***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: OBJECTIVES --To establish , in a double blind manner , the antiparkinsonian effects of repeated dosing with entacapone , a peripheral COMT inhibitor . METHODS --A one month , cross over study was conducted . During the two four-week treatment periods , entacapone ( 200 mg ) or placebo was given with each levodopa dose four to 10 times daily . Motor responses were repeatedly quantified using the motor part of UPDRS . Plasma levodopa and its metabolites were measured . RESULTS --Entacapone prolonged the availability of levodopa in the plasma and thus to the brain by decreasing its peripheral O-methylation and slowing its elimination rate , without affecting the maximum plasma levodopa concentration or the time to maximum concentration . Corresponding with the pharmacokinetic findings , entacapone prolonged the duration of motor response to an individual levodopa/DDC inhibitor dose by 34 minutes ( 24 % , P = 0.001 ) and dyskinesiae by 39 minutes ( 37 % , P = 0.002 ) compared with placebo , without affecting their magnitude or starting time . Entacapone treatment result ed in a reduction of 16 % in the mean total daily levodopa dose due to dyskinesiae . Also , according to the home diaries , the mean daily " on " time increased by 2.1 hours compared with placebo , despite the lowered mean levodopa intake . CONCLUSION --The efficacy of repeated entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson 's disease with levodopa related fluctuations is verified To evaluate the long-term effects of entacapone on both mean daily ' on ' time and health-related quality of life ( QoL ) in patients with Parkinson 's disease ( PD ) experiencing ' end-of-dose ' motor fluctuations and the benefits of an early therapeutic intervention . A prospect i ve , multicenter , observational , 12-month study was performed with an initial 3-month intervention phase , consisting of a phone call to half of the patients from r and omly selected investigators to assess if dose adjustment was necessary . Effectiveness was determined by home diaries ( ' on ' time ) , subscales II and III of the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , and the Parkinson 's Disease Question naire ( PDQ-8 ) . After 3 months of treatment , 4.0 % of the intervention group patients discontinued the study , versus 18.4 % in the control group ( P < 0.01 ) . The improvement in ' on ' time was significantly increased since the 3-month visit ( 21 % , P < 0.0001 ) until the end of the study ( 23 % at 12 months , P < 0.0001 ) . Entacapone also induced significant reductions in the UPDRS scores for subscales II and III and in the PDQ-8 score . 11.2 % of patients experienced at least one adverse reaction . This study confirms the effectiveness of entacapone in reducing motor fluctuations by increasing ' on ' time , and in improving QoL of PD patients .  An early adjustment of entacapone and levodopa doses reduces the number of treatment discontinuations during the first months of treatment Summary The effects of tolcapone , a catechol-O-methyltransferase inhibitor , on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson 's disease ( PD ) , 8 of whom showed signs of daily motor fluctuations ( wearing-off phenomenon ) . Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson 's Disease Rating Scale ( UPDRS ) . The UPDRS score was improved at all points of determination . Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination . The area under the curve ( AUC ) for levodopa increased by 34 % ( p=0.0059 ) after the administration of tolcapone . The elimination half-life ( T1/2 ) of levodopa was significantly prolonged by 81 % ( p=0.0001 ) after the treatment . The AUC of 3-O-methyldopa , a metabolite of levodopa , was decreased by 79 % ( p=0.0001 ) and the Cmax ( maximum concentration ) was also decreased by 80 % after the administration ( p=0.0001 ) of tolcapone . The combination of tolcapone and levodopa was well tolerated . Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients . It is suggested that tolcapone may be a useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena Objectives To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone ( LCE ) and levodopa/carbidopa ( LC ) . Methods Open-label , r and omized , two-period , active-controlled , cross-over study with four dosing regimens : groups I and II ( healthy volunteers and Parkinson ’s disease patients )  received levodopa 100 mg or 150 mg four times daily , respectively , and groups III and IV ( healthy volunteers )  received the same strengths of levodopa five times daily . Pharmacokinetic ( PK ) parameters determined for levodopa included Cmin , Cmax , Cmax − Cmin , AUC , t1/2 , and tmax . Results In healthy volunteers and PD patients  , mean trough levels ( Cmin ) , Cmax , and AUC of levodopa were , in general , significantly higher during LCE compared to LC administration . Compared to Cmin , Cmax , and AUC , differences between the treatments in variability of levodopa concentrations ( Cmax − Cmin ) were less consistent . Conclusions The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson ’s disease using similar dosing regimens Summary . Objectives : To evaluate the tolerability , safety and efficacy of Stalevo ® ( carbidopa , levodopa and entacapone ) in Parkinson ’s disease ( PD ) . Background : Levodopa provides the most effective symptom control for the treatment of Parkinson ’s disease ( PD ) . However , its long-term use is limited by the development of motor complications such as wearing-off . Catechol-O-methyltransferase ( COMT ) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce ‘ off ’ time . Stalevo is a new levodopa product that combines carbidopa , levodopa and entacapone in one tablet . Clinical studies have not been reported with this compound . Design methods : An open-label , multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off , with ( n = 39 ) and without ( n = 130 ) mild dyskinesia . Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks . Assessment s included tolerability measures , adverse events profile , the disease-specific quality of life instrument PDQ-39 , UPDRS parts II , III , and question 39 and investigator and patient global clinical assessment s. Results : 14 subjects ( 8 % ) discontinued treatment with Stalevo , of which 12 ( 7 % ) were due to adverse events . 11/130 ( 8.5 % ) subjects developed new onset dyskinesia and 17/39 ( 43.6 % ) of patients with existing dyskinesia reported a worsening in their dyskinesia . However , this was managed by a change in dose in 21.4 % of patients and in another 10.7 % dyskinesias resolved without any need for dose adjustment . Other side effects were infrequent and mild , the most common being nausea ( 12.4 % ) dizziness ( 6.5 % ) and somnolence ( 6.5 % ) . Stalevo treatment result ed in significant improvements in PDQ-39 and UPDRS ( II + III ) scores ( p < 0.001 ) . Assessment of ‘ off ’ time demonstrated a reduction in off time in 32 % of patients , compared with an increase in 7 % of patients . Improvements were noted by both investigator ( 68.1 % ) and patient ( 68.6 % ) assessment s. Conclusions : Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe , well tolerated and result ed in clinical improvement This double-blind study examined the efficacy and safety of replacing entacapone with tolcapone in fluctuating Parkinson 's disease ( PD ) patients . Patients receiving entacapone for > or = 15 days were r and omly assigned to continue  entacapone ( n = 75 ) or  switch to tolcapone ( n = 75 ) and were followed up for 3 weeks . Efficacy measures included changes in on time ( without disabling dyskinesia ) and an investigator 's global assessment ( IGA ) . The on time increased by > or = 1 hour/day ( primary efficacy measure ) in 43 % of entacapone-treated patients and 53 % of tolcapone-treated patients , and by > or =3 hours/day in 13 % and 25 % , respectively . The IGA indicated moderate/marked improvements in 25 % of entacapone patients and 39 % receiving tolcapone .  Response rates ( the proportion of patients with > or = 1 hour/day increase in on time and improvements on IGA ) were 17 % with entacapone and 32 % with tolcapone .  Dyskinesia was the most common adverse event affecting 29 % of entacapone and 31 % of tolcapone recipients . One patient in each group had elevated liver enzymes , result ing in treatment withdrawal ( levels returned to normal thereafter in both cases ) . In conclusion , within the limits of the protocol , there was a tendency for tolcapone to offer enhanced efficacy in patients with fluctuating PD , despite optimized entacapone therapy . Tolcapone can be considered , therefore , for patients whose motor fluctuations are inadequately controlled by their existing regimen We performed a 39-week , r and omized , double-blind , multicenter study to compare the efficacy , safety , and tolerability of levodopa/carbidopa/entacapone ( LCE , Stalevo ) with levodopa/carbidopa ( LC , Sinemet IR ) in patients with early Parkinson 's disease ( PD ) . Four hundred twenty-three patients with early PD warranting levodopa were r and omly assigned to treatment with LCE 100/25/200 or LC 100/25 three-times daily . The adjusted mean difference in total Unified Parkinson 's disease Rating Scale ( UPDRS ) Parts II and III between groups using the analysis of covariance model ( prespecified primary outcome measure ) was 1.7 ( st and ard error = 0.84 ) points favoring LCE ( P = 0.045 ) . Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living ( ADL ) scores ( P = 0.025 ) , Schwab and Engl and ADL scores ( blinded rater , P = 0.003 ; subject , P = 0.006 ) and subject-reported Clinical Global Impression ( CGI ) scores ( P = 0.047 ) . There was no significant difference in UPDRS Part III or investigator-rated CGI scores . Wearing-off was observed in 29 ( 13.9 % ) subjects in the LCE group and 43 ( 20.0 % ) in the LC group ( P = 0.099 ) . Dyskinesia was observed in 11 ( 5.3 % ) subjects in the LCE group and 16 ( 7.4 % ) in the LC group ( P = 0.367 ) . Nausea and diarrhea were reported more frequently in the LCE group . LCE provided greater symptomatic benefit than LC and did not increase motor complications We aim ed to investigate whether treatment with levodopa/carbidopa/entacapone when compared with levodopa/carbidopa improves quality of life in Parkinson 's disease ( PD ) patients with no or minimal , nondisabling motor fluctuations . This is a multicenter , r and omized , double-blind study . One hundred eighty-four patients on 3 to 4 equal doses of 100/25 to 200/50 mg levodopa/carbidopa or levodopa/benserazide , 0 to 3 hours of nondisabling OFF time over a 48 hour period and no dyskinesia were r and omized to levodopa/carbidopa/entacapone or levodopa/carbidopa treatment for 12 weeks . The primary outcome measure was quality of life as assessed by the PDQ-8 . Secondary outcome measures were the UPDRS parts I-IV , and the Wearing Off Card . Treatment with levodopa/carbidopa/entacapone result ed in significantly greater improvements in PDQ-8 scores compared to treatment with levodopa/carbidopa ( mean difference 1.4 points , P = 0.021 ) . Statistically significant improvements were seen predominantly in nonmotor domains ( depression , personal relationships , communication , stigma , all 
    Output:
    
RESULTS All these 3 drugs have proved to be effective in improving wearing-off and significantly reduce the daily dose of levodopa at the number of daily intakes .
Tolcapone is undoubtedly the most effective drug , although in clinical practice sporadic cases of hepatotoxicity have limited its use in patients unresponsive to entacapone .
Nebicapone is effective , and its safety is still under evaluation .
Entacapone is generally well tolerated , and no significant adverse events are reported .
Tolcapone is used as a second choice in patients with severe motor fluctuations not responsive to entacapone