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American Journal of Translational... 2021Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic... (Review)
Review
Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.
PubMed: 35035679
DOI: No ID Found -
Annals of Pediatric Cardiology 2021Junctional ectopic tachycardia (JET) is more common in its postoperative form. A thorough understanding of its etiology, pathophysiology, and management strategies is... (Review)
Review
Junctional ectopic tachycardia (JET) is more common in its postoperative form. A thorough understanding of its etiology, pathophysiology, and management strategies is essential. Classically, postoperative JET is considered to arise from surgical trauma. Genetic susceptibility and an intrinsic morphologic/functional defect in the conduction system inherent in congenital heart diseases likely play a significant role. The devastating effects on postoperative hemodynamics warrant prompt attention. A multipronged management approach with general measures, pharmacotherapy, and pacing has decreased morbidity and mortality. Amiodarone and procainamide remain the preferred drugs, while ivabradine appears promising. Carefully planned randomized trials can go a long way in developing a systematic management protocol for postoperative JET.
PubMed: 34667411
DOI: 10.4103/apc.apc_35_21 -
Expert Opinion on Drug Metabolism &... Jan 2021The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous... (Review)
Review
INTRODUCTION
The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs.
AREAS COVERED
We describe and review data that more clearly defines the effects of haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for phenotype-dependent dosing strategies.
EXPERT OPINION
Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.
Topics: Acetylation; Amines; Arylamine N-Acetyltransferase; Genotype; Hepatocytes; Humans; Hydrazines; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 33094670
DOI: 10.1080/17425255.2021.1840551 -
Heart Rhythm O2 Dec 2021Antiarrhythmic therapy for recurrent ventricular arrhythmias in patients who have undergone catheter ablation, and in whom amiodarone and/or beta-blockers were...
BACKGROUND
Antiarrhythmic therapy for recurrent ventricular arrhythmias in patients who have undergone catheter ablation, and in whom amiodarone and/or beta-blockers were ineffective or contraindicated, is a controversial issue.
OBJECTIVE
The present study sought to evaluate the efficacy and tolerability of oral procainamide in patients with recurrent ventricular arrhythmias when the standard therapy strategy had failed.
METHODS
All patients treated with procainamide for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) in our institution between January 2010 and May 2019 were enrolled. The primary endpoint was the total number of implantable cardioverter-defibrillator (ICD) interventions after the beginning of procainamide therapy. Secondary endpoints were the total number of VTs and VFs recorded on the ICDs' controls and discontinuation of therapy. The events occurring during procainamide treatment were compared with a matched-duration period before the initiation of therapy with procainamide. Patients therefore served as self-controls.
RESULTS
A total of 34 consecutive patients (32 male, 94.1%; mean age 74.4 ± 9.7 years) were included in the retrospective analysis. The mean time of procainamide treatment was 12.9 ± 13.7 months (median 9 [2-20] months). The mean dose of procainamide was 1207 ± 487 mg/day. Procainamide therapy significantly decreased ICD interventions (median 5 [0-22.5] vs 15.5 [3-32.25], < .05). Procainamide also decreased the total number of VT/VF episodes (median 5.5 [0.75-30] vs 19 [7.5-30], < .05). Only 3 patients (8.8%) presented severe side effects (dyspnea or hypotension), requiring discontinuation of therapy.
CONCLUSION
Oral procainamide was associated with a significant decrease in ICD therapies and ventricular arrhythmias, showing an acceptable profile of tolerability.
PubMed: 34988535
DOI: 10.1016/j.hroo.2021.10.002 -
Journal of Community Hospital Internal... Jun 2020The Brugada pattern is identified on the EKG by a coved ST-segment elevation accompanied by a negative T wave in the early precordial leads in the absence of a cardiac... (Review)
Review
BACKGROUND
The Brugada pattern is identified on the EKG by a coved ST-segment elevation accompanied by a negative T wave in the early precordial leads in the absence of a cardiac structural abnormality. Brugada pattern and Brugada syndrome should be differentiated, as the latter is associated with an increased risk of sudden cardiac death.
METHODS
The literature was searched using multiple databases to identify all the articles on Brugada pattern. Data were screened and analyzed by independent authors.
RESULTS
Sixty articles, comprising 71 patients, were included in the study. The mean age of patients was 42.6 years, with a higher prevalence of Brugada pattern in men (83%) than women (17%). The most frequent findings associated with Brugada pattern was fever (83%). Other less common presentations included cough (21%), sore throat (10%), syncope (18%), abdominal pain (8%), and chest pain (7%). Comorbidities included pneumonia (30%), upper respiratory tract infections (14%) and smoking (14%). Among treatment modalities, 39% of patients had ICD placement performed, 44% received antibiotics, while 14% had supportive care. Adenosine was given to 3% of patients, while other antiarrhythmics like milrinone, amiodarone, sotalol, procainamide, flecainide, and nitroglycerin were given to 1% of patients. Most patients with Brugada syndrome had a satisfactory outcome, with only 4% mortality rate(WHAT ABOUT THE OTHER 11%?). Out of the 71 patients, 3% had persistent Brugada patterns, while 86% of patients recovered completely. There was no significant effect of ICD on mortality or Brugada pattern resolution (p 0.37).
CONCLUSION
Our study shows that fever is the main reason for unmasking the Brugada pattern in patients with this channelopathy. ICD placement in such patients is not recommended as it has no mortality benefits.
PubMed: 32850069
DOI: 10.1080/20009666.2020.1767278