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Therapeutische Umschau. Revue... Dec 2015Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related... (Review)
Review
Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related injuries. This article provides an overview of the pathophysiological mechanisms involved in nephrotoxicity, the most common nephrotoxic drugs, and the risk factors for the occurrence of drug-induced acute kidney injuries. NSAIDs, diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs} are the most frequent prerenal causes of an acute elevation in creatinine levels. Primary vascular damage arises from thrombotic microangiopathy (e. g. due to cic/osporin, tacrolimus, muromonab-CD3, mitomycin C, quinine, ticlopidine, clopidogrel}. Anticoagulants and thrombolytic medications lead to secondary blood vessel damage by cholesterol emboli, embolism of thrombus material into the periphery or bleeding. Tubulopathies can be observed on treatment with ifosfamide and cisplatin (rarely with cyclophosphamide or carboplatin), aminoglycosides, vancomycin, and radiocontrast agents. Immunological mechanisms underlie interstitial nephritides, which are induced by drugs in about 85% of cases. In drug-induced glomerulopathies;- renal biopsy allows closer identification of the triggering medication. Drug-induced systemic lupus erythematosus (SLE} represents a special form of immune complex glomerulonephritis and can be triggered by procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine, and propylthiouracil. Crystal-induced kidney injury is caused by precipitation of drugs (e. g. aciclovir, sulfonamide antibiotics, methotrexate, indinavir) in the renal tubules and the urine-conducting organs with consecutive obstruction thereof.
Topics: Acute Kidney Injury; Drug-Related Side Effects and Adverse Reactions; Germany; Humans; Medication Errors; Pharmacovigilance
PubMed: 26654816
DOI: 10.1024/0040-5930/a000742 -
The American Journal of Emergency... May 2022With recent negative studies of amiodarone and lidocaine for cardiac arrest, research into other antiarrhythmics is warranted. Literature on procainamide in cardiac...
BACKGROUND
With recent negative studies of amiodarone and lidocaine for cardiac arrest, research into other antiarrhythmics is warranted. Literature on procainamide in cardiac arrest is limited. We evaluated procainamide for out-of-hospital cardiac arrests (OHCA) from the Resuscitation Outcomes Consortium (ROC).
METHODS
We included all ROC Epistry 3 OHCAs with an initial shockable rhythm that received an antiarrhythmic. We stratified cases by antiarrhythmic: procainamide, amiodarone, or lidocaine. The outcomes were prehospital return of spontaneous circulation (ROSC), ROSC in the ED, and survival to hospital discharge. We defined propensity scores based on possible confounders utilizing 1:1 propensity score matching to compare procainamide to amiodarone and lidocaine. We analyzed the matched data using logistic regression. We also used multivariable logistic regression to evaluate the association between antiarrhythmic and outcomes.
RESULTS
3087 subjects met inclusion criteria; 51 patients received only procainamide, 1776 received amiodarone, and 1418 received lidocaine. On propensity score analysis and compared to procainamide, amiodarone had similar prehospital ROSC (OR 0.7, 95% CI 0.3-1.8), ED ROSC (OR 0.6, 95% CI 0.3-1.3), and survival (OR 1.0, 95% CI 0.3-3.1). Lidocaine also had a similar prehospital ROSC (OR 0.9, 95% CI 0.4-2.2), ED ROSC (OR 1.2, 95% CI 0.5-2.7), and survival (OR 1.4, 95% CI 0.5-4.0). However, using multivariable regression, amiodarone had lower prehospital ROSC than procainamide (aOR 0.3, 95% CI 0.1-0.6).
CONCLUSIONS
While associated with increased prehospital ROSC when compared with amiodarone using multivariable regression, procainamide otherwise had similar prehospital ROSC, ED ROSC, and survival. The role of procainamide in OHCA remains unclear.
Topics: Amiodarone; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Emergency Medical Services; Humans; Lidocaine; Out-of-Hospital Cardiac Arrest; Procainamide; Retrospective Studies
PubMed: 35325787
DOI: 10.1016/j.ajem.2022.02.031 -
Acta Physiologica (Oxford, England) Jul 2017In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization... (Review)
Review
In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).
