Drug induced liver injury with analysis of alternative causes as confounding variables

Teschke, Rolf; Danan, Gaby

doi:10.1111/bcp.13593

Cited by 50 publications

(74 citation statements)

References 48 publications

(247 reference statements)

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Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

“…Idiosyncratic DILI is a rare event compared with other liver diseases [20]. This suggests that abnormal LTs in patients taking drugs are more likely due to chronic liver disease than DILI [20], which in turn explains why so many cases initially diagnosed as DILI were actually not DILI but due to causes unrelated to drugs [2][3][4]17]. This problem still haunts the LiverTox database because many assumed DILI cases, which had not been submitted to established causality assessments, are included and presented as DILI reference cases [2][3][4].…”

Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

See 1 more Smart Citation

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Teschke

Eickhoff

Brown

et al. 2019

IJMS

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Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.

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Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Teschke

Eickhoff

Brown

et al. 2019

IJMS

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“…Exposure to CCl 4 results in centrilobular hepatic necrosis. Ethanol and CCl 4 are both metabolized by cytochrome P450 2E1 (CYP2E1) to a highly reactive free radical, which in turn causes hepatotoxicity through lipid peroxidation [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective Activity of BV‐7310, a Proprietary Herbal Formulation of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata, in Alcohol‐Induced HepG2 Cells and Alcohol plus a Haloalkane, CCl₄, Induced Liver Damage in Rats

Dey¹,

Chaskar²,

Bhatt³

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Excessive alcohol consumption is a worldwide threat with severe morbidity and mortality. Other than abstinence, there is still no FDA-approved drug for alcoholic liver disease (ALD). Liver is the primary site of ethanol metabolism and hence gets the most damage from excessive drinking. It triggers multiple signalling events including inflammation, leading to an array of hepatic lesions like steatosis, hepatitis, fibrosis, and cirrhosis. Similarly, when medications or xenobiotic compounds are ingested orally, the liver gets the highest exposure of those metabolites, which in turn can cause severe liver toxicity. BV-7310 is a standardized mixture of four Ayurvedic plants, namely, Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata. In different systems of traditional medicine, each of these plants has been known to have use in gastrointestinal disorders. We wanted to assess the combined effect of these plant extracts on alcohol-induced liver damage. First, we investigated the hepatoprotective activity of BV-7310 against alcohol-induced toxicity in human liver HepG2 cells. Ethanol treatment (120 mM for 48 hours) significantly showed toxicity (around 42%) in these cells, and coincubation with BV-7310 prevented ethanol-induced cell death in a dose-dependent manner. Interestingly, the formulation BV-7310 showed synergistic activity than any individual extract tested in this assay. BV-7310 also showed potent antioxidant activity in 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. Next, we induced hepatitis in Sprague–Dawley (SD) rats using repeated alcohol (40%) dosing, and carbon tetrachloride (CCl4) 24 hours before termination. Both oral doses of BV-7310 (250 and 500 mg/kg body weight) protected the alcohol-induced body weight loss and significantly improved the elevated levels of liver enzymes compared to the vehicle treated group. Thus, BV-7310 prevents alcohol-induced toxicity in both in-vitro and in-vivo models and could be beneficial for the treatment of ALD or other conditions, which may cause liver toxicity.

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“…7 In detail, dapsone resistance in Ml had been indicated in codons 53 and 55, coding threonine (Thr53), and proline (Pro55). 2,10 Furthermore, dapsone causes nausea, vomiting, and hepatic toxicity, inherently 11,12 ; nevertheless, it is the ensconced drug for leprosy treatment due to structure activity relationship. 2,10 Furthermore, dapsone causes nausea, vomiting, and hepatic toxicity, inherently 11,12 ; nevertheless, it is the ensconced drug for leprosy treatment due to structure activity relationship.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy

Swain

Paidesetty

Dehury

et al. 2018

J of Cellular Biochemistry

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Leprosy (causative, Mycobacterium leprae) continues to be the persisting public health problem with stable incidence rates, owing to the emergence of dapsone resistance that being the principal drug in the ongoing multidrug therapy. Hence, to overcome the drug resistance, structural modification through medicinal chemistry was used to design newer dapsone derivative(s) (DDs), against folic acid biosynthesis pathway. The approach included theoretical modeling, molecular docking, and molecular dynamic (MD) simulation as well as binding free energy estimation for validation of newly designed seven DDs, before synthesis. Theoretical modeling, docking, and MD simulation studies were used to understand the mode of binding and efficacy of DDs against the wild-type and mutant dihydropteroate synthases (DHPS). Principal component analysis was performed to understand the conformational dynamics of DHPS-DD complexes. Furthermore, the overall stability and negative-binding free energy of DHPS-DD complexes were deciphered using Molecular Mechanics/Poisson-Boltzmann Surface Area technique. Molecular mechanics study revealed that DD3 possesses higher binding free energy than dapsone against mutant DHPS. Energetic contribution analysis portrayed that van der Waals and electrostatic energy contributes profoundly to the overall negative free energy, whereas polar solvation energy opposes the binding. Finally, DD3 was synthesized and characterized using Fourier-transform infrared spectroscopy, UV, liquid chromatography-mass spectrometry, and proton nuclear magnetic resonance techniques. This study suggested that DD3 could be further promoted as newer antileprosy agent. The principles of medicinal chemistry and bioinformatics tools help to locate effective therapeutics to minimize resources and time in current drug development modules.

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Drug induced liver injury with analysis of alternative causes as confounding variables

Cited by 50 publications

References 48 publications

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Hepatoprotective Activity of BV‐7310, a Proprietary Herbal Formulation of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata, in Alcohol‐Induced HepG2 Cells and Alcohol plus a Haloalkane, CCl₄, Induced Liver Damage in Rats

Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy

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Drug induced liver injury with analysis of alternative causes as confounding variables

Cited by 50 publications

References 48 publications

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Hepatoprotective Activity of BV‐7310, a Proprietary Herbal Formulation of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata, in Alcohol‐Induced HepG2 Cells and Alcohol plus a Haloalkane, CCl4, Induced Liver Damage in Rats

Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy

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Product

Resources

About

Hepatoprotective Activity of BV‐7310, a Proprietary Herbal Formulation of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata, in Alcohol‐Induced HepG2 Cells and Alcohol plus a Haloalkane, CCl₄, Induced Liver Damage in Rats