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: Background and aims : Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis ( UC ) , while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies . Methods : Patients with refractory active UC were r and omly assigned to a high trough concentration ( 10–15 ng/ml ) group ( HT group ) ( n = 21 ) , low trough concentration ( 5–10 ng/ml ) group ( LT group ) ( n = 22 ) , or placebo group ( n = 20 ) . Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily . Efficacy was evaluated in 60 patients based on a disease activity index ( DAI ) score .  Fifty eight patients had additional treatment with tacrolimus  and were evaluated for efficacy in a 10 week open label extension . Results : An improvement in DAI score ( ⩾4 points , all categories improved ) was observed for 68.4 % of cases in the HT group compared with 10.0 % in the placebo group ( p<0.001 ) . In the HT group , 20.0 % of patients had clinical remission and 78.9 % had mucosal healing . In the open label extension , 55.2 % of all patients had an improved DAI score at week 10 . Mean dose of prednisolone  was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10 . The incidence of side effects in the HT group was significantly higher than that of the placebo group ( p = 0.043 ) . The most common event was mild finger tremor . Conclusions : Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC . The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy Background : We report a multicenter study of oral tacrolimus ( FK506 ) therapy in steroid‐refractory ulcerative colitis ( UC ) . Methods : In a placebo‐controlled , double‐blind study , 62 patients with steroid‐refractory , moderate‐to‐severe UC were r and omized into either a tacrolimus group or a placebo for 2 weeks . Patients were evaluated using the Disease Activity Index ( DAI ) . As an entry criterion , patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3 .  Clinical response was defined as improvement in all DAI subscores . Mucosal healing was defined as mucosal appearance subscore of 0 or 1 . Clinical remission was defined as a total DAI score ≤2 with an individual subscore of 0 or 1 . Results : The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group . At week 2 the clinical response rate was 50.0 % ( 16/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.003 ) . The rate of mucosal healing observed was 43.8 % ( 14/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.012 ) and the rate of clinical remission observed was 9.4 % ( 3/32 ) in the tacrolimus group and 0.0 % ( 0/30 ) in the placebo group ( P = 0.238 ) . The therapies in this study were well tolerated , with only minor side effects . Conclusions : Oral tacrolimus therapy in patients with steroid‐refractory UC shortened the acute phase and induced rapid mucosal healing . These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid‐refractory UC . ( Inflamm Bowel Dis 2011 ; BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids . We compared the efficacy and safety of these drugs for this indication . METHODS In this parallel , open-label , r and omised controlled trial , patients were aged at least 18 years , had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points , and had been given an unsuccessful course of high-dose intravenous steroids . None of the patients had previously received ciclosporin or infliximab .  Between June 1 , 2007 , and Aug 31 , 2010 , patients at 27 European centres were r and omly assigned ( via computer-derived permutation tables ; 1:1 ) to receive either intravenous ciclosporin ( 2 mg/kg per day for 1 week , followed by oral drug until day 98 ) or infliximab ( 5 mg/kg on days 0 , 14 , and 42 ) . In both groups , azathioprine was started at day 7 in patients with a clinical response . Neither patients nor investigators were masked to study treatment . The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7 , a relapse between day 7 and day 98 , absence of steroid-free remission at day 98 , a severe adverse event leading to treatment interruption , colectomy , or death . Analysis was by intention to treat . This trial is registered with EudraCT ( 2006 - 005299 - 42 ) and Clinical Trials.gov ( NCT00542152 ) . FINDINGS 115 patients were r and omly assigned ; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab .  Treatment failure occurred in 35 ( 60 % ) patients given ciclosporin and 31 ( 54 % ) given infliximab ( absolute risk difference 6 % ; 95 % CI -7 to 19 ; p=0·52 ) . Nine ( 16 % ) patients in the ciclosporin group and 14 ( 25 % ) in the infliximab group had severe adverse events .  INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids . In clinical practice , treatment choice should be guided by physician and centre experience . FUNDING Association François Aupetit , Société Nationale Française de Gastroentérologie , and the International Organization for the study of Inflammatory Bowel Disease BACKGROUND In previous comparative studies tacrolimus was superior to the st and ard formulation of ciclosporin in preventing acute rejection  after renal transplantation . We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre r and omised trial . METHODS The 6-month open study involved 560 patients in 50 European centres . 287 patients were r and omly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids .  The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8 - 10 mg/kg for ciclosporin . The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event . FINDINGS The two study groups were similar in terms of baseline characteristics . Three patients did not receive study treatment or did not undergo transplantation ( one tacrolimus , two ciclosporin ) . The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion ( 56 patients [ 19.6 % ] vs 101 [ 37.3 % ] ; 17.7 % difference [ 95 % CI 10.3 - 25.1 ] ; p<0.0001 ) . Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus ( 27 [ 9.4 % ] vs 57 [ 21.0 % ] ; 11.6 % difference [ 5.7 - 17.5 ] ; p<0.0001 ) . Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 ( 0.3 % ) tacrolimus-group patients and 27 of 271 ( 10.0 % ) ciclosporin-group patients ( p<0.0001 ) . There were no significant differences in survival of patients or grafts or in renal function . The overall frequency of adverse events was similar in the two groups , though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group . INTERPRETATION Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile BACKGROUND There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago . In an uncontrolled study , 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy . METHODS We conducted a r and omized , double-blind , controlled trial in which cyclosporine ( 4 mg per kilogram of body weight per day ) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy .  A response to therapy was defined as an improvement in a numerical symptom score ( 0 indicated no symptoms , and 21 severe symptoms ) leading to discharge from the hospital and treatment with oral medications . Failure to respond to therapy result ed in colectomy , but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine . RESULTS Nine of 11 patients ( 82 percent ) treated with cyclosporine had a response within a mean of seven days , as compared with 0 of 9 patients who received placebo ( P < 0.001 ) . The mean clinical -activity score fell from 13 to 6 in the cyclosporine group , as compared with a decrease from 14 to 13 in the placebo group . All five patients in the placebo group who later received cyclosporine therapy had a response . CONCLUSIONS Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis , whereas the experience with FK506 is limited . In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative ( n = 33 ) or indeterminate ( n = 5 ) colitis .  FK506 was started intravenously in the first group ( n = 18 ) at a dose of 0.01 to 0.02 mg/kg up to 14 days , followed by 0.1 to 0.2 mg/kg orally , or was started orally at this dose in a second group ( n = 20 ) . Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients , followed by a dose reduction of FK506 . Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety . Primary objectives were the induction of remission ( Truelove index of mild ) and colectomy-free survival . Treatment lasted for a mean of 7.6 months , and the mean observation period was 16.2 months . Eighteen of 38 patients improved within 14 days , and a complete remission was achieved in 13 patients after 1 month . A colectomy within 1 month was performed in 3 of 38 patients . The overall colectomy rate was 34 % . One-half of the patients with a minimum follow-up of 2 years required a colectomy . Intravenous and per oral administration were equally safe and effective . The most frequent adverse events included tremor , hyperglycemia , hypertension , and infection , but none were severe . Renal impairment was rare and subsided upon drug withdrawal . In conclusion , FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration BACKGROUND The medical management of refractory ulcerative colitis ( UC ) remains a significant challenge . Two r and omised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC . However , the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain . AIMS This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC . METHODS A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed . Clinical outcomes were assessed at six months , at the end of tacrolimus treatment , or at the last follow-up for patients continuing tacrolimus treatment . Modified Truelove-Witts score ( mTW ) and Mayo endoscopy subscores were calculated . RESULTS 25 patients with UC , treated with oral tacrol 
    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: Background and aims : Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis ( UC ) , while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies . Methods : Patients with refractory active UC were r and omly assigned to a high trough concentration ( 10–15 ng/ml ) group ( HT group ) ( n = 21 ) , low trough concentration ( 5–10 ng/ml ) group ( LT group ) ( n = 22 ) , or placebo group ( n = 20 ) . Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily . Efficacy was evaluated in 60 patients based on a disease activity index ( DAI ) score .  Fifty eight patients had additional treatment with tacrolimus  and were evaluated for efficacy in a 10 week open label extension . Results : An improvement in DAI score ( ⩾4 points , all categories improved ) was observed for 68.4 % of cases in the HT group compared with 10.0 % in the placebo group ( p<0.001 ) . In the HT group , 20.0 % of patients had clinical remission and 78.9 % had mucosal healing . In the open label extension , 55.2 % of all patients had an improved DAI score at week 10 . Mean dose of prednisolone  was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10 . The incidence of side effects in the HT group was significantly higher than that of the placebo group ( p = 0.043 ) . The most common event was mild finger tremor . Conclusions : Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC . The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy Background : We report a multicenter study of oral tacrolimus ( FK506 ) therapy in steroid‐refractory ulcerative colitis ( UC ) . Methods : In a placebo‐controlled , double‐blind study , 62 patients with steroid‐refractory , moderate‐to‐severe UC were r and omized into either a tacrolimus group or a placebo for 2 weeks . Patients were evaluated using the Disease Activity Index ( DAI ) . As an entry criterion , patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3 .  Clinical response was defined as improvement in all DAI subscores . Mucosal healing was defined as mucosal appearance subscore of 0 or 1 . Clinical remission was defined as a total DAI score ≤2 with an individual subscore of 0 or 1 . Results : The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group . At week 2 the clinical response rate was 50.0 % ( 16/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.003 ) . The rate of mucosal healing observed was 43.8 % ( 14/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.012 ) and the rate of clinical remission observed was 9.4 % ( 3/32 ) in the tacrolimus group and 0.0 % ( 0/30 ) in the placebo group ( P = 0.238 ) . The therapies in this study were well tolerated , with only minor side effects . Conclusions : Oral tacrolimus therapy in patients with steroid‐refractory UC shortened the acute phase and induced rapid mucosal healing . These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid‐refractory UC . ( Inflamm Bowel Dis 2011 ; BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids . We compared the efficacy and safety of these drugs for this indication . METHODS In this parallel , open-label , r and omised controlled trial , patients were aged at least 18 years , had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points , and had been given an unsuccessful course of high-dose intravenous steroids . None of the patients had previously received ciclosporin or infliximab .  