Clinical trial: controlled,open, randomized multicentre study comparing the effects of treatment on quality of life,safety and efficacy of budesonide or mesalazine enemas in active left‐sided ulcerative colitis

Aliment Pharmacol Ther 2010; 32: 368–376

Summary

Background Therapy for active left‐sided ulcerative colitis usually involves topical application of mesalazine (mesalamine) or budesonide. Aim To compare the efficacy and safety of budesonide enema and mesalazine enema in the treatment of active left‐sided ulcerative colitis. Methods A total of 237 patients with mild–moderate ulcerative colitis were randomized open 1:1 to receive either budesonide (n = 118) or mesalazine enemas (n = 119) for 8 weeks. Efficacy variables were clinical activity index, endoscopic, histological index and IBDQ scores after 4 and 8 weeks. Results Clinical remission (intention‐to‐treat analysis) at week 4 was 63.5% for budesonide enemas and 77.2% for mesalazine enemas (P < 0.05). The respective values for the per protocol population (PP) were 59.9% examined in the budesonide group and 77.5% in the mesalazine group (P < 0.02). At the final visit (W8), clinical remission was diagnosed in the ITT analysis for 64.4% of the budesonide group and 77.4% of the mesalazine group (P < 0.05). The respective values for the PP analysis were 59.5% in the budesonide group and 75.3% in the mesalazine group (P < 0.02). Conclusions Compared with budesonide, mesalazine enema was associated with a significantly higher remission rate; this was supported by favourable trends in endoscopic, histological remission rates and the IBDQ score.     

Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis

Background: Budesonide is a new corticosteroid with high topical anti-inflammatory activity but little systemic effect. The aim of the present study was to compare the efficacy and safety of budesonide enema (2 mg/100 mL) and 5-ASA enema (mesalazine 1 g/ 100 mL) given for 4 weeks in the treatment of active distal ulcerative colitis and proctitis. Methods: Ninety-seven patients were studied in a multicentre single-blind randomized group-comparative trial. The primary efficacy variables were endoscopy and histopathology scores obtained at 0, 2 and 4 weeks. Clinical symptoms were the secondary efficacy variables. Haematology, chemistry and adverse events were the safety variables. Results: Budesonide and 5-ASA enemas both resulted in a significant improvement in endoscopy and histopathology scores but no difference could be demonstrated between the two treatment groups. There was also a significant improvement of symptoms (number of bowel movements per day, quality of stools, presence of blood and mucus, and state of well-being) within both groups but no difference between the two treatment groups. The clinical remission rate at 4 weeks was, however, 38% for patients treated with budesonide enema but 60% for those treated with 5-ASA enema (P= 0.03). No adverse events attributed to the study drugs were recorded in either of the groups. Conclusions: Budesonide enema 2 mg/100 mL appears to be as efficient and well-tolerated as 5-ASA enema in the treatment of active distal ulcerative colitis and proctitis.     

Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis

BACKGROUND: Rectal budesonide is an effective treatment of active ulcerative proctitis or proctosigmoiditis. AIM: To compare the therapeutic efficacy, tolerability and safety, and patient's preference of budesonide foam vs. budesonide enema. METHODS: Patients with active ulcerative proctitis or proctosigmoiditis (clinical activity index > 4 and endoscopic index > or = 4) were eligible for this double-blind, double-dummy, randomized, multicentre study. They received 2 mg/25 mL budesonide foam and placebo enema (n = 265), or 2 mg/100 mL budesonide enema and placebo foam (n = 268) for 4 weeks. Primary endpoint was clinical remission (clinical activity index < or = 4) at the final/withdrawal visit (per protocol). RESULTS: A total of 541 patients were randomized--533 were evaluable for intention-to-treat analysis and 449 for per protocol analysis. Clinical remission rates (per protocol) were 60% for budesonide foam and 66% for budesonide enema (P = 0.02362 for non-inferiority of foam vs. enema within a predefined non-inferiority margin of 15%). Both formulations were safe and no drug-related serious adverse events were observed. Because of better tolerability and easier application most patients preferred foam (84%). CONCLUSION: Budesonide foam is as effective as budesonide enema in the treatment of active ulcerative proctitis or proctosigmoiditis. Both budesonide formulations are safe, and most patients prefer foam.     

