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PubMed1987

The influence of drug sorption on pharmacokinetic studies of chlormethiazole and lignocaine.

The influence of drug sorption on the measurement of dose and blood concentrations during pharmacokinetic studies of chlormethiazole and lignocaine in a chronically catheterized sheep preparation has been examined. There was no sorption to soda glass tubes, borosilicate glass volumetric flasks or soda glass microlitre syringes but minor sorption to polypropylene syringes, polypropylene pipette tips and rubber bottle stoppers after 240 min contact. During infusions through administration sets including either polyvinyl chloride or polyethylene catheters, no significant loss of lignocaine occurred, but only 41.7-63.9% of the chlormethiazole dose was delivered. No significant decreases in either drug occurred from blood sampled through an intravascular catheter and stopcock system. There was negligible degradation of the samples over 4 h. Sorption of chlormethiazole or lignocaine to the laboratory equipment used was not a significant source of error but polyvinyl chloride infusion catheters could result in significant reductions in chlormethiazole dose.

Absorption↗
PubMed1978

Effect of cirrhosis of the liver on the pharmacokinetics of chlormethiazole.

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.

Administration, Oral↗
PubMed1980

Improved hypnotic treatment using chlormethiazole and temazepam.

The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.

Adult↗
PubMed1978

Piracetam and chlormethiazole in acute alcohol withdrawal: a controlled clinical trial.

Sixty in-patient alcoholics, presenting with an alcohol withdrawal syndrome after at least one week's drinking bout, were randomly allocated to fixed dose regimens of either piracetam or chlormethiazole in a one-week double-blind trial. The patients were studied in respect to physical and biochemical parameters as well as symptom reduction and side-effects. The battery of rating scales demonstrated a good symptom reduction in both drug groups. On the whole a small tendency to more symptom items being reduced on piracetam in comparison with chlormethiazole was found. But the tree items, sleep disturbances, decreased libido at the initial phase, and the staff's assessment showed statistically significant differences in favour of chlormethiazole. This study demonstrated that piracetam was just as efficient as chlormethiazole in patients not requiring sedation.

Adult↗
PubMed1980

Low dose chlormethiazole infusion as a supplement to central neural blockade: blood concentrations and clinical effects.

Chlormethiazole ethanedisulphonate (Hemineurin) was administered to provide light sedation in patients undergoing surgery with neural blockade. A two stage intravenous infusion system was used and consisted of a loading dose 1520 mg over 30 minutes followed by a maintenance rate of 10 mg/min for the desired period. Patients were sedated smoothly and reliably but could be roused by verbal contact. Recovery from effects was rapid and this is a result of a high clearance of chlormethiazole from the body (approximately 2 l/min). Blood concentrations of chlormethiazole (base, mean +/- SD) associated with light sedation were 5.5 +/- 3.0 mg/l, while a sleep-like state was achieved with concentrations of 6.7 +/- 3.0 mg/l. Given by controlled intravenous infusion under close supervision, chlormethiazole appears close to being an ideal sedative to supplement neural blockade techniques.

Adolescent↗
PubMed1984

Failure of IV atropine to abolish nasal irritation caused by chlormethiazole infusion in elderly patients undergoing spinal anaesthesia.

The efficacy of intravenous atropine in abolishing the nasal irritation of chlormethiazole was assessed. Forty elderly patients undergoing transurethral resection of prostate under spinal anaesthesia were studied. One ml of either atropine sulphate (0.6 mg) or normal saline was administered intravenously in a double-blind fashion 10 minutes prior to infusion of 0.8% chlormethiazole edisylate. A loading infusion of 5 ml X min-1 of the chlormethiazole solution was followed by a variable rate of infusion in order to maintain a predetermined state of sedation--i.e. where the patient lapsed into sleep but was easily awakened to obey commands. Sneezing was the commonest side-effect occurring in 45% and 70% of patients in atropine and saline groups respectively. This was not effectively abolished by IV atropine in incremental doses of 0.6 mg up to 1.8 mg. Because of the sneezing and restlessness, four patients in the atropine group required general anaesthesia to improve operating conditions. These side-effects of chlormethiazole may limit its use as a sedative for surgery in this elderly age group.

