Liver Safety Research Articles

Acaricidal activity and enzyme inhibitory activity of active compounds of essential oils against Psoroptes cuniculi

Plant essential oils and its chemical compositions are commonly applied in medicinal and other industries due to their broad advanced pharmacological activities. In the present study, we systematically evaluated the acaricidal activities of twelve compounds of essential oils against Psoroptes cuniculi in vitro and in vivo. In addition, to support the clinic uses, their toxicities against immortalized human keratinocytes (HaCaT) and human liver cells (HL-7702) and skin irritation were studied for evaluating the liver and skin safety. The possible mechanism of action of certain chemical were investigated by determining the inhibitory activities against cytochrome P450 (P450) acetylcholinesterase (AChE) and glutathione-S-transferase (GST). Among all tested compounds, eugenol exhibited the best acaricidal activity with LC50 value of 56.61 μg/ml in vitro. Meanwhile, after the treatment of eugenol for five times within 10 days, the P. cuniculi were eliminated in the naturally infested rabbits, no skin irritation was found in rabbits treated by eugenol. Moreover, eugenol presented no or weak cytotoxicity against HaCaT cells and HL-7702 cells with IC50 values of greater than 100 μg/ml. Furthermore, the moderate inhibitory activities of eugenol against mites P450 and AChE were demonstrated. Above results indicated that eugenol presented the promising acaricidal activity against P. cuniculi in vitro and in vivo, is safe for both humans and animals at the given doses. This work lays the foundation for the development of eugenol as an environmentally friendly acaricide agent.

Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications.

Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the "gold standard" liver safety signal is the occurrence of "Hy's Law Cases." Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or "signatures." In a clinical trial, it is sometimes possible to identify an overlooked "signature" of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.

Serum biomarkers of drug-induced liver injury: Current status and future directions.

Drug-induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data-driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.

Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles.

GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development.

Correction to: Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

In the original publication of the article, the ALT and AST values in Fig.5a-e were capped at 10× ULN, which did not accurately reflect the narrative provided for each case. In this correction, the original Fig.5a-e (Fig.1a-e) and the correct Fig.5a-5e (Fig.2a-e) are published.

Safety liver profile of teriflunomide versus interferon β in multiple sclerosis: Systematic review and indirect comparison meta-analysis

ObjectivesTo compare the liver safety profile of interferon β (IFN β) and teriflunomide in patients with multiple sclerosis. MethodsA network meta-analysis was carried out following the Cochrane Collaboration methodology. All trials comparing all types of IFN β with teriflunomide, or disease-modifying drugs, or placebo in RRMS were included. An indirect comparison network meta-analysis within a Bayesian framework with STATA (version 13.0) was done for this study. ResultsThe database searches yielded 284 titles, with 15 records as duplicates. One study was identified by manually searching. Thirteen articles were included in the systematic review. Twelve studies compared IFN β (4203 patients) vs another DMT. Four studies evaluated the effectiveness and safety of teriflunomide (906 patients) vs another DMT. Six studies reported drug-induced liver injury as per the Hy's Law. However, only one study had a direct comparison and reported no cases of liver toxicity in either group, so it was not possible to estimate the OR. The indirect comparisons metanalysis shows that there was no statistically-significant difference between teriflunomide and IFN β (OR 1.09, 95% CI 0.02–2.16). ConclusionsThere were no significant difference when comparing IFN β and teriflunomide in terms of liver failure or elevation of transaminases.

Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice

Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12–2.52; and 2.53; 2.40–2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09–1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Ulipristal acetate (UPA) treatment of uterine fibroids (UF): integrated liver safety results from venus I and II

Ulipristal acetate (UPA) treatment of uterine fibroids (UF): integrated liver safety results from venus I and II

Long-term Liver Safety of Lomitapide in Patients with Homozygous Familial Hypercholesterolemia: Three-year Data from LOWER

Long-term Liver Safety of Lomitapide in Patients with Homozygous Familial Hypercholesterolemia: Three-year Data from LOWER

Improving Interpretation of New and Old Serum Biomarkers of Drug-Induced Liver Injury Through Mechanistic Modeling.

The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates.

FRI-501 - Long-term liver safety of lomitapide in patients with homozygous familial hypercholesterolemia: Three-year data from the lomitapide observational worldwide evaluation registry (LOWER)

FRI-501 - Long-term liver safety of lomitapide in patients with homozygous familial hypercholesterolemia: Three-year data from the lomitapide observational worldwide evaluation registry (LOWER)

Endoscopic diagnosis and treatment of biliary complications after orthotopic liver transplantation

Aim. The aim of the study was to investigate the endoscopic diagnostic and treatment techniques for biliary complications after orthotopic liver transplantation, their efficacy and safety. Material and methods. The study was based on the results of endoscopic treatment of 29 patients with biliary complications occurred after orthotopic liver transplantation in N.V. Sklifosovsky Research Institute for Emergency Medicine in the period from December 2001 to January 2017. Conclusions. The state-of-the-art methods of therapeutic endoscopy enable a successful treatment of most cases of biliary strictures and biliary-biliary anastomosis incompetence, thus achieving good long-term results using a minimally invasive methodology.

Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience

Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n=5359, fasiglifam group), fasiglifam and sitagliptin (n=123), or a comparator agent (n=3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations>3×upper limit of normal (ULN), 5×ULN, and 10×ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations>3×ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50mg daily. The cumulative incidence of elevations in serum ALT>3×ULN was higher in the first 6months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT>3×ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases. Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Safety data and withdrawal of hepatotoxic drugs

The occurrence of drug induced liver injury (DILI) is the most common reason of post-marketing withdrawals. DILI in humans is difficult to predict using in vitro cytotoxicity screening and animal studies. A review of hepatotoxicity data was performed with the aim of identifying relevant factors that could have predicted the occurrence of serious DILI. The drugs withdrawn from the market due to hepatotoxicity in Europe and/or in USA either by marketing authorization holders or by Regulatory agencies from 1997 to 2016 were selected. The liver safety data and the withdrawal decisions were identified from a search within the European medicine agency (EMA) website, the Food and drug administration (FDA) orange book and PubMed®. From 1997 to 2016, eight drugs were withdrawn from the market for hepatotoxicity reason: tolcapone, troglitazone, trovafloxacin, bromfenac, nefazodone, ximelagatran, lumiracoxib and sitaxentan. The safety data suggest that while liver test abnormalities have been detected during clinical trials, other relevant factors leading to the discontinuation of these drugs have been identified: lack of predictability of animal models, inappropriate liver function test, non-compliance with drug treatment, less attention paid to rare adverse drug reactions, unpredictable occurrence and irreversible outcome of liver toxicity. Several relevant factors may contribute to an inadequate risk management leading to the discontinuation of the drugs. Preclinical safety data are not sufficient to allow early prediction of DILI in humans and post-marketing safety monitoring and signal detection still should be used to identify potential serious cases of DILI. However, it seems that changes in Pharmacovigilance legislation with a closer management of drug safety may have contributed to the improvement of the risk minimization.

Effect of Stains on LDL Reduction and Liver Safety: A Systematic Review and Meta-Analysis.

Background and Aim Statin is a class of medications used to decrease low-density lipoprotein cholesterol level to prevent cardiovascular disease. However, the risk of hepatic damage caused by statin therapy is still controversial. We conducted a systematic review and meta-analysis summarizing the existing evidence of the effect of statin therapy on incidence of liver injury to clarify whether statin therapy could lead to liver function test abnormalities. Methods We searched the Cochrane Library, PubMed, and Embase database for the relevant studies update till Jan. 2017 regarding statin therapy and liver injury. Two researchers screened the literature independently by the selection and exclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models, and subgroup analyses were performed by study characteristics. This meta-analysis was performed by STATA 13.1 software. Results Analyses were based on 74,078 individuals from 16 studies. The summary OR of statin therapy was 1.18 (95% CI: 1.01–1.39, p = 0.04; I2 = 0.0%) for liver injury. Subgroup analysis indicated that fluvastatin increased the risk of liver injury significantly (OR, 3.50; 95% CI: 1.07–11.53, p = 0.039; I2 = 0.0%) and dose over 40 mg/daily had an unfavorable effect on the liver damage (OR, 3.62; 95% CI: 1.52–8.65, p = 0.004; I2 = 0.0%). The sensitivity analysis indicated that the results were robust. Conclusion Our findings confirm that statin therapy substantially increases the risk of liver injury, especially using fluvastatin over 40 mg/d.

Mast cells and pro-inflammatory cytokines roles in assessment of grape seeds extract anti-inflammatory activity in rat model of carrageenan-induced paw edema.

