scholarly journals Correction possibilities of drug-induced liver toxicity in the treatment of patients with blood system tumors

2020 ◽  
Vol 15 (4) ◽  
pp. 65-81
Author(s):  
V. B. Larionova ◽  
A. V. Snegovoy
Keyword(s):  
Alkaline Phosphatase ◽  
Liver Injury ◽  
Biochemical Parameters ◽  
Metabolic Disorders ◽  
Liver Toxicity ◽  
Blood System ◽  
Drug Induced ◽  
Laboratory Parameters ◽  
Drug Induced Liver Injury ◽  
Glutamyl Transpeptidase

Background. In modern oncohematology achieved notable success due to the intensification and development of new chemotherapy regimens. However, the side effects of anticancer drugs, due to low selectivity of most of them, are a serious limitation to achieve their maximal therapeutic effect. Although doctors are aware of the possibility of hepatotoxic reactions to various drugs, in clinical practice, the diagnosis of drug-induced liver injury is formulated unreasonably rarely. This speculation is due to several factors: in some cases, the latent course of drug-induced liver injury, often inadequate interpretation of clinical symptoms and laboratory parameters, and sometimes insufficiently thorough collection of anamnesis. A particularly difficult problem for a doctor is the development of drug-induced hepatotoxicity in patients for whom the “causal” drug is prescribed for vital indications, in particular, polychemotherapy in cancer patients, complex antimicrobial therapy and antiviral therapy for febrile neutropenia or sepsis, etc. In these situations, on the one hand, treatment cancellation is impossible due to the risk of disease progression, on the other hand, its continuation is undesirable due to the risk of severe hepatitis. In addition, multicomponent therapy, which is a complex of potentially hepatotoxic substances, often does not allow specifying the substance that caused the pathological reaction. At the same time, it is obvious that the hepatocyte, the main cell of the hepatic parenchyma, remains the center of the organ pathology. The variety of biochemical processes occurring with ademetionine participation served as the basis for conducting clinical studies in order to correct drug-induced liver toxicity in the treatment of patients with blood system tumors.The objective of the study is to assess laboratory and clinical parameters of drug-induced liver injury (DILI), intrahepatic cholestasis in the study of homeostasis disorders in patients with hematological malignancies and chemotherapy-induced hepatotoxicity.Materials and methods. The study involved 45 patients with blood system tumors, who had chemotherapy-induced hepatocellular failure. To describe the population of DILI patients, we collected demographic data, clarified the underlying liver disease in each patient, and analyzed the diagnostic criteria for chronic liver disease due to DILI. Clinical signs and symptoms of cholestasis (jaundice, pruritus, weakness), as well as manifestations of a depressive state and asthenic syndrome – mood (mild, moderate and severe), normalization of sleep rhythm, memory improvement, general health were assessed. Changes in laboratory parameters of liver function were studied. In 20 patients with blood system tumors, the biochemical parameters associated with cell metabolism were analyzed – lipid peroxidation, nitric oxide (NOx ) level, impaired liver detoxification capacity by glutathione level and glutathione-S-transferase activity. The treatment regimens for drug-induced hepatotoxicity included the Heptral, which was prescribed until stable normalization of liver function.Results. All patients with developed liver failure showed metabolic disorders. The use of ademetionine has shown significant effect. The NO and superoxide dismutase in most patients decreased significantly and almost corresponded to the norm. Normalization of the glutathione system parameters was also observed. One of the mechanisms of Heptral protective effect is an increase in the glutathione synthesis. The improvement in laboratory parameters was accompanied by the disappearance of DILI and intrahepatic cholestasis symptoms. This is confirmed by significant statistical correlations between them and indicates the ademetionine efficacy to recovery of hepatocytes function. When using ademetionine, the most pronounced reduction among biochemical parameters was observed in alkaline phosphatase and γ-glutamyl transpeptidase, markers of cholestasis syndrome. In addition, serum bilirubin concentration and alanine and aspartic transaminases activity (albeit to a lesser extent) decreased significantly. Clinical and biochemical effects, as a rule, persisted for several months after completion of therapy. Decrease in biochemical parameters characterizing cholestasis and cytolysis (positive dynamics of alanine and aspartic transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, bilirubin) was accompanied by an improvement and normalization of patients’ well-being. When assessing the depression and asthenic syndrome, it was noted that the duration of Heptral therapy is important.Conclusion. The results obtained were the basis for the development of supportive therapy programs to prevent and reduce liver toxicity during chemotherapy. Rational approaches to the liver metabolic disorders correction – a real way to increase the treatment efficacy and improve the quality of life of patients with blood system tumors.

