human
***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: CONTEXT Hypothetically , topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol 's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system . OBJECTIVE To determine if topiramate is a safe and efficacious treatment for alcohol dependence . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , placebo-controlled , 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence , conducted between January 27 , 2004 , and August 4 , 2006 , at 17 US sites . INTERVENTIONS Up to 300 mg/d of topiramate ( n = 183 ) or placebo ( n = 188 ) , along with a weekly compliance enhancement intervention . MAIN OUTCOME MEASURES Primary efficacy variable was self-reported percentage of heavy drinking days . Secondary outcomes included other self-reported drinking measures ( percentage of days abstinent and drinks per drinking day ) along with the laboratory measure of alcohol consumption ( plasma gamma-glutamyltransferase ) . RESULTS Treating all dropouts as relapse to baseline , topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 ( mean difference , 8.44 % ; 95 % confidence interval , 3.07%-13.80 % ; P = .002 ) . Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days ( mean difference , 16.19 % ; 95 % confidence interval , 10.79%-21.60 % ; P < .001 ) and all other drinking outcomes ( P < .001 for all comparisons ) . Adverse events that were more common with topiramate vs placebo , respectively , included paresthesia ( 50.8 % vs 10.6 % ) , taste perversion ( 23.0 % vs 4.8 % ) , anorexia ( 19.7 % vs 6.9 % ) , and difficulty with concentration ( 14.8 % vs 3.2 % ) . CONCLUSION Topiramate is a promising treatment for alcohol dependence . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00210925 Objective : Anticonvulsant drugs have been used in the treatment of alcohol dependence . The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence . Methods : Open-label zonisamide  was examined in 22 out patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition alcohol dependence .  Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d . Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition and the Severity of Alcohol Dependence Scale . Alcohol craving and alcohol consumption were assessed at weeks 2 , 4 , 6 , 8 , 10 , and 12 . The concentration of & ggr;-glutamyltransferase was used as an indirect measure of alcohol consumption . Results : Significant improvement was observed in visual analog scale for craving severity scores , weekly drink consumption , and & ggr;-glutamyltransferase .  Zonisamide was well tolerated , with only a dropout due to adverse events . Conclusions : Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption . A placebo-controlled study would be of interest Fifteen volunteers received cannabidiol ( CBD ) ( 320 μg/kg ) or placebo ( both orally , T0 ) , and 60 min later they consumed an ethanolic beverage ( 0.54 g/kg ) or placebo . The effects were measured at T1 ( 100 min after CBD ingestion ) , T2 ( 160 min ) and T3 ( 220 min ) using cognitive , perceptual and motor function tests . Factorial analysis indicated that test procedures could be adequately expressed by three rotated factors : A reaction speed factor ( I ) , a st and ing steadiness factor ( II ) and a psychomotor coordination/cognitive factor ( III ) . Ethanol produced a significant decrement in factor III . There was no demonstrable effect of CBD , either alone or in combination with ethanol . Neither CBD nor ethanol produced any significant effect on pulse rate . Prior administration of CBD did not significantly affect the blood ethanol levels . Whilst the subjects were able to identify correctly when they were given ethanol , they did not report any subjective effects of CBD AIM Cannabinoid receptor type 1 ( CB1 ) antagonists show central side effects , whereas beneficial effects are most likely peripherally mediated . In this study , the peripherally selective CB1 antagonist TM38837 was studied in humans . METHODS This was a double-blind , r and omized , placebo-controlled , crossover study . On occasions 1 - 4 , 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg , 500 mg or placebo , or placebos only . During occasion 5 , subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups . Blood collection s and pharmacodynamic ( PD ) effects were assessed frequently . Pharmacokinetics ( PK ) and PD were quantified using population PK-PD modelling . RESULTS The TM38837 plasma concentration profile was relatively flat compared with rimonabant . TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high , body sway and heart rate were partly antagonized by rimonabant 60 mg [ -26.70 % [ 90 % confidence interval ( CI ) -40.9 , -12.6 % ] ; -7.10 % , ( 90%CI -18.1 , 5.3 % ) ; -7.30 % , ( 90 % CI -11.5 % , -3.0 % ) respectively ] and TM38837 500 mg [ -22.10 % ( 90 % CI -34.9 , -9.4 % ) ; -12.20 % ( 90 % CI -21.6 % , -1.7 % ) ; -8.90 % ( 90 % CI -12.8 % , -5.1 % ) respectively ] . TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects . CONCLUSIONS Rimonabant showed larger effects than TM38837 , but the heart rate effects were similar . TM38837 100 mg had no impact on CNS effects , suggesting that this dose does not penetrate the brain . This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models . These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders , with a reduced