A Mechanistic Model of Drug‐Induced Liver Injury Aids the Interpretation of Elevated Liver Transaminase Levels in a Phase I Clinical Trial

Howell, Brett A.; Siler, Scott Q.; Shoda, Lisl K. M.; Yang, Yuching; Woodhead, Jeffrey L.; Watkins, Paul B.

doi:10.1038/psp.2013.74

Cited by 39 publications

(28 citation statements)

References 24 publications

(64 reference statements)

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“…It is well known that many toxic compounds accumulate in the liver where they are detoxified [30]. Liver transaminases such as AST (aspartate transaminase) or SGOT (serum glutamic oxaloacetic transaminase), and ALT (alanine transaminase) or SGPT (serum glutamic pyruvic transaminase) have still remained the gold standards for the assessment of liver injury [31]. So in the present investigation, there were significant (p>0.0001) increased levels of SGOT, SGPT and total bilirubin along with increased LDH enzyme activity in paracetamol hepatic damage group in comparison to control group.…”

Section: Discussionmentioning

confidence: 99%

Efficacy Study of Livartho against Paracetamol Induced Hepatotoxicity in Adult Sprague Dawley Rats

Dwivedi¹

2016

J Drug Metab Toxicol

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Liver disease is a worldwide problem. It is an exposed to many kinds of xenobiotics and therapeutic agents. The purpose of this study was to evaluate therapeutic effect of Livartho drug in paracetamol induced hepatic damage Sprague dawley rats. Paracetamol at the dose level of 900mg/kg body weight administered through intraperitoneal route once daily for one week to produced liver damage in rats as manifested by the significantly decrease body weight and feed consumption along with significantly increase liver organ weight and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total bilirubin, cholesterol and triglyceride and decrease the total protein and albumin levels along with significantly increase myloperoxidase enzyme activity, lipid peroxidation and protein carbonyl levels as compared to control group. The antioxidant parameters such as reduced glutathione (GSH), oxidized glutathione (GSSG), total thiol and GSH/ GSSG ratio were also found lowered in paracetamol treated group as compared with control. After treatment with Livartho drug (206.6 mg/kg body weight) once daily for 16 days to paracetamol treated rats shows significantly lowered the afore mentioned biochemical parameter whereas protein and albumin levels were increased along with significant increased above mentioned antioxidant enzymatic parameters. The results of this study strongly indicate that Livartho drug is most effective medicine which has potent hepatoprotective action and free radical scavenger against paracetamol induced hepatic damage in Sprague dawley rats.

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Section: Discussionmentioning

confidence: 99%

Efficacy Study of Livartho against Paracetamol Induced Hepatotoxicity in Adult Sprague Dawley Rats

Dwivedi¹

2016

J Drug Metab Toxicol

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“…However, the peak serum ALT values occurred very quickly after dosing and the levels then fell very rapidly, indicating a very short duration of hepatocyte death. Based on serial ALT measurements collected from these responders, DILIsym software was able to estimate that at most a loss of 4.9% of hepatocytes occurred in the most affected participant receiving Entolimod . To put this into context, liver biopsy data collected from patients suffering from an acetaminophen overdose has demonstrated that about 30% of liver volume must be lost before liver function decline is sufficient to result in TBIL >2× ULN …”

Section: Making the Most Of Traditional Biomarkers: In Silico Modelingmentioning

confidence: 99%

“…In the case of Entolimod, ALT peaked quickly and returned to baseline quickly. In a different scenario an ALT peak of a similar magnitude but gradual reduction would be predicted to cause a much greater loss of hepatocytes . Recently, a mathematical equation incorporating ALT peak the area under the receiver operating characteristic curve values has been proposed to approximate values obtained with DILIsym, especially with DILI events of short duration …”

Section: Making the Most Of Traditional Biomarkers: In Silico Modelingmentioning

confidence: 99%

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

Church

Watkins

2018

J of Digest Diseases

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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.

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“…Enzyme such as AST and ALT are main liver transaminases have been used for the assessment of liver damage (Howell et al, 2014).…”

Section: Biological Activitymentioning

confidence: 99%

Hepatoprotective effect of Phytosome Curcumin against paracetamol-induced liver toxicity in mice

Tùng¹,

Hải

Phan

2017

Braz. J. Pharm. Sci.

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Curcuma longa, which contains curcumin as a major constituent, has been shown many pharmacological effects, but it is limited using in clinical due to low bioavailability. In this study, we developed a phytosome curcumin formulation and evaluated the hepatoprotective effect of phytosome curcumin on paracetamol induced liver damage in mice. Phytosome curcumin (equivalent to curcumin 100 and 200 mg/kg body weight) and curcumin (200 mg/kg body weight) were given by gastrically and toxicity was induced by paracetamol (500 mg/kg) during 7 days. On the final day animals were sacrificed and liver function markers (ALT, AST), hepatic antioxidants (SOD, CAT and GPx) and lipid peroxidation in liver homogenate were estimated. Our data showed that phytosome has stronger hepatoprotective effect compared to curcumin-free. Administration of phytosome curcumin effectively suppressed paracetamol-induced liver injury evidenced by a reduction of lipid peroxidation level, and elevated enzymatic antioxidant activities of superoxide dismutase, catalase, glutathione peroxidase in mice liver tissue. Our study suggests that phytosome curcumin has strong antioxidant activity and potential hepatoprotective effects.Uniterms: Curcumin/effects. Curcumin/antioxidant activity. Curcuma longa. Phytosome. Hepatoprotective.

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A Mechanistic Model of Drug‐Induced Liver Injury Aids the Interpretation of Elevated Liver Transaminase Levels in a Phase I Clinical Trial

Cited by 39 publications

References 24 publications

Efficacy Study of Livartho against Paracetamol Induced Hepatotoxicity in Adult Sprague Dawley Rats

Efficacy Study of Livartho against Paracetamol Induced Hepatotoxicity in Adult Sprague Dawley Rats

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

Hepatoprotective effect of Phytosome Curcumin against paracetamol-induced liver toxicity in mice

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