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1.
BACKGROUND & AIMS: alpha4 integrins are important mediators of leukocyte migration across vascular endothelium. This pilot placebo-controlled study aimed to assess the safety and efficacy of natalizumab, a recombinant humanized monoclonal antibody to alpha4 integrin, in patients with mild to moderately active Crohn's disease. METHODS: Thirty patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =151 and < or =450) received a 3-mg/kg infusion of natalizumab (n = 18) or placebo (n = 12) by double-blind randomization. The study's primary endpoint was change in CDAI at week 2. RESULTS: At week 2, the CDAI decreased significantly from baseline after infusion of natalizumab (mean 45 points) but not placebo (mean 11 points). Seven (39%) natalizumab-treated patients achieved remission at week 2, compared with 1 (8%) treated with placebo. In contrast, 4 (33%) of the placebo-treated patients required rescue medication by week 2, compared with 2 (11%) natalizumab-treated patients. Significant increases in circulating B and T lymphocytes were detected only after natalizumab administration. The frequency of commonly reported adverse events did not differ significantly between groups. CONCLUSIONS: A single 3-mg/kg natalizumab infusion was well tolerated by Crohn's disease patients, although the dose used may have been suboptimal. Elevated circulating lymphocyte levels after natalizumab suggest interrupted lymphocyte trafficking. Natalizumab therapy in active Crohn's disease merits further investigation.  相似文献   

2.
Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease. Methods: Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months. Results: At the end of treatment, 47% (7 of 15) of ISIS 2302–treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302–treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302–treated patients. These findings were corroborated by significant increases in β7 and αd bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period. Conclusions: ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.GASTROENTEROLOGY 1998;114:1133-1142  相似文献   

3.
BACKGROUND: We assessed the tolerability and clinical benefit of adalimumab, a human antibody to tumor necrosis factor (TNF), in patients with Crohn's disease who had previously received and responded to the chimeric anti-TNF antibody infliximab, but who no longer had a sustained response and/or tolerance to infliximab. METHODS: A total of 24 patients with Crohn's disease who had lost responsiveness or developed intolerance (acute or delayed infusion reactions) to infliximab were enrolled in a 12-wk uncontrolled trial and treated with subcutaneous adalimumab 80 mg at week 0 and then 40 mg every other week starting at week 2. After week 4, the dose could be escalated to 40 mg weekly in patients who did not achieve clinical remission, complete fistula closure, and complete steroid withdrawal. Outcome measures included the ability to tolerate adalimumab and clinical remission (defined as a Crohn's disease activity index (CDAI) score < or =150 points) and clinical response (defined as a decrease in the CDAI) > or =100 points) in patients who had a baseline CDAI score > or =220. RESULTS: None of the patients experienced acute or delayed hypersensitivity reactions during treatment with adalimumab (including 14 who previously experienced treatment-limiting acute hypersensitivity reactions and 6 who previously experienced delayed hypersensitivity reactions with infliximab). Of 17 patients with baseline CDAI scores > or =220: clinical remission occurred at weeks 4 and 12 in 2 (12%) and 5 (29%), respectively; and clinical response occurred in 7 (41%) and 10 (59%), respectively. Nineteen patients (79%) escalated their dose during weeks 4-6. CONCLUSIONS: Adalimumab is well tolerated and appears to be a clinically beneficial option for patients with Crohn's disease who have previously lost their response to, or cannot tolerate infliximab.  相似文献   

4.
Sandborn WJ  Feagan BG  Radford-Smith G  Kovacs A  Enns R  Innes A  Patel J 《Gut》2004,53(10):1485-1493
BACKGROUND: Targeting tumour necrosis factor alpha (TNF-alpha) has demonstrated efficacy in Crohn's disease. AIM: To evaluate CDP571, a humanised antibody to TNF-alpha, for treating active Crohn's disease. PATIENTS: A total of 396 patients with moderate to severe Crohn's disease. METHODS: In a 28 week, randomised, double blind, placebo controlled trial, patients received intravenous CDP571 (10 mg/kg) or placebo every eight weeks to week 24. The primary outcome measure was clinical response (a decrease in the Crohn's disease activity index (CDAI) to > or =100 points or remission (CDAI score < or =150 points)) at week 28. A secondary outcome measure was clinical response (using the same definition) at week 2. RESULTS: Clinical response occurred at week 28 in 80/263 (30.4%) CDP571 patients and 31/132 (23.5%) placebo patients (p = 0.102). Clinical response at week 2 occurred in 90/263 (34.2%) CDP571 patients and 28/132 (21.2%) placebo patients (p = 0.011). Post hoc exploratory subgroup analysis of 159 patients with baseline C reactive protein (CRP) > or =10 mg/l demonstrated significant differences between CDP571 and placebo in clinical response rates at weeks 2 (CDP571, 50/101 (49.5%); placebo, 9/58 (15.5%); p<0.001) and 28 (CDP571, 29/101 (28.7%); placebo, 7/58 (12.1%); p = 0.018). Adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: CDP571 is modestly effective for short but not long term treatment of unselected patients with moderate to severe Crohn's disease. The clinical relevance of this short term effect is unclear. Post hoc analysis suggests both short and long term efficacy of CDP571 in patients with elevated baseline CRP (> or =10 mg/l). CDP571 is well tolerated.  相似文献   

5.
BACKGROUND: Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease. MATERIALS AND METHODS: We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity. RESULTS: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%). CONCLUSIONS: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.  相似文献   

