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International Journal of Molecular... Mar 2023The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global concern since its outbreak in 2019, with one of the main solutions being...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global concern since its outbreak in 2019, with one of the main solutions being vaccination. Altered glycosylation has been described in patients after SARS-CoV-2 infection, while the effect of vaccination on serum glycoproteins remained unexplored. In this study, total serum glycosylation was analyzed in patients after SARS-CoV-2 infection and/or mRNA vaccination in order to identify potential glycosylation-based alterations. Enzyme-linked immunosorbent assay was applied to identify post-COVID-19 and post-Vaccinated patients and rule out potential outliers. Serum samples were deglycosylated by PNGase F digestion, and the released glycans were fluorescently derivatized using procainamide labeling. Solid-phase extraction was used to purify the labeled glycans followed by the analysis of hydrophilic-interaction liquid chromatography with fluorescence and mass-spectrometric detection. Alterations of serum N-glycome in response to SARS-CoV-2 infection and mRNA vaccination were revealed by linear discriminant analysis.
Topics: Humans; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Vaccination; RNA, Messenger
PubMed: 37047177
DOI: 10.3390/ijms24076203 -
The American Journal of Emergency... Feb 2022Flecainide is a commonly used IC antiarrhythmic. Clinical presentations of Flecainide toxicity are not commonly described.
BACKGROUND
Flecainide is a commonly used IC antiarrhythmic. Clinical presentations of Flecainide toxicity are not commonly described.
CASE REPORT
A 62 year old man on dialysis presented for evaluation of outpatient bradycardia and hypotension. In the ED, patient had wide-complex rhythm with heart rates ranging from 76 to 127. The previous day, Flecainide and Metoprolol were discontinued and patient was dialyzed and discharged. The patient was treated empirically for possible hyperkalemia. No significant change in ECG was noted with administration of calcium. Sodium bicarbonate produced questionable benefit. Potassium level was 4.6 mmol/L. Cardiac rhythm fluctuated between sinus rhythm and wide complex tachycardia in the ED & ICU. Flecainide level was 2.1 μg/ml (normal <1 μg/ml). Toxicity developed despite previous discontinuation and dialysis prior to presentation because of Flecainide's large volume of distribution and lipopholicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although Flecainide toxicity is uncommon, it has a high mortality rate, requiring early identification and treatment. Flecainide toxicity can develop in patients with hepatic or renal insufficiency, and can manifest with ventricular tachycardia or bradycardia. If suspicion of Flecainide toxicity arises, lidocaine and procainamide should be avoided to prevent further sodium channel blockade. Absence of response to calcium for a very wide complex QRS should raise clinicians' suspicion that WCT is not due to hyperkalemia, emphasizing the importance of reviewing patients' home medications. Sodium bicarbonate should be administered early to treat widened QRS. Amiodarone, intralipid emulsion therapy and ECMO may be considered in severe cases.
Topics: Anti-Arrhythmia Agents; Electrocardiography; Flecainide; Humans; Hyperkalemia; Male; Middle Aged; Tachycardia
PubMed: 34391584
DOI: 10.1016/j.ajem.2021.08.004 -
PloS One 2016Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a... (Comparative Study)
Comparative Study
Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.
Topics: Acidosis; Animals; Bicarbonates; Biomarkers; Creatinine; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; Drug Evaluation, Preclinical; Electrolytes; Endotoxemia; Endotoxins; Hydralazine; Hypertension; Interleukin-6; Kidney; Lung; Male; Muscle, Skeletal; Neutrophils; Procainamide; Random Allocation; Rats; Rats, Wistar; Rhabdomyolysis; Superoxides; Tachycardia; DNA Methyltransferase 3B
PubMed: 26918767
DOI: 10.1371/journal.pone.0150319 -
Journal of Cardiology Cases May 2015A 65-year-old male on hemodialysis three times a week due to end-stage renal failure underwent cardiac surgery one year previously, and complained of breathlessness on...
A 65-year-old male on hemodialysis three times a week due to end-stage renal failure underwent cardiac surgery one year previously, and complained of breathlessness on exertion after surgery. Echocardiograms evidenced a significant obstruction in the left ventricular outflow with intraventricular pressure gradient of 62 mmHg, and the patient was started on beta-blocker. After a maximal dose of carvedilol was given, a class 1A antiarrhythmic drug of Na channel blocker, procainamide, was added because of insufficient relief of symptoms. Electrocardiogram (ECG) showed prolonged QT intervals (523 ms) on a regular visit one month after the administration of procainamide, and the dose of procainamide was decreased. On the next day, he was brought to our hospital due to cardiac pulmonary arrest. Initial rhythm was ventricular fibrillation and the corrected QT intervals (QTc) were prolonged (531 ms). Blood examination revealed that N-acetyl procainamide (NAPA), metabolite of procainamide, was significantly higher than the recommended threshold. NAPA was identified as the cause of prolonged QTc and procainamide was stopped. NAPA decreased under the recommended threshold on the seventh day and the QT intervals were normalized. This case report outlines the first case of long QT syndrome caused by NAPA in a hemodialysis patient. < Administration of procainamide could be dangerous even in patients undergoing hemodialysis whose serum procainamide level is within normal limits. We should pay careful attention to it and must not forget to measure the concentrations of procainamide and NAPA. The measurement of QT intervals could help to avoid a fatal side effect.>.
