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Harrison SA, Loomba R, Dubourg J, Ratziu V, Noureddin M. Clinical Trial Landscape in NASH. Clin Gastroenterol Hepatol 2023; 21:2001-2014. [PMID: 37059159 DOI: 10.1016/j.cgh.2023.03.041] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/16/2023]
Abstract
Nonalcoholic fatty liver disease consists of a spectrum starting from nonalcoholic fatty liver disease that may progress to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, hepatocellular carcinoma, or even liver failure. The prevalence of NASH has increased in parallel with the rising rate of obesity and type 2 diabetes. Given the high prevalence and deadly complications of NASH, there have been significant efforts to develop effective treatments. Phase 2A studies have assessed various mechanisms of action across the spectrum of the disease, while phase 3 studies have focused mainly on NASH and fibrosis stage 2 and higher, as these patients have a higher risk of disease morbidity and mortality. The primary efficacy endpoints also vary, by using noninvasive tests in early-phase trials while relying on liver histological endpoints in phase 3 studies as required by regulatory agencies. Despite initial disappointment due to the failure of several drugs, recent phase 2 and 3 studies have shown promising results, with the first Food and Drug Administration-approved drug for NASH expected to be approved in 2023. In this review, we discuss the various drugs under development for NASH, their mechanisms of action, and the results of their clinical trials. We also highlight the potential challenges in developing pharmacological therapies for NASH.
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Affiliation(s)
- Stephen A Harrison
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Pinnacle Clinical Research, San Antonio, Texas.
| | - Rohit Loomba
- NAFLD Liver Center, Division of Gastroenterology, University of California San Diego, San Diego California
| | | | - Vlad Ratziu
- Institute for Cardiometabolism and Nutrition, Hospital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Mazen Noureddin
- Houston Research Institute, Houston Methodist Hospital, Houston, Texas
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Identification of New Toxicity Mechanisms in Drug-Induced Liver Injury through Systems Pharmacology. Genes (Basel) 2022; 13:genes13071292. [PMID: 35886075 PMCID: PMC9315637 DOI: 10.3390/genes13071292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 02/05/2023] Open
Abstract
Among adverse drug reactions, drug-induced liver injury presents particular challenges because of its complexity, and the underlying mechanisms are still not completely characterized. Our knowledge of the topic is limited and based on the assumption that a drug acts on one molecular target. We have leveraged drug polypharmacology, i.e., the ability of a drug to bind multiple targets and thus perturb several biological processes, to develop a systems pharmacology platform that integrates all drug–target interactions. Our analysis sheds light on the molecular mechanisms of drugs involved in drug-induced liver injury and provides new hypotheses to study this phenomenon.
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Yet Kwong Horman J, Patel P, Schultz M, Kraschnewski J. Amlodipine-Induced Liver Injury. Cureus 2022; 14:e23441. [PMID: 35481325 PMCID: PMC9034656 DOI: 10.7759/cureus.23441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2022] [Indexed: 11/21/2022] Open
Abstract
This is a case of an 88-year-old female with a history of hypertension who was started on amlodipine about three weeks prior to presentation. After about two weeks of amlodipine therapy, she developed intermittent right upper quadrant pain as well as pruritus which continued for a few days before she presented to medical attention. Her labs showed significantly elevated liver enzymes so she presented to the hospital for further evaluation. Imaging was unremarkable, her infectious and autoimmune workups were all negative. The amlodipine was discontinued and her liver enzymes slowly normalized after about seven weeks.
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Girish C, Sanjay S. Role of immune dysfunction in drug induced liver injury. World J Hepatol 2021; 13:1677-1687. [PMID: 34904037 PMCID: PMC8637670 DOI: 10.4254/wjh.v13.i11.1677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/15/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is one of the leading causes of liver failure and withdrawal of drugs from the market. A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable. Recent literature suggests that some drugs can alter the liver’s repair systems resulting in injury. The pathophysiology of DILI is complex, and immune dysfunction plays an important role in determining the course and severity of the disease. Immune dysfunction is influenced by the host response to drug toxicity. A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development. This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.
