Development And Validation Of A Stability Indicating Rp-Hplc Method For The Determination Of Prucalopride Succinate In Bulk And Tablet

A very simple, precise, economical, accurate, robust, and reproducible reverse phase-high-performance liquid chromatography method along with stability indicating attributes has been developed for estimating of prucalopride succinate (PRU) in both bulk and tablet formulation (PRUVICT 2). The estimation of the solutes was performed on a Grace C18 column of dimension 150 mm × 4.6 mm, 5 μm. PRU was eluted with acetonitrile: 0.02 M potassium dihydrogen phosphate in the ratio of 20:80 v/v in a 10 min isocratic mode at a flow rate of 1 ml/min at 30°C column temperature and monitored at a wavelength of 277 nm. The retention time of PRU was found to be 5.416 minutes. The Q2b validation of the analytical method revealed good linearity over the concentration range 2–12 μg/mL for IVA with r2 of 0.999. The mean recovery % over the three tested ranges of 50%, 100%, and 150% were found to be 100.173%, 99.077%, and 98.575%, respectively. In intra-day variability study, the % RSDs was detected to be 0.754, 1.032, and 0.482 whereas the inter-day variability study demonstrated % RSDs of 0.797, 0.559, and 0.524, respectively. The acid, alkali, boiled water, hydrogen peroxide, dry heat, and UV radiations based stress studies presented the formation of a variety of characteristic degradation products. The developed analytical method may be employed for the routine analysis of PRU in bulk and tablet formulations.

Systematic review on the treatment of functional constipation with electroacupuncture and gastro-kinetic drugs / 针刺研究

OBJECTIVE: To compare the therapeutic effect and safety in treatment of functional constipation between electroacupuncture (EA) and gastro-kinetic drugs. METHODS: Using "functional constipation"， "prucalopride"， "mosapridecitrate"， "electro-acupuncture" and "randomized controlled trial"， both in Chinese and English, as search terms, the articles of randomized controlled trial (RCT) regarding to the comparison of therapeutic effect on functional constipation in the patients between EA and gastro-kinetic drugs were retrieved from CMB, Wanfang, VIP, CNKI, OpenGrey, CINAHL, Cochrane Library, JBI, PubMed, WOS and Ovid databases. The retrieval time was from the establishment date to June 2018. The two researchers screened articles, extracted data and assessed literature quality in reference to Cochrane Handbook. Using RevMan 5.3 software, the meta-analysis was conducted. RESULTS: A total of 11 articles were included finally, with 744 patients involved. It was found after meta-analysis that in EA group, the weekly spontaneous defecation frequency, constipation related quality of life in patients, depression relief and incidence of adverse reaction were all better than those in gastro-kinetic medication group. The therapeutic effect of the improvements in stool character and defecation difficulty in EA group were better or similar to that in gastro-kinetic medication group. CONCLUSION: Regarding the therapeutic effect and safety in treatment of functional constipation, the results of electroacupuncture are superior or similar to gastro-kinetic medication, presenting a satisfactory therapeutic prospect.

Prucalopride: novel drug for chronic idiopathic constipation

Chronic Idiopathic Constipation (CIC), defined as constipation in which the underlying cause is unknown, is a common medical illness with a profound negative impact on health-related quality of life and increased propensity for life threatening complications. Current treatment for CIC includes lifestyle modifications, over-the-counter medications, and prescription medications. Presently, the only approved, prescription products for CIC in the US are prosecretory agents. However, the current knowledge that serotonin plays an important role in colonic motility has opened new horizons in the treatment of CIC promoting use of prokinetic agents with a different mechanism of action. Prucalopride is a highly selective 5-hydroxytryptamine type 4 (5-HT4) receptor agonist that enhances propulsive motor patterns in the large intestine due to a high affinity for 5-HT4 receptors in gastrointestinal (GI) tissues. The onset of action of Prucalopride is fast, shows rapid absorption, oral bioavailability of 93% and linear pharmacokinetics. Most common adverse reactions seen are headache, nausea, diarrhea, and abdominal pain. Clinical trials for Prucalopride have been positive, and results suggest that the drug may be a new safe and effective option for CIC treatment, especially for patient’s refractory to prosecretory agents. As a prescription drug for the management of constipation and given the virtual demise of other prokinetic agents for this indication, prucalopride competes primarily with another class of agents: those that stimulate secretion. With Shire Pharmaceuticals having already received US FDA approval in Dec 2018, Prucalopride may soon be a new addition to the mounting armoury of drugs against CIC.

