The present study aimed to investigate whether prucalopride, as a 5‑hydroxytryptamine 4 (5‑HT4) receptor agonist, improved intestinal motility by promoting the regeneration of the enteric nervous system (ENS) in rats with diabetes mellitus (DM). A rat model of DM was established using an intraperitoneal injection of streptozotocin. The rats were randomly divided into four groups of 6 rats/group: Control, DM (DM model), DM + A (5 µg/kg prucalopride) and DM + B (10 µg/kg prucalopride). The rats in the Control group were given an equal volume of citric acid solvent. After successful model establishment, high blood glucose levels were maintained for 2 weeks before administration of prucalopride. The colonic transit time was measured using the glass bead discharge method. It was revealed that the colonic transit time of diabetic rats was the longest, and this was significantly shortened in the DM + B group. Subsequently, the colons were collected. The expression levels of Nestin, glial fibrillary acidic protein (GFAP), SOX10, RNA‑binding protein human antigen D (HuD) and ubiquitin thiolesterase (PGP9.5) were determined via immunohistochemical analysis. Immunofluorescence double staining of 5‑HT4 + Nestin and Ki67 + Nestin was performed. The 5‑HT level was measured using ELISA. Compared with that in the control group, Nestin expression was significantly increased in the DM and DM + A groups, and it was concentrated in columnar epithelial cells and the mesenchyme. Furthermore, the expression levels of Nestin in the DM + A group were higher than those in the DM group. No difference was observed in the expression levels of Nestin between the DM + B group and the Control group. The expression levels of 5‑HT protein were highest in the Control group; however, the expression levels of 5‑HT protein in the DM group, DM + A group and DM + B group exhibited an increasing trend. Similar trends in the expression of 5‑HT4 and Nestin were not observed; however, similar trends in the expression of Nestin and Ki67 were observed. The expression levels of GFAP, SOX10, PGP9.5 and Ki67 in the DM + A and DM + B groups were higher compared with those in the DM group. In the DM + A group, HuD expression was decreased compared with that in the Control group but it was markedly higher compared with that in the DM group. In conclusion, prucalopride may improve intestinal motility by promoting ENS regeneration in rats with DM.

Prucalopride was widely used for chronic constipation, which is difficult to be adequately relieved by laxatives in adult patients in clinic. Due to the difficulty in metabolite identification, metabolic process of prucalopride had not been investigated in vivo. In this study, an efficient strategy was proposed for comprehensive metabolite profiling of prucalopride after oral administration in rat plasma, urine, and feces samples. This strategy was composed of five steps. First, the samples at multiple time points after oral administration were collected to increase the representativeness of the samples. Second, different sample preparation methods were investigated to obtain superior extraction efficiency. Third, the raw data of test sample and blank sample were acquired using ultra-performance liquid chromatography with Q-Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry under the positive and negative full-scan/dd MS2 mode. Fourth, combined mass defect filter with background subtraction model in soft of compound discovery, all peaks were constructed to filter potential metabolites after retention time alignment and ion filtration, which could remove large amounts of interference ions. Besides, it can predict potential biotransformation, promoting to understand how to metabolize the drug. This provides multiple possibilities and prevents us conjecturing the potential metabolites blindly. Finally, the verification procedure was implemented through exporting the structure and MS2 spectrum to the analytical tool of Mass Frontier. The proposed strategy significantly improved the targeted detection and identification for metabolites in vivo. A total of 47 metabolites were tentatively characterized in the plasma, urine, and feces samples after oral administration of prucalopride. This study could provide a valuable reference for systematic metabolite profile of drug in vivo.

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson\'s disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson\'s disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.

OBJECTIVE: The aim of this study was to compare the effects of colonic electrical stimulation (CES) and prucalopride on gastrointestinal transit and defecation and to verify the safety of CES in a canine model of constipation.
METHODS: Eight beagles received CES implantation and induction drugs for slow transit constipation (STC). In the STC model, the gastrointestinal transit time (GITT), colonic transit time (CTT), stool frequency and stool consistency were assessed to compare the effects of CES and prucalopride on gastrointestinal transit and defecation. The histocompatibility of the implantable device was evaluated.
RESULTS: The individualized parameters for CES varied greatly among the animals, and the GITTs were not significantly shortened by CES or prucalopride; however, both the CES and prucalopride treatment significantly accelerated CTT and improved stool consistency compared with sham stimulation. CES treatment also resulted in significantly higher stool frequency than prucalopride treatment, which did not significantly change the stool frequency. No severe inflammation response was detected in the gross and microscopic appearance around the implants.
CONCLUSIONS: CES and prucalopride treatment may yield similar short-term effects for improving gastrointestinal transit and stool consistency, and CES outperformed prucalopride treatment in terms of defecation inducement in the short term. There were ideal levels of endurance and histocompatibility for the animals that underwent CES.

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.
CONCLUSIONS: 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.

The objectives of the present study were to evaluate the bioequivalence of 2 tablet formulations of prucalopride, generic and branded, and to investigate relevant pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, fasting, single-dose, crossover, and dual-period trial. After overnight fasting, 12 subjects were given prucalopride tablets via oral administration, and blood specimens were obtained up to 96 hours after dosing. Prucalopride concentrations in plasma were measured using ultraprecision liquid chromatography-tandem mass spectrometry followed by calculation of pharmacokinetic parameters. The safety of prucalopride was assessed throughout the study. The pharmacokinetics of prucalopride can be defined as a 2-compartment model with a long elimination phase. No significant differences were observed between the pharmacokinetic profiles of the generic and branded prucalopride tablets. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve over 96 hours, log area under the concentration-time curve to infinity, and log peak concentration from generic and branded tablets, which were 100.06-109.94%, 100.63-110.32%, and 95.84-113.08%, respectively. During administration of the medication, there were 18 adverse events in 6 subjects in the test formulation group and 19 cases of adverse events in 6 subjects in the reference formulation group (P > .05). No severe adverse effects were detected. These results suggest that generic and branded prucalopride tablets are bioequivalent and show similar safety profiles.