Pharmacokinetics of budesonide enema in patients with distal ulcerative colitis or proctitis

Pharmacokinetic data obtained after one dose of a 2-mg budesonide enema were compared with data obtained after the last dose of four weeks of daily treatment in 24 patients with active distal ulcerative colitis or proctitis. This open multicentre study involved 28 eligible patients. Sigmoidoscopy and biopsy scores improved significantly (P < 0.002) during the four-week treatment period. Maximal plasma concentration (C_max) of budesonide was 2.1 nmol/L 1.3 h after the first dose and 2.5 nmol/L 1.2 h after the last dose; the difference was not significant. The area under the curve (AUC) of plasma concentration vs. time was after the first dose 9.7 nmol h/L and after the last dose 11.6 nmol h/L (P < 0.03). The small increase in AUC may be attributed to improved absorption. During the last dose interval, minimal plasma concentration was below the limit of quantitation in most subjects. The C_max and AUC of budesonide increased slightly after four weeks of treatment, but budesonide did not accumulate. Mean morning plasma cortisol values did not change significantly during treatment (P= 0.083), although a small change in cortisol levels between the first visit (pre-treatment) and last visit was positively correlated to the C. of budesonide measured at the last visit (P= 0.012).     

磷酸铝凝胶和维生素B_（12）灌肠治疗溃疡性直肠炎的疗效观察

目的观察磷酸铝凝胶和维生素B12灌肠治疗溃疡性直肠炎的疗效。方法将56例溃疡性直肠炎患者随机分为两组,进行临床前瞻性研究,治疗组28例用磷酸铝凝胶、维生素B12及布地奈德治疗,对照组28例采用单纯布地奈德灌肠治疗。结果治疗4周,治疗组和对照组的近期治愈率和总有效率的差异均有统计学意义（P〈0.05）。结论磷酸铝凝胶和维生素B12联合布地奈德灌肠治疗溃疡性结肠炎较单纯的布地奈德有更好的疗效,为一种值得推广的治疗方法。     

Budesonide enema active haemorrhagic proctitis—a controlled trial against hydrocortisone foam enema

Background: The aim was to compare budesonide enema, 2 mg/100 mL (Entocort) and hydrocortisone acetate foam enema, 125 mg (Colifoam) in patients with active haemorrhagic proctitis. Methods: The trial was a controlled, randomized, investigator-blind study with two parallel groups. Endoscopy, histology and diary cards were used to assessed the response to therapy. Safety was assessed by laboratory tests and adverse event recording. Results: Seventy-two patients were included. Investigations were made before treatment and after 2 and 4 weeks. Both treatment groups showed statistically significant improvement in endoscopic scores but significant differences between the groups were not found. In the hydrocortisone group, plasma cortisol was significantly lowered after 4 weeks compared with budesonide. Bowel habits and quality of life variables did not differ between the treatments. The recorded adverse events were mild or moderate and may have been due to the proctitis. Conclusions: These results suggest that budesonide enema is as effective as hydrocortisone foam enema, but without the potential for side-effects associated with suppression of plasma cortisol.     

Oral versus combination mesalazine therapy in active ulcerative colitis: a double-blind, double-dummy, randomized multicentre study

