Serotonin 5-HT4 Receptor Agonists Research Articles

Thermosensitive mucoadhesive in situ gel for intranasal delivery of Almotriptan malate: Formulation, characterization, and evaluation

The present investigation deals with development, characterization, and evaluation of thermosensitive in-situ nasal gel of Almotriptan malate (selective serotonin 5-HT1 receptor agonist), serving as a substitute for drug delivery to the brain. Gels were prepared by cold technique varying the concentration of Pluronics (PF127 and PF68) and carboxymethyl chitosan as thermoreversible and mucoadhesive polymers respectively. Drug content before and after gelation was ranged between 96.42-98.92% and 95.8–98.66% respectively. The pH value was observed in the range of 5.56–6.31. Notably, the results obtained were in agreement with the phase transition and formulations exhibited pseudoplastic rheology. Mucoadhesive strengths of all the formulations increased with the chitosan concentration and were in the range of 3300–5193.65 dyn/cm2. The in-vitro drug diffusion data of the optimized formulation i.e. 17% w/v PF127, 2% w/v PF68, 0.1% w/v carboxymethyl chitosan, revealed 89.36% release at the end of 6 h. Histopathological studies confirmed the non-toxic effect of optimized formulation on the microscopic structure of nasal mucosa during ex-vivo permeation studies. Short term stability study exhibited 4±1 °C as an appropriate storage condition for the formulations. In nutshell, a thermosensitive in-situ gel of Almotriptan malate can be intended as an effective approach of migraine treatment.

Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson's Disease.

Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study

IntroductionThe serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA.MethodsThis observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding.ResultsThe pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses.ConclusionsThe pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Effects of preoperative cisapride on postoperative aspiration pneumonia in dogs with laryngeal paralysis.

Retrospective evaluation of a preoperative prokinetic protocol using a constant-rate infusion of a serotonin 5-HT4 receptor agonist, cisapride, and its association with frequency of postoperative aspiration pneumonia in dogs undergoing unilateral arytenoid lateralisation as compared to a historical population at the same institution. Medical records of dogs undergoing unilateral arytenoid lateralisation for laryngeal paralysis were reviewed for historical findings, imaging findings, anaesthesia and surgery durations, perioperative medications and if surgery was performed as an emergency. Aspiration pneumonia events in the first 72 hours after surgery were recorded. The study group received a preoperative cisapride constant-rate infusion; historical 'controls' did not receive the cisapride protocol. One of 50 dogs in the cisapride group and six of 52 dogs in the historical group developed aspiration pneumonia within the immediate postoperative period. The cisapride protocol was largely well tolerated. A markedly lower rate of aspiration pneumonia in patients administered butorphanol with acepromazine preoperatively and buprenorphine postoperatively was noted, but the overall low frequency of aspiration pneumonia and variation in case management protocols precluded definitive conclusions with respect to optimal perioperative drug choices. Laryngeal paralysis is commonly treated by unilateral arytenoid lateralisation, and aspiration pneumonia is one of the most serious potential complications of this procedure. This study suggests that further investigation of a cisapride constant-rate infusion to prevent this complication is warranted.

Sumatriptan inhibits the electrophysiological activity of ASICs in rat trigeminal ganglion neurons

Sumatriptan, a selective serotonin 5-HT1 receptor agonist, is an effective therapeutic for migraine attacks. However, the molecular mechanisms underlying sumatriptan migraine relief are still not fully understood. Here, we found that acid-sensing ion channels (ASICs), pH sensors, are peripheral targets of sumatriptan against migraine. Sumatriptan can inhibit the electrophysiological activity of ASICs in the trigeminal ganglion (TG) neurons. In the present study, sumatriptan decreased proton-gated currents mediated by ASICs in a concentration-dependent manner. In addition, sumatriptan shifted concentration-response curves for protons downwards, with a decrease of 37.3 ± 4.6% in the maximum current response but with no significant change in the pH0.5 value. Sumatriptan inhibition of ASIC currents was blocked by 5-HT1D receptor antagonist BRL 15572, but not by 5-HT1B antagonist SB 224289. Moreover, the sumatriptan inhibition of ASICs can be mimicked by the 5-HT1D receptor agonist L-694,247, but not by the 5-HT1B agonist CP-93129. Sumatriptan inhibition of ASIC currents was also reversed by G-protein αi subunit inhibitor PTX and 8-Br-cAMP, suggesting the inhibition may involve the intracellular signal transduction. Finally, sumatriptan decreased the number of action potentials induced by acid stimuli in rat TG neurons. Our results indicated that the anti-migraine drug, sumatriptan, inhibited ASICs in rat TG neurons via 5-HT1D receptor subtype and a cAMP-dependent signal pathway. These observations add to the understanding of the mechanisms that underlie the clinical effectiveness of anti-migraine sumatriptan.

