Antineoplastic drugs and drug-induced liver damage with cholestasis

2020 ◽  
Vol 1 (19) ◽  
pp. 47-54 ◽  
Author(s):  
A. P. Pereverzev ◽  
O. D. Ostroumova
Keyword(s):  
Alkylating Agents ◽  
Interleukin 1 ◽  
Clinical Manifestations ◽  
Antineoplastic Drugs ◽  
Targeted Drugs ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Treatment And Prevention ◽  
The Russian Federation ◽  
Novel Drug

The number of cases of drug-induced liver injury (DILI) has been increasing since the 1990s. DILIs cause up to 40,000 deaths each year. One of the leaders in the number of DILIs are antineoplastic drugs ms, such as alkylating agents, antimetabolites, targeted drugs, monoclonal antibodies, etc. One of the most effective and safe strategies for the treatment and prevention of DILI is to use hepatoprotective drugs. Currently, on the market of the Russian Federation, is available novel drug Heptrong® (does not have an International Non-proprietary Name), which has anti-inflammatory, antioxidant activity and the ability to stabilize and reduce the permeability of hepatocyte membranes, suppress the activity 5-lipoxygenase, a decrease in the synthesis of leukotriene B4, interleukin-1, interleukin-6, which are pro-inflammatory cytokines. The drug activates the antitoxic function of the liver, improves its protein- and lipid-synthesizing functions. Heptrong® neutralizes the processes of inflammation in the liver, thereby reducing the severity of the clinical manifestations of drug-induced lesions.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

scholarly journals Drug-Induced Heart Failure (Part 2: Mechanisms of Development, Clinical Signs, Differential Diagnosis, Risk Factors, Treatment and Prevention)

2020 ◽  
Vol 8 (2) ◽  
pp. 57-65
Author(s):  
O. D. Ostroumova ◽  
I. V. Goloborodova
Keyword(s):  
Heart Failure ◽  
Beta Blockers ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Clinical Syndrome ◽  
Channel Blockers ◽  
Drug Induced ◽  
Treatment And Prevention ◽  
Developing Heart

Heart failure is a complex clinical syndrome caused by an impaired pumping function of the heart muscle, etiologically associated with cardiovascular disease and, in the vast majority of cases, requiring complex therapeutic regimens and simultaneous prescription of several drugs. To date, we know several classes of drugs (including those used for heart failure) which can induce development/progression of heart failure in both patients with left ventricular dysfunction, and in patients who do not have cardiovascular diseases. The aim of the study was to analyse and systematize data on development mechanisms, as well as methods of prevention and treatment of drug-induced heart failure when using diff erent groups of drugs. It has been established that drug-induced heart failure is most often associated with the use of calcium channel blockers (verapamil, diltiazem, nifedipine), beta-blockers, antiarrhythmic drugs (disopyramide, fl ecainide, propafenone, amiodarone, ibutilide, dofetilide, dronedarone), anthracyclines (doxorubicin) and other antitumor drugs (trastuzumab, bevacizumab, infl iximab), hypoglycemic drugs (thiazolidinediones, saxagliptin, alogliptin), and nonsteroidal anti-infl ammatory drugs, including selective cyclooxygenase-2 inhibitors. The study revealed various mechanisms of heart failure development following drug treatment. In some patients, heart failure development is associated with the cardiotoxic eff ect of a particular drug, in others with adverse eff ects on hemodynamics. Much depends on risks of developing heart failure, including specifi c risks attributable to groups of drugs and individual drugs. The identifi cation of drugs that can contribute to the development/ progression of heart failure, and possible clinical manifestations of drug-induced heart failure, as well as provision of timely information to physicians, and engagement of clinical pharmacologists with the aim of optimizing treatment of patients can facilitate timely diagnosis, treatment and prevention of drug-induced heart failure. 

Ginsenoside Rb1, A Major Saponin from Panax ginseng, Exerts Protective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice

2019 ◽  
Vol 47 (08) ◽  
pp. 1815-1831 ◽  
Author(s):  
Shen Ren ◽  
Jing Leng ◽  
Xing-Yue Xu ◽  
Shuang Jiang ◽  
Ying-Ping Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Panax Ginseng ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Protective Effects ◽  
Ginsenoside Rb1 ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Oxide Synthase

