Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro.
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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. (+info)
The effect of chlormethiazole on the hypoxic drive to breathing in normal man.
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We have studied the effects of chlormethiazole infusion on the ventilatory response to progressive isocapnic hypoxia in seven healthy volunteers, during both normocapnia and induced hypercapnia. The dose of chlormethiazole was such that it produced the same degree of hypnosis as would be expected from oral administration of two capsules each containing 192 mg of base in arachis oil. Ventilation did not change significantly during chlormethiazole administration. The ventilatory response to hypoxia was unaffected by chlormethiazole during normocapnia and was enhanced during hypercapnia. In these subjects, giving chlormethiazole intravenously was not associated with depression of the resting ventilation nor the hypoxia ventilatory response. (+info)
Chlormethiazole in the treatment of neonatal status epilepticus.
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A pre-term neonate with status epilepticus resistant to conventional treatment but who responded to a chlormethiazole infusion is reported. Nineteen days of continuous infusion was required before treatment could be discontinued and oral phenytoin substituted. Chlormethiazole should be considered in the treatment of resistant convulsions in the newborn. (+info)
Effect of cirrhosis of the liver on the pharmacokinetics of chlormethiazole.
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The pharmacokinetics of chlormethiazole were studied in eight patients with advanced cirrhosis of the liver and in six healthy volunteers after oral and intravenous administration of the drug. In the patients the systemic bioavailability of oral chlormethiazole was increased about tenfold, whereas its elimination was only slightly retarded. The increased bioavailability was clearly due to decreased first-pass metabolism of chlormethiazole in the cirrhotic liver. The results indicate that chlormethiazole should be used in reduced dosage when given by mouth to patients with cirrhosis of the liver. (+info)
Cardiac arrest following chlormethiazole infusion in chronic alcoholics.
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Two chronic alcoholics who had cardiac arrests (one fatal) while receiving chlormethiazole by infusion are reported. Although a causal relationship has not been indisputably established, caution is advised when administering this drug to chronic alcoholics during withdrawal. (+info)
Direct measurement of chlormethiazole extraction by liver, lung and kidney in man.
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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. (+info)
A study of the mechanism of MDMA ('ecstasy')-induced neurotoxicity of 5-HT neurones using chlormethiazole, dizocilpine and other protective compounds.
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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. (+info)
The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.
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1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied. 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. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol kg-1) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-1 respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained for 110 min with no protection observed at 10 nmol ml-1. 4. In contrast, when a plasma concentration of 10 nmol ml-1 was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug. (+info)