Prospective randomized controlled trial comparing efficacy of 1-L Peg-Asc with prucalopride and 2-L Peg-Asc for the bowel preparation.

597 Background: Though numerous researches enabled decrease of the bowel preparation solution volume, it is still a major complaint of patients preparing colonoscopy. There have been studied that additional administration of laxatives could lessen the amount of aqueous formula with prokinetic effect. Prucalopride is a serotonin (5-HT4) receptor agonist which stimulate colonic mass movements and provide main propulsive force for defecation. The aim of this study is to compare 2-L PEG-Asc and 1-L PEG-Asc plus prucalopride for quality of bowel cleansing while preparing for colonoscopy and patient compliance. Methods: Two hundred patients were prospectively enrolled. Patients referred for colonoscopy were divided into group A (the split-dose 2-L PEG-Asc) and group B (1-L PEG-Asc + prucalopride) randomly. During colonoscopy, each patient’s bowel preparation quality was evaluated with The Boston Bowel Preparation Scale (BBPS) and Aronchick Preparation Scale (APS). The tolerability and satisfaction of patients was determined based on a questionnaire-based survey. Results: One hundred patients received either 2-L PEG-Asc or 1-L PEG-Asc with prucalopride. Regarding colon cleansing outcome (BPPS and APS), the 1-L PEG-Asc with prucalopride group showed similar, but non-inferior results compared to the 2-L PEG-Asc group on both BBPS (7.65±1.27 vs 7.52±1.40, p = 0.586) and APS scales (93.3% vs 95%, p = 0.717). Tolerability was similar for both 1-L PEG-Asc with prucalopride and 2-L PEG-Asc. Conclusions: 1-L PEG-Asc plus prucalopride preparation showed comparable result to traditional 2-L PEG-Asc preparation. 1-L PEG-Asc plus prucalopride preparation method could be an alternative method for bowel preparation which can relieve patient’s discomfort. Clinical trial information: KCT0002409.

Efficacy of Prucalopride in bowel cleansing before colonoscopy: Results of a pilot study

Colonoscopy is a crucial diagnostic instrument for colorectal cancer screening and an adequate bowel preparation is definitely decisive for the success of the procedure. Especially in elderly patients, bowel cleansing is considered a big issue, because it is often poorly tolerated for many reasons (like inability to swallow large volume of liquids or unlikable taste); this can cause a suboptimal preparation that may lead to miss a neoplastic lesion. There is relatively little data about how to improve preparation tolerability. The purpose of our pilot study was to analyze the effect of prucalopride (Resolor®), a highly selective serotonin 5HT4 receptor agonist used for chronic constipation for its ability to stimulate gastrointestinal peristalsis, undertaken the day before colonoscopy, followed by half volume of polyethylene glycol solution. We found that this can be a good and safe method to achieve an adequate and better-tolerated colon cleansing.

Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study

BackgroundProkinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed.MethodsForty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods.ResultsThere were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035).ConclusionsThe safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating.Trial registrationEU Clinical Trial Registry, EudraCT2012-005348-92. Registered on 19 February 2013.

Development of assay for determination of eletriptan hydrobromide in loaded PLGA nanoparticles

Eletriptan Hydrobromide is a serotonin 5-HT1 receptor agonist and it used for the treatment of migraine headaches with or without aura. Even if the drug is well absorbed after oral administration, it has some drawbacks like first pass metabolism and decrease in bioavailability after migraine attacks. Encapsulation of drug into polymeric nanoparticles is one of the methods for protecting the drug against degradation. The present work described a preparation of Eletriptan Hydrobromide loaded poly (d,l-lactide-co-glycolide) nanoparticles prepared using o/w single emulsion solvent evaporation method. In order to determine the factors affecting the physicochemical properties of the nanoparticles on the particle size of poly (d,l-lactide-co-glycolide) nanoparticles, D-Optimal design is used. Moreover, novel, simple, sensitive, selective, and fully validated chromatographic technique for the quantification of Eletriptan Hydrobromide from Eletriptan Hydrobromide loaded poly(d,l-lactide-co-glycolide) nanoparticles was developed. Poly(d,l-lactide-co-glycolide) concentration, sonication time and sonication energy were found as significant factors (p<0.05) on particle size of nanoparticles. Limit of detection and limit of quantification values were calculated as 0.28μgmL−1and 0.86μgmL−1, respectively.

