-
Nano Letters Jun 2024Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic...
Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both and studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.
PubMed: 38865330
DOI: 10.1021/acs.nanolett.4c01794 -
The Cochrane Database of Systematic... Jun 2024Atrial fibrillation (AF) is the most frequent sustained arrhythmia. Cardioversion is a rhythm control strategy to restore normal/sinus rhythm, and can be achieved... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Atrial fibrillation (AF) is the most frequent sustained arrhythmia. Cardioversion is a rhythm control strategy to restore normal/sinus rhythm, and can be achieved through drugs (pharmacological) or a synchronised electric shock (electrical cardioversion).
OBJECTIVES
To assess the efficacy and safety of pharmacological and electrical cardioversion for atrial fibrillation (AF), atrial flutter and atrial tachycardias.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science (CPCI-S) and three trials registers (ClinicalTrials.gov, WHO ICTRP and ISRCTN) on 14 February 2023.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) at the individual patient level. Patient populations were aged ≥ 18 years with AF of any type and duration, atrial flutter or other sustained related atrial arrhythmias, not occurring as a result of reversible causes.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodology to collect data and performed a network meta-analysis using the standard frequentist graph-theoretical approach using the netmeta package in R. We used GRADE to assess the quality of the evidence which we presented in our summary of findings with a judgement on certainty. We calculated differences using risk ratios (RR) and 95% confidence intervals (CI) as well as ranking treatments using a P value. We assessed clinical and statistical heterogeneity and split the networks for the primary outcome and acute procedural success, due to concerns about violating the transitivity assumption.
MAIN RESULTS
We included 112 RCTs (139 records), from which we pooled data from 15,968 patients. The average age ranged from 47 to 72 years and the proportion of male patients ranged from 38% to 92%. Seventy-nine trials were considered to be at high risk of bias for at least one domain, 32 had no high risk of bias domains, but had at least one domain classified as uncertain risk, and one study was considered at low risk for all domains. For paroxysmal AF (35 trials), when compared to placebo, anteroapical (AA)/anteroposterior (AP) biphasic truncated exponential waveform (BTE) cardioversion (RR: 2.42; 95% CI 1.65 to 3.56), quinidine (RR: 2.23; 95% CI 1.49 to 3.34), ibutilide (RR: 2.00; 95% CI 1.28 to 3.12), propafenone (RR: 1.98; 95% CI 1.67 to 2.34), amiodarone (RR: 1.69; 95% CI 1.42 to 2.02), sotalol (RR: 1.58; 95% CI 1.08 to 2.31) and procainamide (RR: 1.49; 95% CI 1.13 to 1.97) likely result in a large increase in maintenance of sinus rhythm until hospital discharge or end of study follow-up (certainty of evidence: moderate). The effect size was larger for AA/AP incremental and was progressively smaller for the subsequent interventions. Despite low certainty of evidence, antazoline may result in a large increase (RR: 28.60; 95% CI 1.77 to 461.30) in this outcome. Similarly, low-certainty evidence suggests a large increase in this outcome for flecainide (RR: 2.17; 95% CI 1.68 to 2.79), vernakalant (RR: 2.13; 95% CI 1.52 to 2.99), and magnesium (RR: 1.73; 95% CI 0.79 to 3.79). For persistent AF (26 trials), one network was created for electrical cardioversion and showed that, when compared to AP BTE incremental energy with patches, AP BTE maximum energy with patches (RR 1.35, 95% CI 1.17 to 1.55) likely results in a large increase, and active compression AP BTE incremental energy with patches (RR: 1.14, 95% CI 1.00 to 1.131) likely results in an increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: high). Use of AP BTE incremental with paddles (RR: 1.03, 95% CI 0.98 to 1.09; certainty of evidence: low) may lead to a slight increase, and AP MDS Incremental paddles (RR: 0.95, 95% CI 0.86 to 1.05; certainty of evidence: low) may lead to a slight decrease in efficacy. On the other hand, AP MDS incremental energy using patches (RR: 0.78, 95% CI 0.70 to 0.87), AA RBW incremental energy with patches (RR: 0.76, 95% CI 0.66 to 0.88), AP RBW incremental energy with patches (RR: 0.76, 95% CI 0.68 to 0.86), AA MDS incremental energy with