Inhibitory effect of chlormethiazole on the toxicokinetics of diethylnitrosamine in normal and hepatofibrotic rats.

The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with DEN-induced liver fibrosis. Twelve rats were treated with DEN (50 mg/kg) alone and in combination with a single dose of CMZ (10, 50, or 100 mg/kg) by intraperitoneal (i.p.) injection. In a multiple dose test, six rats were treated with CMZ (50 mg/kg) for 7 d with addition of DEN (50 mg/kg) on days 1 and 7. Lastly, 12 rats were treated with DEN (50 mg/kg) by i.p. injection twice a week for 4 consecutive weeks, followed by weekly injections for another 8 weeks to build the model of liver fibrosis. Following this induction, the 12 rats were given CMZ (50 mg/kg) combined with DEN (50 mg/kg) to study the inhibitory effect of CMZ on DEN metabolism in hepatofibrotic rats. Serial blood samples were also collected and analyzed by a validated high-performance liquid chromatography (HPLC) method. A single-dose CMZ treatment decreased DEN clearance (CL), prolonged the t1/2, and increased the 'area under the curve' (AUC) for DEN in normal and hepatofibrotic rats relative to rats that did not receive CMZ. Treatment with CMZ for 7 d further prolonged the t1/2 for DEN but did not alter the CL and AUC relative to a single CMZ treatment. These results suggest that CMZ significantly inhibits the metabolism of DEN in normal and hepatofibrotic rats.

Oral clomethiazole treatment for paediatric non-convulsive status epilepticus.

We report a retrospective case study of the use of clomethiazole for treatment of non-convulsive status epilepticus in a patient not responding to benzodiazepines, illustrated by EEG and video. Clomethiazole can be considered as a safe oral option for management of non-convulsive status epilepticus when conventional treatment has failed. [Published with video sequences online].

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.

Angiogenesis as a predictive marker of neurological outcome following hypoxia-ischemia.

Cerebral ischemia induces angiogenesis within and around infarcted tissue. The protection of existing and growth of new blood vessels may contribute to a more favorable outcome. The present study assessed whether angiogenesis can be used as a marker for neurodegeneration/neuroprotection in a model of hypoxia-ischemia (HI). Increased CD31 immunoreactivity 7 days post-HI indicated increased angiogenesis compared to controls (P<0.001). Treatment with the GABA(A) receptor modulator, clomethiazole (CMZ; 414 mg/kg/day), normalized the level of angiogenesis compared to HI + saline (P<0.001). Conversely, the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (5 mg/kg/day), markedly decreased angiogenesis compared to controls (P<0.001). Circulating plasma levels of IL-1alpha, IL-1beta and GM-CSF were significantly elevated post-HI. CMZ treatment attenuated these increases while also stimulating IL-10 levels. L-NAME treatment did not alter IL-1alpha or IL-1beta levels, but decreased endogenous IL-10 levels and exacerbated the ischemic lesion (P<0.001). CMZ treatment has been shown to increase NOS levels, while L-NAME halted the HI-induced increase in NOS activity (P<0.001). We conclude that angiogenesis can be used as a marker of neurodegeneration/neuroprotection for cerebral HI and is correlated to NOS activity and circulating inflammatory mediators.

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.

Effect of intravenous magnesium sulphate in reducing irritability and restlessness in pure and polysubstance opiate detoxification.

The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of intravenous magnesium sulphate (MgSO(4)) on the need for chlormethiazole in pure or polysubstance opiate detoxification. Forty-one inpatients suffering from pure and polysubstance opiate dependence were treated with morphine sulphate pentahydrate in a gradual detoxification program. Morphine reduction took about 11 days. Additionally, 5% MgSO(4) was administered intravenously to the intervention group (Mg group, n=22) over 24 h by perfusor (150-200 mg MgSO(4)/h; plasma level of 2.36+/-0.29 mmol/l), whereas NaCl 0.9% was intravenously administered in the placebo group (n=19). In case of withdrawal symptoms (irritability, restlessness, and insomnia), patients received chlormethiazole p.o. Our hypothesis that the need for chlormethiazole would be decreased by adjunctive administration of Mg was not confirmed in our study population (2180 mg/day in the Mg group vs. 2360 mg/day in the placebo group). There was neither a difference in the quantity of chlormethiazole required nor a difference in the severity of withdrawal symptoms measured with the Wang scale between the two comparison groups. We observed that calcium plasma levels decreased and phosphate plasma levels increased significantly during intravenous therapy with Mg. Despite promising pilot studies, the administration of Mg did not enable a dose reduction of tranquilizing medication (chlormethiazole) in pure and polysubstance opiate detoxification.

Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat.

Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.

Polysomnography during withdrawal with clomethiazole or placebo in alcohol dependent patients--a double-blind and randomized study.

INTRODUCTION: The present study was designed to assess if the routine application of clomethiazole to ameliorate withdrawal symptoms in chronic alcohol dependent patients perpetuates sleep disturbances. METHODS: Twenty inpatients with alcohol dependence according to DSM-IV criteria received clomethiazole or placebo in a double-blind, randomized design upon admission. 11 patients were randomized to the clomethiazole group and 9 patients to the placebo group. During the first 5 days of treatment the patients received either clomethiazole (1st day: 3 x 384 mg, 2nd day: 4 x 384 mg, 3rd day: 3 x 384 mg, 4th day: 2 x 384 mg and 5th day: 1 x 384 mg) or placebo capsules at constant intervals. The patients spent two consecutive nights in the sleep laboratory at each of three assessment times: the first time at the beginning of abstinence (night 1 and 2, T0), the second time 6 days later (i. e. after 5 days of treatment and one day of discontinuation of clomethiazole or placebo: nights 6 and 7, T1) and the third time after 13 days (nights 13 and 14, T2). The first night at each of the three assessment times was an adaptation night. RESULTS: During the first two weeks of abstinence, the analysis of variance demonstrated a significant variation of Rapid Eye Movement (REM) sleep variables in the clomethiazole group. The placebo group showed no such variation. Clomethiazole evidently had a pronounced REM sleep suppressing effect, whereas the discontinuation of clomethiazole led to a REM sleep rebound. Furthermore, analysis of sleep continuity and sleep architecture variables showed that the clomethiazole group had significantly disturbed sleep at T1 in comparison to the placebo group. Simultaneous statistical testing with alcohol intake as covariate reduced the test power so that contrasts between the groups became nonsignificant. CONCLUSIONS: The REM sleep results are in line with earlier findings that REM sleep disinhibition in primary alcohol dependency is partly due to a REM sleep rebound after withdrawal from medication. Differences in the polysomnographic variables of sleep continuitiy and sleep architecture at T0 and T1 found between the clomethiazole and the placebo patients correspond to rebound insomnia following discontinuation of clomethiazole. Our findings indicate that drugs enforcing GABAergic neurotransmission may perpetuate the neuroadaptative effects caused by chronic alcohol consumption.

Treatment of alcohol withdrawal: chlormethiazole vs. carbamazepine and the effect on memory performance--a pilot study.

Although relatively little attention has been paid to the question how acute alcohol withdrawal might affect cognitive functions, this factor remains of particular interest because it influences psychotherapeutic treatment during detoxification. The clinical outcome and neuropsychological state of 37 inpatients with alcohol withdrawal was investigated in a randomized single-blind approach. Two different medical strategies [chlormethiazole (CMZ) vs. carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal syndrome were compared. Among comparable groups (related to gender, age, initial alcohol level, severity of abuses, severity of initial withdrawal symptoms such as tremor, perspiration, psychomotor agitation, hallucinations, orientation, intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of withdrawal symptoms (circulatory function, vegetative function, psychomotor activity). Patients in both groups showed initial impairments in some neuropsychological tests (d2, Zahlen-Verbundings test, Beck Depression Inventory, Anxiety Sensitivity Index) with significant improvement during detoxification. Additionally, CBZ-treated patients showed significantly better verbal memory performance during the first days of treatment. Without any addictive potential, CBZ therapy could be very supportive in alcohol detoxification. In addition a higher verbal memory performance state could be favourable for a psychotherapeutic approach.

Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients.

AIMS: This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. METHODS: One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. RESULTS: Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. CONCLUSIONS: The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

Clinical trial of the neuroprotectant clomethiazole in coronary artery bypass graft surgery: a randomized controlled trial.