PubMed: 30546552
DOI: 10.1016/j.jccase.2015.02.005 -
Applied Biochemistry and Biotechnology Aug 2017The problem of gelation of concentrated protein solutions, which poses challenges for both downstream protein processing and liquid formulations of pharmaceutical...
The problem of gelation of concentrated protein solutions, which poses challenges for both downstream protein processing and liquid formulations of pharmaceutical proteins, is addressed herein by employing previously discovered viscosity-lowering bulky salts. Procainamide-HCl and the salt of camphor-10-sulfonic acid with L-arginine (CSA-Arg) greatly retard gelation upon heating and subsequent cooling of the model proteins gelatin and casein in water: Whereas in the absence of additives the proteins form aqueous gels within several hours at room temperature, procainamide-HCl for both proteins and also CSA-Arg for casein prevent gel formation for months under the same conditions. The inhibition of gelation by CSA-Arg stems exclusively from the CSA moiety: CSA-Na was as effective as CSA-Arg, while Arg-HCl was marginally or not effective. The tested bulky salts did not inhibit (and indeed accelerated) temperature-induced gel formation in aqueous solutions of all examined carbohydrates-starch, agarose, alginate, gellan gum, and carrageenan.
Topics: Animals; Arginine; Camphor; Carbohydrates; Caseins; Cattle; Excipients; Gelatin; Gels; Procainamide; Salts; Solutions; Sulfones; Temperature; Viscosity
PubMed: 28116573
DOI: 10.1007/s12010-017-2413-8 -
Diagnostics (Basel, Switzerland) Feb 2021In the last few years, cardiac magnetic resonance (CMR) imaging has progressively acquired a central role in the diagnosis and management of patients with ventricular...
In the last few years, cardiac magnetic resonance (CMR) imaging has progressively acquired a central role in the diagnosis and management of patients with ventricular arrhythmias (VA) [...].
PubMed: 33672729
DOI: 10.3390/diagnostics11020357 -
JACC. Clinical Electrophysiology Aug 2022The diagnosis of Brugada syndrome by 12-lead electrocardiography (ECG) is challenging because the diagnostic type 1 pattern is often transient.
BACKGROUND
The diagnosis of Brugada syndrome by 12-lead electrocardiography (ECG) is challenging because the diagnostic type 1 pattern is often transient.
OBJECTIVES
This study sought to improve Brugada syndrome diagnosis by using deep learning (DL) to continuously monitor for Brugada type 1 in 24-hour ambulatory 12-lead ECGs (Holters).
METHODS
A convolutional neural network was trained to classify Brugada type 1. The training cohort consisted of 10-second standard/high precordial leads from 12-lead ECGs (n = 1,190) and 12-lead Holters (n = 380) of patients with definite and suspected Brugada syndrome. The performance of the trained model was evaluated in 2 testing cohorts of 10-second standard/high precordial leads from 12-lead ECGs (n = 474) and 12-lead Holters (n = 716).
RESULTS
DL achieved a receiver-operating characteristic area under the curve of 0.976 (95% CI: 0.973-0.979) in classifying Brugada type 1 from 12-lead ECGs and 0.975 (95% CI: 0.966-0.983) from 12-lead Holters. Compared with cardiologist reclassification of Brugada type 1, DL had similar performance and produced robust results in experiments evaluating scalability and explainability. When DL was applied to consecutive 10-second, clean ECGs from 24-hour 12-lead Holters, spontaneous Brugada type 1 was detected in 48% of patients with procainamide-induced Brugada syndrome and in 33% with suspected Brugada syndrome. DL detected no Brugada type 1 in healthy control patients.
CONCLUSIONS
This novel DL model achieved cardiologist-level accuracy in classifying Brugada type 1. Applying DL to 24-hour 12-lead Holters significantly improved the detection of Brugada type 1 in patients with procainamide-induced and suspected Brugada syndrome. DL analysis of 12-lead Holters may provide a robust, automated screening tool before procainamide challenge to aid in the diagnosis of Brugada syndrome.
Topics: Brugada Syndrome; Deep Learning; Electrocardiography; Humans; Procainamide; Wearable Electronic Devices
PubMed: 35981788
DOI: 10.1016/j.jacep.2022.05.003 -
Bioorganic & Medicinal Chemistry Letters Nov 2023Malignant melanoma has an aggressive nature and a high metastatic propensity resulting in the highest mortality rate of any skin cancer. In this study, we synthesized...
Malignant melanoma has an aggressive nature and a high metastatic propensity resulting in the highest mortality rate of any skin cancer. In this study, we synthesized F-labeled procainamide (PCA) for detection of melanoma using positron emission tomography (PET), and evaluated its biological characteristics. The non-decay-corrected radiochemical yield of F-PCA was 10-15% and its in vitro stability was over 98% for 2 h. At 1 h, cellular uptake of F-PCA was 3.8-fold higher in a group with the presence of l-tyrosine than in a non-l-tyrosine-treated group. Furthermore, F-PCA permitted visualization of B16F10 (mouse melanoma) xenografts on microPET after intravenous injection, and was retained in the tumor for 60 min, with a high tumor-to-liver uptake ratio. F-PCA showed specific melanoma uptake in primary lesions with a high melanin targeting ability in small animal models. F-PCA may have potential as a PET imaging agent for direct melanoma detection.
Topics: Animals; Mice; Humans; Procainamide; Melanoma; Skin Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Cell Line, Tumor; Fluorine Radioisotopes; Melanoma, Cutaneous Malignant
PubMed: 37852422
DOI: 10.1016/j.bmcl.2023.129528 -
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 -
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