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At least 19 recordsLinked to original sources

PubMed1986

Chlormethiazole--mode of action.

Studies in mice demonstrated that the anticonvulsant profile of chlormethiazole differs from that of diazepam and the barbiturates. Chlormethiazole protects animals from convulsions induced by a wide variety of chemoconvulsants known to block the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), such as bicuculline, picrotoxin, isoniazid and pentetrazol, thus confirming and extending earlier studies on its broad anticonvulsant characteristics. Chlormethiazole is particularly potent against isoniazid-induced convulsions, which are probably induced by reductions of GABA levels in the brain. Chlormethiazole was found to have a weak action on benzodiazepine receptor binding, GABA receptor binding and kainic acid receptor binding. Chlormethiazole inhibited picrotoxin binding at very high concentrations, but lowered the functional effects of picrotoxin at much lower concentrations than those affecting picrotoxin binding. Moreover, chlormethiazole failed to change GABA or glutamate levels in the brain and did not affect glutamic acid decarboxylase (GAD) activities in the rat brain. Muscimol (a GABAA agonist) enhanced the anticonvulsant activity of chlormethiazole against picrotoxin but not against bicuculline-induced convulsions. Muscimol enhanced the anticonvulsant potency of diazepam against both chemoconvulsants. These data suggest that the anticonvulsant activity of chlormethiazole is not mediated directly through changes in GABA or glutamate levels or by a direct (agonist) action at the GABA or benzodiazepine receptor complex. These findings suggest that chlormethiazole may enhance GABA transmission beyond the GABA receptors, hypothetically at the level of the GABA receptor coupled ionophore (e.g. the chloride ion channel). Applied micro-iontophoretically, chlormethiazole was found to potentiate the inhibitory responses to GABA, muscimol and glycine, but not to acetylcholine. The potentiation of glycine-mediated inhibition is unique for chlormethiazole and does not occur with any other known anticonvulsant (barbiturates, benzodiazepine, phenytoin or sodium valproate). Studies in primary cultures, derived from spinal cord neurones, showed that chlormethiazole produces hyperpolarization together with an increase in the threshold for action potential generation. Further in vitro studies indicated that chlormethiazole acts on some types of Ca2+-dependent chloride ion channels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Functional tolerance to chlormethiazole and cross-tolerance to ethanol in the rat: importance of test and mode of drug administration.

Tolerance to the effects of chlormethiazole on circular maze performance, and cross-tolerance to ethanol, were investigated in rats. Tolerance to chlormethiazole in the moving belt test was also measured in the same rats. Treatment with a total daily dose of subcutaneous chlormethiazole, 200 mg/kg, for 20 days produced clear tolerance to chlormethiazole and cross-tolerance to ethanol in the circular maze test. This treatment, however, failed to produce tolerance to chlormethiazole in the moving belt test. No evidence of physical dependence was found. In other studies, continuous intravenous infusion of chlormethiazole, 30-50 mg/kg/h for 9 days, resulted in clear functional tolerance to chlormethiazole and cross-tolerance to ethanol in the moving belt test. Similarly, chronic ethanol treatment, 4-6 g/kg daily for 3 weeks, resulted in functional tolerance to ethanol and cross-tolerance to chlormethiazole in the same test. These results indicate that the demonstration of functional tolerance to chlormethiazole and cross-tolerance to ethanol is dependent both on the sensitivity of the behavioural measurement tests employed, and on the degree of continuity of exposure of the central nervous system to the drug. It is concluded that, for doses that are equipotent in acute log-dose studies, chlormethiazole produces less tolerance and physical dependence than ethanol, perhaps because of a shorter half-life.

Animals↗

PubMed1989

The modulation by chlormethiazole of the GABAA-receptor complex in rat brain.

1. The interactions of chlormethiazole with gamma-aminobutyric acid (GABA) synthesis and release, and with ligand binding to sites associated with the GABAA-receptor complex and the GABAB-receptor have been studied in the rat. The GABAA-receptor was studied using [3H]-muscimol, [3H]-flunitrazepam was used to label the benzodiazepine modulatory site, and [35S]-butyl-bicyclophosphorothionate ([35S]-TBPS) to label the chloride channel. 2. Chlormethiazole had no effect on GABA synthesis in the cortex, hippocampus and striatum or on GABA release from cortical slices in vitro. Chlormethiazole did not displace [3H]-baclofen binding to the GABAB-receptor. 3. Chlormethiazole (IC50 = 140 microM) and pentobarbitone (IC50 = 95 microM) both inhibited [35S]-TBPS binding by increasing the rate of [35S]-TBPS dissociation. In addition, chlormethiazole caused an apparent decrease in the affinity of [35S]-TBPS binding. 4. Chlormethiazole enhanced the binding of [3H]-muscimol but had no effect on [3H]-flunitrazepam binding. In contrast, the sedative barbiturate pentobarbitone enhanced both [3H]-muscimol and [3H]-flunitrazepam binding. 5. It is concluded that the sedative and anticonvulsant effects of chlormethiazole are probably mediated through an action at the GABAA-receptor. However, chlormethiazole does not interact with the GABAA-receptor complex in an identical manner to the sedative barbiturate pentobarbitone.