scholarly journals Computational Models Using Multiple Machine Learning Algorithms for Predicting Drug Hepatotoxicity with the DILIrank Dataset

2020 ◽  
Author(s):  
Robert Ancuceanu ◽  
Marilena Viorica Hovanet ◽  
Adriana Iuliana Anghel ◽  
Florentina Furtunescu ◽  
Monica Neagu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Liver Injury ◽  
Computational Models ◽  
Liver Toxicity ◽  
Learning Algorithms ◽  
Machine Learning Algorithms ◽  
Drug Induced ◽  
Reference Drug ◽  
Drug Induced Liver Injury

Drug induced liver injury (DILI) remains one of the challenges in the safety profile of both authorized drugs and candidate drugs and predicting hepatotoxicity from the chemical structure of a substance remains a challenge worth pursuing, being also coherent with the current tendency for replacing non-clinical tests with in vitro or in silico alternatives. In 2016 a group of researchers from FDA published an improved annotated list of drugs with respect to their DILI risk, constituting “the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans”, DILIrank. This paper is one of the few attempting to predict liver toxicity using the DILIrank dataset. Molecular descriptors were computed with the Dragon 7.0 software, and a variety of feature selection and machine learning algorithms were implemented in the R computing environment. Nested (double) cross-validation was used to externally validate the models selected. A number of 78 models with reasonable performance have been selected and stacked through several approaches, including the building of multiple meta-models. The performance of the stacked models was slightly superior to other models published. The models were applied in a virtual screening exercise on over 100,000 compounds from the ZINC database and about 20% of them were predicted to be non-hepatotoxic.

Lighting up alkaline phosphatase in drug-induced liver injury using a new chemiluminescence resonance energy transfer nanoprobe

2018 ◽  
Vol 54 (88) ◽  
pp. 12479-12482 ◽  
Author(s):  
Xueting Liu ◽  
Nannan Fan ◽  
Lijie Wu ◽  
Chuanchen Wu ◽  
Yongqing Zhou ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Energy Transfer ◽  
Liver Injury ◽  
Alkaline Phosphatase Level ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Ultra-sensitive imaging of the alkaline phosphatase levelin vivoin drug-induced liver injury with a new chemiluminescence resonance energy transfer nanoprobe.

scholarly journals Computational Models Using Multiple Machine Learning Algorithms for Predicting Drug Hepatotoxicity with the DILIrank Dataset

2020 ◽  
Vol 21 (6) ◽  
pp. 2114
Author(s):  
Robert Ancuceanu ◽  
Marilena Viorica Hovanet ◽  
Adriana Iuliana Anghel ◽  
Florentina Furtunescu ◽  
Monica Neagu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Liver Injury ◽  
Computational Models ◽  
Liver Toxicity ◽  
Learning Algorithms ◽  
Machine Learning Algorithms ◽  
Drug Induced ◽  
Reference Drug ◽  
Drug Induced Liver Injury

Drug-induced liver injury (DILI) remains one of the challenges in the safety profile of both authorized and candidate drugs, and predicting hepatotoxicity from the chemical structure of a substance remains a task worth pursuing. Such an approach is coherent with the current tendency for replacing non-clinical tests with in vitro or in silico alternatives. In 2016, a group of researchers from the FDA published an improved annotated list of drugs with respect to their DILI risk, constituting “the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans” (DILIrank). This paper is one of the few attempting to predict liver toxicity using the DILIrank dataset. Molecular descriptors were computed with the Dragon 7.0 software, and a variety of feature selection and machine learning algorithms were implemented in the R computing environment. Nested (double) cross-validation was used to externally validate the models selected. A total of 78 models with reasonable performance were selected and stacked through several approaches, including the building of multiple meta-models. The performance of the stacked models was slightly superior to other models published. The models were applied in a virtual screening exercise on over 100,000 compounds from the ZINC database and about 20% of them were predicted to be non-hepatotoxic.

