Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood

Background A lack of reliable treatments for abdominal pain‐related functional gastrointestinal disorders prompts interest in new therapies. Aim To evaluate systematically the effect of Lactobacillus rhamnosus GG (LGG) for treating abdominal pain‐related functional gastrointestinal disorders in children. Methods MEDLINE, EMBASE, CINAHL, the Cochrane Library, trial registries and proceedings of major meetings were searched for randomised controlled trials (RCTs) evaluating LGG supplementation in children with abdominal pain‐related functional gastrointestinal disorders based on the Rome II or Rome III criteria. Risk of bias was assessed for generation of the allocation sequence, allocation concealment, blinding and follow‐up. Results Compared with placebo, LGG supplementation was associated with a significantly higher rate of treatment responders (defined as no pain or a decrease in pain intensity) in the overall population with abdominal pain‐related functional gastrointestinal disorders (three RCTs, n = 290; risk ratio, RR 1.31, 95% CI 1.08–1.59, number needed to treat, NNT 7, 95% CI 4–22) and in the irritable bowel syndrome (IBS) subgroup (three RCTs, n = 167; RR 1.70, 95% CI 1.27–2.27, NNT 4, 95% CI 3–8). However, no difference was found in the rate of treatment responders between children with functional abdominal pain or functional dyspepsia who received placebo or LGG. The intensity of pain was significantly reduced in the overall study population and in the IBS subgroup. The frequency of pain was significantly reduced in the IBS subgroup only. Conclusion The use of Lactobacillus rhamnosus GG moderately increases treatment success in children with abdominal pain‐related functional gastrointestinal disorders, particularly among children with IBS.     

Factors modifying drug and placebo responses in randomized trials for bipolar mania

Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for bipolar mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for mania, fewer sites may limit placebo response and enhance drug-placebo contrasts.     

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.     

Antipsychotics, antidepressants, anticonvulsants, and placebo on the symptom dimensions of borderline personality disorder: a meta-analysis of randomized controlled and open-label trials

The aim of this study was to quantitatively review randomized controlled trials (RCTs) and open-label trials analyzing the efficacy of antidepressants, mood stabilizers, and antipsychotics for the treatment of the core symptoms of borderline personality disorder (BPD). Using a similar meta-analytic approach, the efficacy of placebo on the same core symptoms of BPD was evaluated. The risk of discontinuation of each of the medication classes reported in the studies was also analyzed to establish the major causes of discontinuation. MEDLINE (1966 to June 2010) and EMBASE (1980 to June 2010) databases were systematically searched to identify relevant RCTs and open studies. The primary outcome was improvement in the specific core symptoms of the disorder: affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual symptoms. Evidence from RCTs and open studies suggests that drug treatment, especially with mood stabilizers and antipsychotics, may be effective for treating affective dysregulation and impulsive-behavioral dyscontrol. Antipsychotics were also effective in reducing cognitive-perceptual symptoms. Antidepressants failed to show efficacy in treating BPD symptom dimensions other than affective dysregulation. Our analyses of the placebo arm of RCTs showed a significant improvement of symptomatology in these patients also. There were no significant differences in overall dropout rates between patients on medications and those on placebo. In conclusion, the efficacy of pharmacological treatment on the symptom dimensions of BPD has been shown by various independent meta-analyses, with a positive effect of drug treatment on the core symptoms of BPD and some documentable differences in terms of efficacy between different drug classes in each of the symptom domains.     

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.     

Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment

Aliment Pharmacol Ther 2010; 32: 1069–1079

Summary

Background Problems with currently recommended Helicobacter pylori eradication therapies include unsatisfactory eradication rates and/or therapy‐associated side effects. Aim To investigate the effects of Saccharomyces boulardii as supplementation to standard triple therapy on H. pylori eradication rates and therapy‐associated side effects. Methods The Cochrane Library, MEDLINE and EMBASE databases were searched in July 2010, with no language restrictions, for randomized controlled trials (RCTs); additional references were obtained from reviewed articles. Results Five RCTs involving a total of 1307 participants (among them only 90 children) met the inclusion criteria. Compared with placebo or no intervention, S. boulardii given along with triple therapy significantly increased the eradication rate [four RCTs, n = 915, relative risk (RR) 1.13, 95% confidence interval (CI) 1.05–1.21] and reduced the risk of overall H. pylori therapy‐related adverse effects (five RCTs, n = 1305, RR 0.46, 95% CI 0.3–0.7), particularly of diarrhoea (four RCTs, n = 1215, RR 0.47, 95% CI 0.32–0.69). There were no significant differences between groups in the risk of other adverse effects. Conclusion In patients with H. pylori infection, there is evidence to recommend the use of S. boulardii along with standard triple therapy as an option for increasing the eradication rates and decreasing overall therapy‐related side effects, particularly diarrhoea.     

