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PubMed1979

Chlormethiazole treatment and breast feeding.

Four mothers receiving chlormethiazole for pre-eclampsia and their babies were the subjects of the investigation. Blood samples at delivery and blood and breast milk samples in the postpartum period were analysed for chlormethiazole. Concentrations ranged from 1.340 to 1.640 micrograms/g of sample of umbilical artery blood at birth, and fell to 0.010 to 0.153 micrograms/g in capillary blood 20 to 26 hours later. After the start of breast feeding, chlormethiazole in the babies was detectable in only 3 out of 27 serial blood samples and was 0.018, 0.009 and 0.006 micrograms/g. The highest calculated amount of chlormethiazole ingested at a breast feed was 37.2 micrograms. It is suggested that breast feeding should not be delayed solely on account of chlormethiazole therapy.

Breast Feeding↗

PubMed1994

Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.

1. In vivo microdialysis has been used to investigate the concentration of various amino acids and lactate in the extracellular fluid of the rat cortex following focal ischaemia, the probe being placed in the core of the infarct area. 2. An ischaemic infarct was produced in the cortex by use of a photochemical dye (Rose Bengal) and light irradiation. There was a marked increase in lactate concentration (300%) over the next 4 h. Substantial increases were also seen in the concentration of the excitatory (glutamate and aspartate), inhibitory (GABA and taurine) and other amino acids (serine, alanine, asparagine). 3. Administration of chlormethiazole (200 mg kg-1, i.p.) 5 min after the onset of ischaemia reduced the ischaemia-induced neurodegeneration by approximately 30%, measured histologically 24 h later. 4. Chlormethiazole (200 mg kg-1, i.p.) administration also reduced the rise in the concentration of lactate and all the amino acids by between 30-60% during the first 4 h after the onset of ischaemia. 5. Analysis of the time course of the amino acid changes suggested that chlormethiazole is not neuroprotective because of the inhibition of excitatory amino acid release but rather that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. 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. 7. Overall the data strengthen the evidence for the neuroprotective effect of chlormethiazole in this model of focal ischaemia.

Amino Acids↗

PubMed1986

The effects of chlormethiazole in EEG recorded sleep in normal elderly volunteers.

Chlormethiazole has sedative, hypnotic and anticonvulsant properties, and is used in the treatment of sleep disorders and confusion in the elderly. In this study we examined the effects of chlormethiazole on EEG recorded sleep in six normal volunteers aged 67-74 years. After baseline registration, chlormethiazole (base), 384 mg p.o. (i.e. 2 capsules), was administered during 5 nights followed by one withdrawal registration. Sleep latency decreased from 52 to 27 min during the treatment period (P less than 0.01) and increased to 57 min during withdrawal. Wakeful periods during sleep decreased from 106 to 62 min during the treatment period and increased during withdrawal to 104 min (P less than 0.001). The sleep efficiency improved slightly during chlormethiazole treatment. The distribution of the sleep stages was essentially unaffected by chlormethiazole. According to subjective assessment the subjects rated their ability to fall asleep and their sleep quality as significantly better during the drug period. Based on sleep recordings and subjective ratings, there was no evidence of rebound insomnia on withdrawal. Psychoperformance tests revealed no evidence of hangover effects.

Age Factors↗

PubMed1986

The influence of chlormethiazole in comparison to thioridazine on body temperature and postural hypotension in healthy adults and healthy elderly volunteers.

Certain drugs used to treat the elderly are known to precipitate hypothermia. In this study, the effects of chlormethiazole and thioridazine in producing postural hypotension were compared. In a study of hypothermia in the elderly the effects of chlormethiazole, thioridazine and lormetazepam were examined. Only three patients showed a postural drop following chlormethiazole, while 11 showed a postural drop following thioridazine. Chlormethiazole showed little variation from the control group in the hypothermia study, while thioridazine and lormetazepam caused a fall in temperature. For behaviour control in the elderly and for a short course as a hypnotic, chlormethiazole seems to be safer than thioridazine or lormetazepam.

Adult↗

PubMed1986

Metabolic and functional aspects of tolerance to chlormethiazole and cross-tolerance to ethanol in the rat.