BACKGROUND: Oral and topical mesalazine formulations are effective in active ulcerative colitis, but little is known on the efficacy of combined treatment. AIM: To compare the efficacy of oral mesalazine vs. combined oral and topical mesalazine in mildly to moderately active ulcerative colitis. METHODS: Patients with mildly to moderately active ulcerative colitis (Clinical Activity Index, CAI 4-12) were identified at 15 participating centres. They were randomized to receive either mesalazine 4 g orally plus placebo enema, or mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema for 6 weeks. The rate of clinical remission (CAI < 4) or clinical remission/improvement (reduction of CAI of 50% from baseline) at 6 weeks and time to clinical remission/improvement were primary end-points; the rate of endoscopic remission was a secondary end-point. RESULTS: 67 patients were assigned to oral treatment and 63 to combined treatment. One patient in the oral group and 2 in the combined group discontinued the treatment due to adverse events. Following an intention-to-treat analysis, the rate of clinical remission was 82% for oral treatment and 87% for combined treatment (P=0.56); the mean time to remission 22.2 and 20.2 days, respectively (P=0.29); the rate of clinical remission/improvement and the rate of endoscopic remission were 85% and 91% (P=0.503) and 58% and 71% (P=0.21), respectively. CONCLUSIONS: In patients with mild active ulcerative colitis, mesalazine 4 g orally and 2 g orally plus 2 g enema are equally effective in inducing disease remission.     

Beclomethasone dipropionate enemas versus prednisolone sodium phosphate enemas in the treatment of distal ulcerative colitis

Aim:

To compare beclomethasone dipropionate 3 mg/60 mL enema (BDP) and prednisolone sodium phosphate 30 mg/60mL enema (PP) once daily in patients with active distal ulcerative colitis.

Methods:

One hundred and fifty-seven patients were enrolled in a multicentre, 4-week, randomized, double-blind trial. Patients were assessed at baseline, 2 and 4 weeks.

Results:

Both treatment groups showed statistically significant improvement of clinical activity after 2 and 4 weeks. Endoscopy and biopsy showed a reduction in the activity score at the end of the treatment period in both groups. No statistically significant difference was observed between the two treatment groups. After 4 weeks, 29% of patients in the BDP group and 25% in the PP group were considered to be in clinical remission; an improvement was observed in 40% of patients on BDP and in 47% on PP. Mean morning plasma cortisol levels showed a slight but significant reduction in the PP group, while the ACTH test showed that neither drug interfered with the hypothalamic–pituitary–adrenal (HPA) axis function. No significant changes were observed in the laboratory tests. Finally, there was a low incidence of adverse events in both groups.

Conclusions:

It is concluded that, in the topical treatment of active distal ulcerative colitis, BDP 3 mg enemas are as efficacious as PP 30 mg enemas, without interference with the HPA axis.

     

A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial

BACKGROUND: A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis. AIM: To evaluate the efficacy, safety and patient tolerability of mesalazine gel enema compared with mesalazine foam enema in the treatment of patients with acute left-sided ulcerative colitis. METHODS: In a randomized multicentre investigator-blind parallel group trial, 103 patients with mild to moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50 evaluable patients) and mesalazine 2 g foam enema (n = 53 evaluable patients) for 4 weeks. Clinical symptoms, endoscopic and histological findings were assessed at entry, 2 and 4 weeks. Patients' evaluation of treatment tolerability and acceptability was assessed at 2 and 4 weeks. RESULTS: After 4 weeks of treatment, clinical remission was achieved by 76% of mesalazine gel enema-treated patients and 69% of patients treated with mesalazine foam enema (P = 0.608). Endoscopic remission rates at week 4 were 51 and 52% for the mesalazine gel and foam enemas, respectively (P = 0.925). Histological remission was achieved by 30% of patients in both groups. Patients reported that the new mesalazine gel preparation was significantly better tolerated than the foam enema. Patients in the foam group had significantly more difficulty in retention (25% vs. 6%, P < 0.05), abdominal bloating (50% vs. 26%, P < 0.005) and discomfort during administration (48% vs. 26%, P < 0.05). CONCLUSION: The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema.     

