cardiovascular-agents and Chemical-and-Drug-Induced-Liver-Injury

Drug induced liver injury (DILI) may be different in the East compared to the West due to differing disease prevalence, prescribing patterns and pharmacogenetic profiles. To review existing literature on causative agents of DILI in the East compared to the West, a comprehensive literature search was performed on electronic databases: MEDLINE/PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure without language restrictions. Studies which involve patients having DILI and reported the frequency of causative agents were included. A random effects model was applied to synthesize the current evidence using prevalence of class-specific and agent-specific causative drugs with 95% confidence intervals. Of 6,914 articles found, 12 showed the distribution of drugs implicated in DILI in the East with a total of 33,294 patients and 16 in the West with a total of 26,069 DILI cases. In the East, the most common agents by class were anti-tuberculosis drugs (26.6%), herbal and alternative medications (25.3%), and antibiotics (15.7%), while in the West, antibiotics (34.9%), cardiovascular agents (17.3%), and non-steroidal anti-inflammatory drugs (12.5%) were the commonest. For individual agents, the most common agents in the East were isoniazid-rifampicin-pyrazinamide (25.4%), phenytoin (3.5%), and cephalosporin (2.9%) while in the West, amoxicillin-potassium clavulanate combination acid (11.3%), nimesulide (6.3%), and ibuprofen (6.1%) were the commonest. There was significant heterogeneity due to variability in single-centre compared to multi-centre studies. Differences in DILI in the East versus the West both in drug classes and individual agents are important for clinicians to recognize.

Topics: Anti-Bacterial Agents; Antitubercular Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Medicine, Traditional; Risk Assessment

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-Infective Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Comorbidity; Dietary Supplements; Female; Humans; Incidence; Male; Middle Aged; Palliative Care; Pharmacokinetics; Phenotype; Plants, Medicinal; Polypharmacy; Risk Factors

In their clinical practice, physicians can face heart diseases (chronic or acute heart failure) affecting the liver and liver diseases affecting the heart. Systemic diseases can also affect both heart and liver. Therefore, it is crucial in clinical practice to identify complex interactions between heart and liver, in order to provide the best treatment for both. In this review, we sought to summarize principal evidence explaining the mechanisms and supporting the existence of this complicate cross-talk between heart and liver. Hepatic involvement after heart failure, its pathophysiology, clinical presentation (congestive and ischemic hepatopathy), laboratory and echocardiographic prognostic markers are discussed; likewise, hepatic diseases influencing cardiac function (cirrhotic cardiomyopathy). Several clinical conditions (congenital, metabolic and infectious causes) possibly affecting simultaneously liver and heart have been also discussed. Cardiovascular drug therapy may present important side effects on the liver and hepato-biliary drug therapy on heart and vessels; post-transplantation immunosuppressive drugs may show reciprocal cardio-hepatotoxicity. A heart-liver axis is drafted by inflammatory reactants from the heart and the liver, and liver acts a source of energy substrates for the heart.

Topics: Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Heart; Heart Failure; Humans; Liver; Liver Diseases

Topics: Acetaminophen; Analgesics; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Chromans; Contraceptives, Oral, Hormonal; Gastrointestinal Agents; Humans; Liver Diseases; Liver Function Tests; Psychotropic Drugs; Thiazolidinediones; Time Factors; Troglitazone

Topics: Analgesics; Anti-Infective Agents; Anticonvulsants; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Liver; Pharmaceutical Preparations; Psychotropic Drugs

The incidence of drug-induced liver disease appears to be increasing, reflecting the increasing number of new agents that have been introduced into clinical use over the past several decades. Among the topics covered, the author discusses incidence, diagnosis, risk factors, clinical presentations, hepatitis, and vascular injury. The author also reviews the hepatic injury seen with commonly prescribed drugs, emphasizing newer developments in the field and recent publications and reports.

Topics: Acetaminophen; Alanine Transaminase; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Hypoglycemic Agents; Incidence; Liver; Liver Diseases; Prognosis; Risk Factors; Vascular Diseases

Topics: Acute Disease; Analgesics; Anesthetics; Anti-Infective Agents; Antineoplastic Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Hormones; Humans; Psychotropic Drugs

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Humans; Psychotropic Drugs

Topics: Adult; Aged; Ajmaline; Anti-Arrhythmia Agents; Antihypertensive Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Diuretics; Humans; Male; Methyldopa; Procaine; Quinidine; Warfarin