propensity for psychiatric side effects BACKGROUND Topiramate , a sulphamate fructopyranose derivative , might antagonise alcohol 's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function . We aim ed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence . METHODS We did a double-blind r and omised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence . Of these 150 individuals , 75 were assigned to receive topiramate ( escalating dose of 25 - 300 mg per day ) and 75 had placebo as an adjunct to weekly st and ardised medication compliance management . Primary efficacy variables were : self-reported drinking ( drinks per day , drinks per drinking day , percentage of heavy drinking days , percentage of days abstinent ) and plasma gamma-glutamyl transferase , an objective index of alcohol consumption . The secondary efficacy variable was self-reported craving . FINDINGS At study end , participants on topiramate , compared with those on placebo , had 2.88 ( 95 % CI -4.50 to -1.27 ) fewer drinks per day ( p=0.0006 ) , 3.10 ( -4.88 to -1.31 ) fewer drinks per drinking day ( p=0.0009 ) , 27.6 % fewer heavy drinking days ( p=0.0003 ) , 26.2 % more days abstinent ( p=0.0003 ) , and a log plasma gamma-glutamyl transferase ratio of 0.07 ( -0.11 to -0.02 ) less ( p=0.0046 ) . Topiramate-induced differences in craving were also significantly greater than those of placebo , of similar magnitude to the self-reported drinking changes , and highly correlated with them . INTERPRETATION Topiramate ( up to 300 mg per day ) is more efficacious than placebo as an adjunct to st and ardised medication compliance management in treatment of alcohol dependence Objective To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol ( CBD ) in children with Dravet syndrome . Methods Patients aged 4–10 years were r and omized 4:1 to CBD ( 5 , 10 , or 20 mg/kg/d ) or placebo taken twice daily . The double-blind trial comprised 4-week baseline , 3-week treatment ( including titration ) , 10-day taper , and 4-week follow-up periods . Completers could continue in an open-label extension . Multiple pharmacokinetic blood sample s were taken on the first day of dosing and at end of treatment for measurement of CBD , its metabolites 6-OH-CBD , 7-OH-CBD , and 7-COOH-CBD , and antiepileptic drugs ( AEDs  ; clobazam and metabolite N-desmethylclobazam [ N-CLB ] , valproate , levetiracetam , topiramate , and stiripentol ) . Safety assessment s were clinical laboratory tests , physical examinations , vital signs , ECGs , adverse events ( AEs ) , seizure frequency , and suicidality . Results Thirty-four patients were r and omized ( 10 , 8 , and 9 to the 5 , 10 , and 20 mg/kg/d  CBD  groups , and 7 to placebo )  ; 32 ( 94 % ) completed treatment . Exposure to CBD and its metabolites was dose-proportional ( AUC0–t ) . CBD did not affect concomitant AED levels , apart from an increase in N-CLB ( except in patients taking stiripentol ) . The most common AEs on CBD were pyrexia , somnolence , decreased appetite , sedation , vomiting , ataxia , and abnormal behavior . Six patients taking CBD and valproate developed elevated transaminases ; none met criteria for drug-induced liver injury and all recovered . No other clinical ly relevant safety signals were observed . Conclusions Exposure to CBD and its metabolites increased proportionally with dose . An interaction with N-CLB was observed , likely related to CBD inhibition of cytochrome P450 subtype 2C19 . CBD result ed in more AEs than placebo but was generally well-tolerated . Classification of evidence This study provides Class I evidence that for children with Dravet syndrome , CBD result ed in more AEs than placebo but was generally well-tolerated BACKGROUND Patients with Lennox-Gastaut syndrome , a rare , severe form of epileptic encephalopathy , are frequently treatment resistant to available medications . No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome . We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients . METHODS In this r and omised , double-blind , placebo-controlled trial done at 24 clinical sites in the USA , the Netherl and s , and Pol and , we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome . Eligible patients ( aged 2 - 55 years ) had Lennox-Gastaut syndrome , including a history of slow ( <3 Hz ) spike- and -wave patterns on electroencephalogram , evidence of more than one type of generalised seizure for at least 6 months , at least two drop seizures per week during the 4-week baseline period , and had not responded to treatment with at least two antiepileptic drugs . Patients were r and omly assigned ( 1:1 ) using an interactive voice response system , stratified by age group , to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks . All patients , caregivers , investigators , and individuals assessing data were masked to group assignment . The primary endpoint was percentage change from baseline in monthly frequency of drop se 
    Output:
    
agent
In both rodent and cell culture models , CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus .
In rodent models , CBD was found to attenuate alcohol-induced hepatotoxicity , specifically , alcohol-induced steatosis .
Finally , findings from pre clinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking , alcohol self-administration , withdrawal-induced convulsions , and impulsive discounting of delayed rewards .