Lung cancer is the main cause of cancer incidence and mortality around the world. Prucalopride is an agonist for the 5-hydroxytryptamine 4 receptor, but it was unknown whether prucalopride could be used to treat lung cancer. To investigate the biological effects of prucalopride on proliferation, apoptosis, invasion, and migration of lung cancer cells, and its underlying molecular mechanism in the progression of lung cancer, we performed this study. The Cell Counting Kit 8 assay was used to measure the proliferation of A549/A427 lung cancer cells treated with prucalopride. Transwell assay was applied to evaluate cell invasion and migration. Cell apoptosis was detected by flow cytometry and Western blot analyses. The expression levels of related proteins in the PI3K/AKT/mTor signaling pathway were analyzed by Western blotting. Prucalopride inhibited the proliferation, invasion, and migration of A549/A427 human lung cancer cells. It also induced autophagy and apoptosis and decreased the expression of the phosphorylated protein kinase B (AKT) and mammalian target of rapamycin (mTor) in these cells. This study implied an inhibitory role for prucalopride in the progression of human lung cancer.

OBJECTIVE: Sodium phosphate solution (NaP) in oral form is well known and frequently used for good quality bowel cleansing before a colonoscopy, but it carries the potential risk of electrolyte disturbance and dehydration. Prucalopride mitigates severe constipation by promoting colon motility. We evaluated the hypothesis that prucalopride plus one single dose of 45 mL NaP could be used as an alternative bowel preparation.
METHODS: Consenting adult patients undergoing a screening colonoscopy were randomized to receive 90 mL NaP (90-NaP) in two split doses or prucalopride 2 mg plus 45 mL NaP (P-NaP). Patients completed a questionnaire about adverse gastrointestinal symptoms and acceptability for bowel preparation. The effectiveness of colon preparation was evaluated according to the Ottawa bowel preparation scale.
RESULTS: Bowel cleansing was achieved in 92 patients with 90-NaP and in 97 patients with P-NaP. There was no significant difference in bowel cleansing level and adverse gastrointestinal symptoms between the two groups. However, more patients in the P-NaP group were willing to undertake the same regimen for a subsequent colonoscopy bowel preparation than those in 90-NaP group (82/97; 85% vs 51/92; 55%, P < 0.001).
CONCLUSIONS: The combination of 2 mg prucalopride and 45 mL NaP appeared to provide the same level of bowel cleansing, but it was more acceptable than the 90 mL NaP in split doses.

BACKGROUND: Glioma is the most fatal primary brain glioma in central nervous system mainly attributed to its high invasion. Prucalopride, a Serotonin-4 (5-HT4) receptor agonist, has been reported to regulate neurodevelopment. This study aimed to investigate the influence of the Prucalopride on glioma cells and unveil underlying mechanism.
METHODS: In this study, glioma cells proliferation was evaluated by Cell counting kit-8 (CCK8). Wound healing and transwell assay were used to test cellular migration and invasion. Flow cytometry was utilized to determine cellular apoptosis rate. Apoptosis related markers, autophagy markers, and protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway key molecules were detected using western blot assay.
RESULTS: As a result, the proliferation, migration and invasiveness of glioma cells were impaired by Prucalopride treatment, the apoptosis rate of glioma cells was enhanced by Prucalopride stimulation, accompanied by the increased pro-apoptosis proteins Bax and Cleaved caspase-3 and decreased anti-apoptosis protein Bcl-2. Prucalopride significantly promoted autophagy by increased expression level of Beclin 1 and LC3-II, while decreased expression level of p62. Prucalopride administration resulted in obvious inhibitions of key molecules of AKT-mTOR pathway, including phosphorylated- (p-) AKT, p-mTOR and phosphorylated-ribosomal p70S6 kinase (p-P70S6K).
CONCLUSIONS: Taking together, these results indicate that Prucalopride may be likely to play an anti-tumor role in glioma cells, which suggests potential implications for glioma promising therapy alternation in the further clinics.

A rapid, sensitive, selective and accurate ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the quantitation of prucalopride in rat plasma using carbamazepine as an internal standard (IS). Separation was achieved on a Waters ACQUITY UHPLC(®) HSS C18 column (2.1mm×50mm, 1.8μm) column with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2mL/min. Prucalopride and IS were monitored using positive electrospray triple quadrupole mass spectrometer (Waters Xevo TQD) via multiple reaction monitoring (MRM) mode. The monitored transitions were set at m/z 367.99→195.89 and m/z 236.97→194.04 for prucalopride and IS, respectively. The achieved lower limit of quantitation was 0.1ng/mL. The validated method had an excellent linearity in the range of 0.1-100ng/mL (r>0.996). The intra- and inter-day precisions were both≤7.8% for prucalopride and IS, and the average intra- and inter-day accuracies ranged from -3.0% to 8.5%. Extraction recoveries at three levels QC concentrations were in the range of 90.0-110.0% for prucalopride and 99.6% for IS. Matrix effects were found to be acceptable. The validated assay was successfully applied to a pharmacokinetic study of prucalopride following oral administration of 0.25, 0.5, 1.0mg/kg to female and male rats respectively.