Complete Spontaneous Bowel Movements Research Articles

S0500 Intestinal Methanogen Overgrowth (IMO) in Parkinson's Disease: High Prevalence and Correlation With Constipation

INTRODUCTION: Recent ACG guidelines have defined intestinal methanogenic overgrowth (IMO) and described its clinical significance. The prevalences of small intestinal bacterial overgrowth (SIBO) and IMO in Parkinson's disease (PD) are unclear. SIBO in PD is linked to worse motor symptoms. Treatment of SIBO can improve motor function in PD. Our aim is to quantify the prevalence of SIBO and IMO in Parkinson's disease (PD) subjects with constipation compared to patients with unexplained GI symptoms undergoing glucose breath testing (GBT). METHODS: After an overnight fast and day of low-CHO diet, subjects brushed their teeth and rinsed their mouth with antiseptic mouthwash 2h before test. During GBT, 75 g of glucose dissolved in 250 mL water was administered. Breath samples were obtained at baseline and 15 min intervals for 2 h. Samples are collected in a bag (QuinTron Instrument Company, Inc.) and alveolar gas was analyzed for both H2 and CH4 levels by chromatography (QuinTron Micro Analyzer, QuinTron, Inc.). SIBO was defined as H2 rise of ≥20 ppm from baseline and/or CH4 rise of ≥10 ppm. IMO was defined as any measured CH4 ≥ 10 ppm. Daily bowel movements were assessed by prospective stool diary. Constipation was defined by <3 complete spontaneous bowel movements (CSBMs)/week. RESULTS: Nineteen patients with PD (68.2 ± 7.0 years, F/M = 6/13) underwent breath testing and compared to 158 subjects with unexplained GI symptoms (47.4 ± 15.3 years, F/M = 119/39). 31.6% (6/19) of PD subjects had SIBO versus 23.4% (37/158) of subjects with unexplained GI symptoms (P = 0.95), shown in Table 1. 52.6% (10/19) of PD subjects had IMO compared to 14.6% (23/158) subjects with unexplained GI symptoms (P < 0.001). 36.8% (7/19) had < 3 CSBMs per week. There was significant correlation between constipation and IMO, but not SIBO, Table 2. Higher maximum methane levels during GBT also significantly correlated with the presence of constipation. CONCLUSION: Rates of SIBO are similar between PD subjects with constipation and symptomatic patients undergoing GBT. More than half and significantly more PD subjects with constipation than symptomatic patients undergoing GBT have IMO. IMO and higher methane levels correlate with constipation in PD quantified by a stool diary. Methanogens may play a critical role in non-motor symptoms of PD patients such as constipation. ACKNOWLEDGEMENT: Parkinson's Foundation Translational Research Award.Table 1.: SIBO and IMO prevalence in subjects with PD vs unexplained GI symptomsTable 2.: Correlation between IMO, maximum methane level, and SIBO with constipation

S0506 Efficacy and Safety of Plecanatide in Patients With Chronic Idiopathic Constipation: Pooled Analysis of Two Phase 3 Trials Stratified by Concomitant Acid Suppression Use