Eficacia comparativa de prucaloprida versus tegaserod en pacientes con síndrome de intestino irritable de predominio estreñimiento / Comparative efficacy of prucalopride and tegaserod in patients with predominantly constipated irritable bowel syndrome

Resumen Introducción El síndrome de intestino irritable (SII) afecta del cinco al 20% de los individuos alrededor del mundo. En México (Veracruz) se ha documentado una prevalencia de 16.9%. Su diagnóstico se basa en los criterios de Roma III y su tratamiento tiene diferentes enfoques; dentro del farmacológico están los fármacos agonistas de los receptores de la serotonina (5-HT4). La eficacia del tegaserod ha sido establecida en pacientes con SII con estreñimiento (SII-E); la prucaloprida se considera un fármaco con potencial terapéutico para ese padecimiento, ya que muestra mayor afinidad para el receptor 5-HT4 con respecto al tegaserod y acelera el tránsito colónico. Sin embargo, se requieren mayores datos de estudios clínicos controlados aleatorizados que lo comprueben. Objetivo Comparar la eficacia de la prucaloprida con la del tegaserod en el tratamiento del intestino irritable con estreñimiento, por medio de la escala de Bristol, la escala global de síntomas y síntomas asociados. Material y métodos Se establecieron dos grupos de pacientes (A y B) de forma aleatorizada: hombres y mujeres de entre 18 y 50 años de edad, con criterios de Roma III para SII-E; fueron sometidos a una misma dieta. Al grupo A se le administró prucaloprida en dosis de 2 mg vía oral cada 24 horas por dos semanas. Al grupo B se le administraron 6 mg de tegaserod cada 12 horas por dos semanas. La evolución clínica de cada paciente se valoró cada semana durante las dos semanas del periodo de estudio, incluyendo las evaluaciones de la escala adaptada y validada de Bristol y de la escala global de síntomas y síntomas asociados. Resultados Se incluyeron 22 pacientes, 21 (95.5%) del sexo femenino, con una proporción 1:21; la edad promedio fue de 37.27 años; 11 (50%) recibieron prucaloprida y el resto, tegaserod. Para evaluar la asociación entre el tratamiento otorgado y los síntomas de «plenitud rectal, esfuerzo al evacuar y urgencia al evacuar¼, se utilizó la prueba exacta de Fisher, que no fue estadísticamente significativa (p > 0.05); para «distensión abdominal, movimientos abdominales y escala de Bristol¼, se utilizó U de Mann-Whitney; no fue estadísticamente significativa (p > 0.05). Sin embargo, para «dolor abdominal¼, con la misma prueba, sí se encontró diferencia estadísticamente significativa (p < 0.05). De los tratados con prucaloprida, uno (9%) presentó diarrea, tres (27%) cefalea y uno (9%) cefalea y náuseas; con tegaserod, dos (18%) tuvieron diarrea, dos (18%) cefalea y uno (9%) cefalea y náuseas. Conclusiones Ambos, la prucaloprida y el tegaserod, mejoran en cierto grado todos los síntomas evaluados para el SII-E, pero la prucaloprida mejora de manera significativa y en menor tiempo el síntoma de «dolor abdominal¼. Se evidenció que el evento de diarrea implicó un cambio de tratamiento en ambos grupos.

