Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis

Aliment Pharmacol Ther 2011; 34: 901–910

Summary

Background There is no satisfactory medical treatment for patients with primary sclerosing cholangitis. There are conflicting data regarding the clinical benefit of high doses of ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis. Aim To evaluate using meta‐analysis, if UDCA (standard or high‐dose) is useful in primary sclerosing cholangitis. Methods We searched MEDLINE using the textwords ‘PSC’, ‘treatment’, ‘UDCA’ and retrieved all abstracts from the major Gastroenterology and Liver meetings. We included randomised clinical trials comparing standard or high‐dose of UDCA (>15 mg/kg body weight per day) vs. placebo or no intervention. End‐points: mortality or liver transplantation, pruritus, fatigue, cholangiocarcinoma and histological progression. Results We identified eight randomised clinical trials comprising 567 patients. Five used standard doses and three high doses of UDCA. There was no significant difference in mortality [OR, 0.6 (95% CI, 0.4–1.4)], in pruritus [OR, 1.5 (95% CI, 0.3–7.2)], in fatigue [OR, 0.0 (95% CI, 0.1–7.7)], in cholangiocarcinoma [OR, 1.7 (95% CI, 0.6–5.1)] and in histology stage progression [OR, 0.9 (95% CI, 0.34–2.44)]. No differences were found in the subgroup analyses. Conclusion Neither standard nor high‐dose UDCA influence favourably the progression of primary sclerosing cholangitis.     

Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis

AIM: To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL. METHODS: A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study. RESULTS: The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P < 0.05). No significant differences were observed in terms of improvement of liver enzymes related to cholestasis and cytolysis and of amelioration of pruritus. The Mayo score values increased less above the baseline values at 24 and 36 month-intervals in the UDCA/C group than in the UDCA group. Histological evaluation at baseline and at the end of the study was available for 15 patients with pre-cirrhotic stage. A significant reduction in histological grading score was observed in patients from the UDCA/C group, whereas no changes in these histological scores were observed in the UDCA group. CONCLUSIONS: The addition of colchicine to ursodeoxycholic acid in patients with symptomatic primary biliary cirrhosis results in a small but significant reduction of disease progress.     

Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel)

Aliment Pharmacol Ther 2011; 33: 235–242

Summary

Background Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. Aim To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. Methods We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ≥ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. Results Twenty patients received fenofibrate (160 mg/day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214–779) U/L at baseline vs. 177 (60–384) U/L at 48 weeks, P < 0.05]. A rebound in ALP occurred upon drug discontinuation. Serum aspartate aminotransferase and Immunoglobulin M also decreased significantly, while bilirubin and albumin remained unchanged. Median IL‐1 decreased from 28.9 (2.7–10 000) to 11.3 (2.5–277.7) pg/mL (P = 0.049), and median IL‐6 from 4.6 (3.2–5205) to 3.5 (3.2–73.4) pg/mL (P = 0.027). Heartburn was the most frequent adverse event, leading to discontinuation of two study subjects. Conclusions Combination therapy of fenofibrate and UDCA induced significant biochemical improvement in patients with primary biliary cirrhosis and incomplete response to UDCA. Further studies are warranted.     

Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival

Background Primary sclerosing cholangitis/autoimmune hepatitis (PSC/AIH) and primary biliary cirrhosis/AIH (PBC/AIH) overlap syndromes are poorly defined variants of AIH. Few large patient series exist, and there are little data on long‐term outcomes. Aim To compare presentation, clinical course and outcome of patients with PSC/AIH and PBC/AIH, with patients with definite AIH. Methods Two hundred and thirty‐eight AIH patients were compared with 10 PBC/AIH patients and 16 PSC/AIH patients presenting consecutively between 1971 and 2005 at a single centre. Results Autoimmune hepatitis patients were significantly more likely to present with jaundice (69.4% vs. 25%; P = 0.0145) than PBC/AIH patients. Median serum aspartate aminotransferase activity at presentation was higher in AIH patients compared with PBC/AIH and PSC/AIH patients respectively (620 vs. 94 vs. 224 IU/L; P < 0.05). PBC/AIH patients demonstrated no response to standard AIH therapy more frequently than AIH patients (25% vs. 0.8%; P = 0.0057). Significant reduction in survival was identified between patients with PSC/AIH and those without (hazard ratio: PSC/AIH vs. AIH = 2.08, PSC/AIH vs. PBC/AIH = 2.14; P = 0.039). Conclusions Patients with PSC/AIH have severe disease and significantly worse prognosis than patients with AIH or PBC/AIH. Recognition and close follow‐up of this cohort are warranted.     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

