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JACC. Clinical Electrophysiology Feb 2019
Topics: Bundle-Branch Block; Flecainide; Humans; Procainamide; Syncope
PubMed: 30784694
DOI: 10.1016/j.jacep.2018.10.012 -
The Biochemical Journal Sep 2014Human BChE (butyrylcholinesterase) protects against the toxicity of organophosphorus nerve agents and pesticides. BChE purified from human plasma is limited and pathogen...
Human BChE (butyrylcholinesterase) protects against the toxicity of organophosphorus nerve agents and pesticides. BChE purified from human plasma is limited and pathogen carry-over is a concern. Unlike the native BChE tetrameric complex with a residence time of days, rBChE (recombinant BChE) is produced predominantly as dimers and monomers that are cleared from the circulation within minutes. Assembly into tetramers requires incorporation of proline-rich peptides, a process that was thought to occur intracellularly. Our goal was to determine whether polyproline added to rBChE under cell-free conditions would promote tetramerization. Secreted rBChE was purified by procainamide affinity chromatography, and synthetic polyprolines (8-mer to 300-mer) were tested to determine their effect on tetramer assembly. These studies demonstrated that 90-98% of purified rBChE (65 μM) could be assembled into tetramers when incubated with synthetic 17-mer or 50-mer polyproline peptides (100 μM) for 1.5 h at 25°C. However, rBChE tetramerization was inefficient with smaller 8-mer polyproline peptides and larger 300-mer polyproline proteins. Collectively, these studies demonstrated that the eukaryotic cellular machinery is not required for assembly of active BChE into tetramers and that this process can occur in vitro with purified rBChE in the presence of peptides containing 15-50 consecutive proline residues.
Topics: Animals; Butyrylcholinesterase; CHO Cells; Cell-Free System; Cricetulus; Humans; Peptides; Protein Multimerization; Recombinant Proteins
PubMed: 24916051
DOI: 10.1042/BJ20140421 -
Journal of Veterinary Cardiology : the... Aug 2019The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs.
INTRODUCTION
The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs.
ANIMALS
Six healthy, purpose-bred mixed-breed dogs participated in the study.
METHODS
In phase I, two dogs were administered oral procainamide (30 mg/kg), and plasma was obtained to determine plasma concentration ranges and duration. In phase II, six dogs were administered procainamide (30 mg/kg by mouth every 12 hours) to determine the pharmacokinetics of sustained-release procainamide. Serum procainamide concentration was determined using an immunochemistry assay.
RESULTS
No adverse clinical effects were noted in any of the dogs studied. The average maximum serum concentration, average serum concentration, and average minimum serum concentration were 10.17, 7.13, and 3.07 μg/mL, respectively. The average time over a 12-h period during which procainamide concentration exceeded 12 μg/mL was 2.35 h, was between 4 and 12 μg/mL was 7.19 h, and was less than 4 μg/mL was 2.46 h. The average times at maximum concentration and minimum concentration were 18.67 and 12.25 h, respectively.
CONCLUSIONS
Administration of sustained-release procainamide twice daily achieved targeted plasma concentrations in most dogs. Evaluation of serum trough concentrations should be considered owing to interanimal variability to confirm that serum concentrations are within the reported therapeutic range for an individual patient.
Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Delayed-Action Preparations; Dogs; Female; Male; Procainamide; Reference Values
PubMed: 31405555
DOI: 10.1016/j.jvc.2019.06.002 -
Chemical Research in Toxicology Sep 2016We have previously reported the enhancement of the antiproliferative and apoptotic activities of cis-diamminedichloroplatinum(II) (DDP) when it is coadministered with a...
We have previously reported the enhancement of the antiproliferative and apoptotic activities of cis-diamminedichloroplatinum(II) (DDP) when it is coadministered with a class I antiarrhythmic drug procainamide hydrochloride (PA). Here, we determined the antiproliferative activity of DDP, either in solution or loaded in liposomes, in the presence of PA, in the bulk solution, or directly embedded in liposomes together with DDP. Our results show that PA potentiates the activity of DDP-liposomes and that this effect is maintained at least in some of the investigated cell types when both drugs were mixed and loaded together into liposomes.
Topics: A549 Cells; Animals; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Inhibitory Concentration 50; Liposomes; Procainamide
PubMed: 27501273
DOI: 10.1021/acs.chemrestox.6b00207 -
Fundamental & Clinical Pharmacology Aug 2014Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier... (Comparative Study)
Comparative Study
Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Guinea Pigs; Lidocaine; Long QT Syndrome; Procainamide; Tachycardia, Ventricular; Voltage-Gated Sodium Channel Blockers
PubMed: 23952942
DOI: 10.1111/fcp.12046 -
Pharmacological Research Mar 2024Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of...
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
Topics: Animals; Rats; Acyl-CoA Oxidase; Allografts; Fibrosis; Kidney; Kidney Transplantation; Lipids; Metabolic Diseases
PubMed: 38367917
DOI: 10.1016/j.phrs.2024.107105 -
Cureus Feb 2022While a large proportion of ST-segment elevation on EKG is related to myocardial ischemia, the differential diagnosis must include pericarditis, channelopathies, and...