Animals↗

PubMed1986

Experimental studies and clinical experiences on the dependency potential of chlormethiazole.

The dependency potential of chlormethiazole has been assessed on the basis of animal studies (rat and monkey) and an extensive analysis of human cases reported in the international clinical literature covering a period of 17 years. The results of the animal studies do not show any major physical or psychological dependence on chlormethiazole. Clinical studies of case reports suggest that the evidence for "primary" dependence on chlormethiazole is weak, as most of the analysable cases had a previous history of alcohol and/or other drug abuse/dependence. Moreover, in a high proportion of these cases there was evidence of simultaneous alcohol and/or other drug abuse. It should be stressed that in this group of patients the dependence on chlormethiazole was invariably reported in connection with long-term out-patient medication, that is, in a way that was not in accordance with recommendations for use of the drug in "dried out" alcoholics and/or drug addicts. Reports of chlormethiazole abuse/dependence from the alcohol/drug addiction indication are may involve a population particularly prone to addiction and, therefore, be unrepresentative for general assessment. Conversely, the findings in animal studies provide indirect support for the favourable clinical experiences with chlormethiazole in the geriatric, psychogeriatric and obstetric indication areas where chlormethiazole has been used extensively for more then a decade in a problem-free manner. The risk which applies to long-term use in alcoholics and/or drug addicts or the emotionally unstable, because of their "dependency proneness", does not seem to apply to the treatment of conditions, such as insomnia and agitation, in the elderly in whom the drug has been found to be very useful by various investigators.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

A comparison between chlormethiazole and nitrazepam as hypnotics in psycho-geriatric patients.

A double-blind crossover study was carried out in 68 demented elderly patients (mean age 77 years) to compare the hypnotic effects of chlormethiazole and nitrazepam. Chlormethiazole was administered as a 5% mixture (500 mg. chlormethiazole edisylate) in a 10 ml. dose: the corresponding single dose of nitrazepam was 10 mg. Treatment was discontinued in 6 patients and interrupted for from 1 to 3 days in a further 18 due to side-effects and 'hang-over' problems or because of intercurrent infections. Of these 24 drop-outs, 3 occurred during chlormethiazole treatment (1 severe 'hang-over'; 2 refused to take medication) and 21 during nitrazepam (15 severe 'hang-over' effects, including sleepiness and muscular weakness; 2 nausea; 4 intercurrent infection). Both preparations were equally effective as hypnotics, there being no noteworthy differences in time of onset or in duration of sleep. Of the 44 patients completing the trial without interuption, observations were carried out for 308 nights on each preparation. Chlormethiazole patients slept for more than 6 hours on 244 of the 308 nights without 'hang-over' effect the next day compared with 163 out of 308 nights of those on nitrazepam. The difference is statistically significant in favour of chlormethiazole. The high incidence of 'hang-over' effect during nitrazepam treatment indicates that a single 10 mg. dose is too large for use in the elderly. Overall assessment of treatment was made in 62 patients. Chlormethiazole was judged to be the most suitable drug in 37, nitrazepam in 11, and both preparations equally useful in the remaining 14 patients. This difference is statistically significant.

Aged↗

PubMed1990

Action of chlormethiazole in a model of ethanol withdrawal.

Mice withdrawn from exposure for 14 days to ethanol inhalation showed the expected signs of ethanol withdrawal including convulsive behaviour. Injection of chlormethiazole (100 mg/kg) 5 h after the start of withdrawal, at the time that the convulsive behaviour was near maximal, resulted in the virtual disappearance of the withdrawal-induced behaviour within 30 min, with its reappearance by 60 min. A dose of chlormethiazole of 40 mg/kg was without effect. The time course of the effect of chlormethiazole (100 mg/kg) in the withdrawal test was similar to its effect in raising seizure threshold and decreasing locomotor activity. Chlormethiazole did not alter in vitro binding of [3H]-PN 200-110 to the dihydropyridine sensitive Ca2+ channel. Chlormethiazole, a drug used clinically to treat ethanol withdrawal, has therefore been shown to be effective in this animal model of withdrawal. Dihydropyridine calcium antagonists are also active in the model but chlormethiazole is likely to work by a different mechanism and it is suggested that this may be by increasing GABAergic function.