熊去氧胆酸对原发性硬化性胆管炎疗效的meta分析

目的　基于循证药学方法系统评价熊去氧胆酸（ursodesoxycholic acid,UDCA）对原发性硬化性胆管炎（primary sclerosing cholangitis,PSC）的疗效。方法　纳入国内外有关UDCA治疗PSC的试验,根据标准进行筛选,提取满足条件的高质量文献,采用Q检验及I²检验对纳入研究进行质量评价,用Stata 13.0进行分析。检索文献截止时间限定至2019年5月30日。结果　纳入5篇文献,共364例患者。与安慰剂组相比,UDCA组肝功能指标［碱性磷酸酶（ALP）、天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、白蛋白（ALB）和总胆红素（TBIL）］得到明显改善（SMD=-0.43,95%CI -0.65～-0.22,P<0.001;SMD=-0.90,95%CI -1.24～-0.56,P<0.001;SMD=-0.01,95%CI -0.28～0.27,P<0.001;SMD=0.00,95%CI -0.20～0.21,P<0.001;SMD=-0.31,95%CI -0.52～-0.10,P=0.001）。在免疫球蛋白（Ig）方面,UDCA能显著改善IgA（SMD=-0.02,95%CI -0.28～0.25,P=0.013）,但对IgG（SMD=-0.17,95%CI -0.44～0.09,P=0.399）和IgM（SMD=0.16,95%CI -0.11～0.42,P=0.715）无明显影响。结论　UDCA可显著改善PSC患者肝功能指标,但对免疫学相关指标无明显影响。     

Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol

Background A human betaretrovirus has been characterized from patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti‐retroviral therapy have reported significant biochemical and histological improvement. Aim To conduct a double‐blind, randomized controlled trial as a proof of principal to link infection with PBC. Methods Fifty‐nine patients with an alkaline phosphatase level >1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomized to either 300 mg zidovudine and 150 mg lamivudine b.d. or placebo for 6 months. Results None of the patients normalized alkaline phosphatase and no significant differences were observed in normalizing serum aminotransferase levels. Significant differences were observed in the anti‐viral vs. placebo arms with improvements in serial alkaline phosphatase (P < 0.04), alanine aminotransferase (P < 0.03) and aspartate aminotransferase (P < 0.04) levels as well as clinical score (P < 0.02). After 6 months, 25% of patients in the placebo arm and 4% in the anti‐viral arm had evidence of virus in serum. Conclusions The study endpoints for normalizing hepatic biochemistry were too stringent to show efficacy for zidovudine and lamivudine therapy despite the demonstrable impact on clinical and biochemical improvement. Accordingly, more potent anti‐viral regimens will be required to confirm the efficacy of anti‐viral therapy in PBC patients with human betaretrovirus infection.     

