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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↗
PubMed1999

Protective effect of chlormethiazole, a sedative, against acetaminophen-induced liver injury in mice.

OBJECTIVES: The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazole, an inhibitor of CYP2E1, could prevent acetaminophen-induced liver injury in mice. METHODS: Acetaminophen, at doses ranging from 200 to 600 mg/kg, was injected into the peritoneum of female C57BL/6 inbred mice fasted for four hours. Chlormethiazole (60 mg/kg) or 5% dextrose water was given 30 min before or 2 h after acetaminophen. Serum aminotransferase activities, histologic index score, survival rate and hepatic malondialdehyde levels were compared. RESULTS: Pretreatment with chlormethiazole 30 min before 400 mg/kg of acetaminophen completely inhibited acetaminophen-induced liver injury (median 118.5 U/L, range 75 to 142 vs. 14,070 U/L, range 5980 to 27,680 for AST; 49 U/L, range 41 to 64 vs. 15,330 U/L, range 13,920 to 15,940 for ALT). In mice receiving chlormethiazole 2 h after acetaminophen, the mean AST and ALT levels were also less elevated, reaching only 20% of the value of acetaminophen-only group. These protective effects were confirmed histologically. Whereas more than 50% of mice died at 500 mg/kg of acetaminophen, all the mice pretreated with chlormethiazole survived at the same dose. CONCLUSION: Chlormethiazole effectively reduces acetaminophen-induced liver injury in mice. Further studies are needed to assess its role in humans.

Acetaminophen↗
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↗
PubMed1997

Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

Animals↗
PubMed2002

Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent.

AIMS: Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain. METHODS: Multimodality monitoring including cerebral and peripheral microdialysis was applied to five head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min(-1)) intravenous loading infusion for 5 min followed by a slow (1 ml min(-1)) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bi-spectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids. RESULTS: Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients. CONCLUSIONS: Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.

Adult↗
PubMed1982

Chlormethiazole (Heminevrin), pethidine and nitrous oxide as compared to halothane for general anesthesia.

The anaesthetic and postanaesthetic course in a group of gynaecological patients anaesthetized with chlormethiazole (Heminevrin) was investigated and the results compared to a similar group of patients anaesthetized with halothane. Both drugs were used as the main anaesthetic agent in the respective regimes, supplemented by nitrous oxide/oxygen and muscle relaxants. Because chlormethiazole is devoid of analgetic effects, the importance of using pethidine in combination with chlormethiazole is emphasized. An advantage of using chlormethiazole is that it can serve as both an induction and maintenance agent. The plasma concentrations of chlormethiazole were studied in seven patients. For induction, the mean concentration was 4.5 micrograms/ml. The mean concentration on waking at the termination of operation was 1.3 micrograms/ml. No serious side effects were encountered in either treatment. The results suggested that chlormethiazole in combination with an analgetic drug and nitrous oxide could be suitable in elderly patients, although occasionally less effective in the young.

Aged↗
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↗
PubMed1995

The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.

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.

Animals↗
PubMed1996

The effect of oedema and tissue swelling on the measurement of neuroprotection; a study using chlormethiazole and permanent middle cerebral artery occlusion in rats.

The effect of chlormethiazole on hemispheric swelling and cortical tissue water content has been investigated in a model of permanent middle cerebral artery (MCA) occlusion. Chlormethiazole (1 mmol/kg i.p.) or saline was administered 60 min after the induction of ischaemia and the animals sacrificed after 24 hours. The cross sectional area of the left hemisphere was increased by 21.8 + 1.9% in saline treated rats, but only by 8.4 + 2.4% in chlormethiazole treated rats. However, the reduction in the absolute area of neurodegenerative damage (mm2) following chlormethiazole administration was considerably greater than the reduction in hemispheric swelling. Cortical tissue water content of ischaemic brain increased from 76.4% to 84.2% and this was attenuated to 78.8% by chlormethiazole administration. These data demonstrate that, providing damage is measured by fitting tissue slices onto prematched stereotactic maps, the decrease in oedema which accompanies a decrease in neurodegeneration does not result in erroneous estimates of neuroprotection.

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↗
PubMed1995

The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat.

The ability of chlormethiazole to protect against ischaemic cell damage in a rat model of permanent focal ischaemia has been examined. Chlormethiazole (1 mmol/kg) was administered intraperitoneally either 1 or 3 h after occlusion of the middle cerebral artery with an intraluminal filament. Twenty four hours after the start of occlusion there was histological evidence for ischaemic damage in both cortex and striatum. The volume of ischaemic damage in control (saline injected) animals was 310 +/- 25 mm3 (mean +/- SEM; n = 6). Chlormethiazole administered 1 h after occlusion reduced this damage by 58% (128 +/- 40 mm3; n = 6; P < 0.01), protection being observed in both brain regions. The drug was ineffective when given 3 h after occlusion (304 +/- 25 mm3; n = 5). Chlormethiazole had no effect on body temperature, mean arterial blood pressure, blood pH, pO2 or pCO2, but did induce mild bradycardia. Chlormethiazole therefore appears to be an effective neuroprotective agent in this model of permanent ischaemia, complementing previous data on the efficacy of this drug in other focal and global models of cerebral ischaemia.

Analysis of Variance↗
PubMed1998

Inhibition of CYP2E1 by chlormethiazole as measured by chlorzoxazone pharmacokinetics in patients with alcoholism and in healthy volunteers.

BACKGROUND: Chlormethiazole has been shown in in vitro studies, with use of rat and human liver microsomes, to specifically inhibit cytochrome P4502E1 (CYP2E1)-mediated activity by inhibition of the rate of CYP2E1 gene transcription. It is known that CYP2E1 is involved in the activation of many low-molecular-weight toxins and carcinogens and may be involved in the development of alcohol-induced liver disease. METHODS: The pharmacokinetics of a single oral dose of 250 mg chlorzoxazone, a marker of the activity of CYP2E1, were measured in five healthy drug-free volunteers and in 16 patients with alcoholism receiving 1.2 gm or 2.4 gm chlormethiazole per day for 1, 2, or 3 days. The patients were starting an alcohol-withdrawal program and were supposed to have an induced CYP2E1 activity. RESULTS: The results suggest that chlormethiazole strongly decreased chlorzoxazone clearance in the patients with alcoholism compared with clearance in the control subjects (3.98 +/- 1.8 L/hr versus 12.7 +/- 5.6 L/hr; p < 0.005), prolonged the elimination half-life (3.91 +/- 1.23 hours versus 1.12 +/- 0.34 hours; p < 0.001), and caused a threefold increase in the area under the concentration versus time curve of chlorzoxazone (73.0 +/- 35.5 mg.hr/L versus 21.3 +/- 13.7 mg.hr/L; p < 0.005). They also suggest that chlormethiazole significantly decreased the area under the concentration versus time curve of the metabolite 6-hydroxy-chlorzoxazone (4.56 +/- 1.27 mg.hr/L versus 7.1 +/- 1.84 mg.hr/L; p < 0.05). CONCLUSION: Chlormethiazole administration seems to result in a marked reduction of CYP2E1 activity in subjects with high CYP2E1 activity and could at least partially explain the claimed hepatoprotective action of this drug.

Administration, Oral↗
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↗
PubMed1984

The effect of chlormethiazole on the hypoxic drive to breathing in normal man.

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.

Adult↗
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↗