Aged↗
PubMedDate not supplied

[Chlormethiazole in the treatment of complex partial epileptic status in childhood].

The authors report on the results of clinical investigations, treatment and follow-up of a 9-year old boy with complex partial status epilepticus (CPSE) which occurred after the first onset of partial secondary generalized epileptic seizures. Electroencephalografic recordings during status epilepticus showed a diffuse, generalized, high-voltage delta dysfunction and bilateral epileptiform activity, with local maximum over the posterior right temporal parietal regions. Parenteral administration of diazepam, phenytoin and phenobarbitone as choice anticonvulsant drugs, failed to stop CPSE in the patient. Only by continuous intravenous infusion of chlormethiazole (Heminevrin) status epilepticus was successfully controlled. Paroxysmal discharges on electroencephalogram disappeared and attenuation of slow wave activity was evident. Memory deficits and the elements of nominal dysphasia and tactile dysgnosia were apparent soon after cessation of CPSE and may be related to the signs of maximal local electroencephalographic dysfunction. Later testings after complete seizure control by chlormethiazole and phenytoin given orally, showed almost normal results. No side effects were encountered. A more common chlormethiazole administration as a useful therapeutic agent in the management of CPSE especially in children with refractory and long-time status, would be mandatory. Since chlormethiazole is free from serious side effects, its earlier use in the control of epileptic status may help to preclude some severe cognitive effects and to evade the use of barbiturate anesthesia as the last therapeutic resort.

Child↗
PubMed1993

Effect of chlormethiazole on hepatic monooxygenases activity in vivo.

Chlormethiazole is a strong inhibitor of cytochrome P-450-dependent monooxygenases in isolated human liver microsomes. To assess its effect in vivo, we measured the pharmacokinetic parameters of antipyrine (1.2 g orally) and tolbutamide (0.5 g i.v.) before and after administration of chlormethiazole 314 mg b.d. for 2 days to 8 healthy volunteers. The elimination of neither substance was affected, indicating that chlormethiazole did not inhibit in vivo the cytochrome P-450 isozymes responsible for the elimination of antipyrine and tolbutamide.

Antipyrine↗
PubMed1980

Alcohol intoxication and hangover: modification of hangover by chlormethiazole.

Alcohol intoxication and hangover were studied in 12 healthy male subjects who participated in three 18-h experimental sessions; two sessions in which they consumed 1.43 g alcohol/kg body weight as mixed beverages together with food, and one control session when mineral water was substituted for the alcoholic beverages. In one of the alcohol sessions they received chlormethiazole, 1 g at bedtime and 0.5 g early the following morning, in the other, they were given placebo tablets. The following variables were studied: blood-alcohol concentration; blood pressure; heart rate; blood lactate; blood pyruvate; urinary catecholamines (only during hangover); psychomotor and cognitive capacities; as well as subjective reactions. During intoxication, heart rate and lactate-pyruvate ratio were significantly increased and performance efficiency was significantly deteriorated in comparison with the control condition. During hangover, heart rate, blood pressure, and lactate-pyruvate ratio were significantly elevated, and cognitive performance was still affected, in some tests to a significant degree. During this stage there was a great variation between subjects as regards subjective hangover. Chlormethiazole was found to lower blood pressure and adrenaline output and, furthermore, to relieve unpleasant physical symptoms, but did not affect fatigue and drowsiness. The cognitive test results were only slightly influenced by this agent, while psychomotor performance was significantly impaired. Subjects with severe subjective hangover seemed to benefit more from the chlormethiazole treatment than subjects with a mild hangover.