INTRODUCTION: Plecanatide, an approved treatment for chronic idiopathic constipation (CIC), replicates the pH-sensitive activity of uroguanylin in binding to guanylate cyclase-C receptors on intestinal epithelium. Since many individuals with CIC experience reflux and use concomitant acid suppression therapy, we explored the impact of concomitant acid suppressor use on the efficacy and safety of plecanatide in adults with CIC. METHODS: Data on two 12-week, randomized, double-blind, placebo-controlled phase 3 clinical trials of plecanatide were pooled and results were stratified by concomitant acid suppressor use. For each group, durable overall complete spontaneous bowel movement (CSBM) response rates, changes from baseline in bowel movement frequency, stool consistency (Bristol Stool Form Scale), and daily CIC symptom scores (Likert Scale, 0 = none to 4 = very severe) were assessed. Safety was analyzed in patients who received ≥1 dose. RESULTS: The intention-to-treat population (N = 2639) included 12.6% of patients with concomitant acid suppressor use. Patients using acid suppressors were 54.8 years (mean), vs 43.9 years in those not using acid suppressors. Gastroesophageal reflux disease was more common in patients using acid suppressors (83.1%), compared to those not on acid suppressors (6.1%). Proton pump inhibitors (PPIs) were used by 86.4% of patients using acid suppressors with omeprazole as the most common PPI (45.1%); H2 blockers were used by 17.8% of subjects with ranitidine as the most common H2 blocker (9.8%). Regardless of acid suppressor use, plecanatide-treated patients demonstrated significant improvements in the durable overall CSBM responder rates (Figure 1) and greater efficacy across almost all reported endpoints (Table 1) vs placebo, with benefits observed as early as Week 1. Comparisons between acid suppressor use groups (yes vs no) were not significantly different for plecanatide-treated patients (both doses, Table 1). Of the plecanatide-treated patients on acid suppressors, 6.4% experienced diarrhea, 1.4% discontinued due to diarrhea, and 2.3% had ≥ 1 serious adverse event (SAE), compared to 5.0% (diarrhea), 2.1% (discontinued due to diarrhea), and 1.0% (SAE) of patients not using acid suppressors. CONCLUSION: Plecanatide is a safe and effective treatment for CIC when administered with acid suppression therapy. Regardless of acid suppressor use, efficacy responses in plecanatide groups were significantly greater than placebo.Figure 1.: Percentage of Patients With Durable Overall CSBM Response Stratified by Concomitant Acid Suppressor Use (ITT).Table 1.: Change From Baseline in Bowel Movement Frequency, Stool Consistency, and CIC Symptoms in Patients With and Without Concomitant Acid Suppression Therapy (ITT)

S0505 The Effect of Retreatment and Treatment Cessation in Clinical Studies of Prucalopride in Patients With Chronic Idiopathic Constipation

INTRODUCTION: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for the treatment of chronic idiopathic constipation (CIC) in adults. To assess how prucalopride can be used in clinical practice, we evaluated the effect of re-treatment and treatment cessation on complete spontaneous bowel movements (CSBMs) and adverse events (AEs) using data from two randomized, double-blind, placebo-controlled trials in adults with CIC. METHODS: The effect of re-treatment was assessed in one trial with two 4-week treatment periods (TPs; prucalopride 4mg once daily or placebo) with a drug-free period of 2 weeks or 4 weeks between TPs. During both TPs, the proportion of responders (patients with a mean of ≥3 CSBMs/week) and the incidence of AEs were assessed. In a dose-finding trial, the effect of treatment cessation on these endpoints was assessed during a 4-week drug-free run-out period, which followed a 4-week dose-finding period (prucalopride 0.5, 1, 2 or 4 mg once daily or placebo). Both trials enrolled patients with a mean of <3 CSBMs/week at baseline. RESULTS: In the re-treatment trial (Table 1; responder analysis: placebo, n = 205; prucalopride, n = 189) the proportion of responders in TP2 was similar to that in TP1 and was significantly higher (P ≤ 0.001) with prucalopride 4mg than with placebo (weeks 1–4: TP1, 38.6% vs 10.7%; TP2, 36.0% vs 11.2%; Figure 1); 71.2% (52/73) of prucalopride responders in TP1 responded in TP2. The most common AEs (headache, diarrhea, nausea, abdominal pain) occurred at a lower frequency during TP2 than TP1. In the dose-finding trial (N = 234; 43–48 patients per treatment group [Table 1]), the proportion of responders during the 4-week TP was higher with prucalopride 0.5–4 mg (23.4–55.6%) than with placebo (13.3%). The mean number of CSBMs/week was higher in the prucalopride groups than in the placebo group during the 4-week TP, but was similar between all groups 4 weeks after stopping treatment (Figure 2). Gastrointestinal AEs that were possibly or definitely related to prucalopride treatment were less frequent during the run-out phase than during the TP. CONCLUSION: Over 70% of patients who initially responded to prucalopride responded again when re-treated with prucalopride after a 2- or 4-week drug-free period. The incidence of AEs was lower during re-treatment with prucalopride than during initial treatment. Cessation of prucalopride treatment resulted in a loss of clinical effect after 7 days, indicated by a reduction in the mean number of CSBMs/week.Table 1.: Baseline demographics and disease characteristics of participants in the re-treatment and dose-finding trialsFigure 1.: Proportion of responders during TP1 and TP2 of the re-treatment trial.Figure 2.: Mean number of CSBMs per week in patients with CIC during the 4-week TP and the 4-week run-out period of the dose-finding trial.

