Chlormethiazole as a hypnotic in elderly patients: A systematic review and meta-analysis.

The study objective was to estimate the efficacy and safety of chlormethiazole in older adults experiencing insomnia (sleep disorder). We therefore systematically searched Medline, Scopus, the Cochrane Library, PsycINFO, Ovid, ZB MED and PMC through December 2021 for randomized-controlled trials including patients > 60 years old with insomnia treated with chlormethiazole. Standardized mean differences or odds ratios with 95% confidence intervals were calculated for the main outcome parameters: sleep duration, onset of sleep, quality of sleep, adverse events or drop-out rates compared with placebo and other drugs. Risk of bias was assessed using the Cochrane tool. Eight randomized-controlled trials with 424 patients were included. Chlormethiazole significantly increased the duration of sleep when compared with placebo (standardized mean difference = 0.61; 95% confidence interval = 0.11-1.11; p = 0.02). More patients receiving chlormethiazole had adequate quality of sleep than those receiving other drugs (odds ratio = 1.44; 95% confidence interval = 1.04-1.98; p = 0.03). No differences were found regarding the onset of sleep (standardized mean difference = 1.07; 95% confidence interval = 0.79-1.46; p = 0.65). Drop-out rates were significantly lower under chlormethiazole treatment when compared with other drugs (odds ratio = 0.51; 95% confidence interval = 0.26-0.99; p = 0.05) and did not differ from placebo treatment (odds ratio = 1.37; 95% confidence interval = 0.23-8.21; p = 0.73). Side-effects such as "hangover" and daytime drowsiness occurred less frequently during chlormethiazole treatment compared with other drugs in three out of four studies, but differences were not significant (odds ratio = 0.24; 95% confidence interval = 0.04-1.48; p = 0.12). In conclusion, chlormethiazole showed significant effects on the duration and the quality of sleep with better tolerability if compared with other drugs in older adults with insomnia.

Gamma aminobutyric acid (GABA) receptor agonists for acute stroke.

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane Review first published in 2013, and previously updated in 2014 and 2016. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (accessed May 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) 2018, Issue 4 (accessed May 2018), MEDLINE (from 1949 to May 2018), Embase (from 1980 to May 2018), CINAHL (from 1982 to May 2018), AMED (from 1985 to May 2018), and 11 Chinese databases (accessed May 2018). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trial registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included five trials with 3838 participants (acute ischemic or hemorrhagic stroke patients, 3758 analyzed). Most of the participants recruited had acute ischaemic stroke, with limited data available from participants with other stroke subtypes, including total anterior circulation syndrome (TACS). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. For death and dependency at three months, pooled results did not find a significant difference for chlormethiazole versus placebo (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11; four trials; 2909 participants; moderate-quality evidence) and for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07; one trial; 849 participants; moderate-quality evidence). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; 2527 participants; moderate-quality evidence) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; 2527 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.

Gamma aminobutyric acid (GABA) receptor agonists for acute stroke.

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane review first published in 2013, and previously updated in 2014. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (accessed March 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 3, part of the Cochrane Library (accessed March 2016), MEDLINE (from 1949 to March 2016), Embase (from 1980 to March 2016), CINAHL (from 1982 to March 2016), AMED (from 1985 to March 2016), and 11 Chinese databases (accessed March 2016). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias. MAIN RESULTS: We included five trials with 3838 participants (3758 analyzed). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. Four trials (N = 2909) measured death and dependency at three months for chlormethiazole versus placebo; pooled results did not find a significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11). One trial (N = 849) measured this outcome for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; N = 2527) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; N = 2527). AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.

Gamma aminobutyric acid (GABA) receptor agonists for acute stroke.

