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A "one-step" method which combined the heart rate correction and statistical analysis for conscious nonhuman primate (NHP) QTc assessment was recently published. The principles of this method are applicable to other species. In the current analysis, we demonstrate the utility of the technique in conscious dog QTc studies. Two studies in male dogs (n = 8 and n = 7) implanted with telemetry devices were used. In both studies, treatments were randomized and all animals received all treatments. In the primary study, the effect on QTc of moxifloxacin was compared with vehicle. Each treatment (vehicle and moxifloxacin) was given on two separate occasions. In the second study, dogs were given vehicle or dofetilide. Conventional QTc analysis was compared with the "one-step" method. The effect on QTc relative to vehicle was determined along with the median minimal detectable difference. As expected, both moxifloxacin and dofetilide gave QTc increases with a maximum of ~ 20 ms. There was a significant increase in the sensitivity to detect a QTc effect when using the "one-step" method. The minimal detectable difference was 1.6 ms for the "one-step" method compared with 6.2 ms for the conventional method. These analyses are consistent with the increased sensitivity described for the "one-step" method applied to studies in NHP. The increased sensitivity should enhance the ability to support an integrated assessment of the QTc prolongation liability for new drugs., (© 2024 Eli Lilly and Company. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% ( N  = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.

Background: Left ventricular hypertrophy (LVH) is common in patients with atrial fibrillation (AF), however, many antiarrhythmic drugs (AADs) are contraindicated. US guidelines recommend avoiding pure class III antiarrhythmics such as dofetilide in patients with significant LVH due to concern for an increased risk of death, however, clinical data is lacking. We sought to determine if dofetilide use was associated with increased mortality in patients with LVH., Methods: Patients ≥18 years of age with AF and LVH ≥ 1.4 cm were included. A group of patients treated with dofetilide and a control group of patients without a history of AAD use were propensity matched. The primary outcome was all-cause mortality at 3 years and secondary outcomes were total number of all-cause hospitalizations and hospitalizations related to AF., Results: There were 359 patients in each of the groups. Baseline variables were well-matched. The primary outcome of all-cause mortality occurred in 7% of patients in the dofetilide group and 12% of patients in the control group (hazard ratio: 0.90, 95% confidence interval: 0.53-1.53). Total all-cause hospitalizations were higher in the control group but hospitalizations for AF were no different., Conclusions: In a propensity-matched cohort of 718 patients with AF and LVH, dofetilide was not associated with increased mortality at 3 years. Our study adds to prior data demonstrating the safety of dofetilide in this population despite guideline recommendations against its use. Given the limited options for AF management in LVH patients, dofetilide may be reasonable for symptomatic AF management., (© 2022 Wiley Periodicals LLC.)

Introduction: Dofetilide suppresses atrial fibrillation (AF) in a dose-dependent fashion. The protective effect of AF against QT c prolongation induced torsades de pointe and transient post-cardioversion QT c prolongation may result in dofetilide under-dosing during initiation. Thus, the optimal timing of cardioversion for AF patients undergoing dofetilide initiation to optimize discharge dose remains unknown as does the longitudinal stability of QT c . The purpose of this study was to evaluate the impact of baseline rhythm on dofetilide dosing during initiation and assess the longitudinal stability of QT c-all (Bazzett, Fridericia, Framingham, and Hodges) over time., Methods: Medical records of patients who underwent preplanned dofetilide loading at a tertiary care center between January 2016 and 2019 were reviewed., Results: A total of 198 patients (66 ± 10 years, 32% female, CHADS 2 -Vasc 3 [2-4]) presented for dofetilide loading in either AF (59%) or sinus rhythm (SR) (41%). Neither presenting rhythm, nor spontaneous conversion to SR impacted discharge dose. The cumulative dofetilide dose before cardioversion moderately correlated (r = .36; p = .0001) with discharge dose. Postcardioversion QT c-all prolongation (p < .0001) prompted discharge dose reduction (890 ± 224 mcg vs. 552 ± 199 mcg; p < .0001) in 30% patients. QT c-all in SR prolonged significantly during loading (p < .0001). All patients displayed QT c-all reduction (p < .0001) from discharge to short-term (46 [34-65] days) that continued at long-term (360 [296-414] days) follow-ups. The extent of QT c-all reduction over time moderately correlated with discharge QT c-all (r = .54-0.65; p < .0001)., Conclusion: Dofetilide initiation before cardioversion is equivalent to initiation during SR. Significant QT c reduction proportional to discharge QT c is seen over time in all dofetilide-treated patients. QT c returns to preloading baseline during follow-up in patients initiated in SR., (© 2022 Wiley Periodicals LLC.)

