The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
R Bhattacharya - One of the best experts on this subject based on the ideXlab platform.
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the cyanobacterial toxin microcystin lr induced dna damage in mouse liver in vivo
Toxicology, 1996Co-Authors: R BhattacharyaAbstract:Abstract Microcystin-LR (MCLR) is a potent cyclic heptapeptidic hepatotoxin produced by the cyanobacterium Microcystis aeruginosa. Hepatotoxic and other toxic manifestations of MCLR are well documented. However, information on genotoxicity of MCLR is limited. The present investigation addresses the DNA damage induced by MCLR in mouse liver in vivo. The DNA strand breaks were measured by the fluorimetric analysis of DNA unwinding (FADU). MCLR at 0.5, 1.0 and 2.0 LD50 doses exhibited a dose and time-dependent DNA damage accompanied by similar effects on various enzymes of hepatic origin, e.g. lactate dehydrogenase, alkaline phosphatase and gamma glutamyl transferase. MCLR-induced genomic DNA fragmentation was also assessed qualitatively by agarose gel electrophoresis. MCLR induced random DNA fragmentation and DNA degradation. Glutathione (GSH) pretreatment significantly extended the survival time of animals exposed to 1.0 LD50 MCLR but offered only partial protection with regard to DNA damage. The DNA damage observed in the present study can be ascribed to activation of endonucleases.
Brett A Howell - One of the best experts on this subject based on the ideXlab platform.
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using quantitative systems toxicology to investigate observed species differences in cka mediated Hepatotoxicity
Toxicological Sciences, 2018Co-Authors: Simone Stahl, Christina Battista, Kyunghee Yang, Scott Q Siler, Paul B Watkins, Jerome T. Mettetal, Brett A HowellAbstract:: CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent Hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the Hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the Hepatotoxic potential of drug candidates.
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exploring bsep inhibition mediated toxicity with a mechanistic model of drug induced liver injury
Frontiers in Pharmacology, 2014Co-Authors: Jeffrey L Woodhead, Kyunghee Yang, Scott Q Siler, Paul B Watkins, Kim L R Brouwer, Hugh A Barton, Brett A HowellAbstract:Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the Hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-Hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that Hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in Hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain (ETC) inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors cause DILI.
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systems pharmacology modeling predicts delayed presentation and species differences in bile acid mediated troglitazone Hepatotoxicity
Clinical Pharmacology & Therapeutics, 2014Co-Authors: Kyunghee Yang, Brett A Howell, Paul B Watkins, Jeffrey L Woodhead, Kim L R BrouwerAbstract:Troglitazone (TGZ) caused delayed, life-threatening drug-induced liver injury (DILI) in some patients, but was not Hepatotoxic in rats. This study investigated altered bile acid (BA) homeostasis as a mechanism of TGZ Hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200–600mg/day×6months) resulted in delayed increases in serum ALT>3× ULN in 0.3–5.1% of the population with concomitant bilirubin elevations>2× ULN in 0.3–3.6%. In contrast, pioglitazone (15–45mg/day×6months) did not elicit Hepatotoxicity, consistent with clinical data. TGZ was not Hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on BA effects accurately predicted the incidence, delayed presentation, and species differences in TGZ Hepatotoxicity, and the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate DILI mechanisms and may be useful to predict Hepatotoxic potential of drug candidates.
Mourad Chioua - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of benzochromenopyrimidinones as cholinesterase inhibitors and potent antioxidant non Hepatotoxic agents for alzheimer s disease
Molecules, 2016Co-Authors: Youssef Dgachi, Justyna Godyń, Alexandre Bonet, Hélène Martin, Oscar M Bautistaaguilera, Mohamed Benchekroun, Damijan Knez, Barbara Malawska, Stanislav Gobec, Mourad ChiouaAbstract:We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-Hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-Hepatotoxic on human HepG2 cell line.
