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: Emphasis has been placed on the importance of ? , the type II error , in clinical trials and the corresponding necessity of including large numbers of subjects in a study .1 Large trials are in fashion and small trials?even when they yield statistically significant results ? are regarded with suspicion ; a small trial which does not show a conventional statistically significant difference is often thought worthless . Interpretation of the small trial has increasingly been recognised to be dangerous , and the argument that lack of a significant difference between two treatments must mean that they have equal efficacy is recognised to be false . The need for large trials is undeniable in diseases such as cancer and cardiovascular prob ? lems where earlier trials have excluded large advantages for new treatments and small differences in outcome are still clinical ly and socially important . The unfortunate consequence of the emphasis on large trials in these setting s is that small trials conducted in other diseases where only large differences in outcome are relevant have illogically become unacceptable in many people 's minds . With appropriate statistical analysis , including calculation of the confidence limits for the likely " true " difference , small controlled trials can provide clinical ly useful information . We present three such small clinical trials?none of which show Objectives : To determine the therapeutic equivalence and safety of once daily ( OD ) versus three times daily ( TID ) dosing of a total daily dose of 3 g Salofalk ( mesalazine ) granules in patients with active ulcerative colitis . Design : A r and omised , double-blind , double-dummy , parallel group , multicentre , international , phase III non-inferiority study . Setting : 54 centres in 13 countries . Patients : 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis ( clinical activity index (CAI)>4 and endoscopic index ⩾4 at baseline ) were r and omised and treated . Interventions : 8-week treatment with either 3 g OD or 1 g TID mesalazine granules . Main outcome measures : Clinical remission ( CAI⩽4 ) at study end . Results : 380 patients were evaluable for efficacy and safety by intention-to-treat ( ITT ) ; 345 for per protocol ( PP ) analysis . In the ITT population , 79.1 % in the OD group ( n = 191 ) and 75.7 % in the TID group ( n = 189 ) achieved clinical remission ( p<0.0001 for non-inferiority ) . Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group ( 86 % ; n = 97 ) versus the TID group ( 73 % ; n = 100 ; p = 0.0298 ) . About 70 % of patients in both treatment groups achieved endoscopic remission , and 35 % in the OD group and 41 % in the TID group achieved histological remission . About 80 % of all patients preferred OD dosing . Similar numbers of adverse events occurred in 55 patients ( 28.8 % ) in the OD group and in 61 patients ( 32.3 % ) in the TID group , indicating that the two dosing regimens were equally safe and well tolerated . Conclusions : OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule . With respect to the best possible adherence of patients to the treatment , OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis . Clinical Trials.gov Identifier : The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon . Seventy-six patients received active medication and 77 received a placebo .  There were 20 dropouts ( 6 in the active group and 14 in the placebo group ) during the study because of insufficient efficacy . After 6 wk of therapy , 48 of the 76 patients ( 63 % ) receiving 5-aminosalicylic acid were considered to be " much improved " by the study physician compared to 22 of the 77 patients ( 29 % ) on placebo ( p = 0.001 ) . A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy . Mean disease activity index declined 55 % for patients on 5-aminosalicylic acid and 24 % for patients on placebo ( p = 0.0001 ) . Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20 - 40 cm from the anus . Response was not affected by concurrent sulfasalazine , but patients requiring concurrent oral steroids had a diminished response . Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation . 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon Background and Aims Multiple studies have demonstrated the efficacy of aminosalicylates in maintaining remission in ulcerative colitis ( UC ) . A newer formulation of mesalamine can be administered once daily . We aim ed to examine the efficacy and tolerability of pH-dependent mesalamine for long-term maintenance , and compare the rates of medication consumption between groups over a prolonged period . Methods Subjects whose UC had been quiescent for at least 4 months , and who had been receiving mesalamine for maintenance only , were r and omized to once daily or conventional dosing for 12 months .  