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PubMed1994

Release of adenosine and other purines from hippocampal slices stimulated electrically or by hypoxia/hypoglycemia. Effect of chlormethiazole.

The ATP stores of rat hippocampal slices were labelled with [3H]-adenine. The efflux of endogenous and [3H]-purines was stimulated electrically or by combined hypoxia/hypoglycemia. The efflux of endogenous adenosine, inosine and hypoxanthine was also increased. Chlormethiazole (30-300 microM) decreased the [3H]-purine release evoked by hypoxia/hypoglycemia, but not that evoked by electrical field stimulation. The outflow of endogenous purines was not significantly altered by chlormethiazole, and there was no significant change in the relative proportions of endogenous purines released. Chlormethiazole (10-500 microM) did not block the uptake of adenosine by human erythrocytes. Chlormethiazole does not appear to have any primary effect on purine metabolism, but decreases the breakdown of ATP induced by a reduced supply of metabolites in hippocampal slices.

Adenosine↗

PubMed1994

Attenuation by chlormethiazole of oedema following focal ischaemia in the cerebral cortex of the rat.

When a photochemically-induced infarct was produced in the right cortex of rats, tissue water content was increased markedly 4 and 24 h later (control: 79.00 +/- 0.08% ischaemia, 24 h: 82.96 +/- 0.15%). The left cortex was unaffected. Chlormethiazole (200 mg/kg i.p.) injection 5 min after onset of ischaemia decreased the oedema (ischaemia/chlormethiazole, 24 h: 82.16 +/- 0.21%, P < 0.01). At 24 h, ischaemic tissue Na+ content was increased (61%) and the K+ content decreased (9%). The Na+/K+ ratio therefore increased significantly (P < 0.001), a change that was diminished by chlormethiazole administration (P < 0.02). Chlormethiazole (1 mM), unlike furosemide (5 mM), did not reduce swelling of C6 glioma cells in hypotonic medium. The data suggest that chlormethiazole decreases oedema in this stroke model because of its neuroprotective properties and not because of an effect on anion transport.

Animals↗

PubMed1993

The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat.

Focal ischaemia in the rat cerebral cortex was produced by means of a photochemically induced thrombosis of cerebral arteries. This was achieved by intravenous infusion of the photosensitive dye Rose Bengal and illumination of the skull with focused green light. Initial experiments justified the use of tetrazolium staining as an index of infarct damage. Using this technique it was demonstrated that chlormethiazole (200 mg/kg, i.p.) given 5 min post ischaemia markedly reduced the area of infarcted cortical tissue. A second experiment replicated this observation and showed that, in contrast, nimodipine (0.5 mg/kg, i.p.) given 5 min post infarct was without effect on infarct size. The pattern of Evans Blue extravasation indicated that the infarct developed over a 24-h period with the major damage occurring in the first 4.5 h. The spread of the infarct beyond the initial core of damage was decreased by an estimated value of almost 50% by injection of chlormethiazole (200 mg/kg, i.p.) 5 min after the light exposure. These data indicate that chlormethiazole is an effective drug in protecting against the effects of focal ischaemia in the rat and, taken with earlier observations that chlormethiazole protects against the effects of global ischaemia in the gerbil, suggest that the drug may be an effective treatment against the ischaemic cell death that can occur following a stroke or cardiac arrest.

Animals↗

PubMed2000

Chlormethiazole inhibits epileptiform activity by potentiating GABA(A) receptor function.

Chlormethiazole has sedative, hypnotic, anticonvulsant and neuroprotective properties. Using in vitro grease-gap recordings, we show that it inhibits epileptiform activity in neocortical slices superfused with Mg(2+)-free medium (IC(50) approximately 200 microM). At an antiepileptic concentration (300 microM), chlormethiazole potentiated the action of exogenously applied GABA (1 mM) but did not affect responses to the glutamate receptor agonists N-methyl-D-aspartate (10 microM) or L-quisqualic acid (3 microM). The GABA(A) receptor antagonist N-methyl-bicuculline (50 microM) reduced chlormethiazole's potency to inhibit the epileptiform activity. These results indicate that chlormethiazole's anticonvulsant action is likely mediated by potentiating GABA(A)ergic inhibition rather than by antagonising glutamatergic excitation.

Action Potentials↗

PubMed1998

Chlormethiazole anticonvulsive efficacy diminished by N-methyl-D-aspartate but not kainate in mice.