Tolerability of Angiotensin-Receptor Blockers in Patients with Intolerance to Angiotensin-Converting Enzyme Inhibitors

Background: Between 5% and 20% of patients treated with angiotensin-converting enzyme inhibitors (ACE inhibitors) develop intolerance. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can be used as an alternative treatment. Objective: In this study we aimed to evaluate the tolerability of ARBs in patients with intolerance to ACE inhibitors. Data Sources: The electronic databases PubMed, MEDLINE/EMBASE via Dialog, CENTRAL, and ISI Web of Knowledge were searched. Study Selection: Randomized controlled trials (RCTs) evaluating ARBs in patients with intolerance to ACE inhibitors were selected. Data Synthesis: Risk ratio (RR) and 95% confidence intervals (CIs) were estimated assuming the random effects method. We found 11 RCTs comparing ARBs with ACE inhibitors, diuretics, or placebo, and one RCT comparing high-dose versus low-dose ARB. Results: ARBs had fewer cough events versus ACE inhibitors (RR 0.37; 95% CI 0.28, 0.48). ARBs had drug discontinuation (RR 0.99; 95% CI 0.84, 1.17) and cough risk (RR 1.01; 95% CI 0.74, 1.39) rates similar to placebo. Angioedema risk with ARBs was also similar to placebo (RR 1.62; 95% CI 0.17, 15.79). Compared with placebo, hypotension (RR 2.63; 95% CI 1.77, 3.92), renal dysfunction (RR 2.07; 95% CI 1.45, 2.95) and hyperkalemia (RR 3.37; 95% CI 1.60, 7.11) were more frequent with ARBs. Conclusions: ACE inhibitor rechallenge should be discouraged in patients with previous intolerance to ACE inhibitors due to a higher risk of cough. ARBs had cough and angioedema incidences similar to placebo. Despite a significantly higher incidence of hypotension, renal dysfunction and hyperkalemia, discontinuation of ARBs was similar to placebo.     

Clinical trial: the efficacy of alverine citrate/simeticone combination on abdominal pain/discomfort in irritable bowel syndrome ‐ a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 615–624

Summary

Background Alverine citrate and simeticone combination has been used for almost 20 years in irritable bowel syndrome (IBS), but supportive scientific evidence of efficacy was limited. Aim To evaluate the efficacy of alverine citrate and simeticone combination in patients with IBS‐related abdominal pain/discomfort. Methods A total of 412 IBS patients meeting ROME III criteria were included in this double‐blind randomized placebo‐controlled study if their abdominal pain/discomfort intensity was at least 60 mm on a 0–100 mm visual analogue scale (VAS) during a 2‐week run‐in treatment‐free period. Patients were randomly assigned through the use of Interactive Voice Response System to receive either alverine citrate 60 mg with simeticone 300 mg three times daily or matching placebo for 4 weeks. Results The full analysis set included 409 patients (71.4% female: mean age: 46.2 ± 13.9 years). At week 4, alverine citrate and simeticone group had lower VAS scores of abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with placebo group. Patient receiving alverine citrate and simeticone reported greater global symptom improvement compared with those receiving placebo (P = 0.0001). Reported adverse events were similar in both groups. Conclusion Alverine citrate/simeticone combination was significantly more effective than placebo in relieving abdominal pain/discomfort in patients with IBS.     

Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life--a double-blind, placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 1123–1132