Pioglitazone in the treatment of NASH: the role of adiponectin

Background Plasma adiponectin is decreased in NASH patients and the mechanism(s) for histological improvement during thiazolidinedione treatment remain(s) poorly understood. Aim To evaluate the relationship between changes in plasma adiponectin following pioglitazone treatment and metabolic/histological improvement. Methods We measured in 47 NASH patients and 20 controls: (i) fasting glucose, insulin, FFA and adiponectin concentrations; (ii) hepatic fat content by magnetic resonance spectroscopy; and (iii) peripheral/hepatic insulin sensitivity (by double‐tracer oral glucose tolerance test). Patients were then treated with pioglitazone (45 mg/day) or placebo and all measurements were repeated after 6 months. Results Patients with NASH had decreased plasma adiponectin levels independent of the presence of obesity. Pioglitazone increased 2.3‐fold plasma adiponectin and improved insulin resistance, glucose tolerance and glucose clearance, steatosis and necroinflammation (all P < 0.01–0.001 vs. placebo). In the pioglitazone group, plasma adiponectin was significantly associated (r = 0.52, P = 0.0001) with hepatic insulin sensitivity and with the change in both variables (r = 0.44, P = 0.03). Increase in adiponectin concentration was related also to histological improvement, in particular, to hepatic steatosis (r = ?0.46, P = 0006) and necroinflammation (r = ?0.56, P < 0.0001) but importantly also to fibrosis (r = ?0.29, P = 0.03). Conclusions Adiponectin exerts an important metabolic role at the level of the liver, and its increase during pioglitazone treatment is critical to reverse insulin resistance and improve liver histology in NASH patients.     

Randomised clinical trial: the effects of amitriptyline on drinking capacity and symptoms in patients with functional dyspepsia,a double‐blind placebo‐controlled study

Aliment Pharmacol Ther 2011; 34: 638–648

Summary

Background Functional dyspepsia is one of the most prevalent (15–40%) functional gastrointestinal disorders. Antidepressants such as amitriptyline are often used in these patients, but clinical studies are currently lacking. Aim To evaluate the effect of 8 weeks of treatment with amitriptyline on drinking capacity, symptoms evoked by a standardised drink test (primary endpoint) and clinical symptoms (secondary endpoint). Methods Patients meeting the Rome III criteria for functional dyspepsia (FD) were invited to participate in a double blind, randomised, placebo‐controlled trial and were treated with either amitriptyline (12.5–50 mg) or placebo during 8 weeks. All included patients underwent a nutrient drink test before and after treatment. Drinking capacity and evoked symptoms were recorded. In addition, dyspeptic symptoms were weekly assessed using PAGI SYM (patient assessment of upper gastrointestinal symptom severity index) questionnaire. Results Thirty‐eight patients (amitriptyline n = 18, placebo n = 20; age 41 ± 2 year, 61% F) completed the study. The drinking capacity of liquid meal was not affected by either amitriptyline or placebo treatment. Postprandial symptoms were not significantly different between amitriptyline and placebo. During the entire treatment, total symptom score (0.47 points, P = 0.02) and nausea (0.86 points, P = 0.004) on PAGI SYM were significantly reduced by amitriptyline compared with placebo. Conclusions Amitriptyline did not affect drinking capacity and postprandial symptoms evoked by the drink test in FD patients. However, total clinical symptom score and nausea were reduced during 8 weeks of treatment. Our data suggest that amitriptyline particularly improves nausea in functional dyspepsia, but larger clinical trials are needed to further confirm our findings.     

Clinical trial: short‐term effects of combination of satavaptan,a selective vasopressin V2 receptor antagonist,and diuretics on ascites in patients with cirrhosis without hyponatraemia – a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 834–845

Summary

Background There is little information on the effects of vaptans in patients with cirrhosis. Aim To investigate the short‐term effects of satavaptan, a selective vasopressin V₂ receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double‐blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was ?0.36 kg (±3.03) for placebo vs. ?2.46 kg (±3.11), ?2.08 kg (±4.17) and ?2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. Conclusions The administration satavaptan for a 14‐day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

     

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial

Aliment Pharmacol Ther 2010; 32: 990–999

Summary

Background Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. Aim To evaluate once‐daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. Methods Randomized, double‐blind, placebo‐controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance <2] who took MG 1.5 g or placebo once‐daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse‐free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare. Results The percentage of relapse‐free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent‐to‐treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician’s disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse‐free duration. The incidence of adverse events was similar between groups. Conclusions Once‐daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.     