While a large proportion of ST-segment elevation on EKG is related to myocardial ischemia, the differential diagnosis must include pericarditis, channelopathies, and various genetic conditions. Identifying and working up such abnormalities present a challenge to primary care providers (PCPs). We present two clinical cases of young male patients with ST-segment elevation in anteroseptal leads suspicious for Brugada syndrome and show how to risk stratify and manage them. Our first case presents a 23-year-old male with no past medical history with acute onset substernal chest pain, shortness of breath, and palpitations. Initial workup revealed negative serial troponins and normal B-type natriuretic peptide (BNP). The EKG revealed ST elevation in lead V2. An evaluation for Brugada syndrome was pursued. Upon completion of a procainamide challenge, it was determined that he did not have Brugada syndrome and was shortly discharged. Our second case presents a 33-year-old male with no pertinent cardiac medical history who presented to an outpatient cardiology clinic after discovering an incidental ST elevation in V2 on EKG. His family history was negative for early atherosclerotic cardiovascular events or sudden cardiac death. The patient's initial workup was negative. Suspicion for Brugada syndrome leads to performing a procainamide challenge, which was significant for ST changes in the anterolateral leads. He was asymptomatic during the challenge and initial presentation, and no further intervention was indicated. He was advised to avoid sodium channel blocking medications and treat any fevers and was sent for genetic testing. These cases illustrate the importance of maintaining an appropriate suspicion for Brugada syndrome in young patients with minimal ischemic risk factors. We discuss a guideline-directed algorithmic workup for PCPs in suspicious individuals. Stratifying patients based on the presence of symptoms, history of tachyarrhythmias, and EKG findings before and after drug challenge allows physicians to guide further management of these patients.
PubMed: 35273866
DOI: 10.7759/cureus.21921 -
Pharmaceutics Mar 2018A simple, sensitive, and reliable reversed-phase, Ultra-High-Pressure Liquid Chromatography (UHPLC) coupled with a Diode Array Detector (DAD) method for the simultaneous...
Simultaneous Determination of Procainamide and N-acetylprocainamide in Rat Plasma by Ultra-High-Pressure Liquid Chromatography Coupled with a Diode Array Detector and Its Application to a Pharmacokinetic Study in Rats.
A simple, sensitive, and reliable reversed-phase, Ultra-High-Pressure Liquid Chromatography (UHPLC) coupled with a Diode Array Detector (DAD) method for the simultaneous determination of Procainamide (PA) and its major metabolite, -acetylprocainamide (NAPA), in rat plasma was developed and validated. A simple deproteinization method with methanol was applied to the rat plasma samples, which were analyzed using UHPLC equipped with DAD at 280 nm, and a Synergi™ 4 µm polar, reversed-phase column using 1% acetic acid (pH 5.5) and methanol (76:24, /) as eluent in isocratic mode at a flow rate 0.2 mL/min. The method showed good linearity (² > 0.998) over the concentration range of 20-100,000 and 20-10,000 ng/mL for PA and NAPA, respectively. Intra- and inter-day accuracies ranged from 97.7 to 110.9%, and precision was <10.5% for PA and 99.7 to 109.2 and <10.5%, respectively, for NAPA. The lower limit of quantification was 20 ng/mL for both compounds. This is the first report of the UHPLC-DAD bioanalytical method for simultaneous measurement of PA and NAPA. The most obvious advantage of this method over previously reported HPLC methods is that it requires small sample and injection volumes, with a straightforward, one-step sample preparation. It overcomes the limitations of previous methods, which use large sample volume and complex sample preparation. The devised method was successfully applied to the quantification of PA and NAPA after an intravenous bolus administration of 10 mg/kg procainamide hydrochloride to rats.
PubMed: 29601501
DOI: 10.3390/pharmaceutics10020041 -
Methods in Molecular Biology (Clifton,... 2021The use of sequential exoglycosidase digestion of oligosaccharides followed by LC-FLD, LC-MS or CE analysis provides detailed carbohydrate structural information. Highly...
The use of sequential exoglycosidase digestion of oligosaccharides followed by LC-FLD, LC-MS or CE analysis provides detailed carbohydrate structural information. Highly specific exoglycosidases cleave monosaccharides from the nonreducing end of an oligosaccharide and yield information about the linkage, stereochemistry and configuration of the anomeric carbon. Here we use combinations of exoglycosidases to precisely characterize glycans on the Fc domain of therapeutic antibodies and dimeric fusion proteins. The workflow described includes glycan release with Rapid™ PNGase F (NEB #P0710), direct labeling of released glycans with procainamide (PCA) or 2-aminobenzamide (2AB), cleanup of labeled glycans and a 3 h enzymatic digestion with exoglycosidases. This protocol is designed for completion within an 8 h time frame to allow for subsequent LC-FLD, LC-MS, or CE analysis overnight.
Topics: Antibodies, Monoclonal; Carbohydrate Conformation; Chromatography, High Pressure Liquid; Fluorescent Dyes; Fluorometry; Glycoproteins; Glycoside Hydrolases; Glycosylation; Hydrolysis; Mass Spectrometry; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; Polysaccharides; Procainamide; Protein Processing, Post-Translational; Recombinant Fusion Proteins; Research Design; Substrate Specificity; Workflow; ortho-Aminobenzoates
PubMed: 33908014
DOI: 10.1007/978-1-0716-1241-5_19 -
Heart Rhythm Feb 2024More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved.
BACKGROUND
More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved.
OBJECTIVE
This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF.
METHODS
Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics.
RESULTS
Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Na1.5, Ca1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Na1.8 blocker A-803467.
CONCLUSION
Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Na1.8 blocker.
Topics: Animals; Rats; Action Potentials; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Remodeling; Heart Atria; Inflammation; Mutation; Myocytes, Cardiac; Procainamide; Sodium
PubMed: 37924963
DOI: 10.1016/j.hrthm.2023.10.025