Objective(s):Reactive oxygen species (ROS)-produced oxidative disorders were involved at the pathophysiology of many inflammatory processes via the generation of pro-inflammatory cytokines and antioxidant defense system suppression. Although herbal antioxidants as mono-therapy relief many inflammatory diseases including, autoimmunity rheumatoid arthritis, but as combination therapy with other proven anti-inflammatory drugs in order to decreasing their toxic impacts has not yet been studied clearly, especially against chemical substances that’s induced local inflammation with characteristic edema.Materials and Methods:Grape seeds extract (GSE) at a concentration of 40 mg/kg B. wt alone or in combination with indomethacin (Indo.) at a dose of 5 mg/Kg B. wt orally given for 10 days prior (gps VI, VII, VIII) or as a single dose after edema induction (gps IX, X, XI) in rat’s left hind paw by sub-planter single injection of 0.1 carrageenan: saline solution (1%) (gp. V) to assess the prophylactic and therapeutic anti-inflammatory activities of both through the estimation of selective inflammatory mediators and oxidative damage-related biomarkers as well as tissue mast cell scoring. Furthermore, both substances were given alone (gps II, III, IV) for their blood, liver and kidney safety evaluation comparing with negative control rats (gp. I) which kept without medication.Results:A marked reduction on the inflammatory mediators, edema volume and oxidative byproducts in edema bearing rats’ prophylactic and treated with grape seeds extract and indomethacin was observed. Indomethacin found to induce some toxicological impacts which minimized when administered together with GSE.Conclusion:GSE is a safe antioxidant agent with anti-inflammatory property.

Safety and efficacy analysis of DEB-TACE treatment in elderly patients with hepatocellular carcinoma: a comparative cohort study.

The aim of this study was to explore the difference of liver function change, safety profiles and efficacy of drug-eluting bead transarterial chemoembolization (DEBTACE) therapy between elderly and middle-aged hepatocellular carcinoma (HCC) patients. 91 HCC patients were enrolled in this prospective cohort study. They were treated by DEB-TACE therapy and divided into elderly group (age >= 65 years, n=30) and middle-aged group (age < 65 years, n=61), liver function, safety profiles and treatment response were recorded. No difference of liver function was found between two groups before operation and at 1 week post DEB-TACE treatment. While the portion of abnormal total protein (TP) in elderly group was elevated than that in middleage group at 1-3 months after operation. During operation, elderly group presented with raised incidence of vomiting compared with middle-aged group, whereas elderly patients displayed lower incidence of pain than middle-aged patients at 1 month post treatment. No other difference of safety profiles was found between the two groups. At 1-3 months after treatment, elderly patients achieved complete response (CR) of 26.7% and overall response rate (ORR) of 93.3%, meanwhile, middle-aged patients obtained CR of 23.0% and ORR of 90.2%. No difference of CR and ORR was found between elderly and middle-aged patients, in addition, no difference of OS was observed between the two groups. In conclusion, DEB-TACE therapy was well tolerated in elderly HCC patients, and it possessed equal efficacy in elderly patients compared with middle-aged patients.

In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials.

Current strategies to delineate the risk of serious drug-induced liver injury associated with drugs rely on assessment of serum biomarkers that have been utilized for many decades. In particular, serum alanine aminotransferase and total bilirubin levels are typically used to assess hepatic integrity and function, respectively. Parallel measurement of these biomarkers is utilized to identify patients with drug-induced hepatocellular jaundice ("Hy's Law" cases) which carries at least a 10% risk of death or liver transplant. However, current guidelines regarding use of these biomarkers in clinical trials can put study subjects at risk for life-threatening drug-induced liver injury, or result in over estimation of risk that may halt development of safe drugs. In addition, pharmaceutical companies are increasingly being required to conduct large and expensive clinical trials to "defend" the safety of their new drug when results from smaller trials are inconclusive. Innovative approaches and some novel biomarkers are now being employed to maximize the value of traditional biochemical tests. DILIsym®, a product of the DILIsim Initiative, utilizes serial serum alanine aminotransferase values, along with serum biomarkers of apoptosis vs necrosis, to estimate percent hepatocyte loss and total bilirubin elevations resulting from loss of global liver function. The results from analyses conducted with DILIsym have been reported to the FDA to support the safety of entolimod and cimaglermin alfa after elevations in serum alanine aminotransferase and/or bilirubin halted clinical development. DILIsym can also be utilized to determine whether rises in serum conjugated and unconjugated bilirubin are consistent with mechanisms unrelated to toxicity ( i.e. inhibition of bilirubin transport or metabolism). In silico modeling of traditional and novel drug-induced liver injury biomarker data obtained in clinical trials may be the most efficient and accurate way to define the liver safety profile of new drug candidates. Impact statement Blood tests used in clinical trials to detect and monitor drug-induced liver injury (DILI) have not changed in half a century. These tests have several shortcomings: their use has not completely prevented clinical trial participants from risk of life-threatening DILI, they can give false positive results that halt the development of safe drug candidates, and they can create liver safety "concerns" that require large additional clinical trials to accurately define DILI risk. This review highlights the use of in silico modeling to improve interpretation of the blood tests currently available to detect DILI risk in new drug candidates. This approach is increasingly being applied in clinical trials to more precisely assess the degree of hepatocellular injury and its functional impact. This new approach holds the promise of more accurately defining DILI risk in smaller clinical trials.

Liver Safety of Vedolizumab: A Single-center Experience

Liver Safety of Vedolizumab: A Single-center Experience