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JACC. Clinical Electrophysiology Apr 2019The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge. (Comparative Study)
Comparative Study
OBJECTIVES
The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge.
BACKGROUND
A type 1 Brugada electrocardiographic pattern precipitated by an SCB challenge confers a diagnosis of Brugada syndrome.
METHODS
Patients undergoing an SCB challenge were prospectively enrolled across Canada and the United Kingdom. Patients with no prior cardiac arrest and family histories of sudden cardiac death or Brugada syndrome were included.
RESULTS
Four hundred twenty-five subjects underwent SCB challenge (ajmaline, n = 331 [78%]; procainamide, n = 94 [22%]), with a mean age of 39 ± 15 years (54% men). Baseline non-type 1 Brugada ST-segment elevation was present in 10%. A total of 154 patients (36%) underwent signal-averaged electrocardiography, with 41% having late potentials. Positive results were seen more often with ajmaline than procainamide infusion (26% vs. 4%, p < 0.001). On multivariate analysis, baseline non-type 1 Brugada ST-segment elevation (odds ratio [OR]: 6.92; 95% confidence interval [CI]: 3.15 to 15.2; p < 0.001) and ajmaline use (OR: 8.76; 95% CI: 2.62 to 29.2; p < 0.001) were independent predictors of positive results to SCB challenge. In the subgroup undergoing signal-averaged electrocardiography, non-type 1 Brugada ST-segment elevation (OR: 9.28; 95% CI: 2.22 to 38.8; p = 0.002), late potentials on signal-averaged electrocardiography (OR: 4.32; 95% CI: 1.50 to 12.5; p = 0.007), and ajmaline use (OR: 12.0; 95% CI: 2.45 to 59.1; p = 0.002) were strong predictors of SCB outcome.
CONCLUSIONS
The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.
Topics: Adult; Ajmaline; Brugada Syndrome; Cohort Studies; Electrocardiography; Female; Humans; Male; Middle Aged; Procainamide; Voltage-Gated Sodium Channel Blockers; Young Adult
PubMed: 31000106
DOI: 10.1016/j.jacep.2019.01.026 -
Pharmaceutics Mar 2019Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or -acetylprocainamide (NAPA; the primary metabolite of PA) resulting...
Physiologically-Based Pharmacokinetic Modeling for Drug-Drug Interactions of Procainamide and -Acetylprocainamide with Cimetidine, an Inhibitor of rOCT2 and rMATE1, in Rats.
Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or -acetylprocainamide (NAPA; the primary metabolite of PA) resulting in the increased systemic exposure and the decrease of urinary excretion. Despite an abundance of in vitro and in vivo data regarding pharmacokinetic interactions between PA/NAPA and cimetidine, however, a mechanistic approach to elucidate these interactions has not been reported yet. The primary objective of this study was to construct a physiological model that describes pharmacokinetic interactions between PA/NAPA and cimetidine, an inhibitor of rat organic cation transporter 2 (rOCT2) and rat multidrug and toxin extrusion proteins (rMATE1), by performing extensive in vivo and in vitro pharmacokinetic studies for PA and NAPA performed in the absence or presence of cimetidine in rats. When a single intravenous injection of PA HCl (10 mg/kg) was administered to rats, co-administration of cimetidine (100 mg/kg) significantly increased systemic exposure and decreased the systemic (CL) and renal (CL) clearance of PA, and reduced its tissue distribution. Similarly, cimetidine significantly decreased the CL of NAPA formed by the metabolism of PA and increased the AUC of NAPA. Considering that these drugs could share similar renal secretory pathways (e.g., via rOCT2 and rMATE1), a physiologically-based pharmacokinetic (PBPK) model incorporating semi-mechanistic kidney compartments was devised to predict drug-drug interactions (DDIs). Using our proposed PBPK model, DDIs between PA/NAPA and cimetidine were successfully predicted for the plasma concentrations and urinary excretion profiles of PA and NAPA observed in rats. Moreover, sensitivity analyses of the pharmacokinetics of PA and NAPA showed the inhibitory effects of cimetidine via rMATE1 were probably important for the renal elimination of PA and NAPA in rats. The proposed PBPK model may be useful for understanding the mechanisms of interactions between PA/NAPA and cimetidine in vivo.
PubMed: 30845766
DOI: 10.3390/pharmaceutics11030108 -
JACC. Clinical Electrophysiology Feb 2019
Topics: Bundle-Branch Block; Flecainide; Humans; Procainamide; Syncope
PubMed: 30784694
DOI: 10.1016/j.jacep.2018.10.012 -
JACC. Clinical Electrophysiology Feb 2019This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients...
OBJECTIVES
This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients with syncope and bundle branch block (BBB).
BACKGROUND
Patients with syncope and BBB are at risk of developing atrioventricular block. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal His-ventricular interval. There is little data on differences between different class I drugs.
