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Shire Movetis and Movetis Inc. | Date: 2011-03-29


Camilleri M.,Mayo Medical School | Van Outryve M.J.,University of Antwerp | Beyens G.,Movetis Inc. | Kerstens R.,Movetis Inc. | And 2 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2010

Background Prucalopride is approved in Europe for symptomatic treatment of chronic constipation in women with inadequate relief from laxatives. Aim To evaluate efficacy of prucalopride during long-term treatment of patients with chronic constipation. Methods Patients from three pivotal double-blind, placebo-controlled, 12-week studies with prucalopride could continue treatment in open-label studies up to 24 months. Efficacy was evaluated every 3 months using the Patient Assessment of Constipation-Quality of Life (PAC-QOL) satisfaction scale. Laxative use and reasons for study discontinuation were recorded. Results Eighty-six percent of patients who completed the pivotal studies continued prucalopride treatment in the open-label studies (n = 1455, 90% female). Improvement in average PAC-QOL satisfaction score observed after 12- week, double-blind prucalopride was maintained during open-label treatment for up to 18 months; in each 3 month period, 40-50% of patients did not use any laxatives. Most frequent adverse events (AEs) resulting in discontinuation were gastrointestinal events (3.3%) and headache (1.0%). Only 10% of patients who had normalized bowel function on prucalopride at the end of pivotal trials discontinued due to insufficient response during open- label treatment. Conclusion Satisfaction with bowel function is maintained for up to 18 months of treatment with prucalopride. Gastrointestinal events and headache cause discontinuation of prucalopride treatment in ∼ 5% of patients (ClinicalTrials.gov identifiers: NCT01070615 and NCT00987844). © 2010 Mayo Foundation for Medical Education and Research.

Pusapati G.V.,University of Ulm | Pusapati G.V.,Stanford University | Eiseler T.,Martin Luther University of Halle Wittenberg | Rykx A.,Catholic University of Leuven | And 8 more authors.
Journal of Biological Chemistry | Year: 2012

The members of the protein kinase D (PKD) family of serine/threonine kinases are major targets for tumor-promoting phorbol esters, G protein-coupled receptors, and activated protein kinase C isoforms (PKCs). The expanding list of cellular processes in which PKDs exert their function via phosphorylation of various substrates include proliferation, apoptosis, migration, angiogenesis, and vesicle trafficking. Therefore, identification of novel PKD substrates is necessary to understand the profound role of this kinase family in signal transduction. Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane. Consequently, the S435E rhotekin mutant displayed enhanced stress fiber formation when expressed in serumstarved fibroblasts. Our data thus identify a novel role of PKD as a regulator of RhoA activity and actin stress fiber formation through phosphorylation of rhotekin. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Chai W.,Erasmus Medical Center | Chan K.Y.,Erasmus Medical Center | De Vries R.,Erasmus Medical Center | Van Den Bogeardt A.J.,Erasmus Medical Center | And 6 more authors.
Life Sciences | Year: 2012

Aims: Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine 4 (5-HT 4) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT 4 receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT 3 receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT). Main methods: Atrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT 4 receptor antagonist GR113808. Partial agonism was assessed using 5-HT 4 receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil. Key findings: Like 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC-733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773. Significance: We conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT 4 receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT 4 receptor antagonist. © 2012 Elsevier Inc. All rights reserved.

Muller-Lissner S.,Park Klinik Weissensee | Rykx A.,Movetis Inc. | Kerstens R.,Movetis Inc. | Vandeplassche L.,Movetis Inc.
Neurogastroenterology and Motility | Year: 2010

Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5-HT 4 agonist prucalopride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ≥65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with ≥3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ≥1 SCBM per week, BM frequency, constipation-related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ≥3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P ≤ 0.05). Significantly more patients in each prucalopride group achieved an increase of ≥1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P ≤ 0.05). More patients had improvement in PAC-QOL satisfaction score of ≥1 with 1 mg prucalopride than with placebo (P ≤ 0.05); the same was true for PAC-SYM stool symptoms (1 and 4 mg prucalopride; P ≤ 0.05). Treatment-emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose-range tested (1-4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well-tolerated in elderly patients with chronic constipation. © 2010 Blackwell Publishing Ltd.

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