Treatment Of Chronic Constipation Research Articles

Lubiprostone in constipation: clinical evidence and place in therapy.

Constipation is one of the most common function bowel disorders encountered by primary care providers and gastroenterologists. Disorders of chronic constipation, including irritable bowel syndrome with constipation, chronic idiopathic constipation, and opioid-induced chronic constipation, are associated with significant medical costs and a negative impact on quality of life. Although there is evidence supporting the effectiveness of some over-the-counter laxatives in chronic constipation, currently there is no evidence supporting lifestyle modification, dietary change or over-the-counter laxatives as effective long-term therapy for patients with chronic constipation. Lubiprostone is a prostaglandin-derived bicyclic fatty acid available to use for long-term treatment of constipation. Lubiprostone works by increasing intraluminal chloride ion secretion, which results in a passive influx of water and sodium, leading to increased intestinal peristalsis and colonic laxation with decreased intestinal stool transit time. Randomized, double-blind, placebo-controlled trials of lubiprostone in patients with chronic constipation, irritable bowel syndrome and opioid-induced constipation have shown it to be effective and free of serious adverse effects. The most common side effects associated with lubiprostone are mild to moderate nausea and diarrhea. Currently lubiprostone is approved for treatment of chronic constipation and opioid-induced constipation for men and women at 24 µg twice daily and for treatment of irritable bowel syndrome with constipation in women at 8 µg twice daily. Additional research continues to shed light on the molecular mechanisms of lubiprostone and further work may expand its clinical applications.

Curative effect of mosapride vs prucalopride in treatment of chronic constipation in elderly patients

Curative effect of mosapride <i>vs</i> prucalopride in treatment of chronic constipation in elderly patients

Role of Prucalopride in Treatment of Chronic Constipation and Recurrent Functional Obstruction in a Patient With Steinert Myotonic Dystrophy

Role of Prucalopride in Treatment of Chronic Constipation and Recurrent Functional Obstruction in a Patient With Steinert Myotonic Dystrophy

New Generation Laxatives

A significant proportion of chronic constipation patients are dissatisfied with their treatment. Recently, a number of new medicationshave been introduced for patients refractory to conventional laxatives, such as prucalopride, lubiprostone, linaclotide, andelobixibat. Prucalopride is a novel gastrointestinal prokinetic agent that acts as a 5-hydroxytryptamine type 4 (5-HT4) agonist. Compared with older nonselective 5-HT4 agonists, the higher selectivity of prucalopride for 5-HT4 receptors can reduce the risk ofsignificant adverse cardiovascular events. Prucalopride improves stool frequency and consistency, and reduces the need for rescuemedications. Lubiprostone, a chloride channel activator, increases the secretion of intestinal fluid, improves the stool frequency andconsistency, and reduces straining. Linaclotide, a guanylate cyclase-C agonist, is effective in treating patients with chronic constipationand its effect on visceral sensitivity, as shown mainly in animal studies, provides an attractive pharmaceutical option for patients with irritable bowel syndrome with constipation. Elobixibat is an ileal sodium-dependent bile acid transporter inhibitor thatblocks the enterohepatic circulation of bile acids, increasing the bile acid concentration in the intestine, which accelerates colonictransit and softens the stool. A phase III trial of the treatment of chronic constipation and irritable bowel syndrome with constipationis underway. The clinical application of new-generation laxatives will contribute to the management of chronic constipation refractoryto conventional laxatives.

Acute Respiratory and Renal Failure due to Hypermagnesemia, Induced by Counter Laxatives in an Elderly Man.