Effectiveness and safety of light vegetarian diet and Qingjiang Tiaochang Recipe for functional constipation

Functional constipation is a chronic disease that is common in children and adults around the world. The treatments for functional constipation include diet and lifestyle interventions, medications, and surgery. The diet pattern plays an important role in the occurrence of constipation. We found in clinical practice that simple application of drugs cannot achieve long-term relief of constipation, and a large number of patients are not satisfied with the existing treatment. We have concluded that Qingjiang Tiaochang Recipe (QJTCR) and light vegetarian diet (LVD) can effectively improve constipation. However, there is no enough evidence for the description of the effect. This protocol aims at exploratorily investigating effectiveness and safety of LVD and QJTCR following a rigorous clinical trial. We will recruit 90 patients to participate in this prospective, placebo-controlled, randomized trial, and exploratory study at the China-Japan Friendship Hospital, including traditional Chinese medicine group, placebo + diet group, traditional Chinese medicine + diet group. Patients in the diet intervention group must strictly abide by LVD, and the study will continue for 28 days. During the intervention period, we need to record a designed diary to assess diet quality and defecation. The primary outcomes for this clinical study were weekly complete spontaneous bowel movements. The secondary outcomes were constipation-related symptom rating scale, traditional Chinese medicine syndrome scale, and 48-hour gastrointestinal transit time, high-resolution anorectal manometry, Bristol stool score, constipation quality of life assessment scale, constipation symptoms self-assessment scale, short-chain fatty acids in feces. In addition, the study will determine the safety of the intervention.

Efficacy and safety of moxibustion for patients with functional constipation: A protocol for systematic review and meta analysis.

Introduction:The objective of this review is to assess the efficacy and safety of moxibustion for treating patients with functional constipation (FC).Methods and analysis:We will electronically search the following databases: OVID MEDLINE, EMBASE, PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, Cochrane library, CINAHL, AMED, China Network Knowledge Infrastructure, Wan-fang Database, China Biomedical Literature Database, and other resources from inception to October 2019, without any language restrictions. Randomised-controlled trials will be included. The primary outcome is the improvement in mean complete spontaneous bowel movements and stool form (utilize the Bristol Stool Form Scale [BSFS]). Secondary outcomes involve the degree of difficulty in defecation, proportion of responders, mean transit time, health-related quality of life, and adverse events rate. The methodological quality will be assessed using the Cochrane risk of bias tool.Results:This work will summarize clinical evidence to assess the effectiveness and safety of moxibustion treatment for FC patients.Conclusion:This systematic review and meta-analysis will provide current evidence of the efficacy and safety of moxibustion treating FC.Systematic review registration:PROSPERO, CRD42020157955.

Evaluation of Plecanatide for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation in Patients 65 Years or Older

PurposeChronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are common functional gastrointestinal disorders. The prevalence of constipation-related issues tends to increase with age. This analysis pooled data from Phase III trials in CIC and IBS-C to assess the safety and efficacy of plecanatide in patients aged ≥65 years. MethodsPatients randomized to receive plecanatide (3 or 6 mg) or placebo from two CIC and two IBS-C trials were pooled. Efficacy end points common to all trials included changes in stool consistency (Bristol Stool Form Scale), changes in weekly frequency of complete spontaneous bowel movements (CSBMs) and spontaneous bowel movements (SBMs), and time to first CSBM and SBM. Efficacy and safety profile results are reported per age group (≥65 and <65 years of age). FindingsThe pooled intention-to-treat population comprised 451 patients aged ≥65 years (mean age, 70 years) and 4364 patients aged <65 years (mean age, 41.9 years), of whom 287 and 2914, respectively, were randomized to receive plecanatide. Compared with placebo, plecanatide produced statistically significant improvements in stool consistency from baseline at week 12 (both age groups), CSBM and SBM frequency from baseline at week 12 (plecanatide 3 mg group aged ≥65 years and both plecanatide groups aged <65 years), and time from start of therapy to first CSBM (both age groups) and SBM (plecanatide 6 mg group aged ≥65 years and both plecanatide groups aged <65 years). No new safety issues were observed. ImplicationsPlecanatide is a well-tolerated and effective treatment option for patients aged ≥65 years with CIC or IBS-C. Clinicaltrials.gov identifiersNCT01982240, NCT02122471, NCT02387359, and NCT02493452.