Budesonide enema in pouchitis--a double-blind, double-dummy, controlled trial

BACKGROUND: Pouchitis has been suggested to be a recurrence of ulcerative colitis in a colon-like mucosa. Topical steroids are a valid therapeutic alternative for distal forms of ulcerative colitis. AIM: To investigate the efficacy and tolerability of budesonide enema in the treatment of pouchitis compared with oral metronidazole. MATERIALS AND METHODS: Twenty-six patients with an active episode of pouchitis (defined as a pouchitis disease activity index score >or= 7) and no treatment during the previous month were randomized to receive either budesonide enema (2 mg/100 mL at bedtime) plus placebo tablets or oral metronidazole (0.5 g b.d.) plus placebo enema in a prospective, double-blind, double-dummy, 6-week, controlled trial. RESULTS: Based on the intention-to-treat principle, we detected a significant improvement in disease activity at the end of the first week with both drugs (P < 0.01). After that, improvement was moderated until stabilization at 4 weeks in both treatments. The per protocol analysis showed that both drugs had similar efficacy in terms of disease activity, clinical and endoscopic findings. Fifty-eight per cent and 50% of patients improved (decrease in pouchitis disease activity index >or= 3) with budesonide enema and metronidazole, respectively (odds ratio, 1.4; confidence interval, 0.2-8.9). Adverse effects were observed in 57% of patients given metronidazole and in 25% of patients given budesonide. CONCLUSIONS: Budesonide enemas are an alternative treatment for active pouchitis, with similar efficacy but better tolerability than oral metronidazole.     

Rectal bismuth subsalicylate as therapy for ulcerative colitis

In a prospective open study, 15 patients with ulcerative colitis which was unresponsive to conventional therapy were treated with enemas containing bismuth subsalicylate (700 or 800 mg b.d.). Nine out of the 15 patients showed a significant clinical response, and 6 had gone into complete clinical remission after 8 weeks treatment. Sigmoidoscopoic appearances of the rectal mucosa showed improvement in 9 out of 15 patients at 2 weeks, and 11 out of 15 at 8 weeks. The mucosa appeared sigmoidoscopically normal in 6 out of 15 at 8 weeks. It proved possible to reduce the oral prednisolone dosage from a median of 15 mg/day (range 10 to 35 mg/day) to 6 mg/day (range 0 to 18 mg/day) after 8 weeks of treatment; 5 patients were no longer taking oral steroids at this time. Rectal bismuth subsalicylate appears likely to be an effective therapy in ulcerative colitis and controlled trials are now required.     

A new mesalazine foam enema (Claversal Foam) compared with a standard liquid enema in patients with active distal ulcerative colitis

BACKGROUND: Rectally administered mesalazine (5-aminosalicylic acid) is a recognized therapy for distal ulcerative colitis. It is frequently applied as a liquid enema. However, there are reasons (acceptability to the patient, more uniform topical dispersion and effective adhesion) to prefer a foam-based enema. AIM: This study compared a foam enema (2 g mesalazine per day, Claversal Foam) with a standard liquid enema (4 g mesalazine per day, Salofalk enema). METHODS: Patients with active distal ulcerative colitis, diagnosed according to standardized criteria, were treated for 4 weeks. The primary goal was clinical remission; endoscopic remission, histological changes, global assessment and standard safety measures were also analysed. A major subset of the patients also provided quality-of-life data. RESULTS: Both foam and liquid enema gave good rates of clinical and endoscopic remission. The foam enema was shown to be as efficacious as the reference, even though the daily dose in the foam treatment contained only half as much active drug as in the reference treatment. Minor regional differences in efficacy were seen. The tolerabilities of the two formulations were comparable. CONCLUSIONS: The foam enema offers a safe, efficacious and acceptable treatment for distal ulcerative colitis.     