In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for the assessment of drug proarrhythmic potential through multielectrode array (MEA). HiPSC-CM cultures beat spontaneously with a wide range of frequencies, however, which could affect drug-induced changes in repolarization. Pacing hiPSC-CMs at a physiological heart rate more closely resembles the state of in vivo ventricular myocytes and permits the standardization of test conditions to improve consistency. In this study, we systematically investigated the time window of stable ion currents in high-purity hiPSC-derived ventricular cardiomyocytes (hiPSC-vCMs) and confirmed that these cells could be used to correctly predict the proarrhythmic risk of Comprehensive In Vitro Proarrhythmia Assay (CiPA) reference compounds. To evaluate drug proarrhythmic potentials at a physiological beating rate, we used a MEA to electrically pace hiPSC-vCMs, and we recorded regular field potential waveforms in hiPSC-vCMs treated with DMSO and 10 CiPA reference drugs. Prolongation of field potential duration was detected in cells after exposure to high- and intermediate-risk drugs; in addition, drug-induced arrhythmia-like events were observed. The results of this study provide a simple and feasible method to investigate drug proarrhythmic potentials in hiPSC-CMs at a physiological beating rate.

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD 1 ), dopamine D2 (DRD 2 ), and serotonin 2A (5-HT 2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT 2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD 1 , DRD 2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT 2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential., (© 2019 Society for the Study of Addiction.)

Background: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies., Methods: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation., Results: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently., Conclusion: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Cathinones and amphetamines share many toxicodynamic mechanisms. One of their potentially life-threatening consequences, particularly of MDMA, is serotonin-mediated hyponatraemia. Herein, we review the state of the art on phenethylamine-induced hyponatremia; discuss the mechanisms involved; and present the preventive and therapeutic measures. Hyponatraemia mediated by phenethylamines results from increased secretion of antidiuretic hormone (ADH) and consequent kidney water reabsorption, additionally involving diaphoresis and polydipsia. Data for MDMA suggest that acute hyponatraemia elicited by cathinones may also be a consequence of metabolic activation. The literature often reveals hyponatraemia-associated complications such as cerebral oedema, cerebellar tonsillar herniation and coma that may evolve to a fatal outcome, particularly in women. Ready availability of fluids and the recommendation to drink copiously at the rave scene to counteract hyperthermia, often precipitate water intoxication. Users should be advised about the importance of controlling fluid intake while using phenethylamines. At early signs of adverse effects, medical assistance should be promptly sought. Severe hyponatraemia (<130 mmol sodium/L plasma) may be corrected with hypertonic saline or suppression of fluid intake. Also, clinicians should be made aware of the hyponatraemic potential of these drugs and encouraged to report future cases of toxicity to increase knowledge on this potentially lethal outcome., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Dofetilide is one of the only anti-arrhythmic agents approved for atrial fibrillation (AF) in patients with reduced left ventricular ejection fraction (LVEF). However, postapproval data and safety outcomes are limited. In this study, we assessed the incidence and predictors of LVEF improvement, safety, and outcomes in patients with AF with LVEF ≤35% without prior implantable cardioverter defibrillator, cardiac resynchronization therapy, or AF ablation., Methods: An analysis of 168 consecutive patients from 2007 to 2016 was performed. Incidences of adverse events, drug continuation, implantable cardioverter defibrillator and cardiac resynchronization therapy implantation, LVEF improvement (>35%) and recovery (≥50%), AF recurrence, and AF ablation were determined. Multivariable regression analysis to identify predictors of LVEF improvement/recovery was performed., Results: The mean age was 64±12 years. Dofetilide was discontinued before hospital discharge in 46 (27%) because of QT prolongation (14%), torsades de pointe or polymorphic ventricular tachycardia/fibrillation (6% [sustained 3%, nonsustained 3%]), ineffectiveness (5%), or other causes (3%). At 1 year, 43% remained on dofetilide. Freedom from AF was 42% at 1 year, and 40% underwent future AF ablation. LVEF recovered (≥50%) in 45% and improved to >35% in 73%. Predictors of LVEF improvement included presence of AF during echocardiogram (odds ratio, 4.22 [95% CI, 1.71-10.4], P =0.002), coronary artery disease (odds ratio, 0.35 [95% CI, 0.16-0.79], P =0.01), left atrial diameter (odds ratio, 0.52 per 1 cm increase [95% CI, 0.30-0.90], P =0.01), and LVEF (odds ratio, per 1% increase, 1.09 [95% CI, 1.02-1.16], P =0.006). The C statistic was 0.78., Conclusions: In patients with LVEF ≤35%, who are potential implantable cardioverter defibrillator candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF, drug discontinuation rates were high, and many underwent future AF ablation. However, most patients had improvement in LVEF, obviating the need for primary prevention implantable cardioverter defibrillator.