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebral ischemia. However, the sedation effects of GABA receptor agonists have limited their wider application in acute stroke patients due to the potential risk of stupor. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (February 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 5), MEDLINE (1949 to June 2014), EMBASE (1980 to June 2014), CINAHL (1982 to June 2014), AMED (1985 to June 2014) and 11 Chinese databases (June 2014). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for acute stroke patients (within 12 hours after stroke onset), with the outcomes of death or dependency, functional independence and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. MAIN RESULTS: We included five trials with 3838 patients. The methodological quality of the included trials was generally good, with low risk of bias. Four trials measured death and dependency at three months in chlormethiazole versus placebo without significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.95 to 1.11). One trial measured this outcome between diazepam and placebo (RR 0.94, 95% CI 0.82 to 1.07). In the subgroup analysis of total anterior circulation syndrome (TACS), a higher percentage of functional independence was found in the chlormethiazole group (RR 1.33, 95% CI 1.09 to 1.64). The frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46). AUTHORS' CONCLUSIONS: This review does not provide the evidence to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of patients with acute ischemic or hemorrhagic stroke. Chlormethiazole appeared to be beneficial in improving functional independence in patients with TACS according to the subgroup analysis, but this result must be interpreted with great caution. More well-designed RCTs with large samples of TACS would be required for further confirmation. However, somnolence and rhinitis are frequent adverse events related to chlormethiazole.

Gamma aminobutyric acid (GABA) receptor agonists for acute stroke.

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebral ischemia. However, the sedation effects of GABA receptor agonists have limited their wider application in acute stroke patients due to the potential risk of stupor. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (January 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1949 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), AMED (1985 to March 2012) and 11 Chinese databases (March 2012). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for acute stroke patients (within 12 hours after stroke onset), with the outcomes of death or dependency, functional independence and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. MAIN RESULTS: We included five trials with 3838 patients. The methodological quality of the included trials was generally good, with low risk of bias. Four trials measured death and dependency at three months in chlormethiazole versus placebo without significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.95 to 1.11). One trial measured this outcome between diazepam and placebo (RR 0.94, 95% CI 0.82 to 1.07). In the subgroup analysis of total anterior circulation syndrome (TACS), a higher percentage of functional independence was found in the chlormethiazole group (RR 1.33, 95% CI 1.09 to 1.64). The frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46). AUTHORS' CONCLUSIONS: This review does not provide the evidence to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of patients with acute ischemic or hemorrhagic stroke. Chlormethiazole appeared to be beneficial in improving functional independence in patients with TACS according to the subgroup analysis, but this result must be interpreted with great caution. More well-designed RCTs with large samples of TACS would be required for further confirmation. However, somnolence and rhinitis are frequent adverse events related to chlormethiazole.

Substitution therapy for alcoholism: time for a reappraisal?

A number of compounds already in use as medications for various indications substitute for ethanol at clinically relevant brain pathways, in particular, at gamma-aminobutyric acid (GABA) receptors. Nevertheless, although substitute medications have been recognized for heroin and tobacco dependence, patients with alcohol dependence are rarely offered an analogous approach. Benzodiazepines may have paradoxical effects, and abuse and dependence are known. Baclofen (GABA(B) agonist) has not been associated with dependence or misuse and has been effective in several trials in preventing relapse, although research is required to establish the optimal dosing regimen. GABA-ergic anticonvulsants, helpful in treating withdrawal, have yet to emerge as effective in relapse prevention. Clomethiazole and sodium oxybate, the latter having been shown to be effective in relapse prevention, have incurred a reputation for dependence and abuse. However, data have emerged showing that the risk of abuse of sodium oxybate is lower than many clinicians had foreseen. For a condition where existing therapies are only effective in a proportion of patients, and which has high morbidity and mortality, the time now seems right for reappraising the use of substitute prescribing for alcohol dependence.

Comparison of two oral symptom-triggered pharmacological inpatient treatments of acute alcohol withdrawal: clomethiazole vs. clonazepam.