In human studies , CBD was well tolerated and did not interact with the subjective effects of alcohol .
Collectively , given its favorable effects on alcohol-related harms and addiction phenotypes in pre clinical models , CBD appears to have promise as a c and i date AUD pharmacotherapy .
This is further bolstered by the absence of abuse liability and its general tolerability .
***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: CONTEXT Hypothetically , topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol 's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system . OBJECTIVE To determine if topiramate is a safe and efficacious treatment for alcohol dependence . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , placebo-controlled , 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence , conducted between January 27 , 2004 , and August 4 , 2006 , at 17 US sites . INTERVENTIONS Up to 300 mg/d of topiramate ( n = 183 ) or placebo ( n = 188 ) , along with a weekly compliance enhancement intervention . MAIN OUTCOME MEASURES Primary efficacy variable was self-reported percentage of heavy drinking days . Secondary outcomes included other self-reported drinking measures ( percentage of days abstinent and drinks per drinking day ) along with the laboratory measure of alcohol consumption ( plasma gamma-glutamyltransferase ) . RESULTS Treating all dropouts as relapse to baseline , topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 ( mean difference , 8.44 % ; 95 % confidence interval , 3.07%-13.80 % ; P = .002 ) . Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days ( mean difference , 16.19 % ; 95 % confidence interval , 10.79%-21.60 % ; P < .001 ) and all other drinking outcomes ( P < .001 for all comparisons ) . Adverse events that were more common with topiramate vs placebo , respectively , included paresthesia ( 50.8 % vs 10.6 % ) , taste perversion ( 23.0 % vs 4.8 % ) , anorexia ( 19.7 % vs 6.9 % ) , and difficulty with concentration ( 14.8 % vs 3.2 % ) . CONCLUSION Topiramate is a promising treatment for alcohol dependence . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00210925 Objective : Anticonvulsant drugs have been used in the treatment of alcohol dependence . The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence . Methods : Open-label zonisamide  was examined in 22 out patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition alcohol dependence .  Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d . Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition and the Severity of Alcohol Dependence Scale . Alcohol craving and alcohol consumption were assessed at weeks 2 , 4 , 6 , 8 , 10 , and 12 . The concentration of & ggr;-glutamyltransferase was used as an indirect measure of alcohol consumption . Results : Significant improvement was observed in visual analog scale for craving severity scores , weekly drink consumption , and & ggr;-glutamyltransferase .  Zonisamide was well tolerated , with only a dropout due to adverse events . Conclusions : Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption . A placebo-controlled study would be of interest Fifteen volunteers received cannabidiol ( CBD ) ( 320 μg/kg ) or placebo ( both orally , T0 ) , and 60 min later they consumed an ethanolic beverage ( 0.54 g/kg ) or placebo . The effects were measured at T1 ( 100 min after CBD ingestion ) , T2 ( 160 min ) and T3 ( 220 min ) using cognitive , perceptual and motor function tests . Factorial analysis indicated that test procedures could be adequately expressed by three rotated factors : A reaction speed factor ( I ) , a st and ing steadiness factor ( II ) and a psychomotor coordination/cognitive factor ( III ) . Ethanol produced a significant decrement in factor III . There was no demonstrable effect of CBD , either alone or in combination with ethanol . Neither CBD nor ethanol produced any significant effect on pulse rate . Prior administration of CBD did not significantly affect the blood ethanol levels . Whilst the subjects were able to identify correctly when they were given ethanol , they did not report any subjective effects of CBD AIM Cannabinoid receptor type 1 ( CB1 ) antagonists show central side effects , whereas beneficial effects are most likely peripherally mediated . In this study , the peripherally selective CB1 antagonist TM38837 was studied in humans . METHODS This was a double-blind , r and omized , placebo-controlled , crossover study . On occasions 1 - 4 , 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg , 500 mg or placebo , or placebos only . During occasion 5 , subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups . Blood collection s and pharmacodynamic ( PD ) effects were assessed frequently . Pharmacokinetics ( PK ) and PD were quantified using population PK-PD modelling . RESULTS The TM38837 plasma concentration profile was relatively flat compared with rimonabant . TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high , body sway and heart rate were partly antagonized by rimonabant 60 mg [ -26.70 % [ 90 % confidence interval ( CI ) -40.9 , -12.6 % ] ; -7.10 % , ( 90%CI -18.1 , 5.3 % ) ; -7.30 % , ( 90 % CI -11.5 % , -3.0 % ) respectively ] and TM38837 500 mg [ -22.10 % ( 90 % CI -34.9 , -9.4 % ) ; -12.20 % ( 90 % CI -21.6 % , -1.7 % ) ; -8.90 % ( 90 % CI -12.8 % , -5.1 % ) respectively ] . TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects . CONCLUSIONS Rimonabant showed larger effects than TM38837 , but the heart rate effects were similar . TM38837 100 mg had no impact on CNS effects , suggesting that this dose does not penetrate the brain . This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models . These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders , with a reduced propensity for psychiatric side effects BACKGROUND Topiramate , a sulphamate fructopyranose derivative , might antagonise alcohol 's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function . We aim ed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence . METHODS We did a double-blind r and omised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence . Of these 150 individuals , 75 were assigned to receive topiramate ( escalating dose of 25 - 300 mg per day ) and 75 had placebo as an adjunct to weekly st and ardised medication compliance management . Primary efficacy variables were : self-reported drinking ( drinks per day , drinks per drinking day , percentage of heavy drinking days , percentage of days abstinent ) and plasma gamma-glutamyl transferase , an objective index of alcohol consumption . The secondary efficacy variable was self-reported craving . FINDINGS At study end , participants on topiramate , compared with those on placebo , had 2.88 ( 95 % CI -4.50 to -1.27 ) fewer drinks per day ( p=0.0006 ) , 3.10 ( -4.88 to -1.31 ) fewer drinks per drinking day ( p=0.0009 ) , 27.6 % fewer heavy drinking days ( p=0.0003 ) , 26.2 % more days abstinent ( p=0.0003 ) , and a log plasma gamma-glutamyl transferase ratio of 0.07 ( -0.11 to -0.02 ) less ( p=0.0046 ) . Topiramate-induced differences in craving were also significantly greater than those of placebo , of similar magnitude to the self-reported drinking changes , and highly correlated with them . INTERPRETATION Topiramate ( up to 300 mg per day ) is more efficacious than placebo as an adjunct to st and ardised medication compliance management in treatment of alcohol dependence Objective To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol ( CBD ) in children with Dravet syndrome . Methods Patients aged 4–10 years were r and omized 4:1 to CBD ( 5 , 10 , or 20 mg/kg/d ) or placebo taken twice daily . The double-blind trial comprised 4-week baseline , 3-week treatment ( including titration ) , 10-day taper , and 4-week follow-up periods . Completers could continue in an open-label extension . Multiple pharmacokinetic blood sample s were taken on the first day of dosing and at end of treatment for measurement of CBD , its metabolites 6-OH-CBD , 7-OH-CBD , and 7-COOH-CBD , and antiepileptic drugs ( AEDs  ; clobazam and metabolite N-desmethylclobazam [ N-CLB ] , valproate , levetiracetam , topiramate , and stiripentol ) . Safety assessment s were clinical laboratory tests , physical examinations , vital signs , ECGs , adverse events ( AEs ) , seizure frequency , and suicidality . Results Thirty-four patients were r and omized ( 10 , 8 , and 9 to the 5 , 10 , and 20 mg/kg/d  CBD  groups , and 7 to placebo )  ; 32 ( 94 % ) completed treatment . Exposure to CBD and its metabolites was dose-proportional ( AUC0–t ) . CBD did not affect concomitant AED levels , apart from an increase in N-CLB ( except in patients taking stiripentol ) . The most common AEs on CBD were pyrexia , somnolence , decreased appetite , sedation , vomiting , ataxia , and abnormal behavior . Six patients taking CBD and valproate developed elevated transaminases ; none met criteria for drug-induced liver injury and all recovered . No other clinical ly relevant safety signals were observed . Conclusions Exposure to CBD and its metabolites increased proportionally with dose . An interaction with N-CLB was observed , likely related to CBD inhibition of cytochrome P450 subtype 2C19 . CBD result ed in more AEs than placebo but was generally well-tolerated . Classification of evidence This study provides Class I evidence that for children with Dravet syndrome , CBD result ed in more AEs than placebo but was generally well-tolerated BACKGROUND Patients with Lennox-Gastaut syndrome , a rare , severe form of epileptic encephalopathy , are frequently treatment resistant to available medications . No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome . We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients . METHODS In this r and omised , double-blind , placebo-controlled trial done at 24 clinical sites in the USA , the Netherl and s , and Pol and , we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome . Eligible patients ( aged 2 - 55 years ) had Lennox-Gastaut syndrome , including a history of slow ( <3 Hz ) spike- and -wave patterns on electroencephalogram , evidence of more than one type of generalised seizure for at least 6 months , at least two drop seizures per week during the 4-week baseline period , and had not responded to treatment with at least two antiepileptic drugs . Patients were r and omly assigned ( 1:1 ) using an interactive voice response system , stratified by age group , to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks . All patients , caregivers , investigators , and individuals assessing data were masked to group assignment . The primary endpoint was percentage change from baseline in monthly frequency of drop se 
    Output:
    