Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized,double-blind,placebo-controlled study

Background and AimsBile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohn's disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM-associated diarrhea in CD patients in a randomized, double-blind, placebo-controlled study.MethodsThe primary endpoint was the proportion of patients with > 30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life.Results26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD = .394, 95%CI:[− 0.012; 0.706]; P = .0566). In the per-protocol analysis (n = 22), the risk difference was statistically significant (RD = .470, 95%CI:[0.018; 0.788], P(H₀: RD = 0) = 0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam-treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P = 0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P = 0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P = 0.003).ConclusionsWe found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency.ClinicalTrials.gov number: NCT01203254.     

Studies of cholesterol and bile acid metabolism, and early atherogenesis in hamsters fed GT16-239, a novel bile acid sequestrant (BAS)

The purpose of this study was to compare the efficacy of GT16-239, an alkylated, cross-linked poly(allylamine) bile acid sequestrant with cholestyramine on cholesterol and bile acid metabolism, and early aortic atherosclerosis in hypercholesterolemic male F1B Golden Syrian hamsters. In this controlled study, 42 hamsters were divided into six groups and were fed a chow-based hypercholesterolemic diet supplemented with a 10% oil blend (55% coconut/45% corn), 0.1% cholesterol (w/w) (control) and either 0.9 or 1.2% cholestyramine or 0.2, 0.4 or 0.6% GT16-239 for 13 weeks. Laboratory analyses included evaluating plasma lipoprotein cholesterol and triglyceride concentrations, hepatic HMG-CoA reductase and 7 α-hydroxylase activities, fecal excretion of bile acids and neutral sterols, hepatic cholesterol concentrations, and early atherosclerosis (aortic fatty streak area). Relative to the control diet, the 0.6% GT16-239 versus the 1.2% cholestyramine significantly inhibited the elevation of plasma lipoprotein total cholesterol (TC) (−69% vs −40%), high density lipoprotein-cholesterol (HDL-C) (−49% vs −30%), and non-HDL-C (−81% vs −48%) concentrations; increased the activities of both HMG-CoA reductase (1492% vs 62%) and 7 α-hydroxylase (175% vs 86%); lowered the concentration of hepatic cholesteryl ester (−94% vs −59%); increased fecal cholesterol concentration (+28% vs −10%); and decreased aortic fatty streak area (−100% vs −86%). Unexpected findings of this comparison were increased fecal concentrations of cholic acid (533%) and chenodeoxycholic acid (400%) and the reduction in lithocholic acid (−50%) in the 0.6% GT16-239 compared to the 1.2% cholestyramine group. In summary, GT16-239 had a greater impact on cholesterol metabolism and early atherosclerosis in hypercholesterolemic hamsters than cholestyramine.     

普芦卡必利治疗慢性便秘的中国多中心随机、双盲、安慰剂对照临床研究

目的 评价普芦卡必利(2 mg,每日1次)对中国慢性便秘患者的疗效及安全性.方法 采用多中心、随机、双盲、安慰剂对照方法进行Ⅲ期临床研究,慢性便秘患者连续12周每日口服1次普芦卡必利(2 mg)或安慰剂.主要疗效指标为12周治疗期间平均每周完全自发排便(SCBM)≥3次的受试者比例.关键次要疗效指标为治疗前4周内平均每周完全自发排便(SCBM)≥3次的受试者比例.其他次要疗效指标包括每周平均SCBM次数、首次服药后出现第1次SCBM所需的时间、平均每周使用比沙可啶成灌肠剂的天数,并通过比较治疗前后PAC-SYM评分及PAC-QOL评分的变化评价患者的症状及生活质量改善情况.观察不良反应、实验室检查及心血管事件等安全性指标.结果 共筛选受试者446例,其中313例患者接受治疗,295例患者完成研究.治疗12周时,普芦卡必利组平均每周SCBM≥3次者的比例为39.4％,明显高于安慰剂组(12.7％,x2=29.50,P＜0.01).治疗4周时,普芦卡必利组平均每周SCBM≥3次者的比例为40.0％,明显高于安慰剂组(13.3％,x2=28.58,P＜0.01).患者总体症状及生活质量改善方面,普芦卡必利组优于安慰剂组.治疗期间常见的不良反应为腹泻、恶心、腹痛及头痛,基本为轻至中度,持续数天后即缓解.结论 普芦卡必利能显著且持续改善肠道功能,有效改善慢性便秘患者的相关症状,用以治疗中国慢性便秘患者安全、有效.     

Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials

To evaluate the evidence for the use of probiotics in the prevention of acute diarrhoea, we did a meta-analysis of the available data from 34 masked, randomised, placebo-controlled trials. Only one trial was community based and carried out in a developing country. Most of the remaining 33 studies were carried out in a developed country in a health-care setting. Evaluating the evidence by types of acute diarrhoea suggests that probiotics significantly reduced antibiotic-associated diarrhoea by 52% (95% CI 35-65%), reduced the risk of travellers' diarrhoea by 8% (-6 to 21%), and that of acute diarrhoea of diverse causes by 34% (8-53%). Probiotics reduced the associated risk of acute diarrhoea among children by 57% (35-71%), and by 26% (7-49%) among adults. The protective effect did not vary significantly among the probiotic strains Saccharomyces boulardii, Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus bulgaricus, and other strains used alone or in combinations of two or more strains. Although there is some suggestion that probiotics may be efficacious in preventing acute diarrhoea, there is a lack of data from community-based trials and from developing countries evaluating the effect on acute diarrhoea unrelated to antibiotic usage. The effect on acute diarrhoea is dependent on the age of the host and genera of strain used.     

Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial.

Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract infection in infancy. To date, there is no effective therapy for RSV bronchiolitis. In order to investigate the efficacy of clarithromycin in the treatment of RSV bronchiolitis, the present authors conducted a randomised, double-blind, placebo-controlled trial comparing clarithromycin with placebo in 21 infants with a diagnosis of RSV bronchiolitis. The infants were randomised to receive clarithromycin or placebo daily for 3 weeks. Levels of interleukin (IL)-4, IL-8, eotaxin, and interferon-gamma were determined in plasma, before and after treatment, using ELISA. Six months after treatment, parents were surveyed as to whether their child had experienced wheezing within the previous 6 months. Treatment with clarithromycin was associated with a statistically significant reduction in the length of hospital stay, the duration of need for supplemental oxygen and the need for beta(2)-agonist treatment. There were significant decreases in plasma IL-4, IL-8 and eotaxin levels after 3 weeks of treatment with clarithromycin. Readmission to the hospital within 6 months after discharge was significantly lower in the clarithromycin group. In conclusion, clarithromycin has statistically significant effects on the clinical and laboratory findings in respiratory syncytial virus bronchiolitis. Therefore, clarithromycin treatment may be helpful in reducing the short-term effects of respiratory syncytial virus bronchiolitis.     

Lansoprazole in the treatment of functional dyspepsia: two double-blind, randomized, placebo-controlled trials

PURPOSE: The efficacy of proton pump inhibitor therapy for symptom resolution in patients with functional dyspepsia remains controversial. This study was designed to compare the efficacy of lansoprazole with placebo in relieving upper abdominal discomfort in patients with functional dyspepsia. METHODS: We enrolled 921 patients with functional dyspepsia (defined as persistent or recurrent upper abdominal discomfort during the prior 3 months) and moderate upper abdominal discomfort on at least 30% of screening days; none of the patients had predominant symptoms suggestive of gastroesophageal reflux or endoscopic evidence of erosive or ulcerative esophagitis, or gastric or duodenal ulcer or erosion. Patients were assigned randomly to receive lansoprazole 15 mg (n = 305), lansoprazole 30 mg (n = 308), or placebo (n = 308) daily for 8 weeks. Patients recorded the frequency and severity of symptoms in daily diaries. RESULTS: At week 8, significantly (P <0.001) greater mean reductions in the percentage of days with upper abdominal discomfort were reported in patients treated with lansoprazole 15 mg (35%) or 30 mg (34%) compared with those treated with placebo (19%). Similarly, more patients treated with lansoprazole 15 mg (44%) or 30 mg (44%) reported complete symptom resolution (defined as no episodes of upper abdominal discomfort in the 3 days before the study visit) at 8 weeks than did placebo-treated patients (29%, P <0.001). Improvement of upper abdominal discomfort, however, was seen only in patients who had at least some symptoms of heartburn at enrollment. CONCLUSION: Lansoprazole, at a daily dose of 15 mg or 30 mg, is significantly better than placebo in reducing symptoms of persistent or recurrent upper abdominal discomfort accompanied by at least some symptoms of heartburn.     