Between June 1 , 2007 , and Aug 31 , 2010 , patients at 27 European centres were r and omly assigned ( via computer-derived permutation tables ; 1:1 ) to receive either intravenous ciclosporin ( 2 mg/kg per day for 1 week , followed by oral drug until day 98 ) or infliximab ( 5 mg/kg on days 0 , 14 , and 42 ) . In both groups , azathioprine was started at day 7 in patients with a clinical response . Neither patients nor investigators were masked to study treatment . The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7 , a relapse between day 7 and day 98 , absence of steroid-free remission at day 98 , a severe adverse event leading to treatment interruption , colectomy , or death . Analysis was by intention to treat . This trial is registered with EudraCT ( 2006 - 005299 - 42 ) and Clinical Trials.gov ( NCT00542152 ) . FINDINGS 115 patients were r and omly assigned ; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab .  Treatment failure occurred in 35 ( 60 % ) patients given ciclosporin and 31 ( 54 % ) given infliximab ( absolute risk difference 6 % ; 95 % CI -7 to 19 ; p=0·52 ) . Nine ( 16 % ) patients in the ciclosporin group and 14 ( 25 % ) in the infliximab group had severe adverse events .  INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids . In clinical practice , treatment choice should be guided by physician and centre experience . FUNDING Association François Aupetit , Société Nationale Française de Gastroentérologie , and the International Organization for the study of Inflammatory Bowel Disease BACKGROUND In previous comparative studies tacrolimus was superior to the st and ard formulation of ciclosporin in preventing acute rejection  after renal transplantation . We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre r and omised trial . METHODS The 6-month open study involved 560 patients in 50 European centres . 287 patients were r and omly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids .  The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8 - 10 mg/kg for ciclosporin . The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event . FINDINGS The two study groups were similar in terms of baseline characteristics . Three patients did not receive study treatment or did not undergo transplantation ( one tacrolimus , two ciclosporin ) . The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion ( 56 patients [ 19.6 % ] vs 101 [ 37.3 % ] ; 17.7 % difference [ 95 % CI 10.3 - 25.1 ] ; p<0.0001 ) . Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus ( 27 [ 9.4 % ] vs 57 [ 21.0 % ] ; 11.6 % difference [ 5.7 - 17.5 ] ; p<0.0001 ) . Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 ( 0.3 % ) tacrolimus-group patients and 27 of 271 ( 10.0 % ) ciclosporin-group patients ( p<0.0001 ) . There were no significant differences in survival of patients or grafts or in renal function . The overall frequency of adverse events was similar in the two groups , though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group . INTERPRETATION Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile BACKGROUND There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago . In an uncontrolled study , 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy . METHODS We conducted a r and omized , double-blind , controlled trial in which cyclosporine ( 4 mg per kilogram of body weight per day ) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy .  A response to therapy was defined as an improvement in a numerical symptom score ( 0 indicated no symptoms , and 21 severe symptoms ) leading to discharge from the hospital and treatment with oral medications . Failure to respond to therapy result ed in colectomy , but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine . RESULTS Nine of 11 patients ( 82 percent ) treated with cyclosporine had a response within a mean of seven days , as compared with 0 of 9 patients who received placebo ( P < 0.001 ) . The mean clinical -activity score fell from 13 to 6 in the cyclosporine group , as compared with a decrease from 14 to 13 in the placebo group . All five patients in the placebo group who later received cyclosporine therapy had a response . CONCLUSIONS Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis , whereas the experience with FK506 is limited . In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative ( n = 33 ) or indeterminate ( n = 5 ) colitis .  FK506 was started intravenously in the first group ( n = 18 ) at a dose of 0.01 to 0.02 mg/kg up to 14 days , followed by 0.1 to 0.2 mg/kg orally , or was started orally at this dose in a second group ( n = 20 ) . Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients , followed by a dose reduction of FK506 . Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety . Primary objectives were the induction of remission ( Truelove index of mild ) and colectomy-free survival . Treatment lasted for a mean of 7.6 months , and the mean observation period was 16.2 months . Eighteen of 38 patients improved within 14 days , and a complete remission was achieved in 13 patients after 1 month . A colectomy within 1 month was performed in 3 of 38 patients . The overall colectomy rate was 34 % . One-half of the patients with a minimum follow-up of 2 years required a colectomy . Intravenous and per oral administration were equally safe and effective . The most frequent adverse events included tremor , hyperglycemia , hypertension , and infection , but none were severe . Renal impairment was rare and subsided upon drug withdrawal . In conclusion , FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration BACKGROUND The medical management of refractory ulcerative colitis ( UC ) remains a significant challenge . Two r and omised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC . However , the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain . AIMS This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC . METHODS A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed . Clinical outcomes were assessed at six months , at the end of tacrolimus treatment , or at the last follow-up for patients continuing tacrolimus treatment . Modified Truelove-Witts score ( mTW ) and Mayo endoscopy subscores were calculated . RESULTS 25 patients with UC , treated with oral tacrol 
    Output:
    