Topics: Animals; Arrhythmias, Cardiac; Calcium; Humans; Membrane Potentials; Myocytes, Cardiac
PubMed: 28707396
DOI: 10.1111/apha.12902 -
Xenobiotica; the Fate of Foreign... Jan 2020Over the years, numerous studies have supported the premise that individuals possessing the "slow acetylator" phenotype are more at risk from developing drug... (Review)
Review
Over the years, numerous studies have supported the premise that individuals possessing the "slow acetylator" phenotype are more at risk from developing drug side-effects. Most prominent amongst these reports are those concerned with hepatotoxicity and peripheral neuropathy following treatment with isoniazid, lupus-like symptoms during procainamide therapy and experiencing hypersensitivity reactions to the various sulphonamide derivatives. Similarly, "slow acetylators" undergoing heavy exposure to arylamines and related carcinogens are more likely to develop bladder cancer. Contrariwise, there appears a slight risk of "rapid acetylators" developing pancreatic tumours.Other therapeutic agents for which polymorphic N-acetylation plays a minor role in their metabolism have been investigated but any impact of this metabolic difference on clinical efficacy or associated toxicity is still under question. In the search for clues as to the underlying aetiology, patient groups with many disease states have been examined for association with differences in N-acetylation and the majority have provided data that could be interpreted as equivocal. Studies have given contradictory, often opposing, results, calculated risk factors that are (perhaps) just significant but certainly not high, and patients within the cohorts who are always exceptions. Undoubtedly, other as yet unappreciated factors are at play.
Topics: Acetylation; Arylamine N-Acetyltransferase; Genotype; Humans; Isoniazid; Phenotype; Polymorphism, Genetic
PubMed: 31092097
DOI: 10.1080/00498254.2019.1618511 -
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 -
The Journal of Emergency Medicine Mar 2018Atrial fibrillation (AF) is the most commonly encountered dysrhythmia in the emergency department, and its prevalence is increasing. A substantial proportion of these... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Atrial fibrillation (AF) is the most commonly encountered dysrhythmia in the emergency department, and its prevalence is increasing. A substantial proportion of these patients have recent-onset AF (<48 h). The poor prognosis associated with AF is being increasingly recognized, and there is some evidence for better outcomes in younger patients with recent-onset AF when sinus rhythm is restored. Flecainide is recommended in the latest international guidelines for cardioversion of recent-onset AF, but its safety and efficacy relative to other recommended agents are unclear.
OBJECTIVE
Our aim was to clarify the Level 1 evidence for the use of i.v. flecainide in acute AF.
METHODS
We performed a systematic review and meta-analysis of the literature. Medline, Ovid, Embase, and Cochrane Central databases were searched for relevant studies. Only randomized controlled trials (RCTs) of i.v. flecainide for acute conversion of recent-onset AF were selected for meta-analysis.
RESULTS
Four hundred and three studies were screened, of which 11 RCTs were eligible for meta-analysis. Flecainide had high efficacy for cardioversion within 2 h (number needed to treat [NNT] = 1.8). Efficacy was superior to propafenone, amiodarone, procainamide, ibutilide, and sotalol (NNT = 4.3). There was no statistically significant difference in pro-dysrhythmia compared to these anti-dysrhythmics or placebo.
CONCLUSIONS
Intravenous flecainide cardioversion could be a safe and effective option for emergency physicians to restore sinus rhythm in selected patients with acute AF.
Topics: Administration, Intravenous; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Electric Countershock; Emergency Service, Hospital; Flecainide; Humans; United Kingdom
PubMed: 29269083
DOI: 10.1016/j.jemermed.2017.11.016 -
Best Clinical Practice: Emergency Medicine Management of Stable Monomorphic Ventricular Tachycardia.The Journal of Emergency Medicine Apr 2017Ventricular tachycardia (VT) and ventricular fibrillation are the causes of approximately 300,000 deaths per year in the United States. VT is classified based on... (Review)
Review
BACKGROUND
Ventricular tachycardia (VT) and ventricular fibrillation are the causes of approximately 300,000 deaths per year in the United States. VT is classified based on hemodynamic status and appearance. Stable, monomorphic VT treatment is controversial.