Perhexiline is an anti-anginal drug developed in the late 1960s. Despite its therapeutic success, it caused severe hepatoxicity in selective patients, which resulted in its withdrawal from the market. In the current study we explored the molecular mechanisms underlying the cytotoxicity of perhexiline. In primary human hepatocytes, HepaRG cells, and HepG2 cells, perhexiline induced cell death in a concentration- and time-dependent manner. Perhexiline treatment also caused a significant increase in caspase 3/7 activity at 2 h and 4 h. Pretreatment with specific caspase inhibitors suggested that both intrinsic and extrinsic apoptotic pathways contributed to perhexiline-induced cytotoxicity, which was confirmed by increased expression of TNF-α, cleavage of caspase 3 and 9 upon perhexiline treatment. Moreover, perhexiline caused mitochondrial dysfunction, demonstrated by the classic glucose-galactose assay at 4 h and 24 h. Results from JC-1 staining suggested perhexiline caused loss of mitochondrial potential. Blocking mitochondrial permeability transition pore using inhibitor bongkrekic acid attenuated the cytotoxicity of perhexiline. Western blotting analysis also showed decreased expression level of pro-survival proteins Bcl-2 and Mcl-1, and increased expression of pro-apoptotic protein Bad. Direct measurement of the activity of individual components of the mitochondrial respiratory complex demonstrated that perhexiline strongly inhibited Complex IV and Complex V and moderately inhibited Complex II and Complex II + III. Overall, our data demonstrated that both mitochondrial dysfunction and apoptosis underlies perhexiline-induced hepatotoxicity.

Topics: Apoptosis; Cardiovascular Agents; Cell Line; Chemical and Drug Induced Liver Injury; Hepatocytes; Humans; Membrane Potential, Mitochondrial; Mitochondria; Perhexiline; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Aspirin (acetyl salicylic acid) is used worldwide to treat various inflammatory conditions and prevent cardiovascular disease, along with reducing the risk of cancer. However, administration of aspirin causes toxic effects, especially in the stomach and liver. Thus, our study examined the protective effect of wheat germ oil on aspirin-induced toxicity in the stomach and liver tissues of Swiss albino mice. Administration of wheat germ oil before aspirin has restored normal hepatic and gastric tissue architecture and DNA integrity has become better than that of a negative health control group compared with the aspirin only treated group. The elevated gastric nitric oxide content in the aspirin only treated group was significantly decreased by wheat germ oil prior administration as a result of reduced the expression of inducible nitric synthase and increased the expression of endothelial nitric oxide synthase compared to their expression in the aspirin administered group. Wheat germ oil pre-administration significantly reduced the level of malondialdehyde, increased the level of glutathione and catalase and superoxide dismutase activities compared with those in aspirin only treated group. We conclude that wheat germ oil has a potential protective effect against aspirin induced gastro- and hepato-toxicity because of its free radical scavenging ability.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiovascular Agents; Catalase; Chemical and Drug Induced Liver Injury; Glutathione; Liver; Male; Malondialdehyde; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Plant Oils; Protective Agents; Stomach; Stomach Ulcer; Superoxide Dismutase

Little is known about the emergency department (ED) visits from drug-related injury among older adults in Taiwan. This study seeks to identify risk factors associated with adverse drug events (ADEs) leading to ED visits.. We prospectively conducted a case-control study of patients 65years and older presenting to the ED. ED visits between March 1, 2009 and Feb 28, 2010 identified by investigators for suspected ADEs were further assessed by using the Naranjo Adverse Drug Reaction probability scale. For each patient with an ADE, a control was selected and time-matched from the ED population of the study hospital. The association between the risk of adverse drug events and triage, age, gender, serum alanine transaminase (ALT), serum creatinine, number of medications, and Charlson Comorbidity Index scores were analyzed using logistic regression.. Of 20,628 visits, 295 ADEs were physician-documented in older adults. Independent risk factors for ADEs included number of medications (adjusted odds ratio [OR]=4.1; 95% confidence interval [CI] 2.4-6.9 for 3-7 drugs; adjusted OR=6.4; 95% CI 3.7-11.0 for 8 or more drugs) and increased concentration of serum creatinine (adjusted OR=1.5; 95% CI 1.1-2.2). Diuretics, analgesics, cardiovascular agents, anti-diabetic agents and anticoagulants were the medications most commonly associated with an ADE leading to ED visits.. This study suggests that prevention efforts should be focused on older patients with renal insufficiency and polypharmacy who are using high risk medications such as anticoagulants, diuretics, cardiovascular agents, analgesics, and anti-diabetic agents.

Topics: Age Factors; Aged; Aged, 80 and over; Alanine Transaminase; Analgesics; Anticoagulants; Cardiovascular Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Creatinine; Diuretics; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Female; Humans; Hypoglycemic Agents; Logistic Models; Male; Polypharmacy; Prospective Studies; Renal Insufficiency; Risk Factors; Sex Factors; Taiwan