Abstract Introduction Irritable bowel syndrome (IBS) affects 5-20% of all individuals around the world. In Mexico (Veracruz), a prevalence of 16.9% has been documented. Its diagnosis is based on the Rome III criteria, and its treatment has different approaches; within the pharmacological options are the serotonin receptor agonist drugs (5-HT4). The effectiveness of tegaserod has been established in patients with IBS with constipation (IBS-C), considering prucalopride as a drug with therapeutic potential for this condition, since it shows greater affinity for the 5-HT4 receptor than tegaserod, and accelerates colonic transit. However, more data from randomized controlled trials that prove this are required. Objective To compare the efficacy of prucalopride versus tegaserod in the treatment of irritable bowel with constipation, by means of the Bristol scale, the global scale of symptoms and associated symptoms. Material and methods Two groups of patients were established (A and B) in a randomized manner: men and women between 18 and 50 years of age with Rome criteria III for IBS-C; all were given the same diet. In group A, Prucalopride was administered at a dose of 2 mg orally every 24 hours for two weeks. In group B, 6 mg of tegaserod were administered every 12 hours for two weeks. The clinical evolution of each patient was assessed each week during the two weeks of the study period, including the assessments of the adapted and validated Bristol scale, and the global scale of symptoms and associated symptoms. Results Twenty-two patients were included, 21 (95.5%) female, with a 1:21 ratio; the average age was 37.27 years; 11 (50%) received prucalopride, and the rest, tegaserod. To evaluate the association between the treatment given and the symptoms of «rectal fullness, evacuation effort and evacuation urgency¼, Fisher's exact test was used, being not statistically significant (p > 0.05); for «abdominal distension, abdominal movements and Bristol scale¼, Mann-Whitney U was used, being not statistically significant (p > 0.05); however, for «abdominal pain¼, with the same test, a statistically significant difference was found (p < 0.05). Of those treated with prucalopride, one (9%) had diarrhea, three (27%) headache, and one (9%) headache and nausea; with tegaserod, two (18%) had diarrhea, two (18%) headache, and one (9%) headache and nausea. Conclusions Both, prucalopride and tegaserod improve to some degree all the symptoms evaluated for IBS-C, but prucalopride significantly and more promptly improves the symptom of «abdominal pain¼. It was evidenced that the diarrhea event implied change of treatment in both groups.

Efficacy and safety of prucalopride in the treatment of chronic constipation

Background: Chronic constipation is a common condition that significantly impacts health care utilization, productivity, and quality of life. Laxatives are commonly used, although often insufficient in restoring normal bowel function or providing adequate relief. There remains a significant need for the development of novel agents to optimize treatment of this condition. Prucalopride, a selective, high-affinity 5-hydroxytryptamine 4 receptor agonist, stimulates gastrointestinal and colonic motility and alleviates common symptoms of chronic constipation. Here authors are evaluating efficacy and safety study of this drug in chronic constipation patient.Methods: This is a prospective observational study where chronic constipation patient treated with prucalopride 2 mg daily once were enrolled during 6 month period. Data at one week and four weeks were observed along with adverse effects. Efficacy assessed by the number of Spontaneous Complete Bowel Movements (SCBMs) per week recorded by patient diaries. Patients were defined as responders when they had a mean of three or more SCBMs per week over the whole treatment period. The primary efficacy end point was proportion of responders after 1 week and after 4 weeks of treatment.Results: A total of 43 patients diagnosed with chronic constipation and treated with prucalopride were included in study. The proportions of patients in the present study with at least three SCBMs per week (responders) were 44.2% (19 out of 43 patients) at 1 week and 46.5% (20 out of 43 patients) at 4 weeks. Treatment was well tolerated with minimal side effects. Common adverse effects reported in our study were gastrointestinal disorders like diarrhea, nausea and abdominal pain and nervous system disorders like headache and dizziness.Conclusions: Prucalopride is effective, has a good safety profile, and is well tolerated in chronic constipation treatment.

Clinical Observation of Prucalopride in the Treatment of Chronic Constipation / 中国药房