Heat stress hinders growth and well-being in livestock, an effect that is perhaps exacerbated by the β1 agonist ractopamine. Heat stress deficits are mediated in part by reduced feed intake, but other mechanisms involved are less understood. Our objective was to determine the direct impact of heat stress on growth and well-being in ractopamine-supplemented feedlot lambs. Commercial wethers were fed under heat stress (40 °C) for 30 d, and controls (18 °C) were pair-fed. In a 2 × 2 factorial, lambs were also given a daily gavage of 0 or 60 mg ractopamine. Growth, metabolic, cardiovascular, and stress indicators were assessed throughout the study. At necropsy, 9th to 12th rib sections (four-rib), internal organs, and feet were assessed, and sartorius muscles were collected for ex vivo glucose metabolic studies. Heat stress increased (P < 0.05) rectal temperatures and respiration rates throughout the study and reduced (P < 0.05) weight gain and feed efficiency over the first week, ultrasonic loin-eye area and loin depth near the end of the study, and four-rib weight at necropsy. Fat content of the four-rib and loin were also reduced (P < 0.05) by heat stress. Ractopamine increased (P < 0.05) loin weight and fat content and partially moderated the impact of heat stress on rectal temperature and four-rib weight. Heat stress reduced (P < 0.05) spleen weight, increased (P < 0.05) adrenal and lung weights, and was associated with hoof wall overgrowth but not organ lesions. Ractopamine did not affect any measured indicators of well-being. Heat stress reduced (P < 0.05) blood urea nitrogen and increased (P < 0.05) circulating monocytes, granulocytes, and total white blood cells as well as epinephrine, TNFα, cholesterol, and triglycerides. Cortisol and insulin were not affected. Heat stress reduced (P < 0.05) blood pressure and heart rates in all lambs and increased (P < 0.05) left ventricular wall thickness in unsupplemented but not ractopamine-supplemented lambs. No cardiac arrhythmias were observed. Muscle glucose uptake did not differ among groups, but insulin-stimulated glucose oxidation was reduced (P < 0.05) in muscle from heat-stressed lambs. These findings demonstrate that heat stress impairs growth, metabolism, and well-being even when the impact of feed intake is eliminated by pair-feeding and that systemic inflammation and hypercatecholaminemia likely contribute to these deficits. Moreover, ractopamine improved muscle growth indicators without worsening the effects of heat stress., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Psychostimulants are a diverse range of substances that encompass cocaine and the phenylethylamines, the latter including the amphetamines, cathinones and some 'novel psychoactive substances'. This paper examines the range of pathophysiological processes, clinical presentations and treatment options involving the heart and cardiovascular system both in the acute setting and where long-term effects of psychostimulant use have affected the cardiovascular system. A common feature of these drugs is their effect on the cardiovascular system, where their major action is that of sympathomimetic amines with short- and long-term stimulation of the adrenergic system and consequent effects on blood pressure, cardiac modelling, atherogenesis and cellular calcium signalling. Cocaine additionally exhibits a variety of prothrombotic effects, effects on inflammatory mediators and alterations in myocardial gene expression. Persistent psychostimulant use results in progressive cardiovascular pathology, largely in the form of accelerated atherosclerosis, hypertension and myocardial ischaemia. Abstinence results in at least partial reversal of pathology. To a large extent, an assumption is made that treatment protocols used for cocaine-associated cardiovascular pathology apply to the amphetamines and other phenylethylamines, but there appears to be little research in this area, despite acknowledgement that cocaine and the better-known amphetamines have different modes of action., (© 2019 Society for the Study of Addiction.)