Animals↗

PubMed1989

Chlormethiazole: neurochemical actions at the gamma-aminobutyric acid receptor complex.

Chlormethiazole has been extensively employed as a sedative/hypnotic and anticonvulsant for more than 25 years. While pharmacological and electrophysiological studies have implicated the GABAA receptor complex in these actions, neurochemical findings have not been consistent with this conclusion. We now present evidence that pharmacologically relevant concentrations of chlormethiazole perturb the GABAA receptor complex. Chlormethiazole was found to increase 36Cl- uptake into rat cortical synaptoneurosomes in a concentration-dependent (EC50 = 48 +/- 3 microM; Emax = 8.9 +/- 0.8 nmol Cl-/mg protein per 5 s), picrotoxin-sensitive fashion. Chlormethiazole was also found to inhibit the binding of the 'cage' convulsant [35S]t-butylbicyclophosphorothionate to rat cortical membranes (IC50 = 58.6 +/- 0.6 microM) through an increase in the apparent KD of this radioligand. Moreover, at these concentrations chlormethiazole did not affect pentobarbital-enhanced [3H]flunitrazepam binding, but inhibited [3H]flunitrazepam binding with a low potency (IC50 = 1.6 +/- 0.2 mM). These findings provide neurochemical evidence that pharmacologically relevant concentrations of chlormethiazole can perturb the GABAA receptor complex, and suggest that this compound acts at a distinct locus from other sedative/hypnotics such as barbiturates, benzodiazepines and GABAmimetics.

Animals↗

PubMed1992

The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: evidence for the protective effect of chlormethiazole.

Studies were undertaken in mice and rats on the neurotoxic effects of methamphetamine on dopaminergic and 5-hydroxytryptaminergic neurones in the brain and the neuroprotective action of chlormethiazole. In initial studies, mice were injected with methamphetamine (5 mg/kg, i.p.) at 2 hr intervals, to a total of 4 times. This procedure produced a 66% loss of striatal dopamine and a 50% loss of tyrosine hydroxylase activity 3 days later. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each dose of methamphetamine, totally prevented the methamphetamine-induced loss of tyrosine hydroxylase activity and partly prevented the loss of dopamine. Phencyclidine (20 mg/kg, i.p.), given in place of chlormethiazole, also prevented the loss of tyrosine hydroxylase. Administration to rats of 4 doses of methamphetamine (15 mg/kg, i.p.) at 3 hr intervals resulted in a 75% loss of striatal dopamine 3 days later and a similar loss of 5-HT and 5-HIAA in cortex and hippocampus. Chlormethiazole (50 mg/kg, i.p.), given 15 min before each injection of methamphetamine, protected against the loss of dopamine and indoleamine content, in the respective regions. Pentobarbital (25 mg/kg, i.p.) also provided substantial protection but diazepam (2.5 mg/kg, i.p.) was without effect. Confirming earlier studies, dizocilpine (1 mg/kg) also provided substantial protection against the methamphetamine-induced neurotoxicity. Preliminary data indicated that chlormethiazole was not neuroprotective because of a hypothermic action. These data therefore demonstrate that chlormethiazole is an effective neuroprotective agent against methamphetamine-induced neurotoxicity and extend the evidence for the possible value of this drug in preventing neurodegeneration.

Animals↗

PubMed1991

Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil.

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. 2. Chlormethiazole (100 mg kg-1, i.p.) and two other drugs previously reported to be neuroprotective (dizocilpine, 3 mg kg-1, i.p. and ifenprodil, 4 mg kg-1, i.p.) were all found to prevent neurodegeneration of CA1/CA2 neurones in the hippocampus when given 30 min before a 5 min episode of bilateral carotid artery occlusion. 3. Chlormethiazole (100 mg kg-1) was neuroprotective when given up to 3 h, after the ischaemic episode. 4. Given 1 h after the cartoid artery occlusion, chlormethiazole produced significant protection against hippocampal neurodegeneration at a dose of 50 mg kg-1, but not at 25 mg kg-1. 5. Phenobarbitone (100 mg kg-1, i.p.) and Saffan (alphaxalone, 45 mg kg-1 plus alphadalone, 15 mg kg-1, i.p.) were not protective when given 1 h after the ischaemic episode while pentobarbitone (30 mg kg-1, i.p.) had a modest protective effect. 6. Evidence is presented to show that neither the operating procedure nor the chlormethiazole administration lowered rectal or cerebral temperature. 7. The data suggest that chlormethiazole may be a useful treatment in the prevention of neurodegeneration following stroke or cardiac arrest.