OBJECTIVE:To observe therapeutic efficacy and safety of prucalopride in the treatment of chronic constipation (CC). METHODS:Totally of 100 CC patients were selected from anorectal department of our hospital during Jun. 2016-Jan. 2017, and then divided into control group and observation group according to random number table,with 50 cases in each group. Control group was given Mosapride citrate tablets 5 mg +Lactulose oral solution 10 mL orally,3 times a day. Observation group was given Prucalopride succinate tablets 2 mg orally,once a day. Both groups were treated for consecutive 4 weeks. Clinical efficacies of 2 groups were observed,and the levels of serum inflammatory factors(IL-6,TNF-α,IFN-γ)and colonic transit time(total colonic transit time,left colonic transit time,right colonic transit time,rectosigmoid colonic transit time)were observed before and after treatment. The occurrence of defecation disorders and ADR were recorded. RESULTS:None of patient in 2 groups was cured. Total response rate of observation group was 94.00%,which was significantly higher than 78.00% of control group,with statistical significance (P＜0.05). Before treatment,there was no statistical significance in the levels of serum inflammatory factors or colonic transit time (P＞0.05). After treatment,the levels of IL-6 and IFN-γ in control group,the levels of IL-6,TNF-α and IFN-γ in observation group were decreased significantly,and the levels of IL-6,TNF-α and IFN-γ in observation group were significantly lower than those of control group;the colonic transit time in 2 groups was shortened significantly,and observation group was significantly shorter than control group,with statistical significance (P＜0.05). After treatment,the incidence of defecation,incomplete emptying,sense of obstruction and sense of rectal tenesmus in observation group were significantly lower than control group,with statistical significance(P＜0.05). There was no statistical significance in the incidence of sense of rectal tenesmus after treatment or ADR between 2 groups (P＞0.05). CONCLUSIONS:Compared with traditional plan of mosapride combined with lactulose,prucalopride can more effectively reduce the levels of serum inflammatory factors,shorten colonic transit time,reduce the occurrence of defecation disorders as defecation and incomplete emptying,with equivalent safety.

Clinical Observation of Baizhu Shengjiang Decoction Combined with Prucalopride Succinate Tablets for Treatment of Chronic Functional Constipation / 广州中医药大学学报

Objective To observe the therapeutic effect of Baizhu Shengjiang Decoction combined with Prucalopride Succinate Tablets for chronic functional constipation. Methods Sixty patients with chronic functional constipation were randomly divided into treatment group and control group, 30 cases in each group. The treatment group was treated with Baizhu Shengjiang Decoction combined with Prucalopride Succinate Tablets orally, and the control group was treated with oral administration of Prucalopride Succinate Tablets alone. The therapeutic effects on traditional Chinese medicine (TCM) symptoms and constipation, and the follow-up therapeutic effect of the two groups were evaluated after treatment. During the three months after the completion of treatment course, the recurrence of constipation was monitored. Results (1) The cure rate of the treatment group was 90.0％ and that of the control group was 60.0％, indicating that the therapeutic effect on TCM symptoms in the treatment group was stronger than that of the control group(P < 0.05).(2) In respect of the relief of constipation, the markedly effective rate was 93.3％ in the treatment group and was 50.0％ in the control group, and the overall effective rate was 100.0％ in the treatment group and was 73.3％ in the control group, the difference being significant between the two groups(P<0.05 or P<0.01).(3) During the treatment, the percentage of patients with weekly completely spontaneous defecation frequency ≥3 was 86.7％ in the treatment group, and was 53.3％ in the control group, the difference being significant (P < 0.05). (4) The results of 3-month follow-up after the completion of treatment course showed that one case from the treatment group had the recurrence of constipation, and the recurred cases from the control group were 6, the difference being significant (P < 0.05). Conclusion Oral use of Baizhu Shengjiang Decoction combined with Prucalopride Succinate Tablets exerts certain therapeutic effect for chronic functional constipation, which is effective both on relieving constipation symptoms and on reducing recurrence rate.

Comparison of short-term curative effects of prucalopride and mosapride respectively combined with low dose polyethylene glycol in treating elderly refractory functional constipation / 重庆医学