Background: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects., Objective: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD., Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points., Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed., Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology.

Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposure-response simulator that converts block-concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify the critical concentration at the onset of torsades de pointes: For dofetilide concentrations of 2x, 3x, and 4x, as multiples of the free plasma concentration C max  = 2.1 nM, the QT interval increased by +62.0%, +71.2%, and +82.3% compared to baseline, and the heart rate changed by -21.7%, -23.3%, and +88.3%. The last number indicates that, at the critical concentration of 4x, the heart spontaneously developed an episode of a torsades-like arrhythmia. Strikingly, this critical drug concentration is higher than the concentration estimated from early afterdepolarizations in single cells and lower than in one-dimensional cable models. Our results highlight the importance of whole heart modeling and explain, at least in part, why current regulatory paradigms often fail to accurately quantify the pro-arrhythmic potential of a drug. Our exposure-response simulator could provide a more mechanistic assessment of pro-arrhythmic risk and help establish science-based guidelines to reduce rhythm disorders, design safer drugs, and accelerate drug development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A 2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A 2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γ null (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A 2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A 2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A 2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A 2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two emerging psychoactive substances, 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe) and N-(2-methoxybenzyl)-2,5-dimethoxy-4-chlorophenethylamine (25C-NBOMe), are being abused, leading to fatal and non-fatal intoxications. However, most of their adverse effects have been reported anecdotally. In the present study, cardiotoxicity was evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, rat electrocardiography (ECG), and human ether-a-go-go-related gene (hERG) assay. Expression levels of p21 (CDC42/RAC)-activated kinase 1 (PAK1), one of known biomarkers for cardiotoxicity, were also analyzed. Both 25D-NBOMe and 25C-NBOMe at 100 μM reduced cell viability in MTT assay. At 2.0 mg/kg and 0.75 mg/kg, they prolonged QT intervals in rat ECG. PAK1 was down-regulated by treatment with these two test compounds. Furthermore, potassium channels were inhibited by 25D-NBOMe treatment in hERG assay. Taken together, these results suggest that both 25D-NBOMe and 25C-NBOMe have potential cardiotoxicity, especially regarding cardiac rhythm. Further studies are needed to confirm the relationship between PAK1 down-regulation and cardiotoxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: There is a significant variation in the clinical approach of initiation and dose adjustment of dofetilide in atrial fibrillation (AF). Excessive QT prolongation could predispose patients to torsades de pointes (TdP), which can be fatal., Methods: We performed a retrospective case-control study at Mayo Clinic Rochester (January 1, 2003 to December 31, 2016). "TdP risk" cases were defined as patients on dofetilide therapy for AF with subsequent TdP or excessive QTc prolongation requiring dose reduction or discontinuation (N = 31). A control group was matched 1:1 with cases by age, gender, year of admission, and dofetilide dose (N = 31)., Results: Using multivariate regression analysis, independent predictors of TdP risk included baseline QTc exceeding recommendations (adjusted odd ratio [AOR] 4.57; P = 0.023); underlying AF with rapid ventricular rate (AOR 16.95; P = 0.004); and diuretic therapy for acute heart failure (AOR 8.42; P = 0.007). Poor inter-observer agreement was identified among QT interval measurement in patients with AF and rapid ventricular rate compared to those in rate controlled AF or sinus rhythm. TdP risk cases receiving diuretics for acute heart failure had a significant decline in creatinine clearance than controls, although serum electrolytes and replacement did not differ among the two groups., Conclusions: Excessive QTc prolongation and AF with rapid ventricular rate at time of dofetilide initiation (likely due to difficulty in measuring QT intervals), and diuretic therapy for acute heart failure were independent factors for dofetilide-related TdP risk. Based on these data, possible preventive strategies could be adapted for safety protocols among hospitalized patients.