OBJECTIVE
Our aim was to provide emergency physicians with an evidence-based review of the medical management of stable, monomorphic VT.
DISCUSSION
Stable, monomorphic VT is part of a larger class of ventricular dysrhythmias defined by a rate of at least 120 beats/min with QRS > 120 ms without regularly occurring P:QRS association. Little controversy exists for the treatment of hemodynamically unstable VT. The medical management of hemodynamically stable monomorphic VT is surrounded by controversy. Direct current cardioversion is most efficacious. Guidelines for the treatment of stable VT from the American Heart Association provide a IIa recommendation for procainamide, compared with a IIb recommendation for both amiodarone and sotalol. Studies evaluating procainamide, lidocaine, amiodarone, and sotalol suffer from poor design, difference in inclusion and exclusion criteria, small sample size, and outcome determination. Procainamide demonstrates the greatest efficacy. If procainamide is selected, a maximum dose of 10 mg/kg at 50-100 mg/min intravenous (IV) over 10-20 min should be provided with monitoring of blood pressure and electrocardiogram. Monomorphic VT with acute myocardial ischemia requires further study.
CONCLUSIONS
Optimal management of stable, monomorphic VT includes direct current cardioversion. If medical management is chosen, procainamide is most efficacious, though current literature suffers from poor design.
Topics: Amiodarone; Anti-Arrhythmia Agents; Electric Countershock; Electrocardiography; Emergency Service, Hospital; Evidence-Based Medicine; Humans; Lidocaine; Procainamide; Pyrimidinones; Review Literature as Topic; Sotalol; Tachycardia, Ventricular
PubMed: 27751700
DOI: 10.1016/j.jemermed.2016.09.010 -
Current Medicinal Chemistry 2020Systemic Lupus Erythematosus (SLE) is a chronic and relapsing heterogenous autoimmune disease that primarily affects women of reproductive age. Genetic and environmental... (Review)
Review
Systemic Lupus Erythematosus (SLE) is a chronic and relapsing heterogenous autoimmune disease that primarily affects women of reproductive age. Genetic and environmental risk factors are involved in the pathogenesis of SLE, and susceptibility genes have recently been identified. However, as gene therapy is far from clinical application, further investigation of environmental risk factors could reveal important therapeutic approaches. We systematically explored two groups of environmental risk factors: chemicals (including silica, solvents, pesticides, hydrocarbons, heavy metals, and particulate matter) and drugs (including procainamide, hydralazine, quinidine, Dpenicillamine, isoniazid, and methyldopa). Furthermore, the mechanisms underlying risk factors, such as genetic factors, epigenetic change, and disrupted immune tolerance, were explored. This review identifies novel risk factors and their underlying mechanisms. Practicable measures for the management of these risk factors will benefit SLE patients and provide potential therapeutic strategies.
Topics: Autoimmune Diseases; Female; Humans; Hydralazine; Lupus Erythematosus, Systemic; Procainamide; Risk Factors
PubMed: 30947650
DOI: 10.2174/0929867326666190404140658 -
PloS One 2016The study of saliva O-glycosylation is receiving increasing attention due to the potential of glycans for disease biomarkers, but also due to easy access and...
The study of saliva O-glycosylation is receiving increasing attention due to the potential of glycans for disease biomarkers, but also due to easy access and non-invasive collection of saliva as biological fluid. Saliva is rich in glycoproteins which are secreted from the bloodstream or produced by salivary glands. Mucins, which are highly O-glycosylated proteins, are particularly abundant in human saliva. Their glycosylation is associated with blood group and secretor status, and represents a reservoir of potential disease biomarkers. This study aims to analyse and compare O-glycans released from whole human mouth saliva collected 3 times a day from a healthy individual over a 5 days period. O-linked glycans were released by hydrazinolysis, labelled with procainamide and analysed by ultra-high performance liquid chromatography with fluorescence detection (UHPLC-FLR) coupled to electrospray ionization mass spectrometry (ESI-MS/MS). The sample preparation method showed excellent reproducibility and can therefore be used for biomarker discovery. Our data demonstrates that the O-glycosylation in human saliva changes significantly during the day. These changes may be related to changes in the salivary concentrations of specific proteins.