AIMS: To compare two inpatient symptom-triggered pharmacological treatments of acute alcohol withdrawal (AWS) (clomethiazole vs. clonazepam). METHODS: Prospective observational comparison within a quality improvement project. Because of a need for extra precautions against complications such as seizures and severe respiratory complaints, patients with a history of withdrawal seizures or complications with clomethiazole in their history were automatically assigned to the clonazepam group. The remaining patients were alternately assigned either to the clonazepam group (n = 38 altogether) or the clomethiazole group (n = 36). Rescue medication could consist of adding either extra clonazepam or clomethiazole. Effectiveness was measured by Clinical Global Impression Scale, Revised Clinical Institute Withdrawal Assessment for Alcohol Scale, Mainz Alcohol Withdrawal Scale, Essen Self-Assessment-Alcohol Withdrawal and attrition rate. Safety and tolerability was estimated from adverse clinical events. Secondary outcome values were heart rate, blood and pulse pressure. RESULTS: There were no significant differences between the treatments with respect to primary and secondary effectiveness measures, safety or tolerability or duration of medication treatment. Both reduced the severity of initial withdrawal symptoms below 20% up to the ending of withdrawal medications. No withdrawal seizure or delirium occurred. CONCLUSION: Both score-driven treatments were equally effective, safe and well tolerated in this setting. This is the first study demonstrating the utility of clonazepam in the treatment of AWS syndrome.

[Diagnostics and therapy of alcohol withdrawal syndrome: focus on delirium tremens and withdrawal seizure]. / Diagnostik und Therapie des Alkoholentzugssyndroms: Fokus auf Delirium tremens und Entzugskrampfanfall.

INTRODUCTION: Delirium tremens and withdrawal seizures are serious complications of an alcohol withdrawal syndrome. This review presents the diagnostic procedures required in case of the occurrence of a withdrawal seizure and delirium tremens as well as possible treatment options including prophylactic medication regimen for alcohol withdrawal syndrome. Furthermore non-pharmacological procedures accompanying delirium tremens and a potential integration of viewing videotapes of delirium tremens in the course of alcohol-specific therapy are discussed. METHODS: A systematic literature research using Pubmed has been carried out to find recent studies and review articles dealing with alcohol withdrawal syndrome. RESULTS AND DISCUSSION: Regarding the diagnostic algorithm in case of the occurrence of a withdrawal seizure or a delirium tremens basic diagnostic procedures and special diagnostics including neuro-imaging or cerebrospinal fluid puncture depending on patients' clinical condition have to be considered. Sedatives are important in treatment of alcohol withdrawal seizures and delirium tremens as well as in the prophylaxis of alcohol withdrawal syndrome. A long-lasting prescription of anticonvulsant medication in patients suffering from withdrawal seizure should be considered critically and can be carried out only under certain conditions.

An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol.

AIMS: Anticonvulsants are increasingly being advocated for the treatment of acute alcohol withdrawal syndrome (AWS) to avoid the addictive properties of established medications. Because earlier works showed that moderate gabapentin doses were too low to clearly ameliorate severe AWS, we tested a higher gabapentin entry dose. METHODS: Inpatients (n = 37) with severe alcohol withdrawal symptoms (Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-AR) score > or =15 points) were given gabapentin 800 mg, and if their symptom score reduced within 2 h, they were termed 'early responders' and were then treated for 2 days with 600 mg gabapentin q.i.d. (i.e. a total of 3200 mg in the first 24 h) before beginning a taper. RESULTS: Twenty-seven (73%) were early responders (baseline CIWA-AR improved from 17.3 +/- 2.6 to 8.0 +/- 3.6 points). In the remaining 10 patients, baseline CIWA-AR deteriorated within 2 h (from 20.1 +/- 4.6 to 21.5 +/- 4.65 points). These patients were switched to clomethiazole (n = 4) or clonazepam (n = 6), which is the usual treatment. Three of the 'early responders' worsened in the next 36 h and were then reclassified and treated as 'non-responders'. Among them, two developed an epileptic seizure. CONCLUSION: Oral 800 mg gabapentin (loaded up to 3200 mg in the first 24 h) is helpful only in reducing less severe and less complicated acute AWS.

Oxcarbazepine in combination with Tiaprid in inpatient alcohol-withdrawal--a RCT.