scholarly journals Ginseng-Related Drug-Induced Liver Injury

2018 ◽  
Vol 12 (2) ◽  
pp. 439-446 ◽  
Author(s):  
Kyawzaw Lin ◽  
Aung Naing Lin ◽  
Sandar Linn ◽  
Pwint Phyu Hlaing ◽  
Viswanath Vasudevan ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Liver Injury ◽  
Total Bilirubin ◽  
Fatty Infiltration ◽  
Well Being ◽  
The United States ◽  
Medicinal Herb ◽  
Direct Bilirubin ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Ginseng is commonly used as a medicinal herb for memory and concentration and general well-being. Drug-induced liver injury (DILI) is one of the most challenging disorders and trending events in the United States which are related to body building and weight loss supplements. Currently, herbal and dietary supplementation is the second most common cause of DILI. Here, we report on a 45-year-old healthy Chinese woman who presented with dull intermittent left upper quadrant abdomen pain for a month. Upon thorough history taking, she had been taking ginseng tea and supplementation for her menopausal symptoms for almost 3 months. Physical examination was unremarkable except mild tenderness in left upper quadrant of the abdomen. Liver function test showed aspartate transaminase (AST) 717 U/L, alanine transaminase (ALT) 343 U/L, total bilirubin 5 mg/dL, direct bilirubin 3.3 mg/dL, alkaline phosphatase 182 U/L, with international normalized ratio (INR) 1.2. Prior liver enzymes (6 months earlier) showed AST 21 U/L, ALT 18 U/L, total bilirubin 0.8 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 34 U/L, with INR 0.7. Viral serology for acute hepatitis B, C, E, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus was negative. She was immune to hepatitis A. Her antinuclear antibody was positive. Her anti-Smith antibody, anti-smooth muscle antibody, HFE gene mutation, ceruloplasmin, alpha-1 antitrypsin serologies were within normal references. An abdomen sonogram showed fatty infiltration. Liver biopsy showed moderate to severe portal inflammation and marked lobular disarray. Portal and lobular inflammatory infiltrates consisted of a mixture of histiocytes, lymphocytes, plasma cells, eosinophils, and neutrophils with centrilobular necrosis and focal bridging necrosis, and necro-inflammation. After 6 weeks of follow-up, the patient improved physically, and the abdomen pain resolved. Ginseng has been widely used in the Chinese community as medicinal herb for a variety of conditions for decades. However, proper research has never been done regarding its pharmacokinetics, efficacy, and safety issues. In our case report, the idiosyncratic DILI resulted from ingestion of ginseng as herbal supplementation for premenopausal symptoms. Physicians should be aware of and suspect DILI in any patient with acute liver injury, and patients should be reminded that all medications and supplements have a potential to cause DILI.

Drug-Induced Liver Injury (DILI) in Patients with Depression Treated with Antidepressants: A Retrospective Multicenter Study

2020 ◽  
Vol 53 (02) ◽  
pp. 60-64 ◽  
Author(s):  
Bianca Ueberberg ◽  
Ulrich Frommberger ◽  
Thomas Messer ◽  
Peter Zwanzger ◽  
Jens Kuhn ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Antidepressant Treatment ◽  
Elevated Serum ◽  
Inpatient Setting ◽  
Drug Induced ◽  
Serious Adverse Events ◽  
Drug Induced Liver Injury ◽  
Retrospective Multicenter Study ◽  
Secondary Diseases