Sir, Increased serum magnesium levels are generally iatrogenic and rare clinical situations with significant cardiovascular, neurological and neuromuscular effects. Patients with bowel disorders, renal insufficiency, and patients with old age are especially at high risk for hypermagnesemia. The treatment of hypermagnesemia includes discontinuing the magnesium intake, gastrointestinal decontamination, intravenous calcium gluconate and hemodialysis [1]. Herein, we report a life threating hypermagnesemia situation induced by a magnesium containing product, used for the treatment of chronic constipation. A 70-year-old man presented with constipation, chest tightness and dyspnea. He had a history of chronic obstructive pulmonary disease, chronic kidney failure and diabetes mellitus. Contrast enema was planned on the first hospital day. The patient became lethargic in the second day of hospitalization. Abdominal pain with diminished bowel sounds was observed. The neurological examination showed symmetric decrease in muscle tone and in deep tendon reflexes. Mechanical ventilation was initiated according to arterial blood gas results. Biochemical results were as follows; magnesium, 9.07 (1.5–2.6) mEq/L; calcium, 7.78 (8.4–10.2) mEq/L, sodium, 140 (135–145) mEq/L; potassium, 5.5 (3.5–5.1) mEq/L; creatine, 3.85 (0.2–1.2) mg/dL; blood urine nitrogen, 202.5 (70–105) mg/dL. Calcium gluconate was infused for antagonizing most of the clinical effects of toxicity. A nasogastric and rectal tube were inserted for gastrointestinal decontamination. Emergency continuous veno-venous haemodialysis (CVVHD) for hypermagnesemia was performed and continued during 48 hours. Finally, after a 48 hour CVVHD treatment, the Mg level decreased to 2.0 mEq/L) and the patient was extubated. The follow up period was uneventful. Magnesium is an important intracellular cation that functions as a co-factor in several enzyme pathways. The magnesium plasma value is generally between 1.4 and 2.1 mEq/L and closely regulated through interaction of the gastrointestinal absorption, bone store and kidney excretion [2]. Hypermagnesemia can occur with various processes such as renal failure, Addison disease, milk alkali syndrome, hypothyroidism and with lithium therapy. Decreased elimination, magnesium overdose and increased absorption are the main causes of hypermagnesemia. Our patient had both decreased elimination as a consequence of kidney failure and magnesium overdose due to laxative usage [3]. Clinical manifestations of hypermagnesemia vary according to the serum Mg concentration. Symptomatic hypermagnesemia typically presents with neurological, neuromuscular and cardiac manifestations including hyporeflexia, sedation, muscle weakness and respiratory depression but many physicians are relatively unfamiliar with these conditions [4]. Especially elder patients are at high risk of magnesium toxicity as the kidney function declines with age [5]. Relationship between hypermagnesemia and laxative usage should induce physicians to pay more attention to hypermagnesemia especially in this subgroup of patients and urgent CVVHD is highly effective in preventing significant morbidity and mortality.

Stimulation of Mucin, Mucus, and Viscosity during Lubiprostone in Patients with Chronic Constipation may Potentially Lead to Increase of Lubrication.

Objectives:The purpose of this clinical trial was to explore whether lubiprostone increases the rate of mucus and mucin secretion and its viscosity in chronic constipation (CC) patients. The secretion of chloride (CS) into the gastrointestinal tract lumen is pivotal in the body's ability to process non-digestible food components. CS sets the optimal rate of hydration for non-digestible food components, their fluidity, and their adequate propulsion along the alimentary tract. Chloride is also instrumental in the secretion of alimentary tract mucus, and the formation of a gel-like, viscous mucus-buffer layer. This layer acts as the first line and vanguard of the mucosal barrier. This barrier is essential in mucosal lubrication and protection. Lubiprostone, a novel chloride channel stimulator ClC-2, is currently approved for the treatment of CC. Its impact on mucus, mucus secretion, and viscosity is not established.Methods:A double-blind, crossover trial was approved by the IRBs at the Kansas University Medical Center (Kansas City, KS) (study site) and at the Texas Tech University HSC (El Paso, TX) (analysis site). The study included 20 patients (17 females (F); mean age: 37 years) with symptoms of CC diagnosed according to the Rome III criteria. Patients were randomized to 1 week of therapy with lubiprostone or placebo followed by a 1 week washout and 1 week of the alternative therapy. Gastric juice was collected basally and during stimulation with pentagastrin (6 μg/kg body weight subcutaneously) at the end of weeks 1 and 3. Pentagastrin stimulation mimics food stimulation. The mucus content in gastric juice was assessed gravimetrically. The mucin content was measured after its purification using ultracentrifugation. The viscosity of the gastric secretion was measured using a digital viscometer.Results:In comparison with placebo, the volume of gastric secretion in patients with CC during administration of lubiprostone increased significantly by 50% (86.3 vs. 57.5 ml/h) (P<0.001) in basal conditions and increased by 25% (210.0 vs. 167.6 ml/h) (P=0.024) during stimulation with pentagastrin. The rate of gastric mucus secretion during therapy with lubiprostone was 91% higher (257.3 vs. 135 mg/h) (P=0.001) in basal conditions and 28% higher (348.1 vs. 270.8 mg/h) (NS) in stimulated conditions, although the latter was not statistically significant. The rate of gastric mucin secretion during lubiprostone therapy was 85% higher (98.4 vs. 65.5 mg/h) (P=0.011) in basal conditions and 38% (98.3 vs. 71.7 mg/h) (NS) higher in stimulated conditions. In basal conditions, the viscosity of gastric secretion during administration of lubiprostone increased by 240% at the lowest (P<0.001) and by 106% at the highest shear rate (P<0.001). In stimulated conditions, it increased by 226% (P<0.01) at the lowest shear rate and by 67% (P<0.01) at the highest shear rate.Conclusions:The significantly higher content of gastric mucus and mucin during therapy in basal conditions with lubiprostone in patients with CC suggests and supports the potentially leading role of lubiprostone and ClC-2 stimulation in their secretion. This increased stimulation results in profoundly increased viscosity, which in turn facilitates and/or accelerates the transit and evacuation of non-digestible food components. Although increases in mucus and mucin were observed in stimulated conditions, neither increase was statistically significant. Based on this experiment, we hypothesize that, in CC patients, the significantly increased rate of mucus and its major component, mucin secretion, during lubiprostone administration may partially explain its clinical effectiveness and also have additional clinically important effects. We propose that since the increased mucus production enhances the protective quality of the mucosal barrier, it also boosts its potential to withstand luminal aggressive components such as acid/pepsin duet, Helicobacter pylori and/or nonsteroidal anti-inflammatory drugs/aspirin, or a combination of all. Further trials are needed to test this hypothesis. As this was crossover clinical trial, the patients serve as their own controls. No interaction was found with body mass index (BMI) and treatment. The observed relationships of BMI and mucus and mucin secretions and gastric juice volume are important considerations in the design of future trials, particularly if a crossover design is not used.

Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non-Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies

Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non-Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies

Pharmacoeconomic study of chronic constipation in a secondary care centre.

The aim of this study was to measure any incremental costs or savings within the health system associated with the introduction of the new technology, prucalopride, for the management of chronic constipation. The study design was based on a budget impact analysis conducted by the National Institute of Clinical Excellence (NICE). To validate the findings of the NICE costing template, a case series audit capturing real world data was used to determine the financial impact of adopting prucalopride in 40 women suffering with chronic constipation. This facilitated the application of local unit costs to the resources used and determined whether the use of prucalopride, as an alternative treatment to laxatives, resulted in a reduction in the use of secondary care resources. Patients were treated with an average of 2.6 laxatives in the baseline (laxatives only) scenario. The total medication costs in the baseline (laxatives only) and the new treatment (prucalopride) scenario amounted to €17,440.84 and €18,417.62, respectively. There was a significant reduction in the number of investigations and procedures in the 12months after commencing prucalopride, with cost savings of €41,923.28 (€1,048.08 per patient per year) demonstrated. Input cost variables were adjusted as part of sensitivity analysis. This study validated the findings of the NICE costing template and suggests that the use of prucalopride for the treatment of chronic constipation in women refractory to laxatives has the potential to reduce secondary care resource use and hence led to cost savings.

Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non-Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies.

Background/AimsTo compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC).MethodsData of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of ≥ 3 spontaneous complete bowel movements (SCBMs)/week; average increases of ≥ 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining).ResultsOverall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of ≥ 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of ≥ 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups.ConclusionsPrucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.

Psychometric validation of patient-reported outcome measures assessing chronic constipation.

BackgroundMeasures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration’s guidance on patient-reported outcomes.AimPsychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures.Study methodsEach study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed.ResultsThe CC Symptom Severity Measures demonstrated satisfactory test–retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change.ConclusionIn large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

Linaclotide: a novel agent for chronic constipation and irritable bowel syndrome.

The pharmacology, pharmaco-kinetics, and clinical efficacy and safety of linaclotide in the management of chronic constipation (CC) and constipation-predominant irritable bowel syndrome (IBS-C) are reviewed. Linaclotide (Linzess, Forest Pharmaceuticals) is a 14-amino acid peptide indicated for the treatment of adults with CC and IBS-C. Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation; the drug is minimally absorbed into the systemic circulation. Linaclotide is approved by the Food and Drug Administration (FDA) for oral once-daily administration at doses of 145 μg for CC and 290 μg for IBS-C. In placebo-controlled Phase III clinical trials, linaclotide significantly increased weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with CC. In patients with IBS-C, linaclotide was demonstrated to be effective in meeting FDA-recommended endpoints such as reductions of at least 30% from baseline in abdominal pain scores and CSBM frequency. The most common adverse effect of linaclotide is diarrhea, which was reported in 16-20% of clinical trial participants. Linaclotide is an important advance in the treatment of CC and IBS-C, with a novel mechanism of action resulting in accelerated intestinal transit. In clinical trials, linaclotide demonstrated efficacy relative to placebo for treatment of both CC and IBS-C. Linaclotide's adverse effects are generally mild and confined to the gastrointestinal tract.