Summary

Background Recent research suggests that an imbalance of the intestinal microbiota and a dysfunctional intestinal barrier might trigger irritable bowel syndrome (IBS). As probiotics have been reported to restore the intestinal microbiota and the gut barrier, the therapeutic potential of probiotics within IBS became of strong interest. Aim To assess the efficacy of Bifidobacterium bifidum MIMBb75 in IBS. Methods A total of 122 patients were randomised to receive either placebo (N = 62) or MIMBb75 (N = 60) once a day for 4 weeks. The severity of IBS symptoms was recorded daily on a 7‐point Likert scale. Results MIMBb75 significantly reduced the global assessment of IBS symptoms by ?0.88 points (95% CI: ?1.07; ?0.69) when compared with only ?0.16 (95% CI: ?0.32; 0.00) points in the placebo group (P < 0.0001). MIMBb75 also significantly improved the IBS symptoms pain/discomfort, distension/bloating, urgency and digestive disorder. The evaluation of the SF12 sum scores showed a significant gain in quality of life within the bifidobacteria group. Furthermore, adequate relief was reported by 47% of the patients in the bifidobacteria and only by 11% of the patients in the placebo group (P < 0.0001). Overall responder rates were 57% in the bifidobacteria group but only 21% in the placebo group (P = 0.0001). MIMBb75 was well tolerated and adverse events were not different from placebo. Conclusions Bifidobacterium bifidum MIMBb75 effectively alleviates global IBS and improves IBS symptoms simultaneously with an improvement of quality of life. Considering the high efficacy of MIMBb75 in IBS along with the good side‐effect profile, MIMBb75 is a promising candidate for IBS therapy.

     

The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials

Posttraumatic stress disorder (PTSD) is a prevalent and disabling mental illness. Small studies found atypical antipsychotics (AAs) to be beneficial in the treatment of patients with PTSD regardless of psychotic symptoms who are unresponsive to conventional pharmacological treatments such as serotonin selective reuptake inhibitors. This study reports the results of a meta-analysis of existing randomized, double-blind, placebo-controlled clinical trials (RCTs) of AAs as a monotherapy or augmentation therapy for the treatment of patients with PTSD. Seven RCTs were identified through extensive scans of databases, which included PubMed, MedLine, the National PTSD Center Pilots database, PsycINFO, Cochrane Central Register of Controlled Trials, and the Abstracts Library of the American Psychiatric Association with predefined inclusion criteria. Dichotomous and continuous measures were performed using a fixed effects model, heterogeneity was assessed, and subgroup analyses were done. Data from seven RCTs involving a total of 192 PTSD patients (102 randomized to AAs and 90 randomized to placebo) were analyzed. The results show that AAs may have a beneficial effect in the treatment of PTSD, as indicated by the changes from baseline in Clinician Administered PTSD Scale total scores [standardized mean difference (SMD)=-0.45, 95% confidence interval (CI) (-0.75, -0.14), P=0.004]. In addition, the overall SMD of the mean changes in the three Clinician Administered PTSD Scale subscores was statistically significant (P=0.007) between AAs and placebo groups, favoring AAs over placebo (SMD=-0.27, 95% CI=-0.47, -0.07). In particular, the symptom of 'intrusion' was mainly responsible for this significance. Clinical significance of the results, however, should be carefully interpreted and translated into clinical practice, given that the quality and availability of currently existing RCTs included in the analysis.     

Evaluation of drug treatment in irritable bowel syndrome

The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. It is contentious whether dietary fibre and bulking agents relieve the symptoms of IBS; constipation probably improves. Anticholinergic and antispasmodic agents are of questionable benefit in IBS despite positive meta-analyses of poor quality trials. A meta-analysis concluded that the tricyclic antidepressants were superior to placebo in IBS, although the individual trial results were variable. Selective serotonin reuptake inhibitors are of uncertain benefit. Laxatives are used for constipation but probably poorly control the IBS symptom complex. Loperamide is superior to placebo in improvement of diarrhoea but not abdominal pain in IBS. Tegaserod is a well- tolerated aminoguanidine indole derivative of serotonin that is a partial 5HT4-receptor agonist with prokinetic properties; a therapeutic gain over placebo of 5% to 15% has been observed in constipation-predominant IBS in females. Alosetron is a 5HT3-receptor antagonist that is efficacious in females with diarrhoea-predominant IBS, with a 12% to 17% therapeutic gain; the risk of ischaemic colitis is 1 in 350, with very severe constipation occurring in about 1 in 1000. Optimizing study design remains a challenge in IBS. New visceral analgesic and motility modifying agents, as well as anti-inflammatory agents are in trials, and hopefully additional efficacious therapeutic options for patients with IBS will soon emerge.     