Systematic review with meta-analysis: efficacy and safety of treatments for opioid-induced constipation.

When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs). To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies. A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea. We included 35 trials at low risk of bias enrolling 13566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide. Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.

Effects of the vibrating capsule on colonic circadian rhythm and bowel symptoms in chronic idiopathic constipation.

BackgroundConstipated patients remain dissatisfied with current treatments suggesting a need for alternative therapies.AimEvaluate the mechanistic effects of oral vibrating capsule in chronic idiopathic constipation (CIC) by examining the temporal relationships between the onset of vibrations, complete spontaneous bowel movements (CSBM), and circadian rhythm.MethodsIn post hoc analyses of two double‐blind studies, CIC patients (Rome III) were randomized to receive 5 active or sham capsules/week for 8 weeks. The capsules were programmed for single vibration (study 1) or two vibration sessions with two modes, 8 hours apart (study 2). Daily electronic diaries assessed stool habit and percentage of CSBMs associated with vibrations. Responders were patients with ≥ 1 CSBM per week over baseline.Results250 patients were enrolled (active = 133, sham = 117). During and within 3 hours of vibration, there were significantly more % CSBMs in the active vs. sham group (50% vs. 42%; P = .0018). In study 2, there were two CSBM peaks associated with vibration sessions. Significantly more % CSBMs occurred in active mode 1 (21.5%) vs. sham (11.5%); (P = .0357). Responder rates did not differ in study 1 (active vs. sham: 26.9% vs. 35.9%, P = .19) or study 2 (mode 1 vs. sham: 50% vs. 31.8%, P = .24; mode 2 vs. sham: 38.1% vs. 31.8%, P = .75). Device was well‐tolerated barring mild vibration sensation.ConclusionsVibrating capsule may increase CSBMs possibly by enhancing the physiologic effects of waking and meals, and augmenting circadian rhythm, although responder rate was not different from sham. Two vibration sessions were associated with more CSBMs.

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

SummaryBackgroundLinaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS‐C) symptoms, but how it improves pain in humans is unknown.AimsTo investigate the effects of linaclotide and placebo on the afferent and efferent gut‐brain‐gut signalling in IBS‐C patients, in a randomised clinical trial.MethodsPatients with IBS‐C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi‐directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal‐anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto‐cortical and cortico‐rectal evoked potentials.ResultsThirty‐nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico‐anorectal and spino‐anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS‐QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13).ConclusionsLinaclotide prolongs afferent gut‐brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS‐C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS‐C patients.ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.

Post-stroke constipation treated with acupoint embedding therapy: a multi-center randomized controlled trial

To verify the clinical effect of acupoint embedding therapy on post-stroke constipation. The multi-central randomized controlled trial was adopted. 210 patients of post-stroke constipation were divided into an acupoint embedding group (105 cases, 4 cases dropped off) and a sham-embedding group (105 cases, 6 cases dropped off). In the acupoint embedding group, the acupoint embedding therapy was used at Tianshu (ST 25), Daheng (SP 15), Xiawan (CV 10), Zhongwan (CV 12), Qihai (CV 6), Guanyuan (CV 4) and Daju (ST 27). In the sham-embedding group, the sham-embedding therapy was given, in which, the acupoint selection, needle devices and manipulation were the same as the acupoint embedding group. But, no absorbable surgical suture was used in the needle tube. The treatment was given once every two weeks and 4 treatments were required in either group. It was to compare the weekly average complete spontaneous bowel movements (CSBMs) during treatment (from the 3rd to the 8th week) between the two groups, the weekly average spontaneous bowel movements (SBMs), Bristol stool form score (BSFS), the score of the patient assessment of constipation quality of life questionnaire (PAC-QOL) and the score of defecation difficulty before and after treatment. The percentage of the cases with weekly average CSBMs ≥ 3 times in the patients of the acupoint embedding group was higher markedly than the sham-embedding group [91.1% (92/101) vs 43.4% (43/99), P<0.01]. Compared with the values before treatment, the weekly average SBMs and BSFS scores after treatment were all increased obviously in the two groups (P<0.01), and PAC-QOL score and the score of defecation difficulty were reduced remarkably (P<0.01). After treatment, the increase range of SBMs and BSFS scores, as well as the decrease range of PAC-QOL score and the defecation difficulty score in the acupoint embedding group were all higher than the sham-embedding group respectively (P<0.05). The acupoint embedding therapy remarkably increases the spontaneous bowel movements, improves in feces form and defecation difficulty and strengthens the quality of life in the patients of post-stroke constipation.