Disease activity and medication consumption was assessed every 3 months . The primary endpoint was the percentage of those with quiescent disease at 12 months . Results We enrolled 20 patients , 12 to once daily and 8 to conventional dosing . Six of the 12 patients ( 50 % ) in the once daily group compared with 5 of the 8 patients ( 62.5 % ) in the conventional group experienced a flare ( p = 0.31 ) . Only 5 of the 12 ( 42 % ) patients in the once daily group were adherent compared with 3 of 8 patients ( 37.5 % ) in the conventional dosing group ( p = NS ) . Median amount consumed in the once daily group was 63 % ( range 0%–100 % ) and in the conventional group 55 % ( range 0%–100 % ) , ( p > 0.5 ) . None of the adherent subjects in the once daily group experienced a flare , while 6 out of 7 ( 86 % ) who were non-adherent experienced a flare ( p < 0.01 ) . In the conventional dosing group , 1 in 3 adherent patients ( 33 % ) experienced a flare compared with 4 out of 5 ( 80 % ) in the non-adherent group ( p < 0.01 ) . Conclusion Adherence , rather than medication regimen , appeared to be important in disease outcome at 12 months Thirty-nine patients with documented active distal proctitis ( less than 20 cm ) received either 5-aminosalicylic acid ( 5-ASA ) enemas ( 2 g in 100 ml ) or suppositories 1 g b.i.d . , in a controlled study . Twenty patients received enemas , while 19 patients received suppositories , for 30 days . No difference could be observed in terms of efficacy ; however , it was the patients ' opinion that treatment with suppositories was easier than that with enemas ( p less than 0.01 ) BACKGROUND & AIMS SPD476 ( MMX mesalamine ) , a novel , once-daily mesalamine formulation , uses MMX Multi Matrix System ( MMX ) technology to delay and extend delivery of active drug throughout the colon . We performed a r and omized , double-blind , parallel-group , placebo-controlled , multicenter phase III study in patients with mild to moderately active ulcerative colitis . METHODS Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily ( n = 93 ) , 4.8 g/day given once daily ( n = 94 ) , or placebo ( n = 93 ) for 8 weeks . The primary end point was the percentage of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index score of < or = 1 , with a score of 0 for rectal bleeding and stool frequency , and at least a 1-point reduction in sigmoidoscopy score ) at week 8 . Patients with mucosal friability were not considered to have achieved this end point . RESULTS Clinical and endoscopic remission at week 8 was achieved by 34.1 % and 29.2 % of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily , respectively , versus 12.9 % receiving placebo ( P < .01 ) . MMX mesalamine was generally well-tolerated . CONCLUSIONS MMX mesalamine given once or twice daily is well-tolerated and , compared with placebo , demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis PURPOSE We conducted a prospect i ve study to determine the effects of nonadherence with mesalamine among patients with quiescent ulcerative colitis . METHODS We followed a cohort of 99 consecutive patients who had ulcerative colitis in remission for more than 6 months and who were taking maintenance mesalamine .  Medication adherence rates were calculated based on pharmacy records and a vali date d formula . Nonadherence was defined as refilling less than 80 % of prescribed medication . Patients were followed prospect ively and evaluated either in clinic or via telephone at 6 , 12 , and 24 months . The primary outcome was clinical recurrence of ulcerative colitis . Proportional hazards models were used to adjust for confounders . RESULTS At 6 months , 12 patients ( 12 % ) had clinical recurrence of disease symptoms , all of whom were nonadherent with medication . At 12 months , 19 of 86 patients had recurrent disease , 13 ( 68 % ) of whom were nonadherent . Patients who were not adherent with medication had more than a fivefold greater risk of recurrence than adherent patients ( hazard ratio = 5.5 ; 95 % confidence interval : 2.3 to 13 ; P < 0.001 ) . CONCLUSION Nonadherence with medication increases the risk of clinical relapse among patients with quiescent ulcerative colitis . Future research should be directed at behavioral interventions to improve adherence BACKGROUND & AIMS This study was conducted to assess , in a small sample , the short-term outcomes of once-daily mesalamine versus conventional dosing in maintaining quiescent ulcerative colitis ( UC ) and to assess adherence rates with both regimens . METHODS Consecutive patients were r and omly assigned to either a once-daily regimen , or they continued current conventional regimen ( twice daily or 3 times daily ) . Patients were assessed at 3 months and 6 months . At each point , a clinical symptom disease score was obtained