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED₅₀) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED₅₀ of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference −3.8 mg, 95% CI −10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI −2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I² 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I² 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.Subject terms: Preclinical research, Translational research     

Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis

Background: To summarize and quantify the evidence supporting rectal 5- or 4-aminosalicylate (ASA) therapies for disease exacerbation or remission maintenance in distal ulcerative colitis, we performed a meta-analysis. Methods: All randomized, double-blind controlled trials involving aminosalicylate therapy were retrieved from a MEDLINE search, review articles on ulcerative colitis therapy or their bibliographies. Of 55 studies retrieved, 19 met the inclusion criteria. Appraisal and data extraction were performed by two observers and scoring disagreements were resolved by consensus. Results: Eleven trials tested 5-ASA and three tested 4-ASA in active ulcerative colitis. 5-ASA was superior to placebo for inducing remission or symptomatic improvement in active ulcerative colitis with a pooled odds ratio of 7.36 (95% Confidence interval (CI): 4.72–11.47). In four trials the pooled odds ratio for endoscopic improvement was 10.04 (95 % CI: 5.72–17.61) and for histological improvement 10.31 (95% CI: 5.85–18.18). Studies evaluating 4–ASA suggest a benefit similar to prednisolone in treating active disease. Five trials assessed remission maintenance with 5-ASA, and when compared to placebo gave a pooled odds ratio of 16.22 (95% CI: 4.71–55.92). No dose-response relationship was observed. ASA compounds were not therapeutically superior to other treatments. Conclusions: We conclude that rectal 5-ASA is effective therapy for active distal ulcerative colitis. More trials are needed to assess 4-ASA, dose-response effects and the ideal regimen for remission maintenance.     

Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy

Aliment Pharmacol Ther 2010; 32: 969–983

Summary

Background The efficacy of re‐treating genotype I hepatitis C virus (HCV) patients who failed combination therapy with interferon/pegylated interferon (PEG‐IFN) and ribavirin remains unclear. Aims To quantify sustained virological response (SVR) rates with different re‐treatment regimens through meta‐analysis of randomized controlled trials (RCTs). Methods Randomized controlled trials of genotype I HCV treatment failure patients that compared currently available re‐treatment regimens were selected. Two investigators independently extracted data on patient population, methods and results. The pooled relative risk of SVR for treatment regimens was computed using a random effects model. Results Eighteen RCTs were included. In nonresponders to standard interferon/ribavirin, re‐treatment with high‐dose PEG‐IFN combination therapy improved SVR compared with standard PEG‐IFN combination therapy (RR = 1.49; 95% CI: 1.09–2.04), but SVR rates did not exceed 18% in most studies. In relapsers to standard interferon/ribavirin, re‐treatment with high‐dose PEG‐IFN or prolonged CIFN improved SVR (RR = 1.57; 95% CI: 1.16–2.14) and achieved SVR rates of 43–69%. Conclusions In genotype I HCV treatment failure patients who received combination therapy, re‐treatment with high‐dose PEG‐IFN combination therapy is superior to re‐treatment with standard combination therapy, although SVR rates are variable for nonresponders (≤18%) and relapsers (43–69%). Re‐treatment may be appropriate for select patients, especially relapsers and individuals with bridging fibrosis or compensated cirrhosis.     

经验性抗真菌治疗血液病恶性肿瘤患者侵袭性真菌感染的Meta分析

目的：系统评价经验性抗真菌治疗血液病恶性肿瘤患者的疗效和安全性.方法：系统性回顾随机,安慰剂或空白对照抗真菌经验性治疗的随机对照试验,采用cochrane协作网提供的RevMan5.0进行数据分析.主要临床结局为全因死亡率和侵袭性真菌感染,汇总分析95%置信区间的相对危险度（RR）.所有研究均为血液病恶性肿瘤患者.结果：共纳入7个RCT（包括6个经验性治疗与空白组或安慰剂组对照的研究和1个经验性治疗与抢先治疗的对照研究）.Meta分析结果显示经验性治疗未明显减少[RR＝0.82.95%Cl（0.50～1.34）]死亡率,但明显降低侵袭性真菌感染的发生[RR＝0.25.95%Cl（0.12～0.54）1.经验性治疗组的不良反应没有明显增多.结论：目前的有限证据表明,经验性抗真菌治疗与降低侵袭性真菌感染发生率有关,但对总体死亡率无明显影响.     

Efficacy and safety of lorcaserin in obesity: a systematic review and meta-analysis of randomized controlled trials

ABSTRACT

Background: Lorcaserin is a novel, selective 5-hydroxytryptamine 2C serotonin receptor agonist, approved for the treatment of obesity. Several phase 3 randomized controlled trials (RCTs) trials have shown a significant reduction in body weight with lorcaserin.

