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Drug induced liver dysfunction

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https://www.readbyqxmd.com/read/28428362/hepatic-lipid-accumulation-cause-and-consequence-of-dysregulated-glucoregulatory-hormones
#1
Caroline E Geisler, Benjamin Jennings Renquist
Fatty liver can be diet, endocrine, genetic, viral, or drug induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic, and ketogenic genes, promoting hyperglycemia, hyperlipidemia, and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency, and elevated sympathetic tone...
April 20, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28424418/the-aryl-hydrocarbon-receptor-is-required-for-induction-of-p21cip1-waf1-expression-and-growth-inhibition-by-su5416-in-hepatoma-cells
#2
Edmond F O'Donnell, Hyo Sang Jang, Martin Pearce, Nancy I Kerkvliet, Siva Kumar Kolluri
The aryl hydrocarbon receptor (AhR) is a potential clinical target for cancer and autoimmune dysfunction. Identifying selective AhR modulators that produce desirable clinical outcomes represents an opportunity for developing new anti-cancer agents. Repurposing clinically-used drugs with established safety profiles that activate the AhR represents a good starting place to pursue this goal. In this study, we characterized the AhR-dependent effects of SU5416 (Semaxanib) following its identification in a small-molecule library screen...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419467/refining-liver-safety-risk-assessment-application-of-mechanistic-modeling-and-serum-biomarkers-to-cimaglermin-alfa-ggf2-clinical-trials
#3
Diane M Longo, Grant T Generaux, Brett A Howell, Scott Q Siler, Daniel J Antoine, Donald Button, Anthony Caggiano, Andrew Eisen, Jennifer Iaci, Ric Stanulis, Tom Parry, Merrie Mosedale, Paul B Watkins
Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase 1 trials were suspended when 2 cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin meeting current FDA criteria for a serious liver safety signal (i.e. "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28417920/evaluation-of-the-potential-risk-of-drugs-to-induce-hepatotoxicity-in-human-relationships-between-hepatic-steatosis-observed-in-non-clinical-toxicity-study-and-hepatotoxicity-in-humans
#4
Keisuke Goda, Akio Kobayashi, Akemi Takahashi, Tadakazu Takahashi, Kosuke Saito, Keiko Maekawa, Yoshiro Saito, Shoichiro Sugai
In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans...
April 12, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28379587/drug-induced-liver-injury-2017-the-diagnosis-is-not-easy-but-always-to-keep-in-mind
#5
G Marrone, F G Vaccaro, M Biolato, L Miele, A Liguori, C Araneo, F R Ponziani, N Mores, A Gasbarrini, A Grieco
A drug-induced liver injury (DILI) is defined as a liver injury caused by exposure to a drug or a non-infectious toxic agent with a variable degree of organ dysfunction. A better understanding of DILI epidemiology has been obtained in recent years with the institution of international registries in the United States and Europe. Despite the advances in the understanding and characterization of the phenomenon, DILI remains an exclusion diagnosis so, probability scores and the analysis of literature reports are useful tools in dealing with a suspected DILI...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28358421/extravasated-platelet-aggregation-in-the-livers-of-rats-with-drug%C3%A2-induced-hepatic-sinusoidal-obstruction-syndrome
#6
Miki Hirata, Hidehiro Tajima, Tomoharu Miyashita, Takashi Miyata, Shinichi Nakanuma, Isamu Makino, Hironori Hayashi, Katsunobu Oyama, Hiroyuki Takamura, Itasu Ninomiya, Sachio Fushida, Hiroki Nakata, Shoichi Iseki, Shinichi Harada, Tomohiko Wakayama, Tetsuo Ohta
Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS...
March 28, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28347174/autophagy-as-a-target-for-development-of-anti-diabetes-drugs-derived-from-natural-compounds
#7
REVIEW
Xiao-Wei Zhang, Ji-Chao Zhou, Zhuo-Wei Hu
Patients with diabetes have a high level of blood glucose because their body cannot produce enough insulin or properly respond to this hormone. In both situations, it has become evident that persistent high concentrations of glucose, insulin, insulin-like growth factor, and insulin resistance lead to dysfunction and destruction of autophagic activity in the cells of islet and other organs involved in complications of diabetes, including the liver, cardiovascular, and nervous systems. Accumulating evidences have revealed that autophagy is a novel therapeutic target with a wide range of beneficial effects on diabetes and that plenty of drugs and natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways...