using patient question naires , and medication rates via pharmacy data . Adherence was defined as consumption of > 80 % of prescribed medication . Information was collected by an investigator blinded to treatment regimen . RESULTS Twenty-two patients were enrolled in the study , 12 in the once-daily group ( QD ) and 10 in the conventional group ( CD ) . At 3 months , no patients had experienced a relapse . All of the patients in the QD group and 70 % of patients in the CD group were adherent ( P = 0.04 ) . The average amount of medication consumed in the QD group was significantly higher than in the CD group ( 90 % vs. 75 % , P = 0.02 ) . At 6 months , 2 patients ( 1 patient from each group ) experienced a clinical relapse ( P = 0.76 ) . Seventy-five percent vs. 70 % of patients were adherent ( P = 0.8 ) ; the amount of medication taken approached significance ( 90 % vs. 76 % , P = 0.07 ) . All patients in the QD group reported being either " very satisfied " or " satisfied " with their regimen . CONCLUSIONS In this r and omized pilot trial , patients taking once-daily mesalamine had outcomes similar to those for patients on conventional regimens . A larger trial is warranted to assess whether true differences between regimens exist OBJECTIVES : Impaired epithelial expression of peroxisome proliferator-activated receptor-γ ( PPARγ ) has been described in animal colitis models and briefly in patients with ulcerative colitis , but the functional significance in humans is not well defined . We examined PPARγ expression and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone ( a PPARγ lig and ) in patients with ulcerative colitis . METHODS : Spontaneous and rosiglitazone-mediated PPARγ and adipophillin expression ( a gene transcriptionally activated by PPARγ ) were measured by reverse transcriptase PCR in colonic biopsies and isolated epithelial cells from patients with ulcerative colitis and controls . Fourteen patients with active distal ulcerative colitis were r and omized to either rosiglitazone ( 4 mg ) or mesalazine ( 1 g ) enema treatment once daily for 14 days . RESULTS : PPARγ expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls . Adipophillin levels were decreased in parallel . Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPARγ activity in epithelial cells from inflamed mucosa in vitro . Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcer 
    Output:
    
agent
***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: Emphasis has been placed on the importance of ? , the type II error , in clinical trials and the corresponding necessity of including large numbers of subjects in a study .1 Large trials are in fashion and small trials?even when they yield statistically significant results ? are regarded with suspicion ; a small trial which does not show a conventional statistically significant difference is often thought worthless . Interpretation of the small trial has increasingly been recognised to be dangerous , and the argument that lack of a significant difference between two treatments must mean that they have equal efficacy is recognised to be false . The need for large trials is undeniable in diseases such as cancer and cardiovascular prob ? lems where earlier trials have excluded large advantages for new treatments and small differences in outcome are still clinical ly and socially important . The unfortunate consequence of the emphasis on large trials in these setting s is that small trials conducted in other diseases where only large differences in outcome are relevant have illogically become unacceptable in many people 's minds . With appropriate statistical analysis , including calculation of the confidence limits for the likely " true " difference , small controlled trials can provide clinical ly useful information . We present three such small clinical trials?none of which show Objectives : To determine the therapeutic equivalence and safety of once daily ( OD ) versus three times daily ( TID ) dosing of a total daily dose of 3 g Salofalk ( mesalazine ) granules in patients with active ulcerative colitis . Design : A r and omised , double-blind , double-dummy , parallel group , multicentre , international , phase III non-inferiority study . Setting : 54 centres in 13 countries . Patients : 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis ( clinical activity index (CAI)>4 and endoscopic index ⩾4 at baseline ) were r and omised and treated . Interventions : 8-week treatment with either 3 g OD or 1 g TID mesalazine granules . Main outcome measures : Clinical remission ( CAI⩽4 ) at study end . Results : 380 patients were evaluable for efficacy and safety by intention-to-treat ( ITT ) ; 345 for per protocol ( PP ) analysis . In the ITT population , 79.1 % in the OD group ( n = 191 ) and 75.7 % in the TID group ( n = 189 ) achieved clinical remission ( p<0.0001 for non-inferiority ) . Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group ( 86 % ; n = 97 ) versus the TID group ( 73 % ; n = 100 ; p = 0.0298 ) . About 70 % of patients in both treatment groups achieved endoscopic remission , and 35 % in the OD group and 41 % in the TID group achieved histological remission . About 80 % of all patients preferred OD dosing . Similar numbers of adverse events occurred in 55 patients ( 28.8 % ) in the OD group and in 61 patients ( 32.3 % ) in the TID group , indicating that the two dosing regimens were equally safe and well tolerated . Conclusions : OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule . With respect to the best possible adherence of patients to the treatment , OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis . Clinical Trials.gov Identifier : The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon . Seventy-six patients received active medication and 77 received a placebo .  There were 20 dropouts ( 6 in the active group and 14 in the placebo group ) during the study because of insufficient efficacy . After 6 wk of therapy , 48 of the 76 patients ( 63 % ) receiving 5-aminosalicylic acid were considered to be " much improved " by the study physician compared to 22 of the 77 patients ( 29 % ) on placebo ( p = 0.001 ) . A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy . Mean disease activity index declined 55 % for patients on 5-aminosalicylic acid and 24 % for patients on placebo ( p = 0.0001 ) . Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20 - 40 cm from the anus . Response was not affected by concurrent sulfasalazine , but patients requiring concurrent oral steroids had a diminished response . Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation . 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon Background and Aims Multiple studies have demonstrated the efficacy of aminosalicylates in maintaining remission in ulcerative colitis ( UC ) . A newer formulation of mesalamine can be administered once daily . We aim ed to examine the efficacy and tolerability of pH-dependent mesalamine for long-term maintenance , and compare the rates of medication consumption between groups over a prolonged period . Methods Subjects whose UC had been quiescent for at least 4 months , and who had been receiving mesalamine for maintenance only , were r and omized to once daily or conventional dosing for 12 months .  Disease activity and medication consumption was assessed every 3 months . The primary endpoint was the percentage of those with quiescent disease at 12 months . Results We enrolled 20 patients , 12 to once daily and 8 to conventional dosing . Six of the 12 patients ( 50 % ) in the once daily group compared with 5 of the 8 patients ( 62.5 % ) in the conventional group experienced a flare ( p = 0.31 ) . Only 5 of the 12 ( 42 % ) patients in the once daily group were adherent compared with 3 of 8 patients ( 37.5 % ) in the conventional dosing group ( p = NS ) . Median amount consumed in the once daily group was 63 % ( range 0%–100 % ) and in the conventional group 55 % ( range 0%–100 % ) , ( p > 0.5 ) . None of the adherent subjects in the once daily group experienced a flare , while 6 out of 7 ( 86 % ) who were non-adherent experienced a flare ( p < 0.01 ) . In the conventional dosing group , 1 in 3 adherent patients ( 33 % ) experienced a flare compared with 4 out of 5 ( 80 % ) in the non-adherent group ( p < 0.01 ) . Conclusion Adherence , rather than medication regimen , appeared to be important in disease outcome at 12 months Thirty-nine patients with documented active distal proctitis ( less than 20 cm ) received either 5-aminosalicylic acid ( 5-ASA ) enemas ( 2 g in 100 ml ) or suppositories 1 g b.i.d . , in a controlled study . Twenty patients received enemas , while 19 patients received suppositories , for 30 days . No difference could be observed in terms of efficacy ; however , it was the patients ' opinion that treatment with suppositories was easier than that with enemas ( p less than 0.01 ) BACKGROUND & AIMS SPD476 ( MMX mesalamine ) , a novel , once-daily mesalamine formulation , uses MMX Multi Matrix System ( MMX ) technology to delay and extend delivery of active drug throughout the colon . We performed a r and omized , double-blind , parallel-group , placebo-controlled , multicenter phase III study in patients with mild to moderately active ulcerative colitis . METHODS Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily ( n = 93 ) , 4.8 g/day given once daily ( n = 94 ) , or placebo ( n = 93 ) for 8 weeks . The primary end point was the percentage of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index score of < or = 1 , with a score of 0 for rectal bleeding and stool frequency , and at least a 1-point reduction in sigmoidoscopy