patches (RR: 0.76, 95% CI 0.67 to 0.86) and AA MDS incremental energy with paddles (RR: 0.68, 95% CI 0.53 to 0.83) probably result in a decrease in this outcome when compared to AP BTE incremental energy with patches (certainty of evidence: moderate). The network for pharmacological cardioversion showed that bepridil (RR: 2.29, 95% CI 1.26 to 4.17) and quindine (RR: 1.53, (95% CI 1.01 to 2.32) probably result in a large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up when compared to amiodarone (certainty of evidence: moderate). Dofetilide (RR: 0.79, 95% CI 0.56 to 1.44), sotalol (RR: 0.89, 95% CI 0.67 to 1.18), propafenone (RR: 0.79, 95% CI 0.50 to 1.25) and pilsicainide (RR: 0.39, 95% CI 0.02 to 7.01) may result in a reduction in this outcome when compared to amiodarone, but the certainty of evidence is low. For atrial flutter (14 trials), a network could be created only for antiarrhythmic drugs. Using placebo as the common comparator, ibutilide (RR: 21.45, 95% CI 4.41 to 104.37), propafenone (RR: 7.15, 95% CI 1.27 to 40.10), dofetilide (RR: 6.43, 95% CI 1.38 to 29.91), and sotalol (RR: 6.39, 95% CI 1.03 to 39.78) probably result in a large increase in the maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: moderate), and procainamide (RR: 4.29, 95% CI 0.63 to 29.03), flecainide (RR 3.57, 95% CI 0.24 to 52.30) and vernakalant (RR: 1.18, 95% CI 0.05 to 27.37) may result in a large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence: low). All tested electrical cardioversion strategies for atrial flutter had very high efficacy (97.9% to 100%). The rate of mortality (14 deaths) and stroke or systemic embolism (3 events) at 30 days was extremely low. Data on quality of life were scarce and of uncertain clinical significance. No information was available regarding heart failure readmissions. Data on duration of hospitalisation was scarce, of low quality, and could not be pooled.
AUTHORS' CONCLUSIONS
Despite the low quality of evidence, this systematic review provides important information on electrical and pharmacological strategies to help patients and physicians deal with AF and atrial flutter. In the assessment of the patient comorbidity profile, antiarrhythmic drug onset of action and side effect profile versus the need for a physician with experience in sedation, or anaesthetics support for electrical cardioversion are key aspects when choosing the cardioversion method.
Topics: Aged; Humans; Middle Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Bias; Electric Countershock; Network Meta-Analysis; Randomized Controlled Trials as Topic; Tachycardia; Male; Female
PubMed: 38828867
DOI: 10.1002/14651858.CD013255.pub2 -
Clinical Rheumatology Jun 2024The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is... (Review)
Review
The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is well established. More recently, cases of immune-related adverse events ranging from inflammatory polyarthritis to necrotizing myositis in patients taking checkpoint inhibitors have been reported. However, data linking drugs to systemic vasculitis are scarce and at times debatable. Propylthiouracil, hydralazine, and minocycline have been associated with rare cases of ANCA-associated syndromes, including life-threatening pulmonary-renal syndromes and systemic polyarteritis nodosa-like diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has been reported in patients taking leukotriene inhibitors. Since the link between the use of leukotriene inhibitors and occurrence of EGPA remains highly controversial, we performed a literature review for cases of EGPA in patients taking montelukast without prior history of oral corticosteroid use. We found 24 cases, along with our own two cases described, making 26 cases in total. The mean age was 43 and a majority (18/26) were female. In majority of cases EGPA-like disease never relapsed after they were taken off leukotriene inhibitors suggesting a clear causal relationship between the use of these drugs and occurrence of eosinophil-rich systemic EGPA.
Topics: Humans; Sulfides; Quinolines; Cyclopropanes; Acetates; Leukotriene Antagonists; Female; Churg-Strauss Syndrome; Male; Granulomatosis with Polyangiitis; Middle Aged; Adult
PubMed: 38720163
DOI: 10.1007/s10067-024-07000-8 -
International Journal of Biological... Jun 2024This work presents a magnetic purification method of human erythrocyte Acetylcholinesterase (EC 3.1.1.7; AChE) based on affinity binding to procainamide (Proca) as...