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imidazopyranotacrines as non Hepatotoxic selective acetylcholinesterase inhibitors and antioxidant agents for alzheimer s disease therapy
Molecules, 2016Co-Authors: Houssem Boulebd, Alexandre Bonet, Hélène Martin, Isabel Iriepa, Ignacio Moraleda, Lhassane Ismaili, Manuela Bartolini, Abdelmalek Bouraiou, Vincenza Andrisano, Mourad ChiouaAbstract:Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-Hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-Hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound).
James H Lewis - One of the best experts on this subject based on the ideXlab platform.
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review article the use of potentially Hepatotoxic drugs in patients with liver disease
Alimentary Pharmacology & Therapeutics, 2008Co-Authors: N K Gupta, James H LewisAbstract:Summary Background Misconceptions surround the use of Hepatotoxic drugs in chronic liver disease. While many prescription and over-the-counter (OTC) agents can be used safely, this often runs counter to labelled warnings/contraindications, especially for the statins and other commonly used agents. Aim To evaluate published data on the use of Hepatotoxic drugs in chronic liver disease including pharmacokinetic changes in cirrhosis and drug interactions, where available, to formulate recommendations on their use. Methods Using a combination of PubMed searches, review texts, the Physicians’ Desk Reference and expert opinion, drugs considered at higher risk of Hepatotoxicity in chronic liver disease were evaluated. Results Most drugs and OTC products including herbals have not been formally studied in chronic liver disease, but available data suggest that several of the most commonly used agents, especially the statins, can be used safely. While there is an increased risk of drug-induced liver injury for drugs used in the treatment of tuberculosis and HIV patients with hepatitis B or C, recommendations for their safe use are emerging. Conclusions Although many clinicians remain hesitant to use Hepatotoxic drugs in chronic liver disease, the database supporting this view is limited to just a few agents. Most medications can be used safely in patients with chronic liver disease with appropriate monitoring.
Vedat Turkoglu - One of the best experts on this subject based on the ideXlab platform.
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hematotoxic and Hepatotoxic effects of dichlorvos at sublethal dosages in rats
Environmental Toxicology, 2009Co-Authors: Ismail Celik, Zeycan Yilmaz, Vedat TurkogluAbstract:The present study was designed to understand the effects of sublethal concentrations of dichlorvos (DIC) on hematological constituent [red blood corpuscles, white blood corpuscles (WBC), mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet counts, hemoglobin and hematocrite levels] and serum damage marker enzymes (aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase, and lactate dehydrogenase) in rats at subacute period under laboratory conditions. DIC at dosages of 5 and 10 ppm was administered orally to six male rats ad libitum during the tests for 4 weeks consecutively. According to the results, DIC treatments increased significantly the levels of serum marker enzyme activities, whereas they did not change hematologic constituent except for WBC number treated with both dosages of DIC. The observations presented led us to conclude that the administrations of subacute DIC induced the levels of damage marker enzymes and leukocytosis. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009.
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hematotoxic and Hepatotoxic effects of dichlorvos at sublethal dosages in rats
Environmental Toxicology, 2009Co-Authors: Ismail Celik, Zeycan Yilmaz, Vedat TurkogluAbstract:The present study was designed to understand the effects of sublethal concentrations of dichlorvos (DIC) on hematological constituent [red blood corpuscles, white blood corpuscles (WBC), mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet counts, hemoglobin and hematocrite levels] and serum damage marker enzymes (aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase, and lactate dehydrogenase) in rats at subacute period under laboratory conditions. DIC at dosages of 5 and 10 ppm was administered orally to six male rats ad libitum during the tests for 4 weeks consecutively. According to the results, DIC treatments increased significantly the levels of serum marker enzyme activities, whereas they did not change hematologic constituent except for WBC number treated with both dosages of DIC. The observations presented led us to conclude that the administrations of subacute DIC induced the levels of damage marker enzymes and leukocytosis.