Efficacy of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: a 3-month follow-up analysis

ObjectivesOpioid-induced constipation (OIC) can affect up to 63% of all patients with cancer. The objectives of this study were to assess quality of life as well as efficacy and safety...

Efficacy of Lactobacillus paracasei HA-196 and Bifidobacterium longum R0175 in Alleviating Symptoms of Irritable Bowel Syndrome (IBS): A Randomized, Placebo-Controlled Study.

Specific probiotic strains can alleviate the gastrointestinal (GI) symptoms and psychiatric comorbidities of irritable bowel syndrome (IBS). In this randomized, double-blind, placebo-controlled study, the efficacy of Lactobacillus paracasei HA-196 (L. paracasei) and Bifidobacterium longum R0175 (B. longum) in reducing the GI and psychological symptoms of IBS was evaluated in 251 adults with either constipation (IBS-C), diarrhea (IBS-D), or mixed-pattern (IBS-M). Following a 2-week run-in period, participants were randomized to one of three interventions: L. paracasei (n = 84), B. longum (n = 83) or placebo (n = 81). IBS symptoms, stool frequency and consistency and quality of life were assessed by questionnaires. The differences from baseline in the severity of IBS symptoms at 4 and 8 weeks were similar between groups. Participants in this study were classified, after randomization, into subtypes according to Rome III. Within the L. paracasei group, complete spontaneous and spontaneous bowel movement frequency increased in participants with IBS-C (n = 10) after 8 weeks of supplementation (both p < 0.05) and decreased in participants with IBS-D (n = 10, p = 0.013). Both L. paracasei and B. longum supplementation improved the quality of life in emotional well-being and social functioning compared with baseline (all p < 0.05). In conclusion, L. paracasei and B. longum may reduce GI symptom severity and improve the psychological well-being of individuals with certain IBS subtypes.

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P = .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P = .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

Chinese Herbal Medicine (MaZiRenWan) Improves Bowel Movement in Functional Constipation Through Down-Regulating Oleamide.

In a prospective, randomized, three-arms, controlled clinical study, Chinese Herbal Medicine MaZiRenWan (MZRW, also known as Hemp Seed Pill) demonstrates comparable efficacy with Senna for functional constipation (FC) during an 8-week treatment period. Both MZRW and Senna are better than a placebo; relative to Senna and a placebo, MZRW displayed a more sustained effect during the 8-week follow-up period. The characteristic pharmacological mechanism responsible for this observation is still unclear. To explore this, we collected pre- and post-treatment serum samples of 85 FC patients from MZRW/Senna/placebo treatment groups for pharmacometabolomic analysis. An ultrahigh-performance liquid chromatography-mass spectrometer (UPLC-MS) was used for metabolic profiling and quantification. In vivo studies were conducted in constipated C57BL/6J mice to verify the effects and corresponding mechanism(s) of the action of MZRW. Pearson correlation analysis, paired t-test, one-way ANOVA analysis, χ2 test, and Student t-test were used to interpret the clinical and preclinical data. Changes in levels of circulating oleamide and its derivatives negatively correlate with improvement in complete spontaneous bowel movement (CSBM) in the MZRW group (Pearson r = -0.59, p = 0.00057). The same did not hold true for either Senna or placebo groups. Oleamide is a known regulator of intestinal motility. MZRW treatment resulted in reduced levels of circulating oleamide in FC patients. Experimental verification showed that MZRW attenuated oleamide-induced slow intestinal motility in mice. MZRW decreased oleamide levels in serum, ileum, and colon in normal mice, but increased expression of colonic fatty acid amide hydrolase (FAAH). In conclusion, MZRW improved bowel movement in FC by down-regulating oleamide, possibly by enhancing FAAH-mediated degradation. Our findings suggest a novel therapeutic strategy for FC.

Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines.

Quantitative information is scarce with regard to guidelines for currently prescribed medications for constipation. Furthermore, these guidelines do not reflect the differences in the number of bowel movements caused by each drug. In this study, we used a model-based meta-analysis to quantitatively estimate the deviations from the baseline number of spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs) associated with pharmacotherapy for chronic constipation to bridge the knowledge gap in the guidelines for current medications. A comprehensive survey was conducted using literature databases. In this study, we also included randomized placebo-controlled trials on chronic constipation. Pharmacodynamic models were established to describe the time course of the numbers of SBMs and CSBMs produced by each drug. Data from 20 studies (comprising 9998 participants and 8 drugs) were used to build this model. The results showed that bisacodyl had the greatest effect on increasing the frequency of bowel movements, whereas plecanatide yielded the lowest increase in the number of SBMs and CSBMs. After eliminating the placebo effect, the maximal increase in bowel movement frequency associated with bisacodyl was 6.8 for SBMs (95% confidence interval: 6.1-7.6) and 4.7 for CSBMs (95% confidence interval: 4.3-5.1) per week. These numbers are ∼4 times higher than the number of bowel movements produced by plecanatide. The change in the frequency of SBMs and CSBMs for other drugs, such as sodium picosulfate, velusetrag, linaclotide, elobixibat, lubiprostone, and prucalopride, was similar. The highest increases in the frequency of SBM and CSBM were 2.5 to 4 and 1 to 2.1 per week, respectively. Bisacodyl had the most noticeable loss of efficacy between week 1 and week 4; it reduced the frequencies of SBMs and CSBMs by 2.3 and 2.2, respectively. By contrast, the changes in the frequencies of SBMs and CSBMs were not as great with other drugs. The data provided in this study may be a valuable supplement to the medication guidelines for the treatment of chronic constipation.

The Effectiveness of Acupuncture in Management of Functional Constipation: A Systematic Review and Meta-Analysis.

Objective The purpose of this study was to assess the effectiveness and safety of acupuncture for functional constipation (FC). Methods A rigorous literature search was performed in English (PubMed, Web of Science, the Cochrane Library, and EMBASE) and Chinese (China National Knowledge Infrastructure (CNKI), Chinese Biological Medical (CBM), Wanfang database, and China Science and Technology Journal (VIP)) electronic databases from their inception to October 2019. Included randomized controlled trials (RCTs) compared acupuncture therapy with sham acupuncture or pharmacological therapies. The outcome measures were evaluated, including the primary outcome of complete spontaneous bowel movement (CSBM) and secondary outcomes of Bristol Stool Form Scale (BSFS), constipation symptoms scores (CSS), responder rate, the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, and safety evaluation. Meta-analysis was performed by using RevMan5.3. Results The merged data of 28 RCTs with 3525 participants indicated that acupuncture may be efficient for FC by increasing CSBMs (p < 0.00001; MD = 0.84 [95% CI, 0.65 to 1.03]; I2 = 0%) and improving constipation symptoms (p=0.03; SMD = −0.4 [95% CI, −0.78 to −0.03]; I2 = 74%), stool formation (p < 0.00001; MD = 0.24 [95% CI, 0.15 to 0.34]; I2 = 0%), quality of life (p < 0.00001; N = 1, MD = −0.33 [95% CI, −0.45 to −0.21]), and responder rates (p=0.02; RR = 2.16; [95% CI, 1.1 to 4.24]; I2 = 69%) compared with the effects of sham treatment. No increased risk of adverse events was observed (p=0.44; RR = 1.18; [95% CI, 0.77 to 1.81]; I2 = 0%). With regard to medication comparisons, the pooled data indicated that acupuncture was more effective in increasing CSBMs (p=0.004; MD = 0.53 [95% CI, 0.17 to 0.88]; I2 = 88%) and improving patients' quality of life (p < 0.00001; SMD = −0.73 [95% CI, −1.02 to −0.44]; I2 = 64%), with high heterogeneity. However, there were no significant differences in responder rate (p=0.12; RR = 1.31; [95% CI, 0.94 to 1.82]; I2 = 53%), BSFS (p=0.5; MD = 0.17 [95% CI, −0.33 to 0.68]; I2 = 93%), or CSS (p=0.05; SMD = −0.62 [95% CI, −1.23 to −0.01]; I2 = 89%). Regarding safety evaluation, acupuncture was safer than medications (p < 0.0001; RR = 0.3; [95% CI, 0.18 to 0.52]; I2 = 30%). Conclusions Current evidence suggests that acupuncture is an efficient and safe treatment for FC. Acupuncture increased stool frequency, improved stool formation, alleviated constipation symptoms, and improved quality of life. However, the evidence quality was relatively low and the relationship between acupuncture and drugs is not clear. More high-quality trials are recommended in the future. PROSPERO registration number: CRD42019143347.