This work presents a magnetic purification method of human erythrocyte Acetylcholinesterase (EC 3.1.1.7; AChE) based on affinity binding to procainamide (Proca) as ligand. Acetylcholinesterase is an acetylcholine-regulating enzyme found in different areas of the body and associated with various neurological disorders, such as Parkinson, Alzheymer and Amyotrophic Lateral Sclerosis. AChE from human erythrocyte purification has been attempted in recent years with low degree of purity. Here, magnetic nanoparticles (MNP) were synthesized and coated with polyaniline (PANI) and procainamide (PROCA) was covalently linked to the PANI. The extracted human erythrocyte AChE formed a complex with the MNP@PANI-PROCA and an external magnet separated it from the undesired proteins. Finally, the enzyme was collected by increasing the ionic strength. Experimental Box-Behnken design was developed to optimize this process of human erythrocyte AChE purification protocol. The enzyme was purified in all fifteen experiments. However, the best AChE purification result was achieved, about 2000 times purified, when 100 mg of MNP@PANI-PROCA was incubated for one hour with 4 ml hemolysate extract. The SDS-PAGE of this preparation presented a molecular weight of approximately 70 kDa, corroborating with few previous studies of AChE from erythrocyte purification.
Topics: Humans; Acetylcholinesterase; Erythrocytes; Magnetite Nanoparticles; Procainamide; Aniline Compounds
PubMed: 38705318
DOI: 10.1016/j.ijbiomac.2024.132094 -
Molecular Medicine Reports May 2024Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase‑activating proteins (GAPs) serve essential roles...
Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase‑activating proteins (GAPs) serve essential roles in cardiac hypertrophy. RhoGAP interacting with CIP4 homologs protein 1 (RICH1) is a RhoGAP that can regulate Cdc42/Rac1 and F‑actin dynamics. RICH1 is involved in cell proliferation and adhesion; however, to the best of our knowledge, its role in cardiac hypertrophy remains unknown. In the present study, the role of RICH1 in cardiomyocyte hypertrophy was assessed. Cell viability was analyzed using the Cell Counting Kit‑8 assay and cells surface area (CSA) was determined by cell fluorescence staining. Reverse transcription‑quantitative PCR and western blotting were used to assess the mRNA expression levels of hypertrophic marker genes, such as Nppa, Nppb and Myh7, and the protein expression levels of RICH1, respectively. RICH1 was shown to be downregulated in isoproterenol (ISO)‑ or angiotensin II (Ang II)‑treated H9c2 cells. Notably, overexpression of RICH1 attenuated the upregulation of hypertrophy‑related markers, such as Nppa, Nppb and Myh7, and the enlargement of CSA induced by ISO and Ang II. By contrast, the knockdown of RICH1 exacerbated these effects. These findings suggested that RICH1 may be a novel suppressor of ISO‑ or Ang II‑induced cardiomyocyte hypertrophy. The results of the present study will be beneficial to further studies assessing the role of RICH1 and its downstream molecules in inhibiting cardiac hypertrophy.
Topics: Humans; Myocytes, Cardiac; Angiotensin II; Isoproterenol; Cardiomegaly; Heart Defects, Congenital; Nitrobenzoates; Procainamide
PubMed: 38456539
DOI: 10.3892/mmr.2024.13193 -
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 -
Journal of the American Veterinary... May 2024To highlight the use of procainamide as a potential alternative treatment modality in cases of ventricular tachycardia that are refractory to lidocaine and magnesium...
OBJECTIVE
To highlight the use of procainamide as a potential alternative treatment modality in cases of ventricular tachycardia that are refractory to lidocaine and magnesium sulfate.
ANIMAL
1 adult horse weighing 380 kg.
CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES
A 25-year-old Arabian gelding presented with severe colic signs. Due to persistent pain, it was elected to carry out an exploratory laparotomy. During the procedure a diagnosis of severe, unstable ventricular tachycardia was made based on the ECG findings, with an initial heart rate of 195 beats per minute and severe hypotension.
TREATMENT AND OUTCOME
Initial treatment consisted of discontinuing dobutamine and the administration of a 2 mg/kg IV lidocaine bolus followed by a continuous rate infusion at 50 μg/kg/min. Twenty grams magnesium sulfate (5 mg/kg) was administered IV in 1 L of lactated Ringer solution as a slow bolus over 30 minutes. Ventricular tachycardia persisted with poor peripheral pulses, a severely dampened arterial waveform, and a MAP of 30 to 45 mm Hg. Two milligrams/kg IV procainamide was administered over 3 minutes, 3 separate times, at 5-minute intervals. Immediately following the third dose sinus rhythm was detected on the ECG, the arterial waveform improved, and MAP increased to 85 mm Hg.
