***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND AND PURPOSE The efficacy and safety of the neuroprotective drug clomethiazole was tested in a double blind placebo controlled trial in patients with a clinical diagnosis of acute hemispheric stroke . METHODS Patients with symptom onset of < /=12 hours before the start of treatment were included in the study .  Clomethiazole ( 75 mg/kg ) or placebo was given as an intravenous infusion over a 24-hour period . Patients were followed up for 90 days . The primary efficacy variable was the proportion of patients reaching relative functional independence ( > /=60 points on the Barthel Index ) at 90 days . RESULTS A total of 1360 patients were included . In the main efficacy analysis ( n=1353 ) , 56.1 % of patients taking clomethiazole and 54.8 % of placebo patients reached relative functional independence . The difference was not statistically significant . An analysis of the effect of time since onset of symptoms showed no difference between the treatment groups . Clomethiazole was generally well tolerated and appeared safe in the population studied . Sedation was the most common adverse event , leading to treatment withdrawal that occurred in 15.6 % of clomethiazole-treated patients compared with 4.2 % of placebo-treated patients . In a subgroup classified before r and omization as having  total anterior circulation syndrome ( TACS ) ( n=545 , or 40 % of all r and omized patients ) , the percentage of those reaching relative functional independence was 40.8 % on clomethiazole and 29.8 % on placebo , a difference of approximately 11 percentage units . TACS patients have clinical symptoms suggesting a " large " stroke . CONCLUSIONS Clomethiazole had no adverse or beneficial effect on long-term outcome for all patients but produced sedation . The hypothesis that clomethiazole is effective in patients with large strokes will be tested in a further study 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 thous and five hundred and forty-six acute stroke patients ( 774 on active treatment ) from 166 centres were included in three r and omized , 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 sample s 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 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 r and omly 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 ≥60 at last follow-up as the primary outcome measure . Results — The patients were r and omly 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 ≥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 , Sc and inavian Stroke Scale , and 30-day CT infa rct 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 r and omly 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 Alpha-5 gamma-aminobutyric acid type A receptors ( α5-GABAARs ) are located extrasynaptically , regulate neuronal excitability through tonic inhibition , and are fundamentally important for processes such as plasticity and learning . For example , pharmacological blockade of α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition . S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site . Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain . Here , we used transcranial magnetic stimulation ( TMS ) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic ( EMG ) and electroencephalographic ( EEG ) measures of cortical excitability in 18 healthy young adults in a r and omized , double-blinded , placebo-controlled , crossover phase I study . A dose of 100 mg , but not 50 mg , of S44819  decreased active motor threshold , the intensity needed to produce a motor evoked potential of 0.5 mV , and the amplitude of the N45 , a GABAAergic component of the TMS-evoked EEG response . The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude . Short-interval intracortical inhibition , a TMS – EMG measure of synaptic GABAAergic inhibition , and other components of the TMS-evoked EEG response remained unaffected . These findings provide first time evidence that the specific α5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability . These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke . SIGNIFICANCE STATEMENT The extrasynaptic α-5 gamma-aminobutyric acid type A receptor ( α5-GABAAR ) regulates neuronal excitability through tonic inhibition in the mammalian brain . Tonic inhibition is important for many fundamental processes such as plasticity and learning . Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain . This study demonstrates that S44819 , a selective α5-GABAAR antagonist , increases cortical excitability in healthy human subjects , as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography . Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods . The actions of S44819 may be suitable to improve plasticity and learning Background The results of pre clinical studies suggest that baclofen may be useful in the treatment of stroke patients with persistent hiccups . This study was aim ed to assess the possible efficacy of baclofen for the treatment of persistent hiccups after stroke . Methods In total , 30 stroke patients with persistent hiccups were r and omly assigned to receive baclofen ( n = 15 ) or a placebo ( n = 15 ) in a double-blind , parallel-group trial . Participants in the baclofen group received 10 mg baclofen 3 times daily for 5 days . Participants assigned to the placebo group received 10 mg placebo 3 times daily for 5 days . The primary outcome measure was cessation of hiccups . Secondary outcome measures included efficacy in the two groups and adverse events . Results All 30 patients completed the study . The number of patients in whom the hiccups completely stopped was higher in the baclofen group than in the placebo group ( relative risk , 7.00 ; 95 % confidence interval , 1.91–25.62 ; P = 0.003 ) . Furthermore , efficacy was higher in the baclofen group than in the placebo group ( P < 0.01 ) . No serious adverse events were documented in either group . One case each of mild transient drowsiness and dizziness was present in the baclofen group . Conclusions Baclofen was more effective than a placebo for the treatment of persistent hiccups in stroke patients .Trial registration Chinese Clinical Trials Register : Objective Early predictors of poor outcome after acute ischemic stroke may be useful in selecting patients for potentially beneficial but high-risk interventions . Design Cohort study of patients given placebo in a r and omized clinical trial . Setting Multicenter trial at 139 U.S. and 14 Canadian hospitals . Patients A cohort of 564 placebo-treated patients with major anterior circulation ischemic stroke enrolled in the Clomethiazole in Acute Stroke Study -Ischemic Stroke ( CLASS-I ) trial . Patients did not have significant impairment in consciousness at baseline and were enrolled within 12 hrs of symptom onset . Interventions Prospect i ve data collection of a number of clinical variables including use of a 6-point  level of consciousness scale ( 1 = awake , 6 = no reaction to pain ) to measure patients ’ level of consciousness at enrollment and 12 additional times during the first 24 hrs after enrollment . The ability of level of consciousness score and additional clinical data to predict 30-day mortality was assessed . Measurements and Main Results At 1 month , 114 of 564 patients ( 20 % ) had died . In univariate analysis , factors significantly associated with mortality included older age , white race , higher National Institutes of Health Stroke Scale score , higher serum glucose , atrial fibrillation , and any impairment in level of consciousness ( p < .05 ) . After controlling for these factors , increasing level of consciousness score at 3 hrs after enrollment and at all but one subsequent time point was significantly associated with increased mortality ( odds ratio , 1.8 per point ; 95 % confidence interval , 1.2–2.6 ; p = .003 at 3-hr time point ) . Maximum level of consciousness score during the initial 24 hrs of monitoring also predicted mortality ( odds ratio , 1.9 per point ; 95 % confidence interval , 1.4–2.5 ; p < .001 ) . Conclusion The development of a decreased level of consciousness within the initial hours after stroke onset , as evaluated by a simple six-point scale , is a powerful independent predictor of mortality after major anterior circulation ischemic stroke The CLASS study showed no significant difference between treatment groups for the neuroprotectant  clomethiazole compared with placebo . However , a beneficial effect of the drug was seen in patients with total anterior circulation syndrome ( TACS ) . These are patients with clinical symptoms suggesting a large stroke . Full results of this subgroup analysis are reported . Patients were classified before r and omization using clinical symptoms into the stroke syndromes TACS , partial anterior circulation syndrome , and lacunar syndrome . Subgroup analyses of stroke syndromes were performed post hoc after detecting a treatment by severity interaction . The primary efficacy variable was relative functional independence defined as the proportion 
    Output:
    
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 .
Somnolence and rhinitis are frequent adverse events related to chlormethiazole