Meta‐analysis: the effects of placebo treatment on gastro‐oesophageal reflux disease

Aliment Pharmacol Ther 2010; 32: 29–42

Summary

Background There appears to be a significant placebo response rate in clinical trials for gastro‐oesophageal reflux disease. Little is known about the determinants and the circumstances associated with placebo response in the treatment of gastro‐oesophageal reflux disease (GERD). Aims To estimate the magnitude of the placebo response rate in randomized controlled trials for GERD and to identify factors that influence this response. Methods A meta‐analysis of randomized, double‐blind, placebo‐controlled trials, published in English language, which included >20 patients with GERD, treated with either a proton pump inhibitor or H₂‐receptor antagonist for at least 2 weeks. Medline, Cochrane and EMBASE databases were searched, considering only studies that reported a global response for ‘heartburn’. Results A total of 24 studies included 9989 patients with GERD. The pooled odds ratio (OR) for response to active treatment vs. placebo was 3.71 (95% CI: 2.78–4.96). The pooled estimate of the overall placebo response was 18.85% (range 2.94%–47.06%). Patients with erosive oesophagitis had a non‐significantly lower placebo response rate than patients without it (11.87% and 18.31%, respectively; P = 0.246). Placebo response was significantly lower in studies of PPI therapy vs. studies of H₂ RAs ( 14.51% vs. 24.69%, respectively; P = 0.05). Conclusions The placebo response rate in randomized controlled trials for GERD is substantial. A lower placebo response was associated with the testing of PPIs, but not the presence of erosive oesophagitis.     

Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis

Aliment Pharmacol Ther 2012; 35: 66–75

Summary

Background Thiazolidinediones (TZDs) have been used in the treatment of non‐alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically. Aim To conduct a meta‐analysis of randomised, placebo‐controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH. Methods Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters. Results Four good quality RPCTs derived from three continents were included. The meta‐analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33–3.36), 2.58 (95% CI, 1.68–3.97) and 3.39 (95% CI, 2.19–5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03–14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02–2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment. Conclusions Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo‐controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis.     

Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis

Background Intestinal microbiota manipulation, one of the pathogenetic components of inflammatory bowel disease (IBD), has become an attractive therapy for ulcerative colitis (UC). Aim To assess in children with active distal UC the effectiveness of Lactobacillus (L) reuteri ATCC 55730 enema on inflammation and cytokine expression of rectal mucosa. Methods A total of 40 patients (median age: 7.2 years range 6–18) with mild to moderate UC were enrolled in a prospective, randomised, placebo‐controlled study. They received an enema solution containing 10¹⁰ CFU of L. reuteri ATCC 55730 or placebo for 8 weeks, in addition to oral mesalazine. Clinical endoscopic and histological scores as well as rectal mucosal expression levels of IL‐10, IL‐1β, TNFα and IL‐8 were evaluated at the beginning and at the end of the trial. Results Thirty‐one patients accomplished the trial (17 males, median age 13 year, range 7–18). Mayo score (including clinical and endoscopic features) decreased significantly in the L. reuteri group (3.2 ± 1.3 vs. 8.6 ± 0.8, P < 0.01) compared with placebo (7.1 ± 1.1 vs. 8.7 ± 0.7, NS); furthermore, histological score significantly decrease only in the L. reuteri group (0.6 ± 0.5 vs. 4.5 ± 0.6, P < 0.01) (placebo: 2.9 ± 0.8 vs. 4.6 ± 0.6, NS). At the post‐trial evaluation of cytokine mucosal expression levels, IL‐10 significantly increased (P < 0.01) whereas IL‐1β, TNFα and IL‐8 significantly decreased (P < 0.01) only in the L. reuteri group. Conclusions In children with active distal ulcerative colitis, rectal infusion of L. reuteri is effective in improving mucosal inflammation and changing mucosal expression levels of some cytokines involved in the mechanisms of inflammatory bowel disease.     

Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 432–442

Summary

Background Otilonium bromide (OB) is a spasmolytic agent that blocks L‐Type Calcium channels in human colonic smooth muscle. Aim To study the efficacy of OB in symptom control in irritable bowel syndrome (IBS). Methods A total of 356 patients (46.16 ± 19 years, 71% female) with IBS participated in a double‐blind, randomised, parallel placebo‐controlled phase IV study. OB (40 mg t.d.s.) or placebo was administered for 15 weeks, and follow‐up was extended 10 additional weeks. Results Otilonium bromide (n = 179) and placebo (n = 177) groups had comparable demographics, symptom severity and IBS subtype. Both OB and placebo reduced abdominal pain and IBS symptoms. The effect of OB was significantly greater than placebo in the reduction of weekly frequency of episodes of abdominal pain at the end of treatment period (primary endpoint, ?0.90 ± 0.88 vs. ?0.65 ± 0.91, P = 0.03), reduction of abdominal bloating (?1.2 ± 1.2 vs. ?0.9 ± 1.1, P = 0.02) and global efficacy by patient assessment (1.3 ± 1.1 vs. 1.0 ± 1.1, P = 0.047). Intensity of abdominal pain, proportion of patient responders, safety and quality of life scores were similarly affected by OB and placebo. During follow‐up, the therapeutic effect of OB remained greater than placebo in terms of withdrawal rate due to symptom relapse (10% vs. 27%, P = 0.009), global efficacy of treatment and relapse‐free probability (P = 0.038). Conclusions This placebo‐controlled double‐blind study shows that otilonium bromide is safe, well tolerated and superior to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and protecting from symptom relapse in IBS. These results further confirm that patients with IBS can improve during and following treatment with otilonium bromide.

     

Clinical trial: chest pain caused by presumed gastro‐oesophageal reflux in coronary artery disease – controlled study of lansoprazole vs. placebo

Aliment Pharmacol Ther 2010; 32: 191–199

Summary

Background Gastro‐oesophageal reflux (GER) and coronary artery disease commonly co‐exist. Coronary artery disease patients may mistake GER‐induced pain for cardiac pain or GER might provoke angina. Aim To investigate if GER might contribute to nocturnal/rest chest pain among coronary artery disease patients. Methods Double‐blind placebo‐controlled crossover study investigating effect of lansoprazole on chest pain; 125 patients with angiographically proven coronary artery disease enrolled with at least one weekly episode of nocturnal/rest pain, randomized to lansoprazole 30 mg daily or placebo with crossover after 4 weeks. Symptoms recorded and QOL assessed by Nottingham Health Profile Questionnaire; ST segment depression episodes counted from 24 h electrocardiographic monitoring in final week of both periods. Statistical analysis: ANCOVA with period and carryover analysis. Results In all, 108 patients completed the study. There was a modest increase in pain‐free days on lansoprazole vs. placebo (P < 0.02), with fewer days with pain at rest (P < 0.05) and at night (P < 0.009) on lansoprazole vs. placebo, but no significant differences in ST segment depression episodes (P = 0.64). There was a trend for reduction in the ‘physical pain’ QOL domain. Conclusions Among coronary artery disease patients, lansoprazole modestly increases pain‐free days and reduces rest/nocturnal pain. As lansoprazole did not affect ST segments, this may be by suppression of GER‐provoked pain misinterpreted as angina, rather than acid‐provoked ischaemia.     

Double-blind,placebo-controlled trial of carisoprodol 250-mg tablets in the treatment of acute lower-back spasm

ABSTRACT

Purpose: The objective of this placebo-controlled trial was to determine the efficacy and safety of carisoprodol (Soma, MedPointe Pharmaceuticals, Somerset, NJ, USA), a centrally acting skeletal muscle relaxant used to treat acute, painful musculoskeletal conditions, at a dosage of 250?mg three times daily and at bedtime in patients with acute, painful muscle spasm of the lower back.