Adult male rats were used to study tolerance to, and physical dependence on, chlormethiazole and cross-tolerance to ethanol. In sleeping time studies, chlormethiazole was given orally at a daily dose rising progressively from 100 to 175 mg/kg over a period of 1 month. The tolerance that developed appeared to be due to altered disposition of the drug rather than to decreased sensitivity of the CNS. In agreement with this conclusion, there was only minimal cross-tolerance to ethanol, and no detectable withdrawal reaction. In studies with the moving belt test, the rats were given chlormethiazole subcutaneously in a total dose of 200 mg/kg daily for 69 days. This resulted in an equivocal manifestation of tolerance on the moving belt test and a small, but significant, tolerance to the hypothermic effect of chlormethiazole. Only an equivocal manifestation of physical dependence was found. These findings suggest that tolerance to the hypnotic and hypothermic effects observed with these chlormethiazole treatment regimens was due to altered pharmacokinetics rather than to functional tolerance of the CNS.

Animals↗

PubMed1986

Hypnotic effect of chlormethiazole in geriatric patients during long-term treatment.

The hypnotic effect of chlormethiazole was studied for 3 months in 20 geriatric in-patients. Registered variables were the percentage of patients asleep at 10 pm and 6 am and the observed number of awakenings. Mental and somatic variables were rated according to the Crichton Geriatric Behavioural Rating Scale. Observations were made every second week. In 11 of the patients the plasma concentration of chlormethiazole was measured at regular intervals. No systematic significant change with time was observed for the percentage of patients asleep at 10 pm or for the number of awakenings. A significant decrease occurred in the percentage of patients asleep at 6 am. The long-term treatment with chlormethiazole did not cause any deterioration in the patients' behaviour, according to the geriatric rating scheme. Observed peak plasma levels of chlormethiazole did not change significantly during the study. Great interindividual variations in the plasma concentrations were observed. The results indicate that chlormethiazole is lastingly effective as a hypnotic agent in geriatric patients.

Aged↗

PubMed1986

A retrospective comparison of delirium tremens cases before and after the availability of chlormethiazole.

To assess the contribution of chlormethiazole to the treatment of delirium tremens (DT), a retrospective analysis was carried out on cases of DT admitted to the Department of Psychiatry, University of Tübingen, West Germany before and after the introduction of chlormethiazole. Following the introduction of chlormethiazole, there was a significant reduction in DT mortality and in duration of DTs. The age and sex distribution of cases of DT were compared and were found to be similar before and after the introduction of chlormethiazole. The incidence of complications in the two periods were analysed. The dose of chlormethiazole on the first 4 days of DT and the doses of additional psychoactive drugs were also noted.

Administration, Oral↗

PubMed1988

Indications of chlormethiazole as a protective agent in experimental endotoxemia.

Chlormethiazole, which is derived from the thiazole moiety of thiamine, possesses sedative, hypnotic and anticonvulsant properties. This anesthetic agent was compared with ketamine in a porcine model of endotoxemia to evaluate effects on cardiovascular and pulmonary function, oxygen delivery and survival. Continuous 6-hour intravenous infusion of Escherichia coli endotoxin caused pronounced pulmonary and cardiovascular derangement and decreases in oxygen delivery and pH in 13 pigs given ketamine anesthesia. Eight of thirteen pigs survived the observation period. Contrastingly, 10 pigs given chlormethiazole anesthesia and endotoxin showed a significantly attenuated response. Thus, the increases in mean pulmonary arterial pressure, venous admixture and extravascular lung water were significantly lower and the decreases in cardiac output, oxygen delivery and pH were significantly modified by chlormethiazole. All 10 pigs survived the observation period. Chlormethiazole may increase the clearance of endotoxin and thus ameliorate the endotoxin response. Although extrapolating from animal data requires great caution, these data may favor the use of chlormethiazole in septic states requiring surgical intervention and anesthesia and as sedation in critically ill septic patients in our intensive care units.

Animals↗

PubMed1983

Acute chlormethiazole poisoning in patients notified to the Poisons Unit, Guy's Hospital, 1978--1981.

1 Out of 493 patients with suspected acute chlormethiazole poisoning notified to the Poisons Unit, Guy's Hospital during 1978--1981, the diagnosis was confirmed either analytically or by detailed clinical information in 108 patients, 40 of whom had ingested chlormethiazole alone. 2 The principal signs reported indicate that the clinical features of acute chlormethiazole poisoning resemble those of barbiturate poisoning, with deep coma (n = 66), respiratory depression (n = 26) and hypotension (n = 17) in the severe cases. Five patients died as a result of early, profound respiratory depression. 3 In 53 survivors in whom toxicological analyses were performed, poisoning with chlormethiazole alone had a better prognosis than when ethanol or other drugs were also present, except in patients with hepatic or pulmonary disease or in the elderly. 4 These results emphasise that although patients poisoned with chlormethiazole who survive to reach hospital generally have a good prognosis, fatal respiratory complications often occur before the patient can be treated.