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Affiliation(s)
- Chandrashekaran Girish
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sukumaran Sanjay
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Abnormal Levels of Liver Enzymes and Hepatotoxicity in HIV-Positive, TB, and HIV/TB-Coinfected Patients on Treatment in Fako Division, Southwest Region of Cameroon. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9631731. [PMID: 32462039 PMCID: PMC7243024 DOI: 10.1155/2020/9631731] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/04/2020] [Accepted: 04/29/2020] [Indexed: 12/20/2022]
Abstract
Hepatotoxicity is historically the 3rd most common reason for drug withdrawal and toxicity-related discontinuation of treatment. This study was aimed at determining the incidence and the onset of hepatotoxicity and at evaluating the relationship of some risk factors for hepatotoxicity among Human Immunodeficiency Virus- (HIV-) positive, tuberculosis (TB), and HIV/TB patients on treatment. This was a prospective follow-up study involving 125 participants from the HIV/AIDS and TB treatment centres in three hospitals in Fako Division of Cameroon. These TB and HIV patients were initiated on RHEZ (R = Rifampicin, H = Isoniazid, E = Ethambutol, and P = Pyrazinamide) and TELE (efavirenz/tenofovir/lamivudine), respectively, and followed up for 12 weeks between September 2018 and November 2019. The levels of liver enzymes (transaminases, gamma-glutamyltransferase, alkaline phosphatase, and unconjugated/total bilirubin) were measured spectrophotometrically using serum. The Chi-squared (χ2) test was used to assess the association between risk factors and hepatotoxicity, while the Kaplan-Meier survival analysis with the log-rank test was used to determine the occurrence of hepatotoxicity in the different groups. We followed the general study population for a total person time of 6580 person-days, with an incidence rate and cumulative incidence of 8 cases per 1000 person-days (53/6580 person-days) and 42.4% (53/125), respectively (95% confidence interval), recorded after 12 weeks of follow-up of all the participants. The onset of hepatotoxicity in the total study population was statistically significant (χ2 = 9.5334; p = 0.022979; CI = 95%), with the majority observed at week eight of follow-up. Also, the incidence rate and cumulative incidence of hepatotoxicity with respect to HIV/AIDS, TB, and HIV/TB patients, respectively, at 95% confidence interval were: 8 cases per 1000 person-days (32/3843 person-days) and 32/76 (42.1%), 6 cases per 1000 person-days (12/1932 person-days) and 12/32 (37.5%), and 11 cases per 1000 person-days (9/805 person-days) and 9/17 (52.9%). This study shows that the incidence rate and cumulative incidence of hepatotoxicity in HIV/AIDS, TB, and HIV/TB patients on treatment were high in Fako Division, Cameroon. Also, it is very important to check these patients' liver function especially within the first 12 weeks of treatment.
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Nguyen XB, Kislyuk S, Pham DH, Kecskés A, Maes J, Cabooter D, Annaert P, De Witte P, Ny A. Cell Imaging Counting as a Novel Ex Vivo Approach for Investigating Drug-Induced Hepatotoxicity in Zebrafish Larvae. Int J Mol Sci 2017; 18:E356. [PMID: 28208716 PMCID: PMC5343891 DOI: 10.3390/ijms18020356] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 01/27/2017] [Accepted: 02/03/2017] [Indexed: 01/16/2023] Open
Abstract
Drug-induced liver injury (DILI) is the most common reason for failures during the drug development process and for safety-related withdrawal of drugs from the pharmaceutical market. Therefore, having tools and techniques that can detect hepatotoxic properties in drug candidates at an early discovery stage is highly desirable. In this study, cell imaging counting was used to measure in a fast, straightforward, and unbiased way the effect of paracetamol and tetracycline, (compounds known to cause hepatotoxicity in humans) on the amount of DsRed-labeled hepatocytes recovered by protease digestion from Tg(fabp10a:DsRed) transgenic zebrafish. The outcome was in general comparable with the results obtained using two reference methods, i.e., visual analysis of liver morphology by fluorescence microscopy and size analysis of fluorescent 2D liver images. In addition, our study shows that administering compounds into the yolk is relevant in the framework of hepatotoxicity testing. Taken together, cell imaging counting provides a novel and rapid tool for screening hepatotoxicants in early stages of drug development. This method is also suitable for testing of other organ-related toxicities subject to the organs and tissues expressing fluorescent proteins in transgenic zebrafish lines.
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Affiliation(s)
- Xuan-Bac Nguyen
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
| | - Stanislav Kislyuk
- Division Pharmaceutical Analysis, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 923, 3000 Leuven, Belgium.
| | - Duc-Hung Pham
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
| | - Angela Kecskés
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
| | - Jan Maes
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
| | - Deirdre Cabooter
- Division Pharmaceutical Analysis, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 923, 3000 Leuven, Belgium.
| | - Pieter Annaert
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 921, 3000 Leuven, Belgium.
| | - Peter De Witte
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
| | - Annelii Ny
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium.
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Mouton JP, Njuguna C, Kramer N, Stewart A, Mehta U, Blockman M, Fortuin-De Smidt M, De Waal R, Parrish AG, Wilson DPK, Igumbor EU, Aynalem G, Dheda M, Maartens G, Cohen K. Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa. Medicine (Baltimore) 2016; 95:e3437. [PMID: 27175644 PMCID: PMC4902486 DOI: 10.1097/md.0000000000003437] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 03/24/2016] [Accepted: 03/28/2016] [Indexed: 01/11/2023] Open
Abstract
Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.
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Affiliation(s)
- Johannes P Mouton
- From the Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Cape Town (JPM, CN, NK, AS, UM, MB, MFDS, RDW, GM, KC); Department of Medicine, East London Hospital Complex and Walter Sisulu University, East London (AGP); Department of Medicine, Edendale Hospital, Pietermaritzburg, South Africa (DPKW), US Centers for Disease Control and Prevention, Pretoria (EUI, GA); National Department of Health, Pretoria (MD); and Pharmaceutical Services, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa (MD)
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