Core Collection (WoSCC), were retrieved on March 15, 2020, using relevant keywords. Four different scientometric software (HistCite, VOSviewer, CiteSpace, and R-bibliometrix) was used to conduct this scientometric study. Results A total of 1,995 publications were retrieved (including 1,550 articles and 445 reviews) from 592 academic journals with 56,273 co-cited references in 10 languages by 2,331 institutions from 79 countries/regions. The majority of publications (n = 727, 36.44%) were published in the United States, and the University of North Carolina contributed the most publications (n = 89, 4.46%). The most productive academic journal on DILI was the Toxicological Sciences [n = 79, 3.96%; impact factor (IF) 2018 = 3.564], and Hepatology was the first co-cited journal (n = 7,383, IF 2018 = 14.971). Fontana RJ and Teschke R may have significant influence on DILI research, with more publications (n = 46; n = 39) and co-citations (n = 382; n = 945). Definition, incidence rate or clinical characteristics, etiology or pathogenesis (such as the character of the innate immune system, the regulation of cell-death pathways, and susceptible HLA-B*5701 genotype), identification of main drugs and causality assessment (criteria and methods) were the knowledge base for DILI research. Exploring the microscopic mechanism (such as the organelle dysfunction and cytotoxicity induced by drugs, and exploration of role of neutrophils in DILI using mouse models) and developed newer approaches to prevent DILI (such as the prospective HLA-B*5701 screening and in vitro approaches for assessing the potential risk of candidate drugs for DILI) were the recent major topics for DILI research. Conclusion This scientometric study comprehensively reviewed the publications related to DILI during the past decade using quantitative and qualitative methods. This information would provide references for scholars, researching on DILI.
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Affiliation(s)
- Lixin Ke
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cuncun Lu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Rui Shen
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingting Lu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Bin Ma
- Key Laboratory of Preclinical Study for New Drug of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou, China
| | - Yunpeng Hua
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Naisbitt DJ, Olsson‐Brown A, Gibson A, Meng X, Ogese MO, Tailor A, Thomson P. Immune dysregulation increases the incidence of delayed-type drug hypersensitivity reactions. Allergy 2020; 75:781-797. [PMID: 31758810 DOI: 10.1111/all.14127] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/05/2019] [Accepted: 11/18/2019] [Indexed: 12/14/2022]
Abstract
Delayed-type, T cell-mediated, drug hypersensitivity reactions are a serious unwanted manifestation of drug exposure that develops in a small percentage of the human population. Drugs and drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the drug-peptide complex to T cells. Multiple forms of drug hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many individuals expressing HLA risk alleles do not develop hypersensitivity when exposed to culprit drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether drug exposure will result in a health benefit, hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards drug hypersensitivity.
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Affiliation(s)
- Dean J. Naisbitt
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Anna Olsson‐Brown
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Andrew Gibson
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Xiaoli Meng
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Monday O. Ogese
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Arun Tailor
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
| | - Paul Thomson
- MRC Centre for Drug Safety Science Department of Clinical and Molecular Pharmacology The University of Liverpool Liverpool UK
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Alhaddad O, Elsabaawy M, Abdelsameea E, Abdallah A, Shabaan A, Ehsan N, Elrefaey A, Elsabaawy D, Salama M. Presentations, Causes and Outcomes of Drug-Induced Liver Injury in Egypt. Sci Rep 2020; 10:5124. [PMID: 32198411 PMCID: PMC7083870 DOI: 10.1038/s41598-020-61872-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 02/26/2020] [Indexed: 02/07/2023] Open
Abstract
Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.
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Affiliation(s)
- Omkolthoum Alhaddad
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Maha Elsabaawy
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Eman Abdelsameea
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt.
| | - Ayat Abdallah
- Epidemiology and Preventive Medicine Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Shabaan
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Nermine Ehsan
- Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Elrefaey
- Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Dalia Elsabaawy
- Clinical Pharmacy, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Mohsen Salama
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
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Drug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study. Curr Ther Res Clin Exp 2020; 92:100580. [PMID: 32280391 PMCID: PMC7138958 DOI: 10.1016/j.curtheres.2020.100580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/02/2020] [Indexed: 12/19/2022] Open
Abstract
Critically ill children on anti-epileptic drugs often receive multiple concomitant drugs with potential to result in liver injury. Antimicrobial drugs followed by drugs for stress ulcer prophylaxis form the major drug classes with the risk of DILI that are concomitantly administered with anti-epileptic drugs in critically ill children. Background Antiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI. Objective We attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital. Methods We carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI. Results Five out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification. Conclusions A significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.
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