Adolescent↗

PubMed1976

Deaths in connection with chlormethiazole (heminevrin) therapy.

Six cases are described where death occurred in connection with chlormethiazole (Heminevrin) infusion. The close time relationship and indirect evidence strongly suggest that chlormethiazole had an important role in the fatal outcome of the patients, but definite proof of this way was not possible to obtain. Present or past alcohol abuse and respiratory, liver, cardiac or CNS diseases of different degrees seemed to be features in common for the patients possibly rendering them susceptible to the suggested detrimental effect of chlormethiazole therapy. Respiratory depression is supposed to be the primary pathogenetic mechanism of the death. Considering the relatively limited use of chlormethiazole in the department in which these cases were observed and the recommended dosage applied, the risk of serious complication during chlormethiazole infusions seems to be surprisingly high.

Adult↗

PubMedDate not supplied

Anticonvulsant action of chlormethiazole is prevented by subconvulsive amounts of strychnine and aminophylline but not by bicuculline and picrotoxin.

The anticonvulsant action of chlormethiazole was evaluated with the use of subthreshold doses of convulsants affecting the purinergic, glycinergic and gamma-aminobutyric acid (GABA)-mediated transmission, i.e. aminophylline, strychnine, bicuculline and picrotoxin in the model of generalized tonic-clonic convulsions. Chlormethiazole protected mice against maximal electroshock-induced seizures with an ED50 of 130.8 mg/kg. Aminophylline (100 mg/kg) and strychnine (0.4 mg/kg) reversed the protective action of chlormethiazole against electroconvulsions raising the ED50 values of this drug to 218.6 and 208.6 mg/kg, respectively. In contrast, GABA antagonists, bicuculline and picrotoxin, neither affected the protection provided by chlormethiazole nor did they alter the protective activity of valproate, phenobarbital, diphenylhydantoin and carbamazepine against electroconvulsions. Our results indicate that (a) the anticonvulsant activity of chlormethiazole might be related to its interaction with strychnine-sensitive glycinergic as well as purinergic neurotransmission, (b) purinergic and strychnine-sensitive glycinergic events contribute more prominently than GABAergic ones to the anticonvulsant activity of the drugs providing protection against maximal electroshock-induced convulsions.

Aminophylline↗

PubMed1983

The plasma levels of chlormethiazole and two of its metabolites in elderly subjects after single and multiple dosing.

Plasma levels of chlormethiazole and two of its metabolites have been estimated in elderly subjects both after single and repeated oral dosage and on withdrawal. A sensitive analytical method was developed to permit the quantitation of chlormethiazole and its two major metabolites in plasma. The two major metabolites were positively identified against authentic standards as 5-acetyl-4-methylthiazole and 5-(1-hydroxyethyl)-4-methylthiazole. Chlormethiazole and its metabolites were shown to have accumulated to varying extents after seven nightly doses. On withdrawal of the drug, the plasma was free of chlormethiazole within 44 h and free of all traces of its metabolites within 84 h. The accumulation was not accompanied by any undue clinical effect and was not in itself considered to be detrimental to the normal use of chlormethiazole in the treatment of sleep disturbances in the elderly.

Journal Article↗

PubMed1991

Uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep: implications for clearance calculations.

Mass balance principles were used to describe the uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep. Sheep received a right atrial infusion of either chlormethiazole (3.71 mg/min) or meperidine (2.70 mg/min) for 180 min, or minaxolone (0.37 mg/min) for 120 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken during and after the infusion. The mean and SD (n = 4) of the time-averaged extraction ratios across the hindquarters (determined from the relevant arterio-venous area under blood concentration--time curves) were 0.12 (0.10), 0.36 (0.13), and 0.27 (0.05) for chlormethiazole, meperidine, and minaxolone, respectively. The rank order of the rate of uptake of the drugs into the hindquarters was the same as the rank order of their lipophilicity, and uptake still continued when both the arterial and inferior vena cava drug concentrations were essentially constant. For chlormethiazole, meperidine, and minaxolone, 48% (44), 4% (6), and 35% (17), respectively, of the drug taken into the hindquarters eluted from the hindquarters after the infusion. Drug uptake and retention in extravisceral tissues, represented here by the hindquarters, can result in the mean total body drug clearance being overestimated when determined by traditional systemic pharmacokinetic methods.