Adult↗
PubMed1980

Sorption of chlormethiazole by intravenous infusion giving sets.

The sorption of chlormethiazole by intravenous infusion giving sets was investigated. Average recoveries of chlormethiazole following 500 ml infusions were 78.5%, 82.2% and 71.2% for the IVAC Volume Infusion Set, Travenol Code AHC 2890 Blood Administration Set and the McGaw Metriset, respectively. The effluent concentration-time profile using set up procedures and infusion rates similar to those used clinically were followed. When compared to solutions flowing at an infusion rate of 75 and 150 ml/h, loss of chlormethiazole from solutions standing static in the infusion sets was higher while that of solutions flowing at a high rate of 999 ml/h was lower. The clinical and pharmacokinetic significance of these phenomena are discussed.

Adsorption↗
PubMed1980

Chlormethiazole and utilization of vitamin B1 in chronic alcoholics.

Blood vitamin B1 status as reflected by erythrocyte transketolase activation tests has been assessed in 12 chronic alcoholic (M = 8; F = 4; mean age +/- 53.4 +/- 12.9) both before and after treatment with chlormethiazole and parenteral polyvitamins including thiamine hydrochloride. 7 out of 12 patients (58.3%) were found to be deficient before treatment but all returned to normal after treatment. Mean +/- SD, of alpha ETK improved pre-treatment level of 1.174 +/- 0.135 to 1.009 +/- 0.009 after treatment with thiamine. Chlormethiazole did not seem to interfere with the utilization of thiamine. It is therefore concluded, that though structurally related to the thiazole nucleus of thiamine, chlormethiazole, like thiamine antagonists, does not antagonize the effect of the co-enzyme - thiamine pyrophosphate at the receptor sites on the apo-enzyme - transketolase.

Adult↗
PubMed1975

Pharmacokinetics of chlormethiazole in humans.

The pharmacokinetics of chlormethiazole have been studied in six healthy volunteers following an intravenous infusion of the drug. The log. plasma concentration-time curve of chlormethiazole after cessation of the infusion was found to be curvilinear and was fitted therefore, by a bi-exponential equation computed by non-linear least squares regression analysis. Half-lives for the initial alpha-phase (0.54+/-0.05 h) and the terminal beta-phase (4.05+/-0.60 h) were calculated together with other pharmacokinetic parameters of the two compartment open model. An explanation for the discrepancy between the presently reported plasma half-lives and those appearing in the literature has been presented. The pharmacokinetic treatment of the plasma concentration-time data obtained following intravenous infusion also enabled the prediction that the maximal systemic availability of an orally administered dose of chlormethiazole would be of the order of 15%.

Administration, Oral↗
PubMed1981

An integrated study of pharmacokinetics and pharmacodynamics of chlormethiazole in healthy young volunteers.

Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n = 5) and 113 min (Phase 2, n = 5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.151 . min-1, SD 0.49; and 1.051 . min-1, SD 0.49; and 1.051 . min-1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (1371, SD 62; and 1251, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (3081, SD 91; and 2241, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg . 1(-1) (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.

Adolescent↗
PubMed1981

Cimetidine impairs the elimination of chlormethiazole.

Cimetidine impairs the systemic clearance of a number of low extraction drugs and this study examines its effect on the oral clearance of the high extraction drug, chlormethiazole. Cimetidine (1 g/day for 7 days) caused the clearance of chlormethiazole to fall to 69% of pretreatment values. It also prolonged the elimination half-life by 60%. The findings indicate that the metabolism of chlormethiazole is inhibited by cimetidine and the co-administration of these drugs may lead to excess sedation and respiratory depression.

Adult↗
PubMed1993

Effect of chlormethiazole, dizocilpine and pentobarbital on harmaline-induced increase of cerebellar cyclic GMP and tremor.