Abstract Introduction Drug-induced liver injury (DILI) is the 4th most common cause of liver damage in Western countries and can be caused by antidepressants. Methods Against the background of increasing antidepressant prescriptions and increasing use of polypharmacy, we analyzed administered antidepressants and other pharmacological substances, liver toxicity, comorbid somatic secondary diseases together with the occurrence of DILI in a patient population of 6 centers throughout Germany. Results The majority of the enrolled 329 patients received polypharmacological treatment in an inpatient setting. During antidepressant treatment 5.1% of the patients had elevated serum transaminase levels, whereby exactly and not more than 1 criterion proposed to be indicative for DILI, was fulfilled by 3 patients (0.9%). Discussion During patient characterization it becomes clear that a sensitization for relevant risk constellations causing liver injury in MDD patients is relevant to prevent further serious adverse events.

scholarly journals Etiology and Pattern of Drug Induced Liver Injury in a Tertiary Care Hospital of Nepal

2019 ◽  
Vol 21 (3) ◽  
pp. 220-223
Author(s):  
Anuj K.C. ◽  
S. Jha ◽  
S. Thapa
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Tertiary Care ◽  
Care Hospital ◽  
Drug Induced ◽  
Common Cause ◽  
Drug Induced Liver Injury ◽  
Common Causes ◽  
The Common ◽  
Mixed Pattern

Drug induced liver injury (DILI) is one of the common cause of liver toxicity. Most of the drugs used today are hepatotoxic. DILI accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. It is the single most common adverse drug reaction leading to a halt in the development of new medication by pharmaceutical company, failure of new drug to obtain regulatory approval, and withdrawal or restriction of existing drug from the market. The aim of this study is to evaluate common causes and patterns of DILI in our setting. Twenty-seven patients were enrolled in the study. Ant tubercular drugs were most common cause of DILI, accounting for 48.2%. Other common causes of DILI were paracetamol (14.8%) and NSAID’s (11.1%). The most common pattern of liver injury seen was mixed pattern which was present in63%, followed by cholestatic and hepatocellular pattern. Hence, we should be very careful while prescribing these frequently used drugs.

Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program

2019 ◽  
Vol 16 (3) ◽  
pp. 253-262 ◽  
Author(s):  
Jay S Shavadia ◽  
Abhinav Sharma ◽  
Xiangqiong Gu ◽  
James Neaton ◽  
Laurie DeLeve ◽  
...  
Keyword(s):  
Adverse Event ◽  
Relative Risk ◽  
Liver Injury ◽  
Confidence Interval ◽  
Active Control ◽  
Liver Toxicity ◽  
Aspartate Transaminase ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Liver Safety

Background Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. Methods This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. Findings Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy’s Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29–4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03–14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18–17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. Conclusion In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Drug-Induced Liver Injury Is a Major Risk for New Drugs

2015 ◽  
Vol 33 (4) ◽  
pp. 458-463 ◽  
Author(s):  
Leonard B. Seeff
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Antiviral Agents ◽  
Elevated Serum ◽  
Rare Condition ◽  
New Drugs ◽  
Treatment Level ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Direct Acting Antiviral

Drug-induced liver injury (DILI), a relatively rare condition, is nevertheless a major reason for not approving a drug in development or for removing one already marketed. With a specific diagnostic biomarker lacking, finding elevated serum enzyme [alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase] activities remains an initial signal for incipient liver injury. Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called ‘Hy's law') there is a high possibility of serious DILI. In 1997 several drugs were approved by the Food and Drug Administration (FDA) of the USA that were later withdrawn from the market for serious liver toxicity. New drugs in development are now required to be monitored for liver injury, and the data is to be considered in the approval decision. A program called e-DISH (evaluation of drug-induced serious hepatotoxicity) was introduced in 2004 to aid medical reviewers to select from all subjects studied those few who show nontrivial liver injury and estimate the most likely cause. The threshold of enzyme elevation comprising a warning for possibly serious DILI is uncertain, although generally accepted as 3-5 times the ‘upper limit of normal'. The new direct-acting antiviral agents for treating chronic hepatitis C virus, which often lead to a reduction of elevated ALTs, mandate that a later increase without viral breakthrough be compared to the new on-treatment level of values. The drug may be discontinued or interrupted for evaluation to exclude other possible causes of liver injury. The FDA has approved no drug since 1997 that has been withdrawn later because of serious hepatotoxicity.

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