Oral budesonide in the treatment of chronic refractory pouchitis

BACKGROUND: Pouchitis is the major long-term complication after ileal-pouch nal anastomosis for ulcerative colitis. Ten to 15% of patients develop a chronic pouchitis, either treatment responsive or treatment refractory. AIM: To evaluate the efficacy of oral budesonide in inducing remission and improving quality of life in patients with chronic refractory pouchitis. METHODS: Twenty consecutive patients with active pouchitis, not responding after 1 month of antibiotic treatment were treated with budesonide controlled ileal release 9 mg/day for 8 weeks. Symptomatic, endoscopic and histological evaluations were undertaken before and after treatment according to Pouchitis Disease Activity Index. Remission was defined as a combination of Pouchitis Disease Activity Index clinical score of < or = 2, endoscopic score of < or = 1 and total Pouchitis Disease Activity Index score of < or = 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire. RESULTS: Fifteen of 20 patients (75%) achieved remission. The median total Pouchitis Disease Activity Index scores before and after therapy were, respectively, 14 (range 9-16) and 3 (range 2-10) (P < 0.001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 105 (range 77-175) to 180 (range 85-220) (P < 0.001). CONCLUSION: Eight-week treatment with oral budesonide appears effective in inducing remission in patients with active pouchitis refractory to antibiotic treatment in this open-label study.     

溃疡性结肠炎中药灌肠治疗的疗效观察及护理体会

目的观察中药灌肠配以优质护理治疗溃疡性结肠炎的疗效。方法选取我院2010年1月至2012年10月收治的溃疡性结肠炎患者104例,随机平均分为观察组52例和对照组52例,对照组采用:水杨酸偶氮磺胺嘧啶4 g,蒙脱石散3 g,加生理盐水200 mL灌肠,治疗组采用中药灌肠,疗程8周。结果对照组以及治疗组和临床总有效率为93.6%、74.2.%,两组差异比较有统计学意义(P<0.05)。结论中药灌肠治疗溃疡性结肠炎操作简单,无明显副作用,临床疗效优于单纯西医治疗组,同时有针对性的科学护理能够有效提高治疗效果。     

益生菌制剂在轻中度溃疡性结肠炎治疗中的作用

目的 观察益生菌制剂对轻、中度溃疡性结肠炎的临床疗效.方法 第一阶段将129例轻、中度溃疡性结肠炎患者随机分成治疗组(65例)和对照组(64例),分别予以益生菌和美拉沙嗪治疗,治疗12周后观察两组缓解率及缓解时间.第二阶段将缓解后91例患者随机分成治疗组(43例)和对照组(48例),分别予以益生菌和美拉沙嗪治疗,治疗12周后观察两组维持时间及复发率.结果 第一阶段两组患者治疗后缓解率及达到临床缓解时间无明显统计学差异(P＞0.05);第二阶段两组患者治疗后维持缓解时间及复发率无明显统计学差异(P＞0.05).结论 益生菌能够有效治疗轻、中度活动性溃疡性结肠炎,并有效预防复发.     

Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis

Methods: The retrograde spread of two budesonide enema formulations with different viscosities was investigated. The study design was open, randomized and two-period crossover. Three female and two male patients (age range: 35–45 years) with distal ulcerative colitis or proctitis participated. Both enema formulations contained a dose of 2 mg budesonide/100 mL. An unabsorbable radioactive marker (^99mTc-labelled human serum albumin microcolloid) was added to the enema just before administration. All doses were given in the evening with the patients lying in a supine position during the whole investigation. The intestinal spread was followed for 8 h using scintigraphic imaging. Plasma samples for budesonide assay were taken during the 12 h after administration of the low viscosity enema. Results: Budesonide plasma levels were measurable for up to 4–6 h. C_max was 2.5 nmol/L (range:0.9–4.5 nmol/L) and was attained in 1.5 h (range 1–3 h). The patients had no difficulty in retaining the enemas. There was a statistically significant difference in spread between the low and high viscosity enema. The low viscosity enema spread over an area situated between the rectum and the splenic flexure. The spread occurred mainly in the first 15 min after administration. In contrast, the high viscosity enema, in most cases, spread only over a minor part of this area and the rate and extent of spreading was also more variable with this formulation. Conclusion: The spread of a low viscosity enema appears to be well suited for the treatment of proctitis and distal colitis.     