INTRODUCTION: Oxcarbazepine (OXC), a derivative of Carbamazepine (CBZ), may represent a solution to metabolic and side effects of CBZ treatment due to the fact that renal excretion is its major route of elimination. The goal of the study is to compare the efficacy and tolerability of OXC/Tiaprid (TIA) combination therapy to the well established Clomethiazole (CLO) therapy in an inpatient setting. METHODS: To investigate the efficacy of OXC/TIA in terms of lower alcohol withdrawal symptoms and better tolerability, 56 alcohol-dependent patients participated in a randomized open-label trial, where OXC/TIA and CLO treatments were compared. RESULTS: Following admission, we observed that severity of alcohol withdrawal syndrome was comparable between OXC/TIA and CLO-patients. Overall tolerability was good. However, significantly more patients in the OXC/TIA-group (48.1%) displayed no AE compared to the CLO-group (24.1%). We found no significant differences between groups regarding total number of recorded adverse events (AEs). DISCUSSION: OXC/TIA inpatient therapy proved to be as effective and participants demonstrated the same tolerance as with CLO. In medication-based alcohol withdrawal, OXC/TIA could have the potential to become a promising alternative for alcohol dependent patients unable to undergo inpatient withdrawal therapy with CLO. Our findings further indicate that it could be worthwhile testing OXC/TIA in alcohol withdrawal in daily care units and outpatient settings. This is an important question for national health care services, since outpatient therapy is more and more asked for as alternative to inpatient settings.

Gamma-hydroxybutyric acid versus clomethiazole for the treatment of alcohol withdrawal syndrome in a medical intensive care unit: an open, single-center randomized study.

BACKGROUND: Clomethiazole (CLO) has been shown to be effective in treating alcohol withdrawal syndrome (AWS). Gamma-Hydroxybutyric acid (GHB) has also been introduced in the treatment of alcoholic patients and is effective in surgical intensive care unit (ICU) patients in preventing and treating AWS. There are no comparative studies between CLO and GHB in a medical ICU setting. METHODS: Twenty-six alcoholic patients with severe AWS and concomitant medical diseases were randomally enrolled in the study. CLO was given orally to 12 patients in a dosage of 250 mg every 4 hours as a liquid; GHB (initially 30 mg/kg body weight (BW) followed by 15 mg/kg BW) was administered intravenously to 14 patients. Four major AWS symptoms (tremor, sweating, nausea, restlessness) were scored, and the administration of additional medication was registered. RESULTS: GHB was more effective in treating AWS symptoms. In the GHB group, AWS score dropped from 6.6 +/- 2.6 to 1.8 +/- 2.1 (p <.01), while in the CLO group, the score dropped from 6 +/- 2.5 to 4.1 +/- 2.4 (n. s.). Differences between groups were significant (p =.021, two-way ANOVA). The treatment did not alter outcome or the duration of ICU stay. No serious side effects were detected. CONCLUSION: GHB effectively controls AWS symptoms in medical ICU patients. The rapid initial treatment response of GHB in contrast to CLO has no influence on duration of patient withdrawal.

Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it.

