Effets antiarythmiques et proarythmiques du d-sotalol sur les arythmies cardiaques ventriculaires étudiés chez le chien

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters

Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies

Background: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride. Methods: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of 14C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02–640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated. Results: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150–10,000 times lower than that for the 5-HT4 receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo. Conclusion: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride

Application of phase coherence in assessment of spatial alignment of electrodes during simultaneous endocardial-epicardial direct contact mapping of atrial fibrillation

AIMS: Mapping and interpretation of wave conduction patterns recorded during simultaneous mapping of the electrical activity on both endocardial and epicardial surfaces are challenging because of the difficulty of reconstruction of reciprocal alignment of electrodes in space. Here, we suggest a method to overcome this difficulty using a concept of maximized endo-epicardial phase coherence. METHODS AND RESULTS: Endo-epicardial mapping was performed in six humans during induced atrial fibrillation (AF) in right atria using two sets of 8 × 8 electrode plaques. For each electrode, mean phase coherence (MPC) with all electrodes on the opposite side of the atrial wall was calculated. Localization error was defined as a distance between the directly opposing electrode and the electrode with the maximal MPC. Overall, there was a linear correlation between MPC and distance between electrodes with R(2) = 0.34. Localization error obtained for electrodes of the plaque in six patients resulted in a mean 2.3 ± 1.9 mm for 25 s electrogram segment length. Eighty-four per cent of the measurements resulted in error smaller than 3.4 mm. The duration of the recording used to compute MPC was negatively correlated with localization error; however, the effect reached plateau for segment durations longer than 15 s. CONCLUSION: Application of the concept of maximized endo-epicardial phase coherence to electrograms during AF allows reconstruction of reciprocal alignment of the electrodes on the opposite side of the atrial wall. This approach may be especially useful in settings where the spatial position of endo- and epicardial electrodes for intracardiac mapping cannot otherwise be determined

Cardiac manifestations of Fabry disease in G3Stg/GlaKO and GlaKO mouse models-Translation to Fabry disease patients.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by mutations in the GLA gene encoding alpha-galactosidase A (α-Gal). Loss of α-Gal activity leads to progressive lysosomal accumulation of α-Gal substrate, predominately globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (lyso-Gb3). FD manifestations include early onset neuropathic pain, gastrointestinal symptoms, and later onset life-threatening renal, cardiovascular and cerebrovascular disorders. Current treatments can preserve kidney function but are not very effective in preventing progression of cardiovascular pathology which remains the most common cause of premature death in FD patients. There is a significant need for a translational model that could be used for testing cardiac efficacy of new drugs. Two mouse models of FD have been developed. The α-Gal A-knockout (GlaKO) model is characterized by progressive tissue accumulation of Gb3 and lyso-Gb3 but does not develop any Fabry pathology besides mild peripheral neuropathy. Reports of minor cardiac function abnormalities in GlaKO model are inconsistent between different studies. Recently, G3Stg/GlaKO was generated by crossbreeding GlaKO with transgenic mice expressing human Gb3 synthase. G3Stg/GlaKO demonstrate higher tissue substrate accumulation and develop cellular and tissue pathologies. Functional renal pathology analogous to that found in early stages of FD has also been described in this model. The objective of this study is to characterize cardiac phenotype in GlaKO and G3Stg/GlaKO mice using echocardiography. Longitudinal assessments of cardiac wall thickness, mass and function were performed in GlaKO and wild-type (WT) littermate controls from 5-13 months of age. G3Stg/GlaKO and WT mice were assessed between 27-28 weeks of age due to their shortened lifespan. Several cardiomyopathy characteristics of early Fabry pathology were found in GlaKO mice, including mild cardiomegaly [up-to-25% increase in left ventricular (LV mass)] with no significant LV wall thickening. The LV internal diameter was significantly wider (up-to-24% increase at 9-months), when compared to the age-matched WT. In addition, there were significant increases in the end-systolic, end-diastolic volumes and stroke volume, suggesting volume overload. Significant reduction in Global longitudinal strain (GLS) measuring local myofiber contractility of the LV was also detected at 13-months. Similar GLS reduction was also reported in FD patients. Parameters such as ejection fraction, fractional shortening and cardiac output were either only slightly affected or were not different from controls. On the other hand, some of the cardiac findings in G3Stg/GlaKO mice were inconsistent with Fabry cardiomyopathy seen in FD patients. This could be potentially an artifact of the Gb3 synthase overexpression under a strong ubiquitous promoter. In conclusion, GlaKO mouse model presents mild cardiomegaly, mild cardiac dysfunction, but significant cardiac volume overload and functional changes in GLS that can be used as translational biomarkers to determine cardiac efficacy of novel treatment modalities. The level of tissue Gb3 accumulation in G3Stg/GlaKO mouse more closely recapitulates the level of substrate accumulation in FD patients and may provide better translatability of the efficacy of new therapeutics in clearing pathological substrates from cardiac tissues. But interpretation of the effect of treatment on cardiac structure and function in this model should be approached with caution

Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone

Abstract Background Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism. Methods Engineered follistatin was administered to C57BL/6 mice for 4 weeks, and muscle mass and myofiber size was measured. In the mdx model, engineered follistatin was dosed for 12 weeks in two studies comparing to an Fc fusion of the activin IIB receptor or an anti-myostatin antibody. Functional measurements of grip strength and tetanic force were combined with tissue analysis for markers of necrosis, inflammation, and fibrosis to evaluate improvement in dystrophic pathology. Results In wild-type and mdx mice, dose-dependent increases in muscle mass and quadriceps myofiber size were observed for engineered follistatin. In mdx, increases in grip strength and tetanic force were combined with improvements in muscle markers for necrosis, inflammation, and fibrosis. Improvements in dystrophic pathology were greater for engineered follistatin than the anti-myostatin antibody. Conclusions Engineered follistatin generated hypertrophy and anti-fibrotic effects in the mdx model