Comparison of Polyethylene Glycol 3350 and Product Made from Saccharum Officinarum L. for Treatment of Chronic Constipation; A Double-Blind Clinical Trial

Comparison of Polyethylene Glycol 3350 and Product Made from Saccharum Officinarum L. for Treatment of Chronic Constipation; A Double-Blind Clinical Trial

929g Efficacy and safety of prucalopride in men with chronic constipation: a phase 3, randomized, double-blind, placebo-controlled trial

Introduction Prucalopride (PRU) is a high-affinity serotonin receptor (5-HT 4 ) agonist approved in Europe for the symptomatic treatment of chronic constipation (CC) in women. The aim of this study was to evaluate the efficacy and safety of PRU in men with CC. Method This was a phase 3, multicentre, parallel-group, double-blind trial (NCT01147926). Men aged ≥ 18 years with CC who had ≤ 2 spontaneous complete bowel movements (SCBMs)/week were randomised to receive placebo (PLA) or PRU 2 mg (starting dose of 1 mg for patients aged ≥ 65 years) once daily for 12 weeks. The primary endpoint was the proportion of men achieving a mean of ≥ 3 SCBMs/week over 12 weeks. Secondary endpoints included Patient Assessment of Constipation-Symptoms (PAC-SYM) and Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire scores. Safety was assessed throughout the study. Results Overall, 374 patients were randomised. More men in the PRU group than in the PLA group (37.9% vs. 17.7%, respectively; p p = 0 .0743) and ≥ 1 SBM/week (65.5% vs. 43.1%; p p = 0 .3152) or abdominal (39.1% vs. 35.1%; p = 0 .4874) or rectal (34.9% vs. 29.2%; p = 0 .2759) subscale scores. However, there was a significant difference in stool symptoms score (53.3% vs. 36.3%; p = 0 .0005). The proportion of men with an improvement of ≥ 1 in total PAC-QOL score was higher with PRU (40.2%) than PLA (32.7%; p = 0 .0755). PRU had a good safety profile and was well tolerated, consistent with previous studies. The incidences of serious adverse events and ischaemic cardiovascular adverse events were low and similar in both treatment groups. Conclusion Results from this study demonstrate that PRU is effective, has a good safety profile and is well tolerated in men with CC, similar to the findings for women with CC. Disclosure of interest Y. Yiannakou Grant/ Research Support from: Shire, Consultant for: Shire, M. Bouchoucha: None Declared, I. Schiefke: None Declared, H. Piessevaux Conflict with: Shire, R. Filip: None Declared, L. Gabalec: None Declared, D. Stephenson Employee of: Shire, R. Kerstens Employee of: Shire, K. Etherson Conflict with: Shire, A. Levine Employee of: Shire.

Challenges and New Treatment in Childhood Constipation

Chronic Constipation is a debilitating condition that is often associated with different abdominal problem. It can cause distress for the child and family and can result in emotional disturbance and family problem. Based on the current algorhytm, the treatment of chronic constipation consists of 4 important phases, 1: education, 2: disimpaction, 3: prevention of re-accumulation of feces and 4: follow up. Challenges in treatment are related to many issues: a) Discussing the importance of problem for parents, b) Family concern about safety and side effects of drugs, c) Adherence to long term treatment, which is often crucial but unacceptable by family, d) Amelioration of withdrawal behavior in toddlers group which don’t understand the facts, e) Planning a appropriate diet for constipation which is again unacceptable by children, f) Cost of treatment g) Anismus Besides of known treatment consist of various drugs: Biofeedback is one of the approaches that have proven benefits but with less emphasis and introduction, so application of this obsolete method needs further works. Tegaserod, a selective agonist that acts at 5-HT4 receptors and increases small bowel transit, stimulates intestinal secretion and inhibits visceral afferent responses has proven effective in the treatment of chronic constipation in adults. In children with hard stools, 5-HT4 agonist might benefit children with constipation and tendency to form hard stools, and large rectal masses. The role of this promising new agent in pediatric constipation has to be established in future studies. Pre and Probiotics: Non-digestible oligosaccharides consist mainly of fructooligosaccharides (FOS). FOS reduces fecal pH, increases the water, holding capacity of stool and fecal weight and decreases intestinal transit time. Furthermore, it has prebiotic effects by selectively stimulating the growth of probiotics bacteria, such as bifidobacteria. Surgery: If conventional therapy (dietary advice, toilet training, Oral and rectal laxatives in combination with behavioral therapy) fails, surgery may then be considered. However it is well known that current surgical approach have significant associated morbidity. An alternative surgical approach to constipation might be sacral nerve stimulation.