6.
BACKGROUND & AIMS: The aim of this study was to perform a meta-analysis of the efficacy results from 3 placebo-controlled multicenter clinical trials of slow-release mesalamine (Pentasa) for the acute treatment of mild to moderate Crohn's disease. METHODS: Three trials fulfilled the selection criteria (double-blind, placebo-controlled, randomized studies in adult patients treated with Pentasa 4 g/day for active Crohn's disease). The efficacy and safety was evaluated in these trials by using the Crohn's Disease Activity Index (CDAI) as the primary efficacy variable. The study duration was 16 weeks in all 3 trials. The total numbers of patients were 304 in the Pentasa 4-g/day treatment groups and 311 in the placebo groups. A meta-analysis was performed based on the study reports. RESULTS: For the intent-to-treat patients in the Pentasa groups, the overall mean reduction of the CDAI from baseline to the final visit was -63 points. The corresponding CDAI change in the placebo groups was -45 points; the net difference was -18 points. Compared with placebo, the 4-g/day dose of Pentasa was associated with a statistically significant overall improvement in the CDAI from baseline to the final visit (P = 0.04). When the meta-analysis was restricted to protocol correct patients, the effect of Pentasa became more pronounced (overall mean reduction of -83 CDAI points; P = 0.02, compared with placebo). Contrary to the consistent effects with Pentasa, the trial-specific reductions of the CDAI with placebo differed significantly between the trials. CONCLUSIONS: The meta-analysis of 3 large, double-blind, randomized studies in the treatment of active Crohn's disease confirms that Pentasa 4 g/day is superior to placebo in reducing the CDAI but the clinical significance of the magnitude of this difference is not clear.  相似文献   

7.
BACKGROUND & AIMS: Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohn's disease. METHODS: Twenty-two patients with refractory Crohn's disease (Crohn's Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all parameters of the GIS (fistula patients). RESULTS: Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). CONCLUSIONS: Thalidomide is efficacious in some patients with refractory Crohn's disease.  相似文献   

8.
Trichuris suis therapy in Crohn's disease   总被引:18,自引:0,他引:18  
BACKGROUND: Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminths diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease. AIMS: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Trichuris suis in the treatment of patients with active Crohn's disease. PATIENTS: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index (CDAI) > or =220 were enrolled in this open label study. METHODS: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100. RESULTS: At week 24, 23 patients (79.3%) responded (decrease in CDAI >100 points or CDAI <150) and 21/29 (72.4%) remitted (CDAI <150). Mean CDAI of responders decreased 177.1 points below baseline. Analysis at week 12 yielded similar results. There were no adverse events. CONCLUSIONS: This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.  相似文献   

9.
BACKGROUND & AIMS: This analysis of Crohn's disease patients treated with infliximab in ACCENT I compared episodic and scheduled treatment strategies under conditions that simulate clinical practice. METHODS: After 5 mg/kg infliximab at week 0, 573 patients were randomized to infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (episodic), infliximab 5 mg/kg at weeks 2 and 6 followed by 5 mg/kg (5 mg/kg scheduled) every 8 weeks, or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg (10 mg/kg scheduled) every 8 weeks. At or after week 14, treatment could be given with a dose of infliximab 5 mg/kg higher upon loss of response. RESULTS: The efficacy of scheduled infliximab therapy was better than episodic treatment. Crohn's Disease Activity Index (CDAI) scores were consistently significantly better in the 10 mg/kg scheduled maintenance group from weeks 10 to 54, and response and remission rates (combined scheduled) were significantly higher from weeks 10 to 30. A greater proportion of patients achieved complete mucosal healing at week 54 (P = 0.041). A lower proportion developed antibodies to infliximab in the scheduled groups than in the episodic group (9% [5 mg/kg], 6% [10 mg/kg], 28% [episodic], respectively). Scheduled strategy patients had fewer Crohn's disease-related hospitalizations (P = 0.014) and surgeries (P = 0.01) than episodic strategy patients. CONCLUSIONS: The scheduled infliximab groups, particularly the 10 mg/kg group, had better CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) responses than those in the episodic group. Both scheduled groups had fewer hospitalizations, higher rates of mucosal healing, and fewer developed antibodies than those in the episodic group, with no increase in side effects.  相似文献   

10.
AIMS: To identify predictive factors of response to infliximab in luminal Crohn's disease (CD). PATIENTS AND METHODS: All consecutive patients with luminal CD treated with infliximab between October 1999 and March 2003 in Bordeaux's referral centers were included. All had at least 3 months follow-up post infliximab infusion and no prior treatment with infliximab. Response rates were determined 2 and 8 weeks after infusion according to Crohn's Disease Activity Index (CDAI) (remission=CDAI<150 and response=CDAI decrease more than 100). RESULTS: Among 44 patients (33 female; mean age 35 +/- 14 yr.), 39 (88%) had a clinical response 2 weeks after infusion (79% in remission). At week 8, the rate of response was 61.4% and exclusive colonic involvement predicted sustained response to treatment (P=0.03). The probability of remission at 56 weeks was 21.4%. Multivariate analysis demonstrated that the only factor associated with response duration was initiating immunosuppressive (IS) therapy in women (RR=3.61 95%CI[1.25-10.41], P=0.017). CONCLUSION: Exclusive colonic involvement is the only predictive factor of sustained response to infliximab in luminal CD. At the time of infliximab infusion, initiation or modification of IS therapy may favor sustained response, at least in women.  相似文献   

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