Acute liver injury (ALI) induced by acetaminophen (APAP) is the main cause of drug-induced liver injury. Previous reports indicated liver failure could be alleviated by saponins (ginsenosides) from Panax ginseng against APAP-induced inflammatory responses in vivo. However, validation towards ginsenoside Rb1 as a major and marker saponin may protect liver from APAP-induced ALI and its mechanisms are poorly elucidated. In this study, the protective effects and the latent mechanisms of Rb1 action against APAP-induced hepatotoxicity were investigated. Rb1 was administered orally with 10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg daily for 1 week before a single injection of APAP (250[Formula: see text]mg/kg, i.p.) 1[Formula: see text]h after the last treatment of Rb1. Serum alanine/aspartate aminotransferases (ALT/AST), liver glutathione (GSH) depletion, as well as the inflammatory cytokines, such as tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1[Formula: see text] (IL-1[Formula: see text]), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were analyzed to indicate the underlying protective effects of Rb1 against APAP-induced hepatotoxicity with significant inflammatory responses. Histological examination further proved Rb1’s protective effects. Importantly, Rb1 mitigated the changes in the phosphorylation of MAPK and PI3K/Akt, as well as its downstream factor NF-[Formula: see text]B. In conclusion, experimental data clearly demonstrated that Rb1 exhibited a remarkable liver protective effect against APAP-induced ALI, partly through regulating MAPK and PI3K/Akt signaling pathways-mediated inflammatory responses.

scholarly journals Applications of Different Biomarkers in the Diagnosis of Drug-induced Liver Injury

2019 ◽  
Vol 9 (1) ◽  
pp. 55-61
Author(s):  
Monika Sharma ◽  
Ishita Yadav ◽  
Chandra K. Sharma
Keyword(s):  
Clinical Practice ◽  
Safety Assessment ◽  
Basic Research ◽  
Biological Processes ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Significant Function ◽  
Treatment And Prevention ◽  
Day By Day

Biomarkers perform a significant function in the process of drug development. Biomarkers have been utilized in the safety assessment of drugs in clinical practice and also for personalization of medicines. To recognize the relation among considerable biological processes as well as clinical outcomes, it is important to increase our potential of treatments for all ailments, in addition to our understanding of normal and healthy physiology. Since the 1980s, using biomarkers is essential for substitutional results in long term assessments of main maladies, for example, cancer, as well as illness related to the heart. Now a days, biomarkers are highly important for unifying discovery of the drug and day by day improvements. The importance of biomarkers is increasing gradually with the advancement of novel therapeutics for the treatment and prevention of a broad range of diseases in order to overcome hepatotoxicity. These biomarkers are extensively used for the identification of disease and the field of medical research. The use of biomarkers in clinical as well as basic research has been promoted rapidly by the different drug regulation authorities for better outcomes in the future.

Drug-induced atrioventricular blockages

2020 ◽  
Vol 1 (19) ◽  
pp. 56-64
Author(s):  
M. I. Kulikova ◽  
O. D. Ostroumova ◽  
A. G. Komarova
Keyword(s):  
Risk Factors ◽  
Heart Rhythm ◽  
Inhibitory Effect ◽  
Antineoplastic Drugs ◽  
Av Node ◽  
Drug Induced ◽  
Treatment And Prevention ◽  
Av Conduction ◽  
Common Risk Factors ◽  
Conduction Disorder

Atrio-ventricular (AV) blockages are a serious violation of the heart rhythm. One of the reasons for the development of this pathology may be taking medications. This effect has a significant number of drugs used for the treatment of diseases of the cardiovascular system, central nervous system, general and local anesthetics, antineoplastic drugs, and many others. The main mechanism for the development of drug-induced AV blockades is the inhibition of AV node conduction. The most common risk factors for the development of drug-induced AV blockades are taking two and more drugs that have an inhibitory effect on AV conduction, the initial duration of the PQ interval more than 0.2 second, initial dysfunction of the AV node, increased plasma concentration of a potential inducer drug due to the presence of kidney and/or liver disease, drugdrug interactions, and specific risk factors for individual drugs. Special attention in solving this problem should be paid to both stopping the developed AV conduction disorder – medication or using an electric cardiostimulator, and its prevention. This article systematizes the literature data on drug-induced AV blockades in order to increase the awareness of practitioners and patients about their prevalence, risk factors, approaches to diagnosis, treatment and prevention.

Developments in the Immunotherapy of Glomerular Disease

2002 ◽  
Vol 15 (6) ◽  
pp. 472-489
Author(s):  
Patrick H. Nachman ◽  
Jeffrey Martin
Keyword(s):  
Alkylating Agents ◽  
Clinical Manifestations ◽  
Calcineurin Inhibitors ◽  
Immunosuppressive Drugs ◽  
Glomerular Disease ◽  
Drug Induced ◽  
Glomerular Diseases ◽  
Care Givers ◽  
Clinical Syndromes ◽  
History Of