Topics: Animals; Cattle; Chromatography, High Pressure Liquid; Fetuins; Glycosylation; Humans; Longitudinal Studies; Mass Spectrometry; Metabolome; Polysaccharides; Procainamide; Reference Standards; Reproducibility of Results; Saliva; Staining and Labeling
PubMed: 27610614
DOI: 10.1371/journal.pone.0162824 -
Clinical Toxicology (Philadelphia, Pa.) Jun 2016Cocaine abuse is a major worldwide health problem. Patients with acute cocaine toxicity presenting to the emergency department may require urgent treatment for... (Review)
Review
INTRODUCTION
Cocaine abuse is a major worldwide health problem. Patients with acute cocaine toxicity presenting to the emergency department may require urgent treatment for tachycardia, dysrhythmia, hypertension, and coronary vasospasm, leading to pathological sequelae such as acute coronary syndrome, stroke, and death.
OBJECTIVE
The objective of this study is to review the current evidence for pharmacological treatment of cardiovascular toxicity resulting from cocaine abuse.
METHODS
MEDLINE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), OpenGrey, Google Scholar, and the Cochrane Library were searched from inception to November 2015. Articles on pharmacological treatment involving human subjects and cocaine were selected and reviewed. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines. Treatment recommendations were compared to current American College of Cardiology/American Heart Association guidelines. Special attention was given to adverse drug events or treatment failure. The search resulted in 2376 articles with 120 eligible involving 2358 human subjects. Benzodiazepines and other GABA-active agents: There were five high-quality (CEBM Level I/II) studies, three retrospective (Level III), and 25 case series/reports (Level IV/V) supporting the use of benzodiazepines and other GABA-active agents in 234 subjects with eight treatment failures. Benzodiazepines may not always effectively mitigate tachycardia, hypertension, and vasospasm from cocaine toxicity. Calcium channel blockers: There were seven Level I/II, one Level III, and seven Level IV/V studies involving 107 subjects and one treatment failure. Calcium channel blockers may decrease hypertension and coronary vasospasm, but not necessarily tachycardia. Nitric oxide-mediated vasodilators: There were six Level I/II, one Level III, and 25 Level IV/V studies conducted in 246 subjects with 11 treatment failures and two adverse drug events. Nitroglycerin may lead to severe hypotension and reflex tachycardia. Alpha-adrenoceptor blocking drugs: There were two Level I studies and three case reports. Alpha-1 blockers may improve hypertension and vasospasm, but not tachycardia, although evidence is limited. Alpha-2-adrenoceptor agonists: There were two high-quality studies and one case report detailing the successful use of dexmedetomidine. Beta-blockers and β/α-blockers: There were nine Level I/II, seven Level III, and 34 Level IV/V studies of β-blockers, with 1744 subjects, seven adverse drug events, and three treatment failures. No adverse events were reported for use of combined β/α-blockers such as labetalol and carvedilol, which were effective in attenuating both hypertension and tachycardia. Antipsychotics: Seven Level I/II studies, three Level III studies, and seven Level IV/V case series and reports involving 168 subjects have been published. Antipsychotics may improve agitation and psychosis, but with inconsistent reduction in tachycardia and hypertension and risk of extrapyramidal adverse effects. Other agents: There was only one high level study of morphine, which reversed cocaine-induced coronary vasoconstriction but increased heart rate. Other agents reviewed included lidocaine, sodium bicarbonate, amiodarone, procainamide, propofol, intravenous lipid emulsion, propofol, and ketamine.
CONCLUSIONS
High-quality evidence for pharmacological treatment of cocaine cardiovascular toxicity is limited but can guide acute management of associated tachycardia, dysrhythmia, hypertension, and coronary vasospasm. Future randomized prospective trials are needed to evaluate new agents and further define optimal treatment of cocaine-toxic patients.
Topics: Benzodiazepines; Calcium Channel Blockers; Cardiovascular System; Cocaine; Cocaine-Related Disorders; Evidence-Based Medicine; Heart Rate; Humans; Hypertension; Nitric Oxide; Randomized Controlled Trials as Topic; Tachycardia; Vasodilator Agents
PubMed: 26919414
DOI: 10.3109/15563650.2016.1142090