Objective To compare the short-term curative effects of prucalopride and mosapride respectively combined with low dose polyethylene glycol in treating elderly refractory functional constipation.Methods Ninety patients with elderly refractory functional constipation in the outpatient department of our hospital from May 2014 to February 2016 were retrospectively analyzed and divided into two groups randomly,45 cases in each group.the prucalopride group:Prucalopride Succinate Tablets,2mg,4 times daily;the mosapride group:Mosapride Citrate Capsules,5mg,3 times daily.Polyethylene Glycol Electrolytes Powder(PEG) was also used in the two groups,13.125g,twice daily.The course of treatment was 4 weeks.The first defecating time and defecation difficulty relief time,average weekly spontaneous complete bowel movements (SCBM),defecating difficulty,stool character,adverse reactions and change of life quality were observed in the two groups.Results The treatment effective rate of slow transit constipation(STC) and defecatory disorder had the statistical difference between the two groups (P0.05).Compared with the mosapride group,the first defecating time and defecation difficulty relief time in the prucalopride group were shorter with statistical difference (P0.05).The total effective rate had statistical difference between the two groups(P<0.05).The incidence rate of adverse reactions had no statistical difference between the two groups(17.78% vs.15.56%,P<0.05).The total average score of PAC-QOL after treatment in the two groups were both decreased,moreover the decrease in the prucalopride group was more obvious;the difference between the two groups had statistical significance(P<0.05).Conclusion Prucalopride +PEG take effect faster in the treatment of elderly refractory functional constipation and has the advantages in the aspects of overall curative effect and life quality improvement,which is specially suitable for STC and defecatory disorder type.

Pharmacotherapy in Patients with Chronic Constipation / 대한소화기학회지

Chronic constipation is one of the most common digestive diseases frequently observed in a clinical setting. It has been known to cause considerable damage to the quality of life of patients. Despite recent developments, there are considerable limitations in the use of constipation-modulating agents in Korea. Chloride channel inhibitors, such as lubiprostone and linaclotide, have not been introduced in Korea yet, and prucalopride and several kinds of polyethylene glycol are not covered under medical insurance. This article assesses medicines that are clinically available for the management of constipation in Korea, with a brief review of agents that have recently developed around the world.

Effects of prucalopride combined with polyethylene glycol electrollytes powder in bowel preparation for colonoscopy in 124 elderly patients / 中华消化杂志

Objective To evaluate the colon cleaning efficacy and safety of prucalopride combined with polyethylene glycol electrollytes powder in bowel preparation for colonoscopy examination and treatment under colonoscopy in elderly patients.Methods Elderly patients who prepared for colonoscopy were enrolled from October 2014 to January 2015.They were divided into group A,B and C.Patients of group A only took polyethylene glycol electrolyte powder (137.12 g dissolved in 2 000 mL warm water,stired until completely dissolved),patients of group B took polyethylene glycol electrolyte powder (same usage as group A) combined with prucalopride 2 mg/d for one day,patients of group C took polyethylene glycol electrolyte powder (same usage as group A) combined with prucalopride 2 mg/d for three days.The bowel preparation effects,especially ascending colon and ileocecal junction and cardiovascular adverse effects in all the patients and constipation patients of three groups were compared.Student t test,chisquare test and analysis of variance were performed for statistical analysis.Results A total of 124 elderly patients were divided into group A (64 cases),group B (23 cases) and group C (37 cases).Bowel preparation scores of total colon and ascending colon-ileocecal junction of group A,B,C were 8.34±0.90 and 2.56±0.56,8.96±0.21 and 2.96±0.21,8.86±0.35 and 2.86±0.35,respectively.The cleaning effects in total colon and ascending colon-ileocecal junction of group B were better than those of group A (t=5.52 and 5.15,both P＜0.05).The cleaning effects in total colon and ascending colon-ileocecal junction of groupCwere better than those of group A (t=4.69,3.65,both P＜0.05).There was no statistically significant difference between group B and group C in cleaning effects in total colon and ascending colon-ileocecal junction (both P＞0.05).There were 33,11 and 29 constipation cases in group A,B and C,respectively.The bowel preparation scores for total colon and ascending colon and ileocecal junction of group A,B,C were 7.85±0.94 and 2.24±0.56,8.91±0.30 and 2.91±0.30,8.83±0.38 and 2.83 ± 0.38,respectively.The cleaning effects in total colon and ascending colon-ileocecal junction of group B were better than those of group A (t=6.72 and 5.49,both P＜0.05).The cleaning effects in total colon and ascending colon-ileocecal junction of group C were better than those of group A (t=104.04 and 59.65,both P＜0.05).There was no significant difference between group B and group C in cleaning effects in total colon and ascending colon ileocecal junction (both P＞ 0.05).No obvious cardiovascular adverse events were observed in the patients of three groups.Conclusions The cleaning effects of prucalopride combined with polyethylene glycol electrolytes powder are good for colonoscopy examination in elderly patients,including elderly patients with constipation,especially in ascending colon and ilecocecal junction.No obvious cardiovascular adverse events are observed.

Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials

This article highlights the role of prucalopride in the management of chronic constipation based upon the principles of meta-analysis using data reported in the published randomized, controlled trials. Sixteen randomized, controlled trials on 3943 patients reported the effectiveness of prucalopride in patients with chronic constipation. Prucalopride successfully increased the frequency of spontaneous bowel movements per week in all variable doses of 1 mg (standardized mean difference [SMD], 0.42 [95% CI, 0.18-0.66; P = 0.006]), 2 mg (SMD, 0.34 [95% CI, 0.11-0.56; P = 0.003]), and 4 mg (SMD, 0.33 [95% CI, 0.22-0.44; P = 0.00001]). The risks of adverse events or side effects such as headache, abdominal cramps, excessive flatulence, dizziness, diarrhea, and rash were higher (odds ratio, 1.70 [95% CI, 1.27 to -2.27; P = 0.0004]) in prucalopride group. Prucalopride is clinically a beneficial pharmacotherapy for chronic constipation and its routine use may be considered in patients with chronic simple laxative-resistant constipation.

Clinical Observation of Prucalopride in the Treatment of Functional Constipation / 中国药房

OBJECTIVE:To observe the clinical efficacy and safety of prucalopride in the treatment of functional constipation (FC). METHODS:In prospective self-controlled study,87 female patients with FC were selected and given prucalopride 2 mg,1 time per day. The total course was four weeks. The defecate frequency,stool property and constipation symptom grade were ob-served before and after treatment. Related adverse drug reaction were observed during treatment. RESULTS:During the period of treatment,the defecate frequency was gradually increased,the stool property was gradually improved,and the constipation symp-tom grade of the patients was also improved. The difference had statistical significance before and after treatment(P<0.01). No sig-nificant adverse drug reaction was found during the study. CONCLUSIONS:Prucalopride is a safe and effective treatment for pa-tients with FC.

Clinical efficacy of prucalopride in the treatment of severe chronic constipation / 中华消化外科杂志

Objective To investigate the clinical efficacy of prucalopride in the treatment of severe chronic constipation.Methods The clinical data of 60 patients with severe chronic constipation [slow transit constipation (STC), functional defecation disorder (FDD) and constipation-predominant irritable bowel syndrome (IBS-C)] who were admitted to the Third Affiliated Hospital of Nanjing University of Chinese Medicine from February to August 2014 were prospectively analyzed.A prospective, clinical observational study was performed.Treatment plans included that patients withdrew the initial treatments of laxative and exema and took orally 2 mg prucalopride once daily for 2 weeks, and continued to be treated by oral prucalopride if frequency of the spontaneous complete bowel movement (SCBM) per week was satisfactory (or improvement of symptoms was more than 50％) till 4 weeks, and then were followed up after stopping prucalopride.If improvement of symptoms was less than 50％ after 2-week treatment, other treatment plans were performed according to symptoms of patients from week 3 to week 6 : (1) for patients with STC, prucalopride + two chain bacillus subtilis probiotic capsules were administered orally if patients were satisfied with frequency of SCBM per week and without improvement of abdominal distension;prucalopride + Chinese herb decoction were administered orally if patients had improvement of frequency of SCBM per week with abdominal distension or poor stool output;oral prucalopride + acupuncture were administered if patients were unsatisfied with frequency of SCBM per week or less bowel movements and without improvement of abdominal distension or poor stool output.(2) For patients with FDD, oral prucalopride + acupuncture + biofeed-back therapy were administered.(3) For patients with IBS-C, prucalopride + two chain bacillus subtilis probiotic capsules were administered orally if patients had abdominal distension;prucalopride Chinese herb decoction were administered orally if patients had improvement of frequency of SCBM per week and no improvement of abdominal distension or poor stool output.All patients used a diary for recording the frequency of SCBM per week, stool consistence, exertion in defecation and adverse reactions, which was submitted to doctors for inputting data at the return visit weekly.Results There was good overall medicine compliance in patients.Of 60 patients, 43 patients completed treatments (21 with STC, 11 with FDD and 11 with IBS-C).After 2-week treatment, there were 19 patients with satisfied therapeutic effects, 14 with improvement of constipation and 10 with poor therapeutic effects.After 4-week treatment, constipation in 17 patients was cured, constipation in 18 patients was improved,and constipation in 8 patients was not improved.Nineteen of 60 patients were complicated with adverse reactions within 1 week of the medication, including 6 patients dropping out of the trial due to medication withdrawal and others with improvement by symptomatic treatment or spontaneous remission.Conclusions Prucalopride is effective for the treatment of severe chronic constipation with a good toleration, and it can improve the overall satisfaction of patients combined with Chinese herb decoction and acupuncture.