Research design and methods: We systematically searched the database of PubMed, Embase, The Cochrane Library and ClinicalTrials.gov up to 31 July 2019 and retrieved all the studies conducted with lorcaserin for ≥1 year that have explicitly reported the efficacy and safety outcomes versus placebo. Subsequently, we studied the effect of lorcaserin on weight reduction, FDA-defined valvulopathy, depression and suicidal risks in RCTs.

Results: The meta-analysis of four RCTs (N = 16,856) demonstrated a significant decrease in body weight (mean ? ?3.076 Kg; 95% CI, ?3.49 to ?2.66; P < 0.00001), compared to placebo. No significant difference in FDA-defined valvulopathy (RR 1.20; 95% CI, 0.89 to 1.63; P = 0.24), depression (RR 1.07; 95% CI, 0.80 to 1.43; P = 0.67) or suicidal risk (RR 1.43; 95% CI, 0.96 to 2.15; P = 0.08) has been observed with lorcaserin compared to placebo.

Conclusions: Lorcaserin reduces body weight modestly, with no obvious serious adverse side effects. The common adverse events noted with lorcaserin include nausea, dizziness, and transient headache.     

Update on the Management of Diarrhea‐Predominant Irritable Bowel Syndrome: Focus on Rifaximin and Eluxadoline

Diarrhea‐predominant irritable bowel syndrome (IBS‐D) is one of the most common diagnoses made by gastroenterologists. Current pharmacologic treatments for IBS‐D include fiber supplements, antidiarrheal over‐the‐counter medications, probiotics, antispasmodics, antidepressants, and a 5‐hydroxytryptophan 3 receptor antagonist. All of these options have limited efficacy in managing IBS‐D. Rifaximin, a nonabsorbable antibiotic, has been evaluated in patients with IBS‐D. In two randomized, double‐blind, placebo‐controlled phase III trials evaluating rifaximin 550 mg by mouth 3 times/day for 14 days, the primary efficacy end point was achieved by 9% more patients randomized to the rifaximin group compared with placebo (40.7% vs 31.7%, p<0.001, number needed to treat ~11). The primary efficacy end point was defined as the proportion of patients having adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the primary follow‐up period (weeks 3–6). In the phase III trial examining the efficacy and safety of repeated courses of rifaximin in patients who responded to the initial 2‐week course, rifaximin given for up to two additional courses provided a statistically significant incremental benefit (33% vs 25%, p=0.02). Eluxadoline is a gut‐targeting μ and κ opioid receptor agonist and a δ opioid receptor antagonist. The dual mechanism of eluxadoline may explain the antidiarrheal and abdominal pain‐modulating properties and lack of profound constipation. In two identically designed randomized, double‐blind, placebo‐controlled phase III studies, 10.3% more patients in an eluxadoline 100 mg by mouth twice/day group met the primary efficacy end point during the follow‐up 1–12 week period compared with placebo (p<0.001). The primary efficacy end point was a composite response, defined as improvement in worst abdominal pain and stool consistency at the same time on most (50% or more) days during the follow‐up period. This review evaluates evidence for the use of rifaximin and eluxadoline in patients with IBS‐D. Rifaximin provides an additional modality for the management of IBS‐D patients; it has mild to moderate efficacy similar to other currently available treatment options. Rifaximin is relatively safe, lacks significant drug‐drug interactions, and can be used for up to two additional retreatment courses. This may make rifaximin a possible initial or second‐line treatment option. Eluxadoline can also offer relief to patients with IBS‐D. While effective, because of several limitations, including drug‐drug interactions and drug disease contraindications, as well as current lack of clinical experience, it may be tried as a second‐ or third‐line agent.     

Meta-analysis: the effects of Lactobacillus rhamnosus GG supplementation for the prevention of healthcare-associated diarrhoea in children