Myocardial fibrosis and QTc are reduced following treatment with spironolactone or amiloride in stroke survivors: A randomised placebo-controlled cross-over trial

Introduction

Myocardial fibrosis is dysrhythmogenic and may contribute to the high incidence of cardiac death in stroke survivors, especially if they have long QTc. We tested the hypothesis that procollagen-1-carboxy terminal peptide (P1CP), a biomarker of myocardial fibrosis, might be improved following treatment with spironolactone or amiloride in stroke survivors. We also tested the hypothesis that both drugs would shorten QTc.

Methods

Study design: randomised, double-blinded, placebo-controlled, cross-over trial (spironolactone vs. amiloride vs. placebo).Duration of Study: 3 months (1 month per drug).Primary endpoints: P1CP, QTc

Results

11 stroke survivors (5 female), aged 71 + 4, BP 139/81 mmHg + 20/11 mmHg, completed the study. Both spironolactone and amiloride significantly reduced P1CP [Spironolactone–Placebo = − 24 ug/L, 95% CI = − 40 to − 6.9; Amiloride–Placebo = − 28 ug/L, 95% CI = − 44 to − 11]. Spironolactone and amiloride both shortened QTc [Spironolactone vs. Placebo = − 18 ms^1/2, 95% CI = − 36 to − 0.55; Amiloride vs Placebo = − 25 ms^1/2, 95% CI = − 42 to − 7.5].

Conclusions

Procollagen-1-carboxy terminal peptide was reduced following treatment with spironolactone within a month. Further, this is the first study demonstrating amiloride could also improve myocardial fibrosis. The beneficial effects of both drugs on myocardial fibrosis, coupled with their effects on raising potassium translated to a shortening of QTc. Future studies should test the hypothesis that these drugs might reduce the risk of sudden cardiac death in stroke survivors.     

Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.

OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.     

Phosalone-induced inflammation and oxidative stress in the colon: evaluation and treatment

AIM: To investigate the side effects of phosalone on intestinal cells and to evaluate benefits of ellagic acid(EA) as a remedy.METHODS: In order to conduct an in vivo study, a rat model was used. The rats were divided into ten groups based on the materials used in the experiment and their dosage. The first group was fed normally. The second group was administered EA through gavage. Next Four groups were given(1/3, 1/5, 1/10, 1/20) LD50 phosalone; an organophosphorus compound. The last four groups received(1/3, 1/5, 1/10, 1/20) LD50 phosalone and of EA. After one month, the rats were sacrificed and their colon cells were examined to evaluate the level of inflammation, proteins and oxidative stress markers.RESULTS: The results of this research show that phosalone elevates oxidative stress and changes the level of tumor necrosis factor-a(TNF-α), interlukin-6β(IL-6β) and nuclear factor(NF)-κB proteins. EA administration reduced phosalone toxicity and changed oxidative stress and inflammatory markers for all phosalone doses. Overall changes in reduction of TNF-α(230.47 ± 16.55 pg/mg protein vs 546.43 ± 45.24 pg/mg protein, P 0.001), IL-6β(15.85 ± 1.03 pg/mg protein vs 21.55 ± 1.3 pg/mg protein, P 0.05), and NF-κB(32.47 ± 4.85 pg/mg protein vs 51.41 ± 0.71 pg/mg protein, P 0.05) manifest that the efficacy of EA is more viable for 1/3 LD50 dose of phosalone. Furthermore, EA is effective to counteract the negative outcomes of oxidative stress. When EA was used to treat 1/3 LD50 of phosalone's side effects, it improved the level of ACh E activity(48.5% ± 6% vs 25% ± 7%, P 0.05), TTM(0.391 ± 0.008 mmol/L vs 0.249 ± 0.032 mmol/L, P 0.05), FRAP(46.04 ± 5.005 μmol/L vs 18.22 ± 1.9 μmol/L, P 0.01) and MPO(0.222 ± 0.019 U/mg protein vs 0.387 ± 0.04 U/mg protein, P 0.05). CONCLUSION: This research highlights that EA is effective to alleviate the side effects of phosalone by reducing the level of oxidative stress and inflammatory proteins.