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At beginning and end of hospital treatment with chlormethiazole (Distraneurin), the EEGs of 41 male alcoholics were analyzed, employing spectral analysis and Hjorth's parameters. Hierarchical regression analysis of selected data showed significant influence of hallucinations and/or personality deterioration on chlormethiazole-induced EEG effects, especially at the beginning of treatment.
In a double-blind crossover trial, chlormethiazole was compared with dichloralphenazone and placebo in 38 elderly patients requiring night-time sedation. Chlormethiazole was significantly superior to dichloralphenazone and placebo for the parameters 'heavy sleep' and'time of onset of sleep'. The incidence of side-effects did not significantly differ whilst on placebo. Because of the high incidence of "placebo reactors', a sub-group who slept badly whilst on placebo were further analysed. The data indicated a definitive trend suggesting that the difference found in the overall material was valid for the sub-group of 17 subjects. Problems of placebo reactors in clinical trials are discussed and the view supported that 'placebo reactors' should be excluded by a preliminary screening test before admission to double-blind controlled trials evalvuating hypnotic drugs.
Although dependency is reported to be one of the side effects of chlormethiazole, very few cases of such dependency have been reported. A detailed report of a female patient with a previous history of other dependencies, and who subsequently became dependent on chlormethiazole, is offered.
The metabolic fate of chlormethiazole in healthy male subjects has been investigated following the oral administration of a single dose of chlormethiazole edisylate. Five urinary C-oxidation metabolites were identified and shown to be identical with previously reported metabolites. A novel metabolite, of molecular formula C5H7NO2S, was shown by trimethylsilylation, deuterium exchange, reduction studies and by its i.r., n.m.r. and mass spectrum, to be 4,5-dimethylthiazole-N-oxide-S-oxide. This is the first reported metabolite which involves the oxidation of the two heterocyclic atoms in aromatic rings. The formation and thermal stability of the compound is ascribed to resonance stabilization.
Seventy-one patients undergoing withdrawal from alcohol were randomly assigned to treatment with oral bromocriptine, chlormethiazole or chlordiazepoxide. Forty-one percent had alcoholic hepatitis and/or cirrhosis. Patients were stratified into two groups: major and minor withdrawal symptoms. The latter group included a placebo tratment. Bromocriptine was ineffective in treating withdrawal symptoms, whilst chlormethiazole and chlordiazepoxide were equally effective. These findings do not support the evidence from animal and clinical studies suggesting that the disturbances in the dopaminergic system found in alcohol dependence and withdrawal can be reversed by dopamine agonists.
The release of proinflammatory cytokines by endotoxins and during oxidative stress is considered to be an early key step in the pathogenesis of alcoholic liver disease (ALD). Ethanol-inducible cytochrome P450 2E1 (CYP2E1) has potentially pro-oxidative and toxicological properties, and its expression is restricted to the perivenous region of liver. 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. Periportal and perivenous cell lysates were obtained by the digitonin pulse technique from livers of rats treated with ethanol and CMZ for 38 days. Cytokine expression on the mRNA and protein levels was quantified using competitive polymerase chain reaction (PCR) and Western blot, respectively. Chronic ethanol treatment significantly increased the expression of CYP2E1, microsomal p-nitrophenol hydroxylase activity (indicative for CYP2E1 enzyme activity), and the expression of transforming growth factor beta1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-1beta (1.4- to 4.6-fold). In contrast, ethanol caused a decrease in IL-4 expression and had no influence on IL-6 expression. CMZ treatment caused a reduction in hepatic CYP2E1 expression and in the ethanol-induced cytokine expression by 40% to 60%. Expression of IL-6, IL-2, and IL-4 mRNA occurred preferentially in the periportal region, whereas ethanol caused a pronounced increase in the perivenous expression of TGF-beta1, which was inhibited by CMZ as monitored both on the mRNA and protein levels. These results show the zonated expression of several cytokines and the counteraction of CMZ on all effects of ethanol on cytokine expression. The data further strengthen a link between increased CYP2E1 expression and enhanced cytokine expression as important events in the development of ALD.
The loss of isosorbide dinitrate from aqueous solutions stored in plastic infusion bags and/or infused through plastic giving sets was investigated. During simulated infusions, the loss of isosorbide dinitrate was found to be flow-rate dependent. The clinical and pharmacokinetic significance of this loss is discussed. Infusion o isosorbide dinitrate from a glass syringe through high density polyethylene tubing overcame the loss associated with its administration via plastic infusion bags and intravenous giving sets. This method was also applied successfully to minimise the previously reported loss of diazepam and chlormethiazole during infusions.
Cellular effects of chlormethiazole (CMZ), a sedative-hypnotic substance, were studied using intracellular recording techniques. As a model system primary cultures of mouse spinal cord neurons were used. CMZ (200 microM) increased the rheobase and decreased the cell input resistance. In addition, the spike after depolarization was decreased. The reversal potential for the CMZ-induced effect was dependent on the chloride ion gradient. It is concluded that CMZ opens calcium dependent chloride ion channels in cultured spinal cord neurons which will result in enhancement of inhibitory neurotransmission.