Aliment Pharmacol Ther 2011; 34: 1079–1087

Summary

Background In children, healthcare‐associated diarrhoea, in particular, due to rotavirus, may prolong the hospital stay and increase medical costs, prompting interest in effective, low‐cost, preventive strategies. Aim To review systematically data on the efficacy of administering Lactobacillus rhamnosus GG (LGG) for the prevention of healthcare‐associated diarrhoea. Methods MEDLINE, EMBASE, Health Source: Nursing/Academic Edition, the Cochrane Library, trial registries and proceedings of major meetings were systematically searched for randomised controlled trials (RCTs) performed in children aged 1 month to 18 years that compared administration of LGG with placebo or no intervention. Two reviewers assessed studies for inclusion and risk of bias and extracted the data. Outcome measures included the incidences of healthcare‐associated diarrhoea and rotavirus gastroenteritis. If appropriate, meta‐analyses were carried out using the fixed effects model. Results Three RCTs involving 1092 children were included. Compared with placebo, LGG administration for the duration of hospital stay was associated with significantly lower rates of diarrhoea (two RCTs, n = 823, relative risk, RR 0.37, 95% confidence interval, CI 0.23–0.59) and symptomatic rotavirus gastroenteritis (three RCTs, n = 1043, RR 0.49, 95% CI 0.28–0.86). There was no significant difference between the LGG and the control groups in the incidence of asymptomatic rotavirus infection, duration of hospitalisation or duration of diarrhoea. LGG was well tolerated, and no harms were reported in any of the trials. Conclusion In hospitalised children, the administration of Lactobacillus rhamnosus GG compared with placebo has the potential to reduce the overall incidence of healthcare‐associated diarrhoea, including rotavirus gastroenteritis.     

Systematic review: the effects of fibre in the management of chronic idiopathic constipation

Aliment Pharmacol Ther 2011; 33: 895–901

Summary

Background Patients with chronic idiopathic constipation are often told to increase dietary fibre intake. Whether this is of any benefit remains unclear. Aim To conduct a systematic review of the efficacy of soluble and insoluble fibre supplementation in the management of chronic idiopathic constipation. Methods MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched to identify randomised controlled trials (RCTs) comparing fibre with placebo or no therapy in adult chronic idiopathic constipation patients. Studies had to report dichotomous data assessing response to therapy, or continuous data examining either effect of therapy on mean number of stools per week, or mean symptom scores. Adverse events data were extracted where reported. Results Six RCTs were eligible. Four used soluble fibre and two used insoluble fibre. Formal meta‐analysis was not undertaken due to concern about methodological quality of identified studies. Compared with placebo, soluble fibre led to improvements in global symptoms (86.5% vs. 47.4%), straining (55.6% vs. 28.6%), pain on defaecation, and stool consistency, an increase in the mean number of stools per week (3.8 stools per week after therapy compared with 2.9 stools per week at baseline), and a reduction in the number of days between stools. Evidence for any benefit of insoluble fibre was conflicting. Adverse events data were limited, with no RCT reporting total numbers. Conclusions Soluble fibre may be of benefit in chronic idiopathic constipation, but data for insoluble fibre are conflicting. More data from high quality RCTs are required before the true efficacy of either fibre type in the treatment of chronic idiopathic constipation is known.     

Additive effect of α-ketoacids in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials

α-Ketoacids (KAs) are widely used in chronic kidney disease (CKD), but their efficacy is not clear. Therefore, we conducted a systematic review of the benefits of KAs. Two reviewers independently searched MEDLINE, EMBASE, the Cochrane library (http://www.cochrane.org), CNKI, and Wan Fang databases from inception to May 31, 2016 for randomized controlled trials (RCTs) comparing KAs plus low protein diet (LPD) with LPD only on CKD patients. Statistical analyses were performed using both a random effects model and a fixed effects model with Rev Man 5.3, followed by sensitivity analysis. We identified 21 randomized controlled trials that enrolled a total of 1448 patients. 726 had received LPD plus KAs and 722 had received only LPD. Compared with simply using of LPD, combining with KAs could decrease serum creatinine (95% CI, 0.46–0.96; P<0.00001), serum cholesterol (95% CI, 0.24–0.77; P = 0.02), serum LDL cholesterol (95% CI, 0.12–0.54; P = 0.31), and serum triglyceride (95% CI, 0.28–0.83; P = 0.02) while increasing serum HDL cholesterol (95% CI, -1.73–0.07; P<0.00001). Likewise, a decrease in P^3– (95% CI, 0.90–1.26; P<0.00001) and PTH (95% CI, 0.70–1.21; P = 0.007) were observed. No hypercalcemia and other ARD or toxicity was reported, which indicated the safety of KAs. Nevertheless, the studies were pooled with considerable heterogeneity. In patients with CKD, there was low-quality evidence suggesting that KAs may perform an additive effect on the improvement of renal function, lipid profile, as well as the correction of calcium-phosphate metabolism disorders. On account of the considerable heterogeneity of the meta-analysis and the costly price and adherence of KAs administration, KAs’ roles in the management of mild or moderate CKD patients may need more RCTs of large scale and high quality to confirm.