Dofetilide is a class III antiarrhythmic drug that has proven efficacious in maintaining sinus rhythm in up to 60% of patients with persistent atrial fibrillation. Dofetilide's most concerning adverse effect is QT prolongation and polymorphic VT, but providers should be aware of other rare significant side effects. We report a case of dofetilide associated Bell's palsy masquerading as stroke that developed shortly after a cardioversion. The patient's facial weakness, a side effect of dofetilide, resolved relatively quickly after discontinuation of the medication and a short course of oral corticosteroids., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia. Drug trials showed neutral mortality in post-myocardial infarction patients and those with heart failure. This is a review of postmarket data, including real-world efficacy and safety in a variety of populations. Dofetilide has been used off-label with success in patients with paroxysmal atrial fibrillation and atrial flutter, as well as atrial tachycardia and ventricular tachycardia. The real-world acute conversion rate of atrial fibrillation and atrial flutter is higher than that reported in clinical trials. Dofetilide has an acceptable safety profile when initiated (or reloaded) under hospital monitoring and dosed according to creatinine clearance. Dofetilide is well tolerated and a good choice for patients with acceptable renal function and a normal QT interval, especially if atrioventricular nodal blockade needs to be avoided.

Ephenidine, diphenidine, and methoxphenidine belong to the family of diarylethylamines that are psychoactive substances derived from lefetamine (N, N-di-methyl-1,2-diphenylethylamine, also called L-SPA). These dissociative anesthetic compounds act as potent and selective N-methyl-d-aspartate receptor antagonists and were recently classified as narcotic drugs in France. The available data suggest a significant risk of psychic and somatic complications. To obtain more information, this retrospective study analyzed all spontaneous notifications of serious cases of ephenidine, diphenidine, and methoxphenidine abuse collected by the French Addictovigilance Network from 2012 to 2016 and classified them as proven, probable, and possible. For each case, age, sex, concomitantly ingested substances, pattern of abuse of psychoactive drugs, and related complications (scored using the poisoning severity score) were collected. Eighteen cases were identified (one in 2013, five in 2015, and 12 in 2016) in 16 men (median age: 31.5 years [IQR 25-75% 27-34]). Ephenidine, diphenidine, and methoxphenidine were involved in four, seven, and 11 cases, respectively. No case was considered proven, 16 cases were considered possible, and two probable due to polysubstance abuse (co-ingestion of other new psychoactive substances). The reported clinical complications were minor in five cases, moderate in six cases, and serious in four cases, and included psychiatric, neurologic, and cardiovascular problems. This analysis indicates that the number of reported cases progressively increased from 2012 to 2016 and mainly concerned methoxphenidine. The addictive potential of these substances seems highly probable; but further investigations are needed to limit their harmful effects., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Background: Published studies state that adherence to regular laboratory assessments for anti-arrhythmic drugs is as low as 20%. Monitoring adherence is important as other studies have shown that up to 93% of patients on amiodarone experience an adverse drug event leading to a potentially lethal event., Objective: To determine whether patients prescribed amiodarone or dofetilide are being monitored according to package labeling and guideline recommendations for adverse events., Methods: Patients prescribed amiodarone or dofetilide from a 2-year period were eligible for inclusion. Patients with ventricular arrhythmias, prescribed more than 1 anti-arrhythmic agent, or received anti-arrhythmic monitoring outside the health-care system were excluded. Adherence to monitoring parameters was assessed according to labeled recommendations and published guidelines. The primary objective was to determine the frequency of baseline and follow-up monitoring recommendations for patients receiving amiodarone or dofetilide. The secondary objective was to determine rates of adverse drug events., Results: One hundred patients were evaluated (amiodarone n = 50, dofetilide n = 50). Average rates of baseline and follow-up amiodarone monitoring parameters were 55% and 57%, respectively. Average rates of baseline and follow-up dofetilide monitoring were 99.6% and 85%, respectively. There was a statistically significant difference in abnormally elevated thyroid-stimulating hormone levels (8%-30%, P ≤ .005) after patients were prescribed amiodarone. Twelve percent of patients taking dofetilide had an increase in QTc interval by >15%., Conclusions: Amiodarone adverse event monitoring was lower than dofetilide in this cohort. Improving the monitoring of these agents may decrease morbidity risk in this population.

Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW.

Background: Dofetilide is an effective antiarrhythmic medication for rhythm control in atrial fibrillation, but carries a significant risk of pro-arrhythmia and requires meticulous dosing and monitoring. The cornerstone of this monitoring, measurement of the QT/QTc interval, is an imperfect surrogate for plasma concentration, efficacy, and risk of pro-arrhythmic potential., Objective: The aim of our study was to test the application of a deep learning approach (using a convolutional neural network) to assess morphological changes on the surface ECG (beyond the QT interval) in relation to dofetilide plasma concentrations., Methods: We obtained publically available serial ECGs and plasma drug concentrations from 42 healthy subjects who received dofetilide or placebo in a placebo-controlled cross-over randomized controlled clinical trial. Three replicate 10-s ECGs were extracted at predefined time-points with simultaneous measurement of dofetilide plasma concentration We developed a deep learning algorithm to predict dofetilide plasma concentration in 30 subjects and then tested the model in the remaining 12 subjects. We compared the deep leaning approach to a linear model based only on QTc., Results: Fourty two healthy subjects (21 females, 21 males) were studied with a mean age of 26.9 ± 5.5 years. A linear model of the QTc correlated reasonably well with dofetilide drug levels (r = 0.64). The best correlation to dofetilide level was achieved with the deep learning model (r = 0.85)., Conclusion: This proof of concept study suggests that artificial intelligence (deep learning/neural network) applied to the surface ECG is superior to analysis of the QT interval alone in predicting plasma dofetilide concentration., Competing Interests: The authors have declared that no competing interests exist.

Background: Dofetilide is a class III antiarrhythmic drug effective for the treatment of atrial fibrillation (AF). Dofetilide initiation (DI) associates with corrected QT interval (QTc) prolongation. Significant QTc prolongation during DI mandates dose adjustment or discontinuation of the drug. Microsatellite DNA are novel genetic markers associated with congenital and acquired health conditions., Hypothesis: DNA microsatellite polymorphism may associate with QTc response to dofetilide initiation in patients with persistent AF., Methods: We performed whole-exome sequencing in a cohort of patients with persistent AF undergoing DI. Electrocardiographic variables and clinical data were assessed. We defined patients as eligible for DI when no significant QTc prolongation (>20% compared with baseline) was seen with a 500-μg dose. We defined patients as ineligible for DI when significant QTc prolongation was seen during DI with 500 μg. We investigated polymorphisms for 11 919 DNA microsatellite loci in relation to QTc response to DI., Results: During the study, 14 consecutive patients with persistent AF presenting for DI were enrolled. Whole-exome sequencing revealed 14 different microsatellite loci in the 2 groups. All genes or proximal genes that harbor these loci are known to have expression in the human heart. Two genes, MYH6 and TRAK2, are known to have expression in the atria. TRAK2 is known to interact with KCNJ2, the inward-rectifier potassium channel 1., Conclusions: Microsatellite DNA polymorphisms seem to associate with QTc response to DI therapy in patients with persistent AF who are deemed otherwise eligible for dofetilide therapy., (© 2018 Wiley Periodicals, Inc.)