Recent Updates on the Treatment of Constipation

The treatment of constipation aims to regulate the frequency and quantity of stool in order to promote successful defecation. Numerous studies on pharmacologic treatments and non-pharmacologic therapies for constipation have attempted to overcome limitations such as temporary and insufficient efficacy. Conventional laxatives have less adverse effects and are inexpensive, but often have limited efficacy. Recently developed enterokinetic agents and intestinal secretagogues have received attention owing to their high efficacies and low incidences of adverse events. Studies on biofeedback and surgical treatment have focused on improving symptoms as well as quality of life for patients with refractory constipation.

New Generation Laxatives / 대한내과학회지

A significant proportion of chronic constipation patients are dissatisfied with their treatment. Recently, a number of new medications have been introduced for patients refractory to conventional laxatives, such as prucalopride, lubiprostone, linaclotide, and elobixibat. 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 of significant adverse cardiovascular events. Prucalopride improves stool frequency and consistency, and reduces the need for rescue medications. Lubiprostone, a chloride channel activator, increases the secretion of intestinal fluid, improves the stool frequency and consistency, and reduces straining. Linaclotide, a guanylate cyclase-C agonist, is effective in treating patients with chronic constipation and 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 that blocks the enterohepatic circulation of bile acids, increasing the bile acid concentration in the intestine, which accelerates colonic transit and softens the stool. A phase III trial of the treatment of chronic constipation and irritable bowel syndrome with constipation is underway. The clinical application of new-generation laxatives will contribute to the management of chronic constipation refractory to conventional laxatives.

Factors Predictive of Treatment-Emergent Adverse Events of Prucalopride: An Integrated Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.

Factors Predictive of Treatment-Emergent Adverse Events of Prucalopride: An Integrated Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.

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/AIMS: To 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). METHODS: Data 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 > or = 3 spontaneous complete bowel movements (SCBMs)/week; average increases of > or = 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS: Overall, 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 > or = 3 SCBMs/week in Asian (34% vs. 11%, P or = 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. CONCLUSIONS: Prucalopride 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.

Current Issues on the Treatment of Chronic Constipation / 대한소화기학회지

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.

The Effects of Prucalopride on Postoperative Ileus in Guinea Pigs

PURPOSE: Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. The aim of this study was to investigate the effects of different 5-hydroxytryptamine 4 (5-HT4) receptor agonists, which stimulate excitatory pathways, on a POI model. MATERIALS AND METHODS: The experimental model of POI in guinea pigs was created by laparotomy, gentle manipulation of the cecum for 60 seconds, and closure by suture, all under anesthesia. Different degrees of restoration of GI transit were measured by the migration of charcoal. Colonic transit was indirectly assessed via measurement of fecal pellet output every hour for 5 hours after administration of various doses of mosapride, tegaserod, prucalopride, and 5-HT. RESULTS: Charcoal transit assay showed that various 5-HT4 receptor agonists can accelerate delayed upper GI transit in a dose-dependent manner. However, fecal pellet output assay suggested that only prucalopride had a significant effect in accelerating colonic motility in POI. CONCLUSION: Although mosapride, tegaserod, and prucalopride produce beneficial effects to hasten upper GI transit in the POI model, prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig. This drug may serve as a useful candidate for examination in a clinical trial for POI.