(1) When people who are physically dependent on alcohol stop drinking, they experience an alcohol withdrawal syndrome. The symptoms generally resolve spontaneously within a week, but more severe forms may be associated with generalised seizures, hallucinations and delirium tremens, which can be fatal. (2) We carried out a literature review in order to obtain answers to the following questions: how to predict or rapidly diagnose a severe alcohol withdrawal syndrome; how to prevent and treat this syndrome; how to manage severe forms; and how to deal with the risk of vitamin B1 deficiency. (3) The main risk factors for severe withdrawal syndrome are: chronic heavy drinking; a history of generalised seizures; and a history of delirium tremens. (4) Anxiety, agitation, tremor, excessive sweating, altered consciousness and hallucinations are signs of a severe withdrawal syndrome. (5) Individual support and effective communication seem to reduce the risk of severe withdrawal syndrome. (6) Oral benzodiazepines are the best-assessed drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures. When given for a maximum of 7 days, the adverse effects are usually mild. (7) Clinical trials of other antiepileptics suggest they are less effective than benzodiazepines, and their addition to benzodiazepine therapy offers no tangible advantage. (8) Betablockers increase the risk of hallucinations, and clonidine increases the risk of nightmares, and the efficacy of these two drugs is not well documented. Neuroleptics increase the risk of seizures. There are no convincing data to support the use of magnesium sulphate or meprobamate (the latter carries a risk of serious adverse effects). Acamprosate, naltrexone and disulfiram are not beneficial in alcohol withdrawal. (9) Gradual withdrawal, i.e. ingestion of decreasing amounts of alcohol, has not been compared with other methods but is generally not recommended. (10) There are no specific recommendations on hydration. Note that excessive water-sodium intake carries a risk of pulmonary oedema in patients with heart disease. (11) As vitamin B1 deficiency is frequent and can lead to serious complications in alcohol-dependent patients, oral vitamin B1 supplementation is widely recommended, despite the absence of comparative trials. High doses must be used to compensate for poor absorption. Intravenous administration is best if patients have very poor nutritional status or severe complications such as Gayet-Wernicke encephalopathy (a medical emergency), even though rare anaphylactic reactions have been reported after vitamin B1 injection. (12) Planned alcohol withdrawal in specialised hospital units has been extensively studied. Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. (13) A large proportion of alcohol-dependent patients were excluded from trials of withdrawal strategies. These include elderly patients, patients with serious psychiatric or somatic disorders, and patients who are also dependent on other substances. (14) An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality. Currently, with appropriate fluid-electrolyte support, continuous monitoring of vital signs, and respiratory support if necessary, the mortality rate for delirium tremens is under 3%. (16) In practice, patients who are attempting to stop drinking alcohol need close personal support and communication, and a reassuring environment, as well as regular monitoring for early signs of a withdrawal syndrome; the latter may require benzodiazepine therapy.

The effects of clomethiazole on polysomnographically recorded sleep in healthy subjects.

Clomethiazole is widely used in European countries to treat alcohol withdrawal symptoms including delirium tremens. The current study aimed to explore the effects of clomethiazole on the sleep of healthy volunteers. We postulated both a hypnotic and a REM suppressive effect as well as the occurrence of a rebound phenomenon following three days of treatment with clomethiazole. The study group was composed of five men and five women. The probands were examined in the sleep laboratory throughout a course of seven nights. The first night was considered as the adaptation night and the second as the baseline night. Prior to nights 3 to 5, probands took 384 mg clomethiazole at 22 hours. The 6th and 7th nights served to record potential effects of medication discontinuation. The current study confirms the indication in the scientific literature with regard to hypnotic and REM-suppressive effects of clomethiazole, as well as a rebound phenomenon following discontinuation of the medication. The effect of clomethiazole on the sleep EEG was most obvious in the first half of the night. The analysis of the polysomnogram in terms of each half of the night gave no indication of a rebound phenomenon during the second half. The REM sleep-suppressing component of clomethiazole is of great interest in connection with its use in treating delirium tremens. The rebound phenomenon in healthy controls after only three days of medication at a relatively low dosage of clomethiazole underscores the need to administer it in doses individually tailored to the extent of the alcohol withdrawal syndrome in the individual patient.

Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole.

OBJECTIVE: Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. METHODS: Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. RESULTS: The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. CONCLUSION: The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

GABA agonist: clomethiazole.

Neuroprotective agents inhibit reactions in the brain ischaemic injury cascade which lead to neuronal death. Gamma-aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter that increases chloride influx into the neuron and counteracts the toxic effects of glutamate. Clomethiazole is a GABA(A) agonist, which causes membrane hyperpolarization, counteracting depolarization and the subsequent cascade of biochemical events that result in neuronal death. Promising results in animal models resulted in clinical trials conducted in humans. However, large randomized placebo controlled trials in Europe, Canada and North America did not show the superiority of clomethiazole over placebo that was seen in animal models.