The aim of this study was to evaluate the effect of N-methyl-D-aspartate (NMDA) and kainate used at nonconvulsive doses upon protective efficacy of chlormethiazole against maximal electroshock-induced seizures. NMDA (50 mg/kg, i.p.) reduced the anticonvulsant potency of chlormethiazole increasing its ED50 value from 126.9 to 155.0 mg/kg. The effect of NMDA was completely reversed by the competitive NMDA receptor antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) (0.06 mg/kg i.p.). Kainic acid (9 mg/kg i.p.) did not affect the anticonvulsive properties of chlormethiazole. Our results suggest that NMDA but not kainate receptor-mediated events participate in the anticonvulsant action of chlormethiazole.

2-Amino-5-phosphonovalerate↗

PubMed1990

A study of the psychometric effects of chlormethiazole in healthy young and elderly subjects.

The pharmacokinetics and effects of chlormethiazole (91 mg intravenously together with 356 mg orally) on psychomotor performance were studied in 10 young (mean age 29 years) and 10 older (mean age 66.2 years) volunteers using an open design. Chlormethiazole affected psychomotor function and decreased subjective arousal in both age groups. The peak effect was found at approximately 30 min, i.e. at the end of the infusion, and performance returned to normal by 3 h. There was no evidence of increased sensitivity of the older subjects to the psychomotor or subjective effects of chlormethiazole. The incidence and type of reported symptoms was also similar in the two age groups. The volume of distribution of chlormethiazole was greater in the old than in the young subjects as was the elimination half-life after intravenous administration. Other pharmacokinetic variables showed no significant differences between young and old subjects.

Administration, Oral↗

PubMed1991

A single-dose study of the pharmacodynamic effects of chlormethiazole, temazepam and placebo in elderly parkinsonian patients.

Nine elderly parkinsonian volunteers took single doses of 384 mg of chlormethiazole, 10 mg of temazepam and placebo capsules in a double-blind three-way cross-over study on separate visits at least one week apart. In the 6 hours following the dose, the level of drowsiness, performance on a series of psychomotor tests, effects on parkinsonian symptoms and signs, and standing and lying blood pressure were recorded. Chlormethiazole produced drowsiness on all tests and impaired psychomotor performance, as compared with placebo, without affecting parkinsonian symptoms and signs, or postural blood pressure. Temazepam was consistently less potent than chlormethiazole on tests of drowsiness and psychomotor performance. Both treatments were well tolerated. It is suggested that chlormethiazole is safe to use as a hypnotic at this dosage in this group of patients with Parkinson's disease, while temazepam did not appear to be effective as a hypnotic at this dosage.

Aged↗

PubMed1975

A comparison of chlormethiazole and diazepam as intravenous sedatives for fibre-endoscopic examination of the upper gastrointestinal tract.

Chlormethiazole and diazepam as intravenous sedatives were compared in 75 patients undergoing fibre-endoscopic examination of the upper gastrointestinal tract. Diazepam was considered to offer greater reliability and ease of administration. Chlormethiazole wqs found to be a safe drug and did not encourage salivation. Local pain caused by chlormethiazole injection can be abolished by the use of lignocaine. Chlormethiazole may be useful in patients who are hypotensive and who require emergency endoscopy.

Adult↗

PubMed1981

Two-stage infusion of chlormethiazole for basal sedation.

The effectiveness of chlormethiazole in providing basal sedation was studied using a two-stage infusion regimen consisting of an initial loading dose of 60 mg min-1 for 25 min (in the lateral position) followed by a maintenance constant-rate infusion of 10 mg min-1 for 60 min (in the supine position). The regimen was evaluated in five healthy young volunteers who were all moderately sedated throughout most of the infusion, lapsing into sleep when left undisturbed, yet awakened easily to obey commands. Varying periods of amnesia, corresponding with a mean chlormethiazole ethanedisulphonate blood concentration of 10.3 mg litre-1 (SD 3.8) were obtained. Light sedation occurred during the first 10 min and the last 20 min of the total infusion period, corresponding to chlormethiazole blood concentrations of 7.9 mg litre-1 (SD 1.9) and 7.4 mg litre-1 (SD 2.3) respectively. Adverse side-effects were transient nasal irritation, flushing and a coryza-like syndrome. Other side-effects of tachycardia and hypertension may be beneficial in counteracting cardiovascular depression associated with central neural blockade. A high total body clearance of chlormethiazole (mean 1.39 litre min-1, SD 0.58) was found and would contribute to the brief duration of action after termination of the infusion.

Adolescent↗

PubMed1983

Comparison of the anaesthetic and haemodynamic effects of chlormethiazole and thiopentone.