Randomised clinical trial: herbal extract HMPL-004 in active ulcerative colitis - a double-blind comparison with sustained release mesalazine

Aliment Pharmacol Ther 2011; 33: 194–202

Summary

Background Andrographis paniculata is an herbal mixture used to treat inflammatory diseases. An extract of the herb, HMPL‐004, inhibits TNF‐α and IL‐1β, and prevents colitis in animal models. Aim To determine the efficacy and safety of HMPL‐004 in patients with mild‐to‐moderate ulcerative colitis. Methods A randomised, double‐blind, multicentre, 8‐week parallel group study was conducted using HMPL‐004 1200 mg/day compared with 4500 mg/day of slow release mesalazine (mesalamine) granules in patients with mild‐to‐moderately active ulcerative colitis. Disease activity was assessed at baseline and every 2 weeks for clinical response, and at baseline and 8 weeks by colonoscopy. Results One hundred and twenty patients at five centres in China were randomised and dosed. Clinical remission and response were seen in 21% and 76% of HMPL‐004‐treated patients, and 16% and 82% of mesalazine‐treated patients. By colonoscopy, remission and response were seen in 28% and 74% of HMPL‐004‐treated patients and 24% and 71% of mesalazine‐treated patients, respectively. There was no significant difference between the two treatment groups. Conclusion HMPL‐004 may be an efficacious alternative to mesalazine in ulcerative colitis.     

Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease

BACKGROUND: Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis. AIM: To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis. METHODS: Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score: 相似文献   

Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab

Aliment Pharmacol Ther 2011; 33: 340–348

Summary

Background The long‐term efficacy of adalimumab in patients with ulcerative colitis is not well known. Aim To evaluate the short‐ and long‐term outcomes of adalimumab in ulcerative colitis patients previously treated with infliximab. Methods Patients with active ulcerative colitis were treated with adalimumab after failure of other therapies including infliximab. Short‐term clinical response and remission were assessed at weeks 4 and 12. The proportion of patients who continued on adalimumab and the proportion of patients who remained colectomy free were assessed over the long term. Results Clinical response at weeks 4 and 12 was achieved in 16 (53%) and 18 (60%) patients, respectively, and clinical remission was obtained in 3 (10%) and 8 (27%) patients, respectively. After a mean 48 weeks’ follow‐up, 15 patients (50%) continued on adalimumab. Six patients (20%) required colectomy. All patients who achieved clinical response at week 12 were colectomy free at long term. Conclusions Adalimumab was well tolerated and induced durable clinical response in many patients with otherwise medically refractory ulcerative colitis. Patients achieving clinical response at week 12 avoided colectomy over the long term.     

Efficacy and tolerability of mesalazine foam enema (Salofalk foam) for distal ulcerative colitis: a double-blind, randomized, placebo-controlled study

BACKGROUND: Rectal formulations of mesalazine are the treatment of choice in mildly to moderately active ulcerative colitis. A new foam formulation of mesalazine was developed to improve both drug delivery and patient acceptance. METHODS: In this multicentre, randomized, double-blind, parallel-group study, 111 patients with mildly to moderately active proctitis, proctosigmoiditis, or left-sided ulcerative colitis received mesalazine foam enema or placebo enema (2 g mesalazine per day) for 6 weeks. Disease activity was monitored on the basis of the Clinical Activity Index, Endoscopic Index, Histological Index, and global efficacy assessment by the investigators. Safety assessments included the recording of adverse events, laboratory variables and vital signs. RESULTS: Clinical remission was more frequent in the mesalazine group than the placebo group (65% vs. 40%; P=0.0082), particularly in patients with mild disease and patients with proctosigmoiditis. The frequency of patients with an endoscopic remission was higher in the mesalazine group (57%) than in the placebo group (37%). Similarly, 59% of patients receiving mesalazine but only 41% of those receiving placebo showed an improved Histological Index. The foam enemas were generally well-tolerated, and no treatment-related changes on laboratory variables and vital signs were noted. CONCLUSIONS: Mesalazine foam enema was well-tolerated and was more effective than placebo in the treatment of patients with distal ulcerative colitis.