The effect and safety of acupuncture on patients with functional constipation: Protocol for a systematic review and meta-analysis of high quality RCTs.

Background:Functional constipation (FC) is a prevalent clinical disease that affects a considerable proportion of the population of all ages. Persistent FC significantly reduces quality of life and influences physical and emotional well-being, as well as consumes many substantial healthcare resources. Acupuncture originates from Traditional Chinese Medicine (TCM), and emerging evidence of several randomized controlled trials (RCTs) published suggest that acupuncture has positive effects for FC. Since 2019, several new results of high quality RCTs about acupuncture treatment for FC have been published. Thus a systematic review will be designed to appraise the effectiveness and safety of acupuncture for improvement of FC in patients based on high quality RCTs.Methods:We carried out a rigorous literature search in English and Chinese electronic database from inception to present. Two reviewers will identify relevant studies, extract and manage trial information, and then assess the risk of bias in included studies by the Cochrane risk of bias assessment tool. Only high quality RCTs will be included. Data will be synthesized by either fixed-effects or random-effects model regarding to a heterogeneity test. The primary outcome measurement will be the change from baseline in mean complete spontaneous bowel movements and stool form. The secondary outcomes involved disappearance rate of symptoms, proportion of responders, mean transit time, health-related quality of life, and safety of intervention. Meta-analysis will be performed by using Cochrane's RevMan software.Results:This systematic review will summarize high quality clinical evidence to assess and appraise the effectiveness and safety of acupuncture treatment for FC patient.Expected conclusion:This systematic review and meta-analysis will provide evidence to determine whether acupuncture treatment is an effective and safe therapy for the prevention and treatment of FC compared with medication treatment.

A Randomized Double-blind Placebo-controlled Trial on the Effect of Magnesium Oxide in Patients With Chronic Constipation.

Background/AimsMagnesium oxide (MgO) has been frequently used as a treatment for chronic constipation (CC) since the 1980s in Japan. The aim of this study is to evaluate its therapeutic effects of MgO in Japanese CC patients.MethodsWe conducted a randomized, double-blind placebo-controlled study. Thirty-four female patients with mild to moderate constipation were randomly assigned to either placebo (n = 17) or MgO group (n = 17) 0.5 g × 3/day for 28 days. Primary endpoint was overall improvement over the 4-week study period. Secondary endpoints were changes from baseline in spontaneous bowel movement (SBM), response rates of complete spontaneous bowel movement (CSBM), stool form, colonic transit time (CTT), abdominal symptom, and quality of life.ResultsOne patient failed to complete the medication regimen and was omitted from analysis: data from 16 placebo and 17 MgO patients were analyzed. The primary endpoint was met by 25.0% of placebo vs 70.6% of MgO group (P = 0.015). MgO significantly improved SBM changes compared to placebo (P = 0.002). However, MgO did not significantly improved response rates of CSBM compared to placebo (P = 0.76). In addition, MgO significantly improved Bristol stool form scale changes (P < 0.001) and significantly improved CTT compared to the placebo group (P < 0.001). MgO significantly improved the Japanese version of the patient assessment of constipation quality of life (P = 0.003).ConclusionOur placebo-controlled study demonstrated that MgO was effective treatment for improving defecation status and shortened CTT in Japanese CC patients with mild to moderate symptoms.