Two groups of eight women (60-85 yr) undergoing gynaecological operations of 50 to 130 min duration were compared. Anaesthesia was induced with either thiopentone (mean 4.5 mg kg-1) or chlormethiazole (mean 6.0 mg kg-1) and maintained with nitrous oxide and pethidine in combination with the drug used for the induction. The hourly maintenance dose and the plasma concentration determined at equilibrium were greater for chlormethiazole (means 4.7 mg kg-1 h-1 and 27 mumol litre-1) compared with 1.3 mg kg-1 h-1 (P less than 0.01) and 16 mumol litre-1 respectively for thiopentone (P less than 0.02). Impedance cardiography showed that cardiac output was decreased by 30-40% in the thiopentone group (P less than 0.01), whereas no significant change was observed in the chlormethiazole group. Chlormethiazole anaesthesia was followed by a significant increase (P less than 0.02) in stroke volume. No correlations were found between the plasma concentrations and changes in the haemodynamic indices for either of the drugs.

Aged↗

PubMed1985

Comparison of the efficacy of chlormethiazole and diazepam as i.v. sedatives for supplementation of extradural anaesthesia.

The clinical efficacy of two sedative agents was compared in 21 young healthy patients undergoing surgery under extradural blockade. A state of sedation and amnesia in which patients lapsed into a sleep-like state when left undisturbed, yet spontaneously opened their eyes to make comments and co-operate with verbal commands, was sought. This was achieved readily by careful titration of responses and required a diazepam loading dose of 20 (+/- 15) mg given at a rate of 1 mg min-1 or 0.8% chlormethiazole edisylate infusion 10 ml min-1 given over 16 (+/- 6) min. Control of this state was easier with chlormethiazole (by varying the rate of infusion) than by giving repeated doses of diazepam. Both agents provided good anterograde amnesia; there was no retrograde amnesia. Considerable postoperative somnolence with a high incidence of relapse into amnesic and sedated states were noted with both agents. However, if the total volume of chlormethiazole infused was less than 300 ml, then a distinct advantage of abrupt and lucid recovery was apparent. Blood concentrations producing the desired clinical state were more variable for diazepam than for chlormethiazole.

Adjuvants, Anesthesia↗

PubMed1981

Direct measurement of chlormethiazole extraction by liver, lung and kidney in man.

1 Chlormethiazole was used as a basal sedative for patients undergoing angiographic procedures. 2 Blood samples were drawn opportunistically to examine chlormethiazole extraction across liver, lungs and kidney. 3 Extraction across liver was typically 70-80% and apparently unrelated to input concentrations. Evidence for extraction across lung and kidney was inconclusive but these could each be approximately 20%. 4 Pharmacokinetics of chlormethiazole derived from compartment models were in accord with previous reports and were characterised by a high total body clearance (1-1.5 l/min). 5 Postural changes associated with the radiological procedures caused fluctuating blood concentrations which appear as noise in curve fitting procedures. 6 Pharmacokinetic properties derived from compartment theory cannot cope with these perturbations because of the restriction imposed by time averaging (i.e. mean clearances, half-lives and volumes are produced). Systematic studies of pharmacokinetic properties of perfusion-limited drugs such as chlormethiazole must be developed in such a way as to allow for independent variation of flow and extraction.

Aged↗

PubMed1983

Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro.

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the gamma-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (+/-)-5-(1,3-dimethylbutyl)-5-ethylbarbituric acid [+/-)-DMBB) = (+/-)-quinalbarbitone = (+/-)-pentobarbitone greater than (+/-)-methyl-phenobarbitone = (-)-methylphenobarbitone greater than butobarbitone = chlormethiazole greater than phenobarbitone greater than barbitone = (+)-methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone. The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (-)-methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol. It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (-)-methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.

Animals↗

PubMed1994

A study of the mechanism of MDMA ('ecstasy')-induced neurotoxicity of 5-HT neurones using chlormethiazole, dizocilpine and other protective compounds.