score ) at week 8 . Patients with mucosal friability were not considered to have achieved this end point . RESULTS Clinical and endoscopic remission at week 8 was achieved by 34.1 % and 29.2 % of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily , respectively , versus 12.9 % receiving placebo ( P < .01 ) . MMX mesalamine was generally well-tolerated . CONCLUSIONS MMX mesalamine given once or twice daily is well-tolerated and , compared with placebo , demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis PURPOSE We conducted a prospect i ve study to determine the effects of nonadherence with mesalamine among patients with quiescent ulcerative colitis . METHODS We followed a cohort of 99 consecutive patients who had ulcerative colitis in remission for more than 6 months and who were taking maintenance mesalamine .  Medication adherence rates were calculated based on pharmacy records and a vali date d formula . Nonadherence was defined as refilling less than 80 % of prescribed medication . Patients were followed prospect ively and evaluated either in clinic or via telephone at 6 , 12 , and 24 months . The primary outcome was clinical recurrence of ulcerative colitis . Proportional hazards models were used to adjust for confounders . RESULTS At 6 months , 12 patients ( 12 % ) had clinical recurrence of disease symptoms , all of whom were nonadherent with medication . At 12 months , 19 of 86 patients had recurrent disease , 13 ( 68 % ) of whom were nonadherent . Patients who were not adherent with medication had more than a fivefold greater risk of recurrence than adherent patients ( hazard ratio = 5.5 ; 95 % confidence interval : 2.3 to 13 ; P < 0.001 ) . CONCLUSION Nonadherence with medication increases the risk of clinical relapse among patients with quiescent ulcerative colitis . Future research should be directed at behavioral interventions to improve adherence BACKGROUND & AIMS This study was conducted to assess , in a small sample , the short-term outcomes of once-daily mesalamine versus conventional dosing in maintaining quiescent ulcerative colitis ( UC ) and to assess adherence rates with both regimens . METHODS Consecutive patients were r and omly assigned to either a once-daily regimen , or they continued current conventional regimen ( twice daily or 3 times daily ) . Patients were assessed at 3 months and 6 months . At each point , a clinical symptom disease score was obtained using patient question naires , and medication rates via pharmacy data . Adherence was defined as consumption of > 80 % of prescribed medication . Information was collected by an investigator blinded to treatment regimen . RESULTS Twenty-two patients were enrolled in the study , 12 in the once-daily group ( QD ) and 10 in the conventional group ( CD ) . At 3 months , no patients had experienced a relapse . All of the patients in the QD group and 70 % of patients in the CD group were adherent ( P = 0.04 ) . The average amount of medication consumed in the QD group was significantly higher than in the CD group ( 90 % vs. 75 % , P = 0.02 ) . At 6 months , 2 patients ( 1 patient from each group ) experienced a clinical relapse ( P = 0.76 ) . Seventy-five percent vs. 70 % of patients were adherent ( P = 0.8 ) ; the amount of medication taken approached significance ( 90 % vs. 76 % , P = 0.07 ) . All patients in the QD group reported being either " very satisfied " or " satisfied " with their regimen . CONCLUSIONS In this r and omized pilot trial , patients taking once-daily mesalamine had outcomes similar to those for patients on conventional regimens . A larger trial is warranted to assess whether true differences between regimens exist OBJECTIVES : Impaired epithelial expression of peroxisome proliferator-activated receptor-γ ( PPARγ ) has been described in animal colitis models and briefly in patients with ulcerative colitis , but the functional significance in humans is not well defined . We examined PPARγ expression and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone ( a PPARγ lig and ) in patients with ulcerative colitis . METHODS : Spontaneous and rosiglitazone-mediated PPARγ and adipophillin expression ( a gene transcriptionally activated by PPARγ ) were measured by reverse transcriptase PCR in colonic biopsies and isolated epithelial cells from patients with ulcerative colitis and controls . Fourteen patients with active distal ulcerative colitis were r and omized to either rosiglitazone ( 4 mg ) or mesalazine ( 1 g ) enema treatment once daily for 14 days . RESULTS : PPARγ expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls . Adipophillin levels were decreased in parallel . Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPARγ activity in epithelial cells from inflamed mucosa in vitro . Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcer 
    Output:
    