A simple method has been developed whereby chlormethiazole, ethchlorvynol and trichloroethanol can be simultaneously detected and measured in biological fluids. The procedure is based upon the rapid extraction of a small (50-microliter) sample volume with an equal volume of chloroform containing an internal standard, followed by the gas-liquid chromatographic analysis of this extract. Specimens of blood plasma or serum, urine and gastric contents can be used, and no interference from either endogenous or exogenous sources has been observed. The method is suitable for the measurement of the plasma concentrations of these compounds attained after overdosage.
Cimetidine has been shown to inhibit hepatic mixed-function oxidase activity and to lower hepatic blood flow. It is not known whether these effects are related to its H2-receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2-receptor antagonist and differs structurally from cimetidine. In our study, ranitidine, 150 mg twice daily, had no effect on oral or systemic clearance of chlormethiazole, a sedative with a high clearance, and no effect on indocyanine green elimination.
Although relatively little attention has been paid to the question how acute alcohol withdrawal might affect cognitive functions, this factor remains of particular interest because it influences psychotherapeutic treatment during detoxification. The clinical outcome and neuropsychological state of 37 inpatients with alcohol withdrawal was investigated in a randomized single-blind approach. Two different medical strategies [chlormethiazole (CMZ) vs. carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal syndrome were compared. Among comparable groups (related to gender, age, initial alcohol level, severity of abuses, severity of initial withdrawal symptoms such as tremor, perspiration, psychomotor agitation, hallucinations, orientation, intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of withdrawal symptoms (circulatory function, vegetative function, psychomotor activity). Patients in both groups showed initial impairments in some neuropsychological tests (d2, Zahlen-Verbundings test, Beck Depression Inventory, Anxiety Sensitivity Index) with significant improvement during detoxification. Additionally, CBZ-treated patients showed significantly better verbal memory performance during the first days of treatment. Without any addictive potential, CBZ therapy could be very supportive in alcohol detoxification. In addition a higher verbal memory performance state could be favourable for a psychotherapeutic approach.
A method of avoiding postoperative confusion when local analgesic techniques are indicated for the elderly is described. Basal sedation using 0.8% chlormethiazole infusion intravenously, was employed. Mental function was not altered when the technique was used and it is suggested that the length of stay in hospital can be reduced.
Extracellular recordings were made of single unit activity in the brainstem of urethane anaesthetized rats. Drugs were applied by microiontophoresis from multibarrelled micropipettes or administered intraperitoneally. Chlormethiazole (CMZ) caused a decrease in spontaneous firing rate when applied with high currents (greater than 40 nA). When applied with lower currents CMZ did not cause changes in firing rate, but enhanced the inhibitory effects of gamma-aminobutyric acid (GABA), muscimol and glycine in a dose-dependent manner. The inhibitory actions of acetylcholine were not affected. Excitatory responses to glutamate and acetylcholine were unaffected by applications of CMZ which caused potentiation of GABA, muscimol and glycine. When applied at higher currents CMZ caused a decrease in the response to glutamate. Intraperitoneal administration of CMZ (50-600 mumol kg-1) also enhanced responses to microiontophoretically applied GABA, muscimol and glycine. These results are compared with those reported for other anticonvulsant drugs and possible mechanisms of action of CMZ are discussed.
The circulatory and respiratory effects of chlormethiazole were studied in volunteers and patients. The only clinically significant cardiovascular change was an increase in heart rate. However, this is only important if associated with a high arterial pressure in the presence of coronary artery disease. The respiratory effects were not significant.
A preliminary analysis of a study of the bioavailability and pharmacodynamics of chlormethiazole in healthy young and elderly volunteers has been performed. The bioavailability assessed by a stable isotope method and the pharmacodynamic effects assessed by psychometric tests were found not to differ between the two age groups.
The neuro-endocrine system is affected by chronic ethanol ingestion. Chlormethiazole is effective in the treatment of the ethanol withdrawal syndrome because of its tolerability, lack of hepatotoxicity, short plasma half-life, lack of any long-acting intermediate metabolites and lack of adverse effects on the neuro-endocrine system in alcoholics.
When managing alcohol withdrawal the aim is to prevent the development of serious complications, such as fitting and delirium tremens. In alcoholics who are heavily chemically dependent, the rational use of sedative-type drugs is generally necessary. Chlormethiazole is effective in preventing the development of serious complications. It is a safe drug and has the additional advantage of a short half-life.
Chlormethiazole (Heminevrin) was successful in controlling fits in seven out of nine episodes of intractable status epilepticus. It was administered as a constant intravenous injection at rates of up to 0.7g/h. No serious side effects were encountered, and the drug deserves wider recognition as a useful therapeutic agent in the management of status epilepticus.