CLINICAL RELEVANCE
Ventricular tachycardia is a rare but potentially life-threatening complication in horses undergoing general anesthesia. The potential of this arrhythmia to progress to ventricular fibrillation is of grave concern, as the option to attempt to externally defibrillate horses back to normal sinus rhythm does not exist. This case highlights procainamide as a potential option for cases of ventricular tachycardia that are refractory to more standard treatment modalities.
PubMed: 38335722
DOI: 10.2460/javma.23.09.0535 -
The International Journal of... Apr 2024Circadian genes play an important role in the field of drug metabolism. Flavin-containing monooxygenase 3 is a well-known phase I enzyme which participates in metabolism...
Circadian genes play an important role in the field of drug metabolism. Flavin-containing monooxygenase 3 is a well-known phase I enzyme which participates in metabolism of many exogenous and endogenous substances, especially production of trimethylamine N-oxide. Here, we aimed to decipher diurnal rhythms of flavin-containing monooxygenase 3 expression and activity, and explore the regulation mechanism by clock genes. Our results showed that its mRNA and protein exhibited robust diurnal rhythms in mouse liver and cell lines. Consistently, significant alterations were observed for in vitro microsomal N-oxidation rates of procainamide, which kept in line with its protein expression at different time in wild-type and reverse erythroblastosis virus α knockout mice. Further, flavin-containing monooxygenase 3 was negatively regulated by E4 promoter-binding protein 4 in AML12 and Hepa1-6 cells, while it was positively influenced by reverse erythroblastosis virus α and brain and muscle ARNT-like protein-1. Moreover, luciferase reporter assays and electrophoretic mobility shift assays showed E4 promoter-binding protein 4 inhibited the transcription of flavin-containing monooxygenase 3 by binding to a D-box1 element (-1606/-1594 bp), while brain and muscle ARNT-like protein-1 positively activated the transcription via direct binding to three E-boxes (-863/-858 bp, -507/-498 bp, and -115/-104 bp) in this enzyme promoter. Taken together, this study would be helpful to reveal the mechanism of clock-controlled drug metabolism and facilitate the practice of chrono-therapeutics.
Topics: Animals; Mice; Mice, Inbred Strains; Oxygenases; Circadian Rhythm; Liver
PubMed: 38320728
DOI: 10.1016/j.biocel.2024.106538 -
Biomolecules Jan 2024Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex...
Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO -glycosylation influences important pharmacological parameters, prominently serum half-life. Therefore, EPO -glycosylation analysis is of the utmost importance in terms of controlling critical quality attributes. In this work, we performed an interlaboratory study of glycoanalytical techniques for profiling and in-depth characterization, namely (1) hydrophilic interaction liquid chromatography with fluorescence detection after 2-aminobenzamide labeling (HILIC-FLD(2AB)) and optional weak anion exchange chromatography (WAX) fractionation and exoglycosidase digestion, (2) HILIC-FLD after procainamide labeling (PROC) optionally coupled to electrospray ionization-MS and (3) matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-MS). All techniques showed good precision and were able to differentiate the unique -glycosylation profiles of the various EPO preparations. HILIC-FLD showed higher precision, while MALDI-TOF-MS covered the most analytes. However, HILIC-FLD differentiated isomeric -glycans, i.e., -acetyllactosamine repeats and -acetylation regioisomers. For routine profiling, HILIC-FLD methods are more accessible and cover isomerism in major structures, while MALDI-MS covers more minor analytes with an attractively high throughput. For in-depth characterization, MALDI-MS and HILIC-FLD(2AB)/WAX give a similar amount of orthogonal information. HILIC-FLD(PROC)-MS is attractive for covering isomerism of major structures with a significantly less extensive workflow compared to HILIC-FLD(2AB)/WAX.
Topics: Humans; Glycosylation; Erythropoietin; Protein Processing, Post-Translational; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Acetylation
PubMed: 38254725
DOI: 10.3390/biom14010125