(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Proctitis

There are a limited number of treatment options for people with corticosteroid-refractory ulcerative colitis. Animal models of inflammatory bowel disease and uncontrolled studies in humans suggest that tacrolimus may be an effective treatment for ulcerative colitis.. To evaluate the efficacy and safety of tacrolimus for induction of remission in people with corticosteroid-refractory ulcerative colitis.. We searched the Cochrane Gut group specialised register, CENTRAL, MEDLINE (PubMed), Embase, Clinicaltrials.gov and WHO ICTRP from inception to October 2021 to identify relevant randomised controlled trials (RCT).. Two review authors independently selected potentially relevant studies to determine eligibility based on the prespecified criteria.. Two review authors independently extracted data and analysed them using Review Manager Web. The primary outcomes were induction of remission and clinical improvement, as defined by the studies and expressed as a percentage of the participants randomised (intention-to-treat analysis).. This review included five RCTs with 347 participants who had active ulcerative colitis or ulcerative proctitis. The duration of intervention varied between two weeks and eight weeks. Tacrolimus versus placebo Tacrolimus (oral and rectal) may be superior in achieving clinical remission compared to placebo (oral and rectal) (14/87 participants with tacrolimus versus 1/61 participants with placebo; risk ratio (RR) 3.76, 95% confidence interval (CI) 1.03 to 13.73; 3 studies). These results are of low certainty due to imprecision and risk of bias. Tacrolimus (oral and rectal) may be superior for clinical improvement compared to placebo (oral and rectal) (45/87 participants with tacrolimus versus 7/61 participants with placebo; RR 4.47, 95% CI 2.15 to 9.29; 3 studies). These results are of low certainty due to imprecision and risk of bias. The evidence is very uncertain about the effects of tacrolimus (oral and rectal) on serious adverse events compared to placebo (oral and rectal) (2/87 participants with tacrolimus versus 0/61 participants with placebo; RR 2.44, 95% CI 0.12 to 48.77; 3 studies). These results are of very low certainty due to high imprecision and risk of bias. Tacrolimus versus ciclosporin One study compared oral tacrolimus to intravenous ciclosporin, with an intervention lasting two weeks and 113 randomised participants. The evidence is very uncertain about the effect of tacrolimus on achievement of clinical remission compared to ciclosporin (15/33 participants with tacrolimus versus 24/80 participants with ciclosporin; RR 1.52, 95% CI 0.92 to 2.50). The results are of very low certainty due to risk of bias and high imprecision. The evidence is very uncertain about the effect of tacrolimus on clinical improvement compared to intravenous ciclosporin (23/33 participants with tacrolimus versus 62/80 participants with ciclosporin; RR 0.90, 95% CI 0.70 to 1.16). The results are of very low certainty due to risk of bias and imprecision. Tacrolimus versus beclometasone One study compared tacrolimus suppositories with beclometasone suppositories in an intervention lasting four weeks with 88 randomised participants. There may be little to no difference in achievement of clinical remission (16/44 participants with tacrolimus versus 15/44 participants with beclometasone; RR 1.07, 95% CI 0.60 to 1.88). The results are of low certainty due to high imprecision. There may be little to no difference in clinical improvement when comparing tacrolimus suppositor. There is low-certainty evidence that tacrolimus may be superior to placebo for achievement of clinical remission and clinical improvement in corticosteroid-refractory colitis or corticosteroid-refractory proctitis. The evidence is very uncertain about the effect of tacrolimus compared to ciclosporin for achievement of clinical remission or clinical improvement. There may be no difference between tacrolimus and beclometasone for inducing clinical remission or clinical improvement. The cohorts studied to date were small, with missing data sets, offered short follow-up and the clinical endpoints used were not in line with those suggested by regulatory bodies. Therefore, no clinical practice conclusions can be made. This review highlights the need for further research that targets the relevant clinical questions, uses appropriate trial methodology and reports key findings in a systematic manner that facilitates future integration of findings with current evidence to better inform clinicians and patients. Future studies need to be adequately powered and of pertinent duration so as to capture the efficacy and effectiveness of tacrolimus in the medium to long term. Well-structured efficacy studies need to be followed up by long-term phase 4 extensions to provide key outputs and inform in a real-world setting.