METHODS
This was a prospective study of all consecutive patients undergoing EPS for syncope and BBB at a single center (January 1, 2012 to June 30, 2017). Of those patients with negative baseline EPS, 2 cohorts were compared: group A (historical cohort: procainamide) and group B (flecainide).
RESULTS
During the study, 271 patients (age 73.9 ± 12.1 years, 64.9% male, QRS duration: 139.4 ± 13.9 ms) underwent EPS. In 166, baseline EPS was negative and class I drug challenge was performed (90 procainamide, 76 flecainide). The final value and percentage increase in the His-ventricular interval (76 ± 16 ms vs. 64 ± 10 ms and 22.5 ± 6.2% vs. 11.8 ± 5.3%; p < 0.001) and diagnostic yield (14.5% vs. 7.8%, p = 0.04) were higher with flecainide. No differences were found in baseline characteristics. During follow-up (25.8 ± 6.3 months), 39 patients (24.8%) with negative EPS (19.2% with flecainide vs. 30.1% with procainamide: relative risk: 5.1; 95% confidence interval: 2.6 to 10.2; p < 0. 001) received a pacemaker.
CONCLUSIONS
Flecainide has a higher diagnostic yield than does procainamide in patients with BBB, syncope, and negative baseline EPS due to a greater increase of the His-ventricular interval. Additionally, there is a lesser need for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.
Topics: Aged; Aged, 80 and over; Bundle-Branch Block; Electrocardiography; Electrophysiologic Techniques, Cardiac; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Procainamide; Syncope
PubMed: 30784693
DOI: 10.1016/j.jacep.2018.09.015 -
Cells Feb 2019Lupus flares when genetically predisposed people encounter exogenous agents such as infections and sun exposure and drugs such as procainamide and hydralazine, but the... (Review)
Review
Lupus flares when genetically predisposed people encounter exogenous agents such as infections and sun exposure and drugs such as procainamide and hydralazine, but the mechanisms by which these agents trigger the flares has been unclear. Current evidence indicates that procainamide and hydralazine, as well as inflammation caused by the environmental agents, can cause overexpression of genes normally silenced by DNA methylation in CD4⁺ T cells, converting them into autoreactive, proinflammatory cytotoxic cells that are sufficient to cause lupus in mice, and similar cells are found in patients with active lupus. More recent studies demonstrate that these cells comprise a distinct CD4⁺ T cell subset, making it a therapeutic target for the treatment of lupus flares. Transcriptional analyses of this subset reveal proteins uniquely expressed by this subset, which may serve as therapeutic to deplete these cells, treating lupus flares.
Topics: Animals; DNA Methylation; Demethylation; Epigenesis, Genetic; Humans; Lupus Erythematosus, Systemic; T-Lymphocyte Subsets
PubMed: 30764520
DOI: 10.3390/cells8020127 -
PloS One 2019Human butyrylcholinesterase (HuBChE) is being developed as a therapeutic for protection from the toxicity of nerve agents. An enriched source of HuBChE is Cohn fraction...
Human butyrylcholinesterase (HuBChE) is being developed as a therapeutic for protection from the toxicity of nerve agents. An enriched source of HuBChE is Cohn fraction IV-4 from pooled human plasma. For the past 40 years, purification of HuBChE has included affinity chromatography on procainamide-Sepharose. The present report supports a new affinity sorbent, Hupresin, for purification of HuBChE from Cohn fraction IV-4. Nine batches of 70-80 kg frozen Cohn fraction were extracted with water, filtered, and chromatographed on 30 L of Q-Ceramic ion exchange sorbent at pH 4.5. The 4% pure Q-eluent was pumped onto 4.2 L Hupresin, where contaminants were washed off with 0.3 M NaCl in 20 mM sodium phosphate pH 8.0, before 99% pure HuBChE was eluted with 0.1 M tetramethylammonium bromide. The average yield was 1.5 g of HuBChE from 80 kg Cohn paste. Recovery of HuBChE was reduced by 90% when the paste was stored at -20°C for 1 year, and reduced 100% when stored at 4°C for 24h. No reduction in HuBChE recovery occurred when paste was stored at -80°C for 3 months or 3 years. Hupresin and procainamide-Sepharose were equally effective at purifying HuBChE from Cohn fraction. HuBChE in Cohn fraction required 1000-fold purification to attain 99% purity, but 15,000-fold purification when the starting material was plasma. HuBChE (P06276) purified from Cohn fraction was a 340 kDa tetramer of 4 identical N-glycated subunits, stable for years in solution or as a lyophilized product.
Topics: Blood Proteins; Butyrylcholinesterase; Chromatography, Affinity; Chromatography, Ion Exchange; Humans; Plasma
PubMed: 30625168
DOI: 10.1371/journal.pone.0209795 -
Glycoconjugate Journal Feb 2019Advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), resulting from non-enzymatic modifications of proteins, are potentially harmful to...
Insights into the effects of N-glycosylation on the characteristics of the VC1 domain of the human receptor for advanced glycation end products (RAGE) secreted by Pichia pastoris.
Advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), resulting from non-enzymatic modifications of proteins, are potentially harmful to human health. They directly act on proteins, affecting structure and function, or through receptor-mediated mechanisms. RAGE, a type I transmembrane glycoprotein, was identified as a receptor for AGEs. RAGE is involved in chronic inflammation, oxidative stress-based diseases and ageing. The majority of RAGE ligands bind to the VC1 domain. This domain was successfully expressed and secreted by Pichia pastoris. Out of two N-glycosylation sites, one (Asn25) was fully occupied while the other (Asn81) was under-glycosylated, generating two VC1 variants, named p36 and p34. Analysis of N-glycans and of their influence on VC1 properties were here investigated. The highly sensitive procainamide labeling method coupled to ES-MS was used for N-glycan profiling. N-glycans released from VC1 ranged from ManGlcNAc- to ManGlcNAc- with major ManGlcNAc- and ManGlcNAc- species for p36 and p34, respectively. Circular dichroism spectra indicated that VC1 maintains the same conformation also after removal of N-glycans. Thermal denaturation curves showed that the carbohydrate moiety has a small stabilizing effect on VC1 protein conformation. The removal of the glycan moiety did not affect the binding of VC1 to sugar-derived AGE- or malondialdehyde-derived ALE-human serum albumin. Given the crucial role of RAGE in human pathologies, the features of VC1 from P. pastoris will prove useful in designing strategies for the enrichment of AGEs/ALEs from plasma, urine or tissues, and in characterizing the nature of the interaction.
Topics: Glycosylation; Humans; Molecular Dynamics Simulation; Pichia; Polysaccharides; Protein Domains; Protein Processing, Post-Translational; Protein Stability; Receptor for Advanced Glycation End Products
PubMed: 30612271
DOI: 10.1007/s10719-018-09855-x -
American Journal of Pharmaceutical... Nov 2018To describe how clinical pharmacokinetics is being delivered across curricula in pharmacy programs, including the curricular position of clinical pharmacokinetic...
To describe how clinical pharmacokinetics is being delivered across curricula in pharmacy programs, including the curricular position of clinical pharmacokinetic topics, topics currently taught, and instructional methods used in delivering the course content. A survey was distributed to one representative faculty member from each pharmacy college who was most able to answer questions about their institution's delivery of clinical pharmacokinetic material. Responses were collected from 82 out of the 108 pharmacy colleges who participated in the study. Clinical pharmacokinetics was integrated within other courses through the curriculum in 41% of colleges and includes a substantial amount of math-based material. The most common instructional methods were lectures and practice with actual pharmacokinetic cases. The majority of the schools used examinations and quizzes to determine students' grades. Certain drugs remain popular (ie, aminoglycosides, vancomycin, digoxin) while others have fallen out of favor (ie, procainamide, phenytoin, theophylline). Various methods were used to deliver the material and assess student learning. The delivery of clinical pharmacokinetic material has changed in the recent past across pharmacy colleges in the United States. Spreading clinical pharmacokinetics throughout the curriculum while maintaining the math-centric nature of the material has occurred. Clinical pharmacokinetics is a changing field and these results can be used to compare an institution's current content and delivery methods with other institutions. These aggregate results may be useful for schools that are redesigning their curriculum or are considering doing so.
Topics: Curriculum; Education, Medical, Undergraduate; Education, Pharmacy; Faculty; Humans; Pharmaceutical Preparations; Pharmacokinetics; Schools; Schools, Pharmacy; Students, Pharmacy; Surveys and Questionnaires; Teaching; United States; Universities
PubMed: 30559497
DOI: 10.5688/ajpe6430 -
American Journal of Medical Case Reports 2018Brugada syndrome is a rare cardiac arrhythmia which is associated with right bundle branch block pattern (RBBB) and ST-segment elevation in right precordial leads. SCNA5...
Brugada syndrome is a rare cardiac arrhythmia which is associated with right bundle branch block pattern (RBBB) and ST-segment elevation in right precordial leads. SCNA5 mutation is the most common genetic abnormality associated with Brugada syndrome. Brugada pattern not related to genetic mutations has been previously reported in the setting of fever, metabolic conditions, lithium use, marijuana and cocaine abuse, ischemia and pulmonary embolism, myocardial and pericardial diseases. Multiple isolated cases of Brugada pattern associated with diabetic ketoacidosis (DKA) have been previously reported. We here present a case of type 1 Brugada pattern in a 23 year-old-male who presented with DKA. Brugada pattern in DKA is attributed to acidosis and multiple electrolyte abnormalities including hyperkalemia which alter ion channel expression in the heart thus leading to Brugada pattern which subsequently resolved with treatment of DKA. In such patients, Brugada pattern is not reproducible on procainamide induction cardiac electrophysiology study (EPS). Our scoping study demonstrates male predominance 20/22 cases of (DELETE this highlighted area) Brugada pattern in DKA, a finding that is consistent with prevalence of this disease among males.
PubMed: 30533520
DOI: 10.12691/ajmcr-6-9-2