Effect of Clomethiazole (Distraneurin®) on CYP2E1 Activity, transaminases, Liver fat content, and liver stiffness during Alcohol Detoxification – a pilot Study - CALvADoS

Start Date11 Feb 2015

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100 Clinical Results associated with Clomethiazole

100 Translational Medicine associated with Clomethiazole

100 Patents (Medical) associated with Clomethiazole

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Literatures (Medical) associated with Clomethiazole

01 Apr 2025·Journal of Medical Toxicology

Acute Acetaminophen Hepatotoxicity And Platelet Dysfunction

Article

Author: Pritt, Trenton A ; Attal, Neha ; McKillop, Iain H ; Ekaney, Michael L ; Murphy, Christine M

INTRODUCTIONAcetaminophen (APAP) overdose remains a common cause of liver injury, primarily due to its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). This study sought to investigate APAP-induced platelet aggregation in vitro, and the implication of CYP2E1 in the metabolism of APAP and hepatic cell toxicity.METHODSCo-cultures of platelets and hepatic cells that do not (HepG2) and do express CYP2E1 (HepG2^E47) were exposed to APAP (0-20 mM), NAPQI (0-250 µM), APAP in the absence/presence of inhibitors of glutathione (50 μM buthionine sulphoximine (BSO)), or APAP in the absence/presence of inhibitors CYP2E1 (chlormethiazole (CMZ, 100 µM), or 4-methylpyrazole (4-MP, 5 mM)). Platelet aggregation, cell viability and reactive oxygen species (ROS) were analyzed. Changes in platelet aggregation was determined in platelets directly exposed to APAP/NAPQI.RESULTSExposure to APAP decreased platelet aggregation under co-culture conditions but not in platelet-only cultures. Conversely, NAPQI exposure decreased platelet aggregation in both co-culture and platelet-only conditions. Both APAP and NAPQI reduced cell viability in HepG2 and HepG2^E47 cells, with BSO enhancing APAP toxicity, while 4-MP mitigated it. Acetaminophen exposure led to ROS production in HepG2^E47 cells, with no effect of CMZ and 4-MP.CONCLUSIONSAcetaminophen exposure impacts platelet aggregation in co-cultures of platelets and HepG2/HepG2^E47 cells with increased ROS production in HepG2^E47 cells and 4-MP preventing APAP-induced cytotoxicity in HepG2^E47 cells. While APAP had no direct effect on platelets, NAPQI exposure acted to decrease platelet aggregation. These findings enhance our understanding of the mechanisms of APAP-induced hepatotoxicity and the potential role of APAP-induced hepatocellular toxicity in platelet aggregation.

25 Mar 2025·Alcohol and Alcoholism

The role of cytochrome P4502E1 in ethanol mediated diseases: a narrative update

Review

Author: Zakhari, Samir ; Neuman, Manuela ; Seitz, Helmut K

AbstractCytochrome P450 (CYPs) superfamily of enzymes metabolize thousands of endogenous and exogenous substrates including ethanol. Results: Cytochrome P4502E1 (CYP2E1) is involved in ethanol metabolism as part of the so-called microsomal ethanol metabolizing system, in the metabolism of fatty acids and some drugs such as acetaminophen and isoniazid, and in the activation of a variety of procarcinogens (PCs). Chronic ethanol consumption induces CYP2E1 which may result in an enhanced metabolism of these drugs to their toxic intermediates, and in the generation of carcinogens. In addition, ethanol oxidation increases and is associated with the generation of reactive oxygen species (ROS). This oxidative stress is an important driver for the development of alcohol-associated liver disease (AALD) and alcohol-mediated cancer (AMC). ROS may bind directly to proteins and to DNA. ROS may also lead to lipid peroxidation (LPO) with the generation of LPO products. These LPO products may bind to DNA forming etheno-DNA adducts. Cell culture studies as well as animal experiments have shown that CYP2E1 knock-out animals or the inhibition of CYP2E1 by chemicals results in a significant improvement of liver histology. CYP2E1 is also involved in pathogenesis of hepatic steatosis and fibrosis. More recent studies in patients with AALD have demonstrated an improvement of serum transaminase activities when CYP2E1 was inhibited by clomethiazole. In addition to its role in the generation of ROS, CYP2E1 also enhances the activation of PCs and decreases the level of retinol and retinoic acid in the liver. Conclusion: Inhibition of CYP2E1 may improve AALD and may inhibit AMC.

01 Mar 2025·European Archives of Psychiatry and Clinical Neuroscience

Naturalistic comparison of clomethiazole and Diazepam treatment in alcohol withdrawal: effects on oxidative stress, inflammatory cytokines and hepatic biomarkers

Article

Author: Meyer-Lotz, Gabriela ; Borucki, Katrin ; Guest, Paul C ; Dobrowolny, Henrik ; Böttcher, Michael ; Schiffner, Conrad J ; Steiner, Johann ; Strischewski, David ; Müller, Ulf J ; Kalmar, Amira ; Relja, Borna ; Jordan, Wolfgang

AbstractEthanol is metabolized by alcohol dehydrogenase to acetaldehyde and induces cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species that cause inflammatory liver damage. Clomethiazole, a drug approved for alcohol withdrawal treatment (AWT) in some European countries, inhibits CYP2E1. We hypothesized that clomethiazole would lead to a faster reduction in oxidative stress, inflammatory cytokines, and liver enzymes compared to diazepam treatment. We analysed respective biomarkers in 50 patients undergoing AWT and 25 healthy individuals but found no statistical difference between the two medication groups over 3–5 days. Hence, our hypothesis was not confirmed during this observation period.

100 Deals associated with Clomethiazole

External Link

KEGG	Wiki	ATC	Drug Bank
D07330	Clomethiazole	N05CM02	DB06470

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Epilepsy	United Kingdom	F. Hoffmann-La Roche Ltd.	01 Jan 1975
Sleep Wake Disorders	United Kingdom	F. Hoffmann-La Roche Ltd.	01 Jan 1975

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Preclinical	United States	F. Hoffmann-La Roche Ltd.	-
Stroke	Preclinical	Canada	F. Hoffmann-La Roche Ltd.	-

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