April 2017: Journal of Asian Natural Products Research
https://www.readbyqxmd.com/read/28331914/effects-and-mechanisms-of-a-new-multivitamin-on-chronic-metabolic-syndromes-and-aging
#8
Su-Xi Wu, Xuewei Jiang, Yu-Ying Liu, Lin-Feng Chen, Jun Tao
BACKGROUND: Increased occurrence of chronic syndromes has prompted researchers to investigate and develop drugs and methods for controlling chronic syndromes with a view to improve human health and reduce early aging. MATERIAL AND METHODS: Human trials: After the allotted multivitamin pills or placebo pills had been taken for a stipulated period of about 2 months, the volunteers filled out feedback forms on curative effects of the pills in line with the health examination reports...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
https://www.readbyqxmd.com/read/28329820/hepatocellular-toxicity-of-imidazole-and-triazole-antimycotic-agents
#9
Patrizia Haegler, Lorenz Joerin, Stephan Krähenbühl, Jamal Bouitbir
Hepatotoxicity has been described for all antimycotic azoles currently marketed. A possible mechanism involving mitochondrial dysfunction has been postulated for ketoconazole, but not for the other azoles. The aim of the current investigations was to study the toxicity of different azoles in human cell models and to find out mechanisms of their toxicity. In HepG2 cells, posaconazole and ketoconazole were cytotoxic starting at 20 and 50 µM and decreased the cellular ATP content starting at 5 and 10 µM, respectively...
January 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28304119/serum-markers-for-mitochondrial-dysfunction-and-cell-death-are-possible-predictive-indicators-for-drug-induced-liver-injury-by-direct-acting-antivirals
#10
Keisuke Kakisaka, Yuichi Yoshida, Yuji Suzuki, Takuro Sato, Hidekatsu Kuroda, Akio Miyasaka, Yasuhiro Takikawa
AIM: We prospectively screened patients treated with direct-acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI). METHODS: The levels of various serum markers among DILI, non-DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, sex and disease severity...
March 17, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/28261831/hydroxyapatite-nanoparticle-induced-mitochondrial-energy-metabolism-impairment-in-liver-cells-in-vitro-and-in-vivo-studies
#11
Yang Xue, Qingqing Chen, Jiao Sun
Hydroxyapatite nanoparticles (HAP-NPs) have been extensively developed as drug carriers, bone implants, coating materials, etc. in the human body. However, research focusing on the potential side effects of HAP-NPs on the mitochondria-associated energy metabolism in liver cells is lacking. In this study, HAP-NPs with a long diameter of 80 nm and a short diameter of 20 nm were evaluated for their ability to induce mitochondrial energy metabolism dysfunction in vitro and in vivo. In the in vitro system, the buffalo rat hepatocyte (BRL) cell line was directly exposed to the HAP-NPs...
March 6, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28242362/intravenous-administration-of-mitochondria-for-treating-experimental-parkinson-s-disease
#12
Xianxun Shi, Ming Zhao, Chen Fu, Ailing Fu
Mitochondrial dysfunction is associated with a large number of human diseases, including neurological and muscular degeneration, cardiovascular disorders, obesity, diabetes, aging and rare mitochondrial diseases. Replacement of dysfunctional mitochondria with functional exogenous mitochondria is proposed as a general principle to treat these diseases. Here we found that mitochondria isolated from human hepatoma cell could naturally enter human neuroblastoma SH-SY5Y cell line, and when the mitochondria were intravenously injected into mice, all of the mice were survived and no obvious abnormality appeared...
February 24, 2017: Mitochondrion
https://www.readbyqxmd.com/read/28224373/drug-induced-liver-injury-in-the-setting-of-glycogenic-hepatopathy
#13
Valmiki Maharaj, Matthew Fitz, Xianzdong Ding
Glycogenic hepatopathy (GH) is an underdiagnosed complication of uncontrolled type 1 diabetes mellitus (T1DM). It appears as an acute relapsing hepatitis with reversible transaminase elevations secondary to excessive hepatic glycogen accumulation. Patients are often asymptomatic but can present with abdominal pain, nausea and vomiting. Physical examination shows hepatomegaly without splenomegaly. GH is diagnosed by biopsy as it is clinically indistinguishable from non-alcoholic fatty liver disease (NAFLD), a more common cause of hepatic dysfunction in diabetics...