Placebo Response in Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo response in randomized controlled trials has not been described. We conducted a search of the medical literature following the protocol outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement using MEDLINE, EMBASE and EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials for all drugs used for the treatment of CIC. Two independent reviewers performed eligibility assessment and data extraction. The mean response rate was examined for the following 2 responder endpoints: (i) greater than or equal to 3 complete spontaneous bowel movements (CSBMs)/wk (≥3 CSBMs/wk responders) and (ii) mean increase of ≥1 CSBM/wk compared with baseline (increase in ≥1 CSBM/wk responders). A total of 23 placebo-controlled trials met our inclusion criteria and were included in this meta-analysis. The placebo response in CIC trials ranged from 4% to 44%. The magnitude of the placebo response was 13% (95% confidence interval 11%-16%) with the ≥3 CSBM/wk responder endpoint and 28% (95% confidence interval 21%-30%) with the increase of ≥1 in the CSBM responder endpoint. Higher baseline CSBM, older age, and trials with more male participants were significantly associated with a stronger placebo response for both the ≥3 CSBMs/wk endpoint and increase in the ≥1 CSBM/wk endpoint. Trial characteristics such as location (Europe vs Asia/United States) and laxative class (prokinetic vs secretagogue) revealed key differences in the placebo response for both endpoints. The placebo response was not significantly affected by the number of study visits, study duration, year of publication, number of drop outs, or likelihood of receiving active drug. The placebo response in CIC trials ranges from 4% to 44% depending on the endpoint. Modifying factors of the placebo response include multiple subject and trial characteristics.

499 Plecanatide for Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome-Constipation: Analysis of Abdominal Bloating From Four Randomized Phase 3 Clinical Trials

INTRODUCTION: Patients with chronic idiopathic constipation (CIC) or with irritable bowel syndrome with constipation (IBS-C) often report bloating. Plecanatide is an analogue of human uroguanylin, an intestinal peptide that induces fluid and ion secretion. Data from 4 large randomized, placebo-controlled trials in CIC (2 studies) or in IBS-C (2 studies) were analyzed to determine whether plecanatide improved bloating in patients with CIC or IBS-C. METHODS: Patients (N = 2683) who met modified Rome III criteria for CIC or patients (N = 2189) who met Rome III criteria for IBS-C were included in separate combined phase III intention-to-treat populations in CIC and IBS-C, respectively. Patients were randomized to placebo, plecanatide 3 mg QD, or plecanatide 6mg QD for 12 weeks. Baseline characteristics were comparable between groups within the CIC studies and within the IBS-C studies. The primary endpoint for the CIC trials was the percentage of durable overall complete spontaneous bowel movement (CSBM) responders (≥3 CSBMs plus increase of ≥1 CSBM over baseline in the same week) for ≥9 of the 12 treatment weeks, including ≥3 of the last 4 weeks. The IBS-C primary endpoint was the percentage of Overall Responders, defined as a patient who was a weekly responder (CSBM + ≥30% improvement in abdominal pain) for ≥6 of the 12 treatment weeks. Electronic diaries recorded daily symptoms of bloating (0 = none to 4 = very severe) and bowel movements. RESULTS: In patients with CIC, pooled efficacy demonstrated a significantly greater percentage of CSBM responders in each of the plecanatide groups when compared to the placebo group. Both plecanatide 3mg and 6mg resulted in a significantly greater percentage of Overall Responders than did placebo in the IBS-C studies (Table 1). In CIC or IBS-C, over the 12-week treatment period, both plecanatide treatment groups experienced a significantly greater reduction in weekly mean abdominal bloating scores compared with the placebo group (Table 2). The most common adverse event (AE) was diarrhea across all studies; discontinuation rates due to AEs including diarrhea were similar across studies (Table 3). CONCLUSION: Patients with CIC or IBS-C who received plecanatide 3 mg and 6 mg demonstrated a significantly greater percentage of responders compared to patients who received placebo. Bloating was significantly improved both in patients with CIC and IBS-C. Plecanatide treatment was associated with a low incidence of diarrhea and other AEs.