Anesthetics↗

PubMed1997

The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists.

Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. 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. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.

Adenosine↗

PubMed1976

The pharmacokinetics of chlormethiazole following intravenous administration in the aged.

Eight healthy aged subjects were administered 1.2 g of chlormethiazole by constant-rate intravenous infusion. The disposition of the drug was found to be multi-exponential in character. Fits of plasma level-time data to two- and three-compartment open models were assessed with the aid of statistical tests. For three of the subjects the experimental data were adequately fitted to a two-compartment pharmakcokinetic model, however a three-compartment model was necessary to fit the data observed for a further four subjects. An anomalous chlormethiazole plasma concentration-time curve was obtained for the remaining subject. The disposition half-life of chlormethiazole was 8.49 +/- 3.28 h and the plasma clearance was 16.14 +/- 5.00 ml/min/kg. These values were significantly different to those reported earlier for young adult subjects and the clinical implications have been discussed. The blood/plasma concentration ratio of chlormethiazole was found to be approximately one with some evidence for concentration dependence.

Aged↗

PubMed1983

The effect of ethanol administration on the disposition and elimination of chlormethiazole.

Acutely administered ethanol has been shown to inhibit the hepatic metabolism of a number of drugs. Ethanol might be expected to decrease the first-pass extraction of chlormethiazole leading to higher blood levels of this high clearance sedative frequently used in the management of alcoholic patients. Chlormethiazole has a narrow therapeutic index and the unexpected deaths reported in alcoholics taking this drug may have been due to an effect of ethanol on the metabolism of chlormethiazole. However in this study, acutely administered ethanol maintained at levels around 22 mmol/l had no significant effect on the disposition or elimination of either daily or intravenously administered chlormethiazole.

Administration, Oral↗

PubMed1993

Chlormethiazole antagonises seizures induced by N-methyl-DL-aspartate without interacting with the NMDA receptor complex.

Administration to mice of N-methyl-DL-aspartate (NMDLA; 680-3400 mumol/kg IP) produced a behavioural syndrome of scratching, running, pawing, clonus, loss of righting and tonic convulsions. Measures of latency to appearance of the behaviours and percentage of animals displaying the behaviour (frequency) indicated that the latency to appearance of running behaviour, clonus and tonic convulsions were all dose dependant. Chlormethiazole (155-622 mumol/kg IP) given 15 min before NMDLA (3400 mumol/kg) dose-dependently inhibited all the behaviours, increasing the latency to appearance of scratching, running and clonus and reducing the incidence of pawing, loss of righting and tonic convulsions. Tonic seizures induced by NMDLA (3400 mumol/kg) were inhibited by the following drugs (ED50 values in mumol/kg in brackets): chlormethiazole (210); pentobarbitone (67); dizocilpine (0.9). The diazepam value (38) was estimated as complete inhibition was not obtained. Chlormethiazole (1 mM) did not affect the binding of [3H]-dizocilpine to rat cortical membranes or the stimulation of this binding by glutamate (10 microM), glycine (10 microM) or spermidine (100 microM). It is therefore concluded that whilst chlormethiazole effectively antagonises the convulsive behavioural syndrome induced by injection of NMDLA, it does not do so by interacting with the NMDA receptor complex but more probably by its known interaction with the GABAA receptor complex.

Animals↗

PubMed1993

Chlormethiazole attenuates the derangement of sensory evoked potential (SEP) induced by ICV administration of NMDA.

Administration to anaesthetized rats of N-methyl-D-aspartate (NMDA 30 nmol ICV) induced a profound derangement of stimulation evoked potential (f-SEP) and also autonomic excitation with an increase in arterial blood pressure and heart rate. These effects were antagonised by pretreatment with dizocilpine (0.5 mg/kg IV). Pretreatment with chlormethiazole (20 mg/kg IV 26 min before NMDA) also markedly diminished the derangement of f-SEP. At the end of the registration period 2 h after NMDA the SEP had recovered to 72.7 +/- 3.4 (% of control; mean +/- SEM) in saline-treated rats as compared to 96.1 +/- 5.6% in chlormethiazole treated animals (P < 0.01). 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. These results demonstrate that chlormethiazole can antagonise some NMDA-receptor mediated functions, even though there is no evidence that it is an NMDA antagonist.

Animals↗