A5075171303- Cardiac electrophysiology and arrhythmias
- Cardiac Arrhythmias and Treatments
- Atrial Fibrillation Management and Outcomes
- Cardiac pacing and defibrillation studies
- Gastrointestinal motility and disorders
- Neuroscience and Neuropharmacology Research
- Gastroesophageal reflux and treatments
- Alzheimer's disease research and treatments
- Lysosomal Storage Disorders Research
- Protein Structure and Dynamics
- Trypanosoma species research and implications
- Pituitary Gland Disorders and Treatments
- Glycogen Storage Diseases and Myoclonus
- Ion channel regulation and function
- Nitric Oxide and Endothelin Effects
- Functional Brain Connectivity Studies
- Congenital gastrointestinal and neural anomalies
- Ion Channels and Receptors
- Parkinson's Disease Mechanisms and Treatments
- Cytomegalovirus and herpesvirus research
- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Polyomavirus and related diseases
- Phosphodiesterase function and regulation
- Vitamin K Research Studies
Flagship Pioneering (United States)
2024
Takeda (United States)
2017-2024
AZ Turnhout
2017
Java Clinical
2017
Amgen (United States)
2012-2014
Montreal Heart Institute
2001-2004
McGill University
2001-2004
Université de Montréal
1991-2003
Hôpital du Sacré-Cœur de Montréal
1991-1998
Coronary artery disease is a significant risk factor for atrial fibrillation (AF), but the basis this association incompletely understood. The present study evaluated hypothesis that ischemia can create substrate AF maintenance.Atrial was induced by occlusion of an arterial branch did not provide blood flow to ventricles. Atrial-arterial increased duration burst pacing from 57+/-32 seconds (control) 803+/-214 (P<0.001) after 0.5 hour and 887+/-209 3 hours occlusion. Prolonged (>20 minutes)...
Ranolazine is a novel anti‐ischemic drug that prolongs the QT interval. To evaluate potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG IsK currents in Xenopus oocytes with two‐electrode voltage clamp; (ii) of ranolazine, compared to D ‐sotalol, effective refractory period (ERP), interval ventricular rhythm dog model acquired long syndrome; (iii) selected native canine atrial myocytes whole‐cell patch‐clamp technique. inhibited different potencies. was an IC...
The human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir is in Phase III clinical trials as antiviral therapy, including use for infections refractory or resistant to standard therapy. To assess its activity combination with approved and experimental CMV antivirals, the mTor rapamycin (sirolimus), drug effects were tested by vitro checkerboard assays data analyzed using a three dimensional model based on an independent definition of additive interactions. Baseline virus representative...
We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on core as a means to increase potency while reducing binding affinity. Further optimization P3 P2' side chains resulted in identification 42 (AMG-8718), compound with balanced profile potency, affinity, Pgp recognition. This produced robust...
Endocardial/Epicardial Mapping of AF. Introduction: It has been suggested that the three‐dimensional structure atria may be crucial in arrhythmogenesis; however, previous vivo atrial activation mapping studies have limited to either endocardial or epicardial approaches. Methods and Results: To investigate role structures their interaction conduction arrhythmias, we used five plaques two intra‐atrial balloon arrays record a total 368 unipolar electrograms from entire surface both atria....
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 combine hypertrophy of myostatin antagonism with anti-inflammatory and anti-fibrotic activin A antagonism. was administered C57BL/6 mice 4 weeks, muscle mass myofiber size measured. In mdx model, engineered dosed 12 weeks in two studies comparing an Fc fusion IIB receptor or anti-myostatin antibody....
During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, limited ECG sampling. These factors confound data interpretation, but may be overcome using non-invasive jacket-based collection (JET). The current study investigated whether jacketed external telemetry system could detect in cardiac intervals heart rate non-human...
The optimization of a series aminooxazoline xanthene inhibitors β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in rat pharmacodynamic model, but advancement was precluded by low therapeutic window to QTc prolongation cardiovascular models consistent with vitro on the hERG ion channel. While introduction polar groups effective reducing binding affinity, this came at expense higher than desired Pgp-mediated...
Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation glycosaminoglycans (GAGs) in tissues. We used knockout (Ids KO) mice investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDSco) encoding human I2S (hI2S) could cross-correct deficiency Ids KO mouse tissues, and we then assessed the translation data non-human primates (NHPs). Treated...
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 α-Gal activity leads to progressive lysosomal accumulation substrate, predominately globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (lyso‐Gb3). FD manifestations include early onset neuropathic pain, gastrointestinal symptoms, later life-threatening renal, cardiovascular cerebrovascular disorders....
Background: Clinical trials suggest that sotalol and dofetilide are much more effective in preventing atrial fibrillation (AF) than terminating it. This study evaluated potential mechanisms of discordant effects on AF termination vs. prevention. Methods: We applied 240-electrode epicardial mapping programmed stimulation a vagotonic dog model before after or sotalol. Results: Under control conditions, sustained could be induced by single S2 extrastimuli caused unidirectional block...
Patients with chronic constipation benefit from treatment 5-hydroxytryptamine 4 (5-HT<sub>4</sub>) receptor agonists. However, the first-generation 5-HT<sub>4</sub> agonists cisapride and tegaserod were withdrawn market owing to rare cardiovascular adverse events that not 5-HT<sub>4</sub>-receptor-related but due lack of selectivity these drugs. Here we report nonclinical profile selective agonist prucalopride. To assess its non-5-HT<sub>4</sub> receptor-mediated effects on...
Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated hypotheses that: (1) activation patterns initial PVT beats would be consistent with an origin conduction system; (2) inhomogeneous prolongation repolarisation intervals can provide refractory barriers for re-entrant activity.Unipolar electrograms were recorded from 127 epicardial (EPI) sites a sock electrode array as well...
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 the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate tissue distribution abuse potential prucalopride.In vitro receptor-ligand binding studies assess affinity prucalopride (≤1 mM) peptide receptors, ion channels, monoamine neurotransmitters 5-HT...
The effects of procainamide were studied in a model atrial flutter around the tricuspid valve seven open chest, chloralose‐anesthetized dogs (31 ± 3 kg). A Y‐shaped incision intercaval area extending to right appendage was made and five bipolar electrodes sutured on epicardium valve. Reentry tachycardia induced absence presence drug by burst pacing. Procainamide (5 mg/kg bolus followed 0.075 mg/kg/min infusion) produced stable plasma levels (38 9μ) during study. At pacing cycle length 200...
The effects of procainamide and propafenone on the composition excitable gap (EG) were studied in a canine model atrial flutter (AFI) around tricuspid valve. In 14 open-chest, chloralose-anesthetized dogs, Y-shaped incision was made intercaval area extending to right appendage. Atrial effective refractory period (ERP) measured at constant stimulation cycle lengths (CLs) (200 300 msec) each five recording sites EG as defined by reset-response curve determined introducing premature stimuli...