Quantitative structure-retention relationship model for the determination of naratriptan hydrochloride and its impurities based on artificial neural networks coupled with genetic algorithm

Mathematical modeling of Quantitative Structure – Property Relationships met great interest in fields of in silico drug design and more recently, pharmaceutical analysis. In our approach we proposed automated method of creation Quantitative Structure-Retention Relationship (QSRR) for analysis of triptans, selective serotonin 5-HT1 receptor agonists used for the treatment of acute headache. The method was created using hybrid machine learning approach, namely Genetic algorithm (GA) coupled with artificial neutral networks (ANN). Performance of proposed hybrid GA-ANN model was evaluated with predicting relative retention times of naratriptan hydrochloride impurities. Several ANN types were coupled with GA and tested: single-layer ANN (SL-ANN), double-layer ANN (D-ANN) and higher order architectures: pi-sigma ANN (PS-ANN) and sigma-pi-sigma ANN (SPS-ANN). Partial Least Squares (PLS) method was used as a reference. The separation of naratriptan hydrochloride and its related products (impurities and degradation products) was obtained by developing a gradient high-performance liquid chromatography method with diode-array detector (HPLC-DAD). Degradation products during acid-basic hydrolysis were identified with an electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS) detector. Independent data for outer validation of QSRR model was obtained from the determination of related products of sumatriptan succinate via an HPLC-DAD method.Accuracy of QSRR was measured by inner-validation on naratriptan data and outer validation on sumatriptan succinate samples. The best performing model were PS-ANN and SPS-ANN with mean errors of 8% (Q2=0.87) and 15% (Q2=0.77) on an inner-validation data set, respectively. Validation on similar samples from an outer validation data set of sumatriptan succinate impurities gave mean errors of 18% (R2pred=0.64) and 17% (R2pred=0.63) for the PS-ANN and SPS-ANN models, respectively.

Prucalopride: A Review in Chronic Idiopathic Constipation

Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.

Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active GLP-1 levels and glucose tolerance in mice

Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

Fast Dissolving Oral Thin Film Drug Delivery Systems Consist of Ergotamine Tartrate and Caffeine Anhydrous

Ergotamine tartrate (ET), a serotonin 5-HT1 receptor agonist, is an anti-migraine drug. Due to high first-pass metabolism, ET shows a very low bioavailability in oral administrations (<1%). Caffeine (CA) increases the rate and extent of water solubility of ET. The present study intended to investigate the possibility of developing ET fast dissolving thin films for the fast drug dissolution in the oral cavity, and thus bypassing first pass metabolism for providing quick onset of action of the drug. Methods: The films (ET and CA) were prepared according to solvent casting method, separately. Low viscosity grade of hydroxylpropyl methylcellulose (HPMC E-15) was employed in preparation as a film forming polymer. Propylene glycol was the plasticizer used. All the films were evaluated for their thickness, weight variations, folding endurance, surface pH, disintegration, drug content, DSC, in-vitro drug release, and ex-vivo permeation. Results: The best polymer drug ratio in ET/CA films was 1:20 (E2) and 1:4 (C2), respectively. The films E2 and C2 showed 9.9, 3.2 mg weight, 74, 45 µm thickness, 120.66, up to 300 folding endurance and 0.38, 0.52 mg/cm2 drug content, respectively. The DSC showed no stable characteristic for ET and CA in the drug loaded films and revealed amorphous form. The results showed that ET films prepared had faster release and CA films had slower release (p<o.o5). Both films (ET and CA) exhibited good mucoadhesion properties and shorter retention time (36-150 s). Conclusion: The formulations were found to be a suitable candidate for the development of oral thin films for migraine therapy.

Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach.

Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 μM) and itopride (1 and 3 μM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 μM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 μM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach.

Prucalopride reduces the number of reflux episodes and improves subjective symptoms in gastroesophageal reflux disease: a case series

IntroductionTreatment of persistence to proton pump inhibitors or non-acid reflux episodes in patients with gastroesophageal reflux disease is challenging. Prucalopride, a selective high affinity serotonin (5-HT4) receptor agonist, might offer a possible new therapeutic alterative.Case presentationsWe report four chronically constipated female gastroesophageal reflux disease-patients with reflux symptoms and an increased number of reflux episodes in combined esophageal pH and multichannel impedance monitoring treated with prucalopride (2mg per day). Symptoms were persistent to proton pump inhibitors and ranitidine. Gastroesophageal reflux was detected by pH or multichannel impedance (MII) monitoring. Numbers of all reflux episodes as well as non-acid reflux episodes were reduced in all of our patients. The objective findings were concordant with subjective reports of symptom relief. There were no major adverse events in any patient during therapy with prucalopride.ConclusionAdministration of prucalopride showed promising results in the treatment of persisting or weakly and/or non-acid reflux episodes in our case series in four constipated patients. Therefore, prucalopride can be regarded as a possible therapeutic option in the treatment of standard proton pump inhibitor-persistent reflux in the chronically constipated patient. However, further prospective trials are needed to prove our findings.