Animals↗

PubMed1992

Modulation of GABAA and glycine receptors by chlormethiazole.

The influence of chlormethiazole, on currents evoked by gamma-aminobutyric acid (GABA) and glycine, was investigated under voltage-clamp conditions, in bovine chromaffin cells and murine spinal neurones, respectively. Chlormethiazole (30 and 100 microM) dose dependently potentiated currents activated by either inhibitory neurotransmitter. The potentiation of the GABA-evoked response occurred without altering the reversal potential and was not influenced by the benzodiazepine receptor antagonist Ro 15-1788 (300 nM). GABA-gated channels, recorded from outside-out membrane patches, showed increased probability of being in the conducting state in the presence of chlormethiazole. High concentrations of chlormethiazole (3 mM) activated bicuculline (1 microM)-sensitive whole-cell currents with a reversal potential similar to the chloride equilibrium potential. Chlormethiazole potentiates GABA- and glycine-activated currents and at higher doses, directly activates the GABAA receptor.

Animals↗

PubMed1986

A sheep preparation for studying interactions between blood flow and drug disposition. VI: Effects of general or subarachnoid anaesthesia on blood flow and chlormethiazole disposition.

Blood flow through and chlormethiazole extraction ratios across lungs, liver, kidneys and gut were measured in awake unrestrained sheep (controls) and with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid blockade with amethocaine. In the control-drug studies, chlormethiazole infused to sub-sedative blood concentrations produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flows). Chlormethiazole was eliminated predominantly by the liver (mean extraction ratio and clearance, respectively, 0.90 and 1.3 litre min-1) and lungs (0.15; 0.6 litre min-1). Renal clearance was absent or negligible (greater than 0.1 litre min-1). Because of pulmonary clearance, mean total body clearance was derived from analysis of pulmonary arterial concentrations. Under general anaesthesia, there were significant reductions in mean cardiac output, hepatic and renal blood flow (to 54%, 63% and 43% of control); chlormethiazole mean hepatic extraction ratios and clearance were reduced, respectively, to 82% and 56% of control, and its pulmonary and renal clearances were abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in chlormethiazole extraction ratios or clearances.

Anesthesia, General↗

PubMed1987

Effects of thiopentone or chlormethiazole on human placental stem villous arteries.

Small placental stem villous arteries were micro dissected from specimens obtained at normal term vaginal delivery (n = 25). Ring preparations of the vessels were mounted in organ baths and isometric tension was measured. Prostaglandin F2 alpha (PGF2 alpha) 10(-7)-10(-4) mol litre-1 produced concentration-dependent contractile responses that were inhibited by thiopentone 10(-4)-10(-3) mol litre-1 and by chlormethiazole 3 x 10(-4)-3 x 10(-3) mol litre-1. Thiopentone 10(-4)-10(-3) mol litre-1 and chlormethiazole 3 x 10(-4)-3 x 10(-3) mol litre-1 decreased the tension in vessels previously treated with PGF2 alpha 10(-5) mol litre-1. Chlormethiazole 3 x 10(-3) mol litre-1 inhibited, and thiopentone 10(-4)-10(-3) mol litre-1 abolished contractile responses to 5-hydroxytryptamine. Contractions induced by angiotensin II were inhibited by thiopentone 10(-3) mol litre-1 and chlormethiazole 3 x 10(-3) mol litre-1. The concentrations of the two drugs needed to affect contractile activation of isolated human stem villous arteries exceeded the free plasma concentrations reached during anaesthesia induced by the agents during Caesarean section, and the present results do not suggest any major effects of thiopentone or chlormethiazole on fetal placental vascular resistance during the clinical use of these drugs.

Angiotensin II↗

PubMed1988

Effects of diazepam and chlormethiazole on ventilatory control in normal subjects.

We have studied the effects of chlormethiazole and diazepam given orally on the ventilatory and mouth occlusion pressure (P0.1) responses to CO2 in a placebo controlled study in 10 healthy volunteers. Diazepam 10 mg produced a significant reduction in both the ventilatory and P0.1 responses to CO2, and this was not associated with any effect on respiratory muscle power. Chlormethiazole 250 mg produced less drowsiness than diazepam 10 mg. Therefore in a subsequent study chlormethiazole 500 mg was compared with placebo. Chlormethiazole in either dose had no effect on CO2 responses or on maximum static respiratory pressures. We conclude that diazepam has a direct depressant effect on chemoreceptors and its effects on indices of ventilatory control are not due to impaired muscle function; chlormethiazole in the doses used has no such effects despite producing drowsiness.

Adult↗

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↗

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↗