Topics: Adrenal Cortex Hormones; Beclomethasone; Colitis, Ulcerative; Cyclosporine; Humans; Proctitis; Remission Induction; Suppositories; Tacrolimus

Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP.. We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test.. Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups.. In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Colitis, Ulcerative; Female; Humans; Male; Mesalamine; Proctitis; Quality of Life; Suppositories; Tacrolimus

Sixty patients with active distal ulcerative colitis participated in a multicentre randomized double-blind trial to compare the effect of a beclomethasone dipropionate (BDP) enema (3 mg/100 ml) with 5-aminosalicylic acid (5-ASA) enemas (2 g/ 100 ml) and enemas with a combination of BDP/5-ASA (3 mg/2 g/100 ml). The patients were treated for 4 weeks and the efficacy of the drugs was evaluated by sigmoidoscopy, histology and subjective symptoms after that time. The overall results after 28 days of treatment were: clinical improvement 100% (BDP/5-ASA) vs. 70% (BDP) and 76% (5-ASA); endoscopic improvement 100% (BDP/5-ASA) vs. 75% (BDP) and 71% (5-ASA); histological improvement 95% (BDP/5-ASA) vs. 50% (BDP) and 48% (5-ASA). After 4 weeks of treatment seven of 19 patients (37%) receiving BDP/5-ASA had healed endoscopically, compared with six of 20 receiving BDP (30%) and two of 21 receiving 5-ASA (10%). Two patients on 5-ASA and three on BDP had a marked deterioration during treatment. The combination of BDP and 5-ASA was significantly superior to single-agent therapy in terms of both improved sigmoidoscopic and improved histological score. No differences in improvement between the 5-ASA vs. BDP-treated patients were noticed. No side effects were seen. The results of the study show that topical treatment of active distal ulcerative colitis with either 5-ASA or BDP is equally efficacious. So far, no data on topical combination therapy have been described. However, combination therapy with BDP/5-ASA seems superior to single-agent therapy and causes no adverse reactions.

Topics: Adult; Aminosalicylic Acids; Analysis of Variance; Anti-Inflammatory Agents; Beclomethasone; Colitis, Ulcerative; Double-Blind Method; Drug Therapy, Combination; Enema; Female; Humans; Male; Middle Aged; Proctitis; Treatment Outcome

Twenty-three patients with attacks of distal ulcerative colitis were treated randomly with either 2 or 3 mg of topically administered beclomethasone dipropionate (BDP) or 30 mg of prednisolone sodium phosphate (PP). The effect of the steroid enemas on adrenocortical function was assessed by ACTH tests, which were performed before and after treatment. Endoscopic, clinical and histological scores were comparable in the three treatment groups in this pilot trial. Fasting cortisol in the PP group decreased significantly from 0.47 +/- 0.12 mumol/l before to 0.22 +/- 0.14 mumol/l (P less than 0.05) after therapy; in the BDP group no significant changes were found. Urinary cortisol excretion in the PP group was not detectable after therapy; in the BDP group no changes were found. It is concluded that in the topical treatment of ulcerative colitis, BDP may be preferable to PP because it exerts a promising anti-inflammatory action without affecting adrenocortical function.

Topics: Adult; Aged; Beclomethasone; Colitis, Ulcerative; Enema; Female; Humans; Hydrocortisone; Male; Middle Aged; Prednisolone; Proctitis

In a double-blind randomized clinical trial 18 patients with exacerbations of distal ulcerative colitis were treated for 4 weeks with enemas containing either prednisolone 21-phosphate 30 mg (PP) or beclomethasone dipropionate 1 mg (BDP) a surface-active corticosteroid. All 8 patients treated with PP showed clinical and endoscopic improvement in contrast with only 4 of 10 patients treated with BDP. Endocrinologic evaluation showed a significant decrease in morning plasma cortisol, in cortisol increase after synacthen, and in urinary free cortisol excretion after PP therapy, but no changes in these variables after BDP therapy. We conclude that PP enemas are more active in the treatment of ulcerative proctitis, but they cause a suppression of the adrenal cortex, in contrast to BDP.

Topics: Adult; Beclomethasone; Clinical Trials as Topic; Cosyntropin; Double-Blind Method; Enema; Female; Humans; Hydrocortisone; Male; Middle Aged; Prednisolone; Proctitis; Random Allocation; Ulcer

To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients.. Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids.. Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance.. Topical medications might have a role in radiation proctitis prevention.

Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Beclomethasone; Enema; Humans; Hyaluronic Acid; Italy; Male; Middle Aged; Organ Sparing Treatments; Proctitis; Prostatic Neoplasms; Radiation Dose Hypofractionation; Radiation Injuries; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Image-Guided; Radiotherapy, Intensity-Modulated; Retrospective Studies

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Drug Resistance; Female; Glucocorticoids; Humans; Male; Mesalamine; Middle Aged; Primary Health Care; Proctitis; Retrospective Studies; Young Adult

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Drug Therapy, Combination; Enema; Female; Glucocorticoids; Humans; Male; Mesalamine; Middle Aged; Proctitis