To evaluate antioxidant, anti-inflammatory, hepatoprotective and vasorelaxant activities of Populus nigra flower buds ethanolic extract.. Antioxidant and anti-inflammatory activities of the extract were assessed using respectively the ABTS test and the animal model of carrageenan-induced paw edema. Protection from hepatic toxicity caused by aluminum was examined by histopathologic analysis of liver sections. Vasorelaxant effect was estimated in endothelium-intact and -rubbed rings of porcine coronary arteries precontracted with high concentration of U46619.. The results showed a moderate antioxidant activity (40%), but potent anti-inflammatory activity (49.9%) on carrageenan-induced mice paw edema, and also as revealed by histopathologic examination, complete protection against AlCl₃-induced hepatic toxicity. Relaxant effects of the same extract on vascular preparation from porcine aorta precontracted with high concentration of U46619 were considerable at 10⁻¹ g/L, and comparable (P>0.05) between endothelium-intact (67.74%, IC₅₀=0.04 mg/mL) and -rubbed (72.72%, IC₅₀=0.075 mg/mL) aortic rings.. The extract exerted significant anti-inflammatory, hepatoprotective and vasorelaxant activities, the latter being endothelium-independent believed to be mediated mainly by the ability of components present in the extract to exert antioxidant properties, probably related to an inhibition of Ca²⁺ influx.

Topics: Aluminum Chloride; Aluminum Compounds; Analysis of Variance; Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Carrageenan; Chemical and Drug Induced Liver Injury; Chlorides; Edema; Female; Flavonoids; Flowers; Liver; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type III; Phenols; Plant Extracts; Populus; Protective Agents; Tannins

We investigated clinical features, therapy, and outcomes of patients hospitalized for drug-induced liver injury (DILI). DILI resolution was defined as liver biochemistry values back to normal or lower than CIOMS laboratory criteria; Chronicity was defined as persistent biochemical abnormality for >6 months after drugs' withdrawal. Three-hundred cases were reviewed retrospectively; mean age 51 (13-86) years, and 204 (68 %) were females. It included 267 (89 %) hepatocellular injury, 16 (5.3 %) cholestatic injury, and 17 (5.7 %) mixed injury cases. In hepatocellular injury group, 197 (73.8 %) patients with TBIL < 10× ULN included 142 (72.1 %) females and 70 (26.2 %) patients with TBIL ≥ 10× ULN included 39 (55.7 %) females (P = 0.012). Of 70 patients (TBIL ≥ 10× ULN), 20 were treated with steroid step-down therapy (79 ± 26 days) and others with non-steroid therapy. The steroid therapy group showed higher DILI resolution rate (P = 0.029) and shorter recovery time (P = 0.012). Notably, 274/300 (91.3 %) patients resolved, 18/300 (6 %) developed chronic liver injury, 7/300 (2.3 %) died, and one patient received liver transplantation. In death group, TBIL, ALB, PT, and PTA revealed more severe abnormality than in recovery group. In 121/300 (40.3 %) patients, use of herbal medicines was the leading cause of liver injury, followed by antibiotics, cardiovascular drugs, and endocrine drugs. We concluded that step-down steroid therapy for DILI improved curative effect, shortened disease course, and was safe.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Anti-Bacterial Agents; Aspartate Aminotransferases; Bilirubin; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Disease Progression; Female; Hospitalization; Humans; Liver; Liver Transplantation; Male; Middle Aged; Plant Preparations; Retrospective Studies; Steroids; Treatment Outcome

In this paper, we investigate various confidence intervals for the risk ratio under inverse sampling (also known as negative binomial sampling). Three existing confidence intervals (namely, the confidence intervals that are based on Fieller's theorem, the delta method and the F-statistic) are reviewed and three new confidence intervals (namely, the score, likelihood ratio and saddlepoint approximation (SA)-based confidence intervals) are developed. Comparative studies among these confidence intervals through Monte Carlo simulations are evaluated in terms of their coverage probabilities and expected interval widths under different settings. Our simulation results suggest that the SA-based confidence interval is generally more appealing. We illustrate these confidence interval construction methods with real data sets from a drug comparison study and a congenital heart disease study.

Topics: Binomial Distribution; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Computer Simulation; Confidence Intervals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Humans; Infant, Low Birth Weight; Infant, Newborn; Likelihood Functions; Monte Carlo Method; Myocardial Infarction; Odds Ratio; Pregnancy; Pregnancy Complications, Cardiovascular; Sample Size

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.

Topics: Adult; Aged; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; Atorvastatin; Azepines; Captopril; Cardiovascular Agents; Central Nervous System Agents; Chemical and Drug Induced Liver Injury; Chronic Disease; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Heptanoic Acids; Humans; Liver; Liver Diseases; Male; Middle Aged; Pyrroles; Registries; Spain

To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem.. A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 times normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin.. Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem.. While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.

Topics: Acute Disease; Acute Kidney Injury; Atorvastatin; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Diltiazem; Drug Interactions; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyrroles; Rhabdomyolysis

Topics: Adult; Aged; Analgesics; Analgesics, Non-Narcotic; Anti-Bacterial Agents; Antibodies, Antinuclear; Anticoagulants; Autoimmune Diseases; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Dopamine Antagonists; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Time Factors