Administration to mice of harmaline (100 mg/kg SC) resulted in a greater than two-fold increase in cyclic GMP in the cerebellum 15 min later. This response was inhibited by pretreatment 5 min before the harmaline with pentobarbital (ED50 6.5 mg/kg), chlormethiazole (ED50 10.4 mg/kg) and dizocilpine (ED50 0.5 mg/kg). Harmaline-induced tremor was inhibited by pentobarbital (ED50 30 mg/kg) and chlormethiazole (ED50 50 mg/kg) but not dizocilpine. The data demonstrate that the harmaline-induced tremor and cerebellar cyclic GMP rise are probably not associated. They also demonstrate that chlormethiazole is able to inhibit a biochemical response (the increase in cerebellar cyclic GMP) which results from increased glutamate function.

Animals↗
PubMed2005

Driving under the influence of chlormethiazole.

This article describes a case of driving under the influence of the sedative-hypnotic-anticonvulsant drug chlormethiazole. The suspect, who was a physician, was driving dangerously on a busy highway and caused a traffic collision. When apprehended by the police, the man had bloodshot and glazed eyes and pupil size was enlarged. He could not answer the questions properly and his gait was unsteady. A roadside breath-alcohol screening test was positive but an evidential breath-alcohol test conducted about one hour later was below the legal limit for driving of 0.10 mg/L (10 microg/100 mL or 0.021 g/210 L). Because of the special circumstances of the traffic crash and the man's appearance and behaviour, the police suspected that drugs other than alcohol were involved and obtained a venous blood sample for toxicological analysis. The blood contained 0.23 mg/g alcohol, which is above the legal limit for driving in Sweden 0.20 mg/g (20 mg/100 mL or 0.020 g/100 mL), and codeine was also present at a therapeutic concentration of 0.02 mg/L. The conflict between the clinical signs of impairment and the toxicology report prompted a reanalysis of the blood sample with major focus on sedative-hypnotic drugs. Analysis by capillary GC-NPD identified chlormethiazole at a concentration of 5mg/L, the highest so far encountered in traffic cases in Sweden. In 13 other impaired driving cases over 10 years the mean (median) and range of concentrations of chlormethiazole were 1.6 mg/L (1.6 mg/L) and 0.3-3.3 mg/L. This case report underscores the need to consider clinical observations and the person's behaviour in relation to the toxicology report when interpreting and testifying in drug-impaired driving cases.

Accidents, Traffic↗
PubMed1987

A comparative study of lormetazepam and chlormethiazole in elderly in-patients.

Sixty-two elderly in-patients suffering from insomnia were studied in a double-blind, double-dummy, placebo-controlled trial. Each group received either lormetazepam 1 mg, chlormethiazole 384 mg or placebo for 7 nights. Both lormetazepam and chlormethiazole significantly increased sleep duration, reduced sleep latency and improved quality of sleep and feelings on awakening. For both drugs, reaction times the next morning were unimpaired and there was no clinical evidence of accumulation after 7 nights continuous dosing. Lormetazepam and chlormethiazole in these doses are effective and safe hypnotics for frail elderly patients.

Aged↗
PubMed1992

Effects of thiopentone and chlormethiazole on human myometrial arteries from term pregnant women.

We have investigated the effects of thiopentone and chlormethiazole on maternal intramyometrial arteries dissected from myometrial biopsies taken during Caesarean section at term. Ring preparations were mounted in organ baths and isometric tension was recorded. Thiopentone 10(-4)-10(-3) mol litre-1 inhibited responses to K+ depolarization, noradrenaline and vasopressin. Chlormethiazole 3 x 10(-5)-3 x 10(-3) mol litre-1 inhibited responses to noradrenaline, while a concentration of 3 x 10(-3) mol litre-1 was required to attenuate responses to vasopressin and K+ depolarization. Neither of the two agents affected relaxant responses to prostacyclin. The results did not yield evidence that clinical use of thiopentone and chlormethiazole should impair uteroplacental vascular perfusion by a direct effect.

Arginine Vasopressin↗