Disease relevance of Clomethiazole

• Results in 95 hemorrhagic stroke patients included in CLASS, a controlled trial of clomethiazole versus placebo in acute stroke patients [1].
• This review discusses the efficacy of clomethiazole (CMZ) in models of global and focal ischemia [2].
• Sedation was the most common adverse event, occurring at a higher incidence in clomethiazole-treated patients (clomethiazole 53%, placebo 17%), followed by rhinitis and coughing [1].
• Severe toxic hepatitis related to chlormethiazole [3].
• Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species [4].

Psychiatry related information on Clomethiazole

• Letter: Chlormethiazol and delirium tremens [5].
• The consensus opinion is taken to be that a risk of psychological dependence does exist, but only one case has appeared in the medical literature to date of physiological dependence on chlormethiazole, with withdrawal symptoms [6].
• Clomethiazole dose-dependently inhibited spontaneous locomotor activity in rats and was approximately 10 times more sedative than either enantiomer of AR-A008055 [7].
• There was no difference between the clomethiazole and placebo group in the postoperative change in neuropsychological test scores [8].
• Varying periods of amnesia, corresponding with a mean chlormethiazole ethanedisulphonate blood concentration of 10.3 mg litre-1 (SD 3.8) were obtained [9].

High impact information on Clomethiazole

• Administration of chlormethiazole, an inhibitor of CYP2E1, to the Pyr/Jo2-treated mice caused a significant decrease of alanine aminotransferase and liver pathological changes in association with a decrease in CYP2E1 protein and activity [10].
• Zonated expression of cytokines in rat liver: effect of chronic ethanol and the cytochrome P450 2E1 inhibitor, chlormethiazole [11].
• Because cytochrome P450 2E1 induction after chronic ethanol consumption has detrimental effects on the liver through free radical formation, treatment of alcohol detoxification with chlormethiazole may be beneficial [12].
• In addition, the effect of chlormethiazole on cytochrome P450 2E1 was studied in vitro using human liver microsomes [12].
• In contrast, chlormethiazole treatment inhibited chlorzoxazone hydroxylation almost totally (0.046 +/- 0.03, P < .001) [12].

Chemical compound and disease context of Clomethiazole

• The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease [13].
• In rats, chlormethiazole antagonises the hyperthermia produced by MDMA and has been shown clinically to block MDMA-induced convulsive activity [14].
• Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome [15].
• Clonidine was as effective as chlormethiazole in suppressing the symptoms and signs of alcohol withdrawal [16].
• A 30-year-old male patient with severe alcohol withdrawal symptoms was successfully treated with an adjuvant administration of 600 mg trazodone per day, while he had remained symptomatic for several days under high doses of diazepam and clomethiazolum [17].

Biological context of Clomethiazole

• Kinetics of chlormethiazole in patients with alcohol withdrawal manifestations [18].
• Chlormethiazole was found to lower blood pressure and adrenaline output and, furthermore, to relieve unpleasant physical symptoms, but did not affect fatigue and drowsiness [19].
• Modeling drug- and system-related changes in body temperature: application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats [20].
• In contrast to dizocilpine, chlormethiazole alone had no effect on heart rate or blood pressure and did not alter the autonomic effects of ICV NMDA [21].
• 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death [22].

Anatomical context of Clomethiazole

• 1. The effect of chlormethiazole has been studied in a transient middle cerebral artery (MCA) occlusion model of cerebral ischaemia in the rat [23].
• 1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined [22].
• Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil [24].
• CONCLUSION: Clomethiazole did not improve cerebral outcome following coronary artery bypass surgery [8].
• Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat [25].

Associations of Clomethiazole with other chemical compounds

• 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex [26].
• 1. The effect of chlormethiazole, and other drugs which potentiate gamma-aminobutyric acid (GABA) function on delayed neuronal death in the hippocampus has been examined in the gerbil [24].
• 6. This conclusion was supported by the observation that the enhanced efflux of glutamate from slices of cerebral cortex which had been induced by incubation of the slices in an hypoxic medium was unaltered by the presence of a high concentration of chlormethiazole (1 mM) in the medium.(ABSTRACT TRUNCATED AT 250 WORDS)[25]
• Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content.(ABSTRACT TRUNCATED AT 250 WORDS)[26]
• If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection [27].

Gene context of Clomethiazole

• Anti-CYP2E1 reactivity showed positive correlation with the levels of hepatic CYP2E1 and was inhibited by the CYP2E1 transcriptional inhibitor chlormethiazole [28].
• OBJECTIVE: To assess the safety of tissue-type plasminogen activator (t-PA) plus clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy [29].
• The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results [29].
• Here the authors suggested that chlormethiazole has anti-inflammatory properties because it potently and selectively inhibited p38 mitogen-activated protein (MAP) kinase in primary cortical glial cultures [30].
• We investigated zonal differences of cytokine expression in rat liver and how these are affected by alcohol exposure and by chlormethiazole (CMZ), a transcriptional and posttranslational inhibitor of hepatic CYP2E1 [11].

Analytical, diagnostic and therapeutic context of Clomethiazole

• Nine patients required mechanical ventilation and three others were sedated with intravenous chlormethiazole [31].
• Treatment was a 24-hour intravenous infusion of 75 mg/kg clomethiazole or placebo [1].
• Death during the 90 days after treatment occurred in 15 clomethiazole and nine placebo patients (p = 0.26) [29].
• BACKGROUND: The neuroprotective property of clomethiazole has been demonstrated in several animal models of global and focal brain ischemia [8].
• A reiterative administration of chlormethiazole, a specific inhibitor of 2E1 in liver, strongly inhibited many CYPs, including 2E1, 1A2, 2G1, and 2A in the nasal mucosa, but did not influence expression of 2B or 3A as determined by immunoblotting or catalytic activities [32].

References