Efficacy of Lubiprostone in Chronic Constipation: Clinical and Work Productivity Outcomes

Objective: Chronic constipation is a common health problem that significantly affects the quality of life of patients and results in high economic burden. This clinical study was performed to assess the efficacy of lubiprostone in the treatment of chronic constipation using a validated constipation scoring system and the work productivity and activity impairment questionnaire. Methods: We prospectively enrolled 35 patients who received lubiprostone. All the patients had chronic constipation as defined by the Rome III criteria. The patients were treated orally with a 24-μg lubiprostone capsule twice a day. Changes in the scores before and 2 weeks after the beginning of administration were recorded and analyzed. Results: Of the 35 patients, 28 completed the study and were included in the efficacy analysis. The total constipation scoring system score was significantly improved from 11.3 ± 4.8 at baseline to 8.0 ± 4.0 after 2 weeks. Although the work activity subscale did not show a significant improvement, such an improvement was statistically significant in the case of non-work-related activities. Conclusion: Our results demonstrate that lubiprostone is effective in improving many chronic constipation related symptoms as well as the quality of life in patients with chronic constipation.

The treatment of constipation with herbal laxatives

Constipation is usual health problem that affects about a quarter of the population. Treatment of constipation remains a challenge because of multiple, multifaceted aetiology and individual response of each patient. The elimination of the constipation significantly improves the quality of life. There is a wide range of herbal remedies that can be used in therapy. The first recommendation in the treatment of constipation should be a diet that contains indigestible fibres with adequate fluid intake and encouragement of physical activity. The laxatives of synthetic or natural origin could be used in the therapy of constipation. Today, the three most important groups of herbal medicines are bulk-producing, osmotic and stimulant laxatives. The most significant bulk-producing laxatives are flaxseed (Lini semen), ispaghula seed and husk (Plantaginis ovatae semen et tegumentum), and psyllium seed (Psyllii semen). Antraquinone drugs are classified in the group of stimulant laxative. Because of the potential habituation, stimulating laxatives should not be used continuously over a long treatment period. In the treatment of chronic constipation are commonly used osmotic laxatives such as fruit of the black mulberry (Mori nigri fructus), figs (Fici fructus), fruit of tamarind (Tamarindi fructus) and Manna. All laxatives are effective but side effects are different from preparation to preparation.

Current issues on the treatment of chronic constipation

Chronic constipation is a very common clinical problem with its prevalence of up to 14% in the general population. It is not a life-threatening disease, but since patient's satisfaction to the treatment is known to be as low as 50%, chronic constipation still remains a clinically challenging problem. Fortunately, many new treatments have been introduced or are to be introduced in the near future. This article will review the basic concepts and the results of recent studies on the new treatments for chronic constipation.

Prucalopride for treatment of chronic constipation: A systematic review

Prucalopride for treatment of chronic constipation: A systematic review

Systematic review with meta‐analysis: highly selective 5‐HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation

Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC). To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC. We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR=1.85; 95% CI 1.23-2.79); mean ≥1 SCBM over baseline (RR=1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5-HT4 agonists in the treatment of chronic constipation.

Chronic constipation and treatment options (Review)

Chronic constipation (CC) is a highly prevalent heterogeneous disorder. Although CC is not known to be associated with the development of serious disease or with excess mortality, it considerably reduces the patients quality of life. In addition, it represents an economic burden to patients and society. The majority of patients with CC successfully manage the disorder by dietary management and the use of laxatives. Patients with functional CC (slow‑transit and non‑slow transit constipation) do not respond to laxatives and are a small fraction of the total population complaining of constipation. Regardless of the low number of these patients, the intractability of their symptoms causes psychological and social stress and greatly impairs their quality of life. Furthermore, these patients consume a disproportionate quantity of medical resources. It appears that these patients have a disturbance in the serotonin transmission system, which results in a cascade of alterations in a number of gut neuroendocrine hormones/transmitters. The effect of prucalopride, a serotonin receptor agonist, in this category of patients appears to be not only a pharmacological prokinetic action, but also a correction of a pre‑existing disturbance. Linaclotide, a member of the guanylin peptide family, binds to the ligand‑binding region of guanylate cyclase‑C on the luminal surface of gastrointestinal epithelia resulting in increased fluid secretion. This drug has also been found to be effective for the treatment of functional CC. In addition, biofeedback and sacral nerve stimulation are effective in the treatment of CC caused by pelvic floor disorders.