Glomerular diseases span a broad spectrum of clinical syndromes, with varied clinical manifestations, underlying etiologies, and pathogenic mechanisms. They can be secondary to underlying infectious, toxic, environmental, or drug exposures, or present as “primary entities.” In the latter case, most glomerular diseases are thought to be due to autoimmune dysregulation, and their treatment is primarily immunosuppressive. The armamentarium for immunomodulation includes corticosteroids, alkylating agents, anti-metabolites, calcineurin inhibitors, and new biological agents designed to block specific inflammatory pathways. The choice of therapy for an individual patient must be based on the specific character of the glomerular disease and its acuity and severity, as well as the patient’s comorbidities, history of prior exposure to immunosuppressive drugs, and risk factors for developing complications of the disease or its treatment. The complexities of such therapy can best be addressed by an experienced team of care givers in which the clinical pharmacist can help minimize, if not eliminate, potential sources of drug induced toxicities and adverse effects. This article will describe the major agents and modalities used in the management of the most common glomerular diseases.

scholarly journals Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

2021 ◽  
Vol 22 (6) ◽  
pp. 2954
Author(s):  
Alison Jee ◽  
Samantha Christine Sernoskie ◽  
Jack Uetrecht
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Liver Injury ◽  
Clinical Manifestations ◽  
Adaptive Immune System ◽  
Human Leukocyte ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Adaptive Immune

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

scholarly journals Role of Ursodeoxycholic Acid in Treating and Preventing Idiosyncratic Drug-Induced Liver Injury. A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Mercedes Robles-Díaz ◽  
Lana Nezic ◽  
Vesna Vujic-Aleksic ◽  
Einar S. Björnsson
Keyword(s):  
Systematic Review ◽  
Liver Injury ◽  
Ursodeoxycholic Acid ◽  
Randomized Clinical Trials ◽  
Case Reports ◽  
Lower Percentage ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Treatment And Prevention

Introduction: Treatment is generally not available for drug-induced liver injury (DILI) patients except in some specific circumstances. The management of DILI is based on the withdrawal of the responsible drug and monitoring the patients and only a few patients need to be referred to a transplant center. Some studies on the role of ursodeoxycholic acid (UDCA) in DILI have been published. The aim of this study was to perform a systematic review of the role of UDCA in the treatment and prevention of DILI.Methods: A search was undertaken in PubMed, with the key words ursodeoxycholic acid, drug-induced liver injury and hepatotoxicity following the PRISMA guidelines.Results: A total of 33 publications were identified: 25 case reports and 8 case series. In 18 of the 25 cases reports (22 patients), authors reported improvement of liver injury associated with UDCA therapy whereas 7 case reports did not show clinical or biochemical improvement after UDCA treatment. There were 4 studies evaluating the role of UDCA in the treatment of DILI, three prospective (one being a clinical trial) and one retrospective studies. Three studies observed liver profile improvements associated with UDCA. In addition, four studies evaluated UDCA in the prevention of DILI: one pilot study, two randomized clinical trials (RCT) and one retrospective study. Three of these studies observed a lower percentage of patients with an increase in transaminases in the groups that used UDCA for DILI prevention.Conclusion: According to available data UDCA seems to have some benefits in the treatment and prevention of DILI. However, the design of the published studies does not allow a firm conclusion to be drawn on the efficacy of UDCA in DILI. A well designed RCT to evaluate the role of UDCA in DILI is needed.

scholarly journals Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals

2021 ◽  
Vol 10 (19) ◽  
pp. 4432
Author(s):  
Ana Delgado ◽  
Stefan Stewart ◽  
Mikel Urroz ◽  
Amelia Rodríguez ◽  
Alberto M. Borobia ◽  
...  
Keyword(s):  
Liver Injury ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Lymphocyte Transformation ◽  
University Hospital ◽  
Small Subset ◽  
Causality Analysis ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Defined Daily Doses

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

Drugs associated with drug-induced hyponatremia

2021 ◽  
pp. 92-99
Author(s):  
A. I. Listratov ◽  
A. G. Komarova ◽  
E. V. Aleshckovich ◽  
M. V. Velichcko ◽  
O. D. Ostroumova
Keyword(s):  
Risk Factors ◽  
Sodium Level ◽  
Clinical Manifestations ◽  
Opioid Analgesics ◽  
Electrolyte Balance ◽  
Antineoplastic Drugs ◽  
Drug Induced ◽  
Low Sodium ◽  
Significant Disturbance ◽  
Fatal Complications

Hyponatremia (HN) is a significant disturbance of the water-electrolyte balance in clinical practice. Drugs are one of the leading causes of low sodium level. Antidepressants, antiepileptic, antipsychotic, antineoplastic drugs and opioid analgesics are the most common medications that induce hyponatremia. Special attention should be paid to people with cancer, who often receive several drugs that induce HN. Risk factors for the development of drug-induced (DI) HN when taking most medications are female sex, weight loss, and old age. In persons receiving therapy with the listed drugs, it is necessary to assess the risk factors for a decrease in the sodium level, clinical manifestations from the nervous system, and to determine the sodium level in dynamics. Special care must be taken when treating elderly patients, since they have several risk factors for the development of DI HN. These measures will help prevent the development of HN and its severe and sometimes fatal complications.

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