February 21, 2017: Journal of General Internal Medicine
https://www.readbyqxmd.com/read/28216958/-1-h-nmr-based-serum-metabolomics-reveals-erythromycin-induced-liver-toxicity-in-albino-wistar-rats
#14
Atul Rawat, Durgesh Dubey, Anupam Guleria, Umesh Kumar, Amit K Keshari, Swati Chaturvedi, Anand Prakash, Sudipta Saha, Dinesh Kumar
INTRODUCTION: Erythromycin (ERY) is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism. OBJECTIVE: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using (1)H NMR based serum metabolomics...
October 2016: Journal of Pharmacy & Bioallied Sciences
https://www.readbyqxmd.com/read/28214329/-p-clphse-2-reduces-hepatotoxicity-induced-by-monosodium-glutamate-by-improving-mitochondrial-function-in-rats
#15
Caroline B Quines, Pietro M Chagas, Diane Hartmann, Nélson R Carvalho, Félix A Soares, Cristina W Nogueira
It is has been demonstrated that mitochondrial dysfunction, oxidative stress and chronic inflammatory process are associated with progress of morbid obesity in human patients. For this reason, the searching for safe and effective antiobesity drugs has been the subject of intense research. In this context, the organic selenium compounds have attracted much attention due to their pharmacological properties, such as antihyperglycemic, antioxidant and anti-inflammatory. The aim of this study was to evaluate the hepatoprotective action of p-chloro-diphenyl diselenide (p-ClPhSe)2 , an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats...
February 18, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28177750/modulatory-role-of-co-enzyme-q10-on-methionine-and-choline-deficient-diet-induced-non-alcoholic-steatohepatitis-nash-in-albino-rats
#16
Dalia O Saleh, Rania F Ahmed, Mohamed M Amin
The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day)(-1)) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded...
March 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
https://www.readbyqxmd.com/read/28161274/valproate-acid-vpa-induced-dysmetabolic-function-in-clinical-and-animal-studies
#17
Rong Li, Lisheng Liang, Xinmou Wu, Xianli Ma, Min Su
BACKGROUND: Valproate acid (VPA), a commonly used antiepileptic medicine, is found to be linked to developing dysmetabolic risk. However, the proposed mechanism remains completely unknown. METHODS: In this study, we collected data from patients with epilepsy and further investigated the preclinical study in mice. RESULTS: As results, the clinical data showed that VPA-used patients resulted in higher levels of blood glucose, urine acid, triglyceride (TG), and immune cells (leucocyte, neutrophil leucocyte) when compared to clinically diagnosed references, while circulating apolipoprotein A1 (Apob A1) and fatty acid binding protein 4 (FABP4) were reduced without visible drug-induced liver injury (DILI)...
February 2, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28146130/effects-of-natural-products-on-fructose-induced-nonalcoholic-fatty-liver-disease-nafld
#18
REVIEW
Qian Chen, Tingting Wang, Jian Li, Sijian Wang, Feng Qiu, Haiyang Yu, Yi Zhang, Tao Wang
As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance...
January 31, 2017: Nutrients
https://www.readbyqxmd.com/read/28115652/editor-s-highlight-candidate-risk-factors-and-mechanisms-for-tolvaptan-induced-liver-injury-are-identified-using-a-collaborative-cross-approach
#19
Merrie Mosedale, Yunjung Kim, William J Brock, Sharin E Roth, Tim Wiltshire, J Scott Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William Valdar, Paul B Watkins
Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains...
April 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28109684/increase-in-the-systemic-exposure-of-primary-metabolites-of-midazolam-in-rat-arising-from-cyp-inhibition-or-hepatic-dysfunction
#20
Tsubasa Hasegawa, Satomi Nakanishi, Keiko Minami, Haruki Higashino, Makoto Kataoka, Yoshihisa Shitara, Shinji Yamashita
The main purpose of this study is to demonstrate the possibility of increase in the systemic exposure of drug metabolites by CYP-inhibition or acute hepatitis. Midazolam (MDZ) was used as a model substrate of CYP3A and 1-aminobenzotriazole (ABT) was used as a CYP-inhibitor. After oral pretreatment with ABT, MDZ was intravenously injected to rats and the plasma profiles of MDZ and its primary metabolites, 1'-hydroxy MDZ and 4-hydroxy MDZ, were observed. In the ABT-pretreatment rats, plasma AUCs of both metabolites were much larger than those in control rats, demonstrating a higher systemic exposure of metabolites under CYP-inhibited condition...
November 23, 2016: Drug Metabolism and Pharmacokinetics
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