Methods: This was a 7-day, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Qualified patients were randomly assigned to treatment with carisoprodol 250-mg tablets (n = 277) or matching placebo tablets (n = 285). The coprimary efficacy endpoints were patient-rated global impression of change and patient-rated relief from starting backache scored on a 5-point rating scale. The primary analysis was on study Day 3. Four secondary endpoints were also assessed: (1) the Roland–Morris Disability Questionnaire (RMDQ), (2) time to symptom improvement, (3) patient-rated medication helpfulness, and (4) physician assessment of range of motion.

Results: Carisoprodol was significantly more effective than placebo for patient-rated global impression of change (2.24 vs. 1.70; p < 0.0001) and patient-rated relief from starting backache (1.83 vs. 1.12; p < 0.0001). Patients experienced clinical improvement with or without sedation. Onset of moderate or marked improvement was 3 days with carisoprodol compared to 6 days with placebo (?p < 0.0001). No patient discontinued treatment with carisoprodol because of drowsiness, and there were no serious adverse events or clinically significant effects on laboratory values or vital signs.

Conclusions: In this study, patients with acute muscle spasm of the lower back had significantly greater and more rapid relief from starting backache, and had improved functional status, as measured by the RMDQ, during treatment with carisoprodol 250-mg tablets compared to placebo. Patients experienced clinical improvement with or without sedation.     

熊去氧胆酸与S-腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症

目的探讨熊去氧胆酸与S-腺苷蛋氨酸联合治疗妊娠期肝内胆汁淤积症(ICP)的疗效及血生化参数变化规律。方法以84例ICP患者为研究对象,给予S-腺甘蛋氨酸静滴1 500 mg/d+熊去氧胆酸250 mg4次/d口服治疗,比较治疗前后的血生化参数。结果治疗后,ICP患者总胆汁酸、甘胆酸、总胆红素、直接胆红素、天门冬氨酸氨基转移酶降低,与治疗前比较,差异有统计学意义(P<0.01)。血浆甘胆酸水平与天门冬氨酸氨基转移酶之间呈低度正相关(r=0.29,P<0.05)。结论 S-腺甘蛋氨酸、熊去氧胆酸治疗ICP疗效良好,血生化参数是对妊娠期肝内胆汁淤积症疗效评价的实用临床指标。     

The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre

Aliment Pharmacol Ther 31 , 625–633

Summary

Background The incidence of cholangiocarcinoma is rising. Accurate predictors of survival at diagnosis are not well defined. Aim To clarify the clinical presentation and prognostic factors of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in a contemporary cohort of patients. Methods Records for consecutive patients at the University of Michigan hospital diagnosed with cholangiocarcinoma between January 2003 and April 2008 were reviewed. Results In all, 136 patients had cholangiocarcinoma (79 intra‐ and 57 extrahepatic cholangiocarcinoma). Median survival was 27.3 months–25.8 months for intrahepatic cholangiocarcinoma and 30.3 months for extrahepatic cholangiocarcinoma. Independent predictors of mortality at presentation on multivariate analysis were elevated bilirubin level (HR 1.04, 95%CI 1.01–1.07), CA 19‐9 levels >100 U/mL (HR 1.90, 95%CI 1.17–3.08) and stage of disease (HR 1.51, 95%CI 1.16–1.96). After adjusting for baseline prognostic factors, surgical therapy was associated with improved survival (HR 0.48; 95% CI 0.26–0.88). There were no significant differences regarding clinical presentation, disease stage (P = 0.98), and survival (P = 0.51) between intra‐ and extrahepatic cholangiocarcinoma. Conclusions Survival for cholangiocarcinoma remains poor with no significant difference in outcomes between intra‐ and extrahepatic cholangiocarcinoma. Stage of disease, bilirubin level and CA 19‐9 level are important prognostic factors at presentation. Surgical therapy provides similar efficacy for both tumours when adjusted for other prognostic variables.