BACKGROUND: The neuroprotective property of clomethiazole has been demonstrated in several animal models of global and focal brain ischemia. In this study the authors investigated the effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery. METHODS: Two hundred forty-five patients scheduled for coronary artery bypass surgery were recruited at two centers and prospectively randomized to clomethiazole edisilate (0.8%), 225 ml (1.8 mg) loading dose followed by a maintenance dose of 100 ml/h (0.8 mg/h) during surgery, or 0.9% NaCl (placebo) in a double-blind trial. Coronary artery grafting was completed during moderate hypothermic (28-32 degrees C) cardiopulmonary bypass. Plasma clomethiazole was measured at several intervals during and up to 24 h after the end of infusion. A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. Analysis of the change in neuropsychological test scores from baseline was used to determine the effect of treatment. RESULTS: Neuropsychological assessments were completed in 219 patients (110 clomethiazole; 109 placebo). The mean plasma concentration of clomethiazole during surgery was 66.2 microm. There was no difference between the clomethiazole and placebo group in the postoperative change in neuropsychological test scores. CONCLUSION: Clomethiazole did not improve cerebral outcome following coronary artery bypass surgery.

The role of the ubiquitin-proteasome pathway in the formation of mallory bodies.

The dynamics of Mallory body (MB) formation are difficult to follow in vivo. Because of the lack of an in vitro mouse hepatocyte culture model, a cellular extract approach was developed. In this model an immunoprecipitate was obtained using an antibody to cytokeratin-8 (CK-8). The isolate contained a large number of compounds: CK-8, ubiquitin, a frameshift mutation of ubiquitin (UBB(+1)), proteasomal subunits beta5 (a catalytic subunit of the 20S proteasome) and Tbp7 (an ATPase subunit of the 26S proteasome), transglutaminase, tubulin, heat shock proteins 90 and 70, and MBs. In Western blots, CK-8 immunoprecipitates showed colocalization of these components in a complex of proteins colocalized in a high-molecular-weight smear. When the CK-8 immunoprecipitate was incubated with the isolate of proteasomes and an energy generating source (ATP), the components of the ubiquitinated protein smear increased. These observations taken together with the in vivo observation that these proteins colocalized at the edge of the MB shown in the present study suggest that these proteins form aggregates through covalent binding of CK-8, ubiquitin, and the proteasomes. Covalent aggregation is suggested by the fact that the protein complex found in the high-molecular-weight smear that forms in vitro fails to dissociate in SDS. This protein complex is present in the CK-8 immunoprecipitates of livers forming MBs but not in control livers. In conclusion, the results support the concept that Mallory bodies are aggresomes which form as the result of the failure of the ubiquitin-proteasome complex to adequately eliminate cytokeratins destined for proteolysis.

[Diagnosis and treatment of delirium]. / Diagnose und Behandlung des Delirs.

Delirium is a common psychiatric complication in somatically ill in-patients and is associated with increased morbidity and mortality, longer lengths of stay and higher cost of treatment. It remains often unrecognized and thus inadequately treated. The main risk factors, differential diagnosis, primary and secondary prevention, non-pharmacological interventions and pharmacological treatment are discussed. For the treatment of the non alcohol associated delirium, haloperidol remains the treatment of choice, whereas for the treatment of delirium related to alcohol withdrawal benzodiazepines and clomethiazole are recommended. Other treatment strategies, especially the use of newer atypical antipsychotic medications are outlined.

Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results.

BACKGROUND AND PURPOSE: A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. METHODS: A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index > or =60 at last follow-up as the primary outcome measure. RESULTS: The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9+/-5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of > or =60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P=0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. CONCLUSIONS: The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results.

OBJECTIVE: To assess the safety of tissue-type plasminogen activator (t-PA) plus clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy. BACKGROUND: Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS-t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke. METHODS: In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index. RESULTS: The number of serious adverse event reports was 47 in the clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23). CONCLUSION: In this pilot study, there were no safety concerns related to the combination of t-PA and clomethiazole. The combination paradigm proved feasible, although many patients received clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and clomethiazole.