Prucalopride: A Review of Its Use in the Management of Chronic Constipation

The highly selective serotonin 5-HT4 receptor agonist prucalopride (Resolor(®), Resotran(®), Resotrans(®)) is indicated for the treatment of chronic constipation. In four randomized, double-blind, multicentre, 12-week trials in patients (predominantly women) with chronic constipation, oral prucalopride 2mg once daily improved bowel function to a significantly greater extent than placebo, with a significantly greater proportion of prucalopride than placebo recipients achieving an average of ≥3 spontaneous, complete bowel movements per week (primary endpoint). Significantly greater improvements in health-related quality of life, patient satisfaction with treatment and bowel habit, and a range of constipation-related symptoms were also seen with prucalopride than with placebo. Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term. Prucalopride was generally well tolerated in patients with chronic constipation, with the most commonly reported adverse events (headache, nausea, abdominal pain, diarrhoea) primarily occurring on the first day of treatment. During the clinical trials, no cardiovascular safety issues have arisen in patients with chronic constipation receiving prucalopride. In conclusion, prucalopride is an important option for use in patients with chronic constipation who have not experienced adequate relief with laxatives.

Changes in the symptom pattern and the densities of large-intestinal endocrine cells following Campylobacter infection in irritable bowel syndrome: a case report

BackgroundIrritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder. Post-infectious IBS (PI-IBS) is a subset of IBS that accounts for a large proportion of IBS patients. The PI-IBS symptoms meet the Rome criteria for IBS with diarrhoea (IBS-D) or IBS with mixed bowel habits (IBS-M). A low-grade inflammation has been reported to occur in PI-IBS. Abnormalities in intestinal endocrine cells have been reported in both sporadic IBS and PI-IBS.Case presentationA 20-year-old female with a diagnosis of IBS with constipation (IBS-C), according to Rome III criteria, contracted Campylobacter-induced gastroenteritis, after which her symptom pattern changed to IBS-M. She showed an intestinal low-grade inflammation that was manifested by an increase in the number of intraepithelial and lamina propria leucocytes and lymphocytes and an increase in the density of mast cells in lamina propria. There was also an increase in the density of intestinal serotonin and peptide YY (PYY) cells and a decrease in the density of rectal somatostatin cells. Follow-up of the patient at 4-months post-infection revealed reduction of IBS symptoms and an improvement in her quality of life. However, 6 months following the Campylobacter infection, the patient switched back from IBS-M to IBS-C, probably due to recovery from PI-IBS. The patient was treated with prucalopride, which is serotonin 5HT4 receptor agonist. Six months later following this treatment, the symptoms were reduced and the quality of life improved in the reported patient.ConclusionsGastroenteritis in patients with IBS-C causes a post-infectious, low-grade inflammation. Interaction between immune-cells and intestinal endocrine cells increases the density of certain endocrine cells, which in turn might be responsible for the change in the symptom pattern, the milder symptoms and the improvement in the quality of life seen in the reported patient. The findings in this case raise the question as to whether intestinal infections are responsible for the previously reported switching of IBS from one subtype to another over time.

Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair

Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans.

Role of prucalopride, a serotonin (5-HT4) receptor agonist, for the treatment of chronic constipation

Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT(4)) agonists have been associated with significant interactions with other receptors (5-HT(1B), 5-HT(1D), and 5-HT(2B) for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT(4) agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride's high selectivity for the 5-HT(4) receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments.

Recent developments in gastrointestinal prokinetic agents

Background: Prokinetic agents are employed to reverse impaired gastrointestinal motility arising from functional disorders such as constipation-dependent irritable bowel syndrome and functional dyspepsia, as well as chronic constipation and gastro-oesophageal reflux disease. Postoperative ileus, diabetic gastroparesis and delayed gastric emptying in critically ill patients may also be treated with prokinetics. Over the last few years, some clinically effective gastro-prokinetic agents have been withdrawn or suspended from the market, which has created additional unmet medical need in this area. Objective: To assess critically the recent literature on prokinetic agents, with a primary focus on patents covering known and novel mechanisms of action, as well as updating the current status of selected compounds in clinical development as prokinetics. Methods: Patents were searched between 2005 and 2007, using a combination of Scifinder, Investigational Drugs Database and Prous databases. Results/conclusion: Prokinetic agents represent a significant unmet medical need and remain an active area of research for the pharmaceutical industry. Recent activities are divided between novel targets such as motilin receptor agonists, ghrelin receptor agonists and prosecretory agents, together with improvement of existing mechanisms of action, especially serotonin 5-HT4 receptor agonists. A number of compounds from both categories are currently in clinical development.