1. An investigation has been made in rats into the neurotoxic effect of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') using chlormethiazole and dizocilpine, both known neuroprotective compounds and also gamma-butyrolactone, ondansetron and pentobarbitone. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in a 50% loss of cortical and hippocampal 5-HT and 5-hydroxyindole acetic acid (5-HIAA) 4 days later. This reflects the long term neurotoxic loss of 5-HT that occurs. Injection of gamma-butyrolactone (GBL; 400 mg kg-1, i.p.) 5 min before and 55 min after the MDMA provided substantial protection. Pentobarbitone (25 mg kg-1, i.p.) using the same dose regime was also protective, but ondansetron (0.5 mg kg-1 or 0.1 mg kg-1, i.p.) was without effect. 3. MDMA (20 mg kg-1) had no significant effect on striatal dopamine concentration 4 days later but did produce a small decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) content. There were few significant changes in rats given MDMA plus GBL, ondansetron or pentobarbitone. 4. A single injection of MDMA (20 mg kg-1, i.p.) resulted in a greater than 80% depletion of 5-HT in hippocampus and cortex 4 h later, reflecting the initial rapid release that had occurred. None of the neuroprotective compounds (chlormethiazole, 50 mg kg-1; dizocilpine, 1 mg kg-1; GBL, 400 mg kg-1; pentobarbitone, 25 mg kg-1) given 5 min before and 55 min after the MDMA injection, altered the degree of 5-HT loss. 5. Acute MDMA injection increased striatal dopamine content (28%) and decreased the DOPAC content. In general, administration of the drugs under investigation did not significantly alter these MDMA-induced changes. Both chlormethiazole and GBL produced a greater increase in dopamine than MDMA alone, but this was apparently an additive effect to the action of either drug alone. 6. The 5-HT loss 4 h following administration of the neurotoxin p-chloroamphetamine (2.5 mg kg-1,i.p.) was not affected by chlormethiazole or dizocilpine. p-Chloroamphetamine did not appear to alter striatal dopamine metabolism.7. None of the protective drugs inhibited the initial 5-HT loss following MDMA, rendering unlikely any proposal that they are protective because they inhibit 5-HT release and the subsequent formation ofa toxic indole derivative. All the protective compounds (unlike ondansetron) probably inhibit dopamine release in the striatum. Since the neurotoxic action of some substituted amphetamines is dependent on the integrity of nigro-striatal neurones, this fact may go some way to explain the protective action of this diverse group of compounds.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

The pharmacology of chlormethiazole: a potential neuroprotective agent?

Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.

Animals↗

PubMed1986

A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly.

This study compared the hypnotic efficacy and the psychometric effects of treatment with either chlormethiazole or triazolam for 9 weeks in elderly patients with sleep disturbance. Chlormethiazole and triazolam were found to be similarly effective in short-term use. However, evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment was obtained for chlormethiazole but not for triazolam. There were daytime withdrawal effects with triazolam, but none with chlormethiazole.

Aged↗

PubMed1986

The efficacy of early chlormethiazole medication in the prevention of delirium tremens. A retrospective study of the outcome of different drug treatment strategies at the Helsingborg psychiatric clinics, 1975-1980.

A clinical analysis of 476 cases of delirium tremens is presented. The sample covers virtually all cases of delirium tremens that occurred in the Helsingborg Health Service District during the period 1975-1980. A retrospective analysis of the incidence of delirium tremens over the observation period shows that there was an increase in the number and severity of cases developing delirium tremens when non-cross-tolerant drugs, such as carbamazepine and neuroleptics, were used as first-line treatment for acute alcohol withdrawal. The results also show that when chlormethiazole (a drug exhibiting a certain degree of cross-tolerance with ethanol) was used either as the first-line treatment for all cases or as the first-line treatment for predetermined "high risk" patients, the incidence of delirium tremens was greatly reduced. The favourable findings when chlormethiazole treatment was initiated at an early stage in the "high risk" patients suggest that chlormethiazole has a protective action against delirium tremens. Moreover, in the occasional case in which delirium tremens occurred during chlormethiazole treatment, the disorder was milder and relatively easy to treat.

Alcohol Withdrawal Delirium↗

PubMed1994

Chlormethiazole and dizocilpine block the behavioural, but not the neurotoxic effects of 5,7-dihydroxytryptamine in mice.

Intracerebroventricular administration to mice of 5,7-dihydroxytryptamine at a dose of 300 micrograms resulted in convulsive behaviour and death (latency 7.6 +/- 1.7 min.). Pretreatment with dizocilpine or chlormethiazole resulted in a dose dependent inhibition of the convulsive behaviour. A dose of dizocilpine of 0.12 mumol/kg or chlormethiazole at a dose of 150 mumol/kg prevented seizures for 30 min. Injection of 5,7-dihydroxytryptamine (75 micrograms, intracerebroventricularly) produced an approximate 50% neurotoxic loss of cerebral 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) 8 days later. This loss was not prevented by administration of either dizocilpine (4.5 mumol/kg intraperitoneally) or chlormethiazole (300 mumol/kg intraperitoneally) given 5 min. before and 55 min. after the 5,7-dihydroxytryptamine injection. It is proposed that chlormethiazole and dizocilpine may protect against 5,7-dihydroxytryptamine-induced seizures because of their anticonvulsant activity, but that they do not prevent the neurotoxic effects of the compound. The data also suggest that the neurotoxic effects of substituted amphetamines such as 3,4-methylene dioxymethamphetamine (MDMA or Ecstasy) do not result from the formation of a 5,7-dihydroxytryptamine like compound.

5,7-Dihydroxytryptamine↗