Background: Compared with men, women have longer corrected QT (QTc) intervals, lower clearance of dofetilide, and higher rates of drug-induced torsades de pointes, but the dofetilide dosing algorithm is the same for men and women., Objective: The purpose of this study was to evaluate the tolerability of the 500 μg twice daily dose of dofetilide for men and women., Methods: Men and women admitted to Duke University Medical Center (January 1, 2006, to October 19, 2012) for the initiation of dofetilide 500 μg twice daily were matched 1:1 on age and estimated creatinine clearance. Electrocardiograms throughout dosing were analyzed, and rates of dofetilide discontinuations and dose reductions were compared in unadjusted and adjusted analyses., Results: For 220 matched men and women, the median age was 62.5 years (interquartile range 55-69 years) and the median eCrCl was 98.1 mL/min (interquartile range 77.6-126.2 mL/min). Women were less likely than men to have hypertension and interventricular conduction delay but were otherwise similar. During dofetilide initiation, women were more likely than men to have their dofetilide dose discontinued or reduced (55% vs 32%; P < .001). In most women (82%) and men (69%), the reason for dose adjustment was significant QTc prolongation. In the adjusted analysis, female sex was associated with higher rates of dofetilide dose discontinuations or reductions (odds ratio 3.01; 95% confidence interval 1.58-5.71; P < .01)., Conclusion: More than half of women who initiated on 500 μg twice daily of dofetilide required medication discontinuations or dose reductions, mostly because of QTc prolongation. Additional studies are needed to evaluate the optimal dosing algorithm of dofetilide in women., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level. Our mechanistic exposure-response simulator translates block-concentration characteristics for arbitrary drugs into three-dimensional excitation profiles and electrocardiogram recordings to rapidly assess torsadogenic risk. For the drug of dofetilide, we show that this risk is highly dose-dependent: at a concentration of 1x, QT prolongation is 55% but the heart maintains its regular sinus rhythm; at 5.7x, QT prolongation is 102% and the heart spontaneously transitions into torsades de points; at 30x, QT prolongation is 132% and the heart adapts a quasi-depolarized state with numerous rapidly flickering local excitations. Our simulations suggest that neither potassium channel blockage nor QT interval prolongation alone trigger torsades de pointes. The underlying mechanism predicted by our model is early afterdepolarization, which translates into pronounced U waves in the electrocardiogram, a signature that is correctly predicted by our model. Beyond the risk assessment of existing drugs, our exposure-response simulator can become a powerful tool to optimize the co-administration of drugs and, ultimately, guide the design of new drugs toward reducing life threatening drug-induced rhythm disorders in the heart.

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine ("Molly"), synthetic cathinones ("bath salts"), and N-methoxybenyl ("NBOMe"), to name a few. Peripheral norepinephrine release mediated by these sympathomimetic agents induces a double-edged sword of heat accumulation through β-adrenoreceptor-dependent activation of uncoupling protein (UCP1 and 3)-regulated thermogenesis and loss of heat dissipation through α 1 -adrenoreceptor-mediated vasoconstriction. Additionally, thyroid hormones are important determinants of the capacity of thermogenesis induced by phenethylamines through the regulation of free fatty acid release and the transcriptional activation of a host of metabolic genes, including adrenergic receptors and mitochondrial uncoupling proteins. Here, we review the central and peripheral mechanistic "triggers" of phenethylamine-induced hyperthermia and outline potential pharmacologic interventions for managing phenethylamine-induced hyperthermia based on these recently discovered hyperthermia mediators., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The occurrence of ractopamine (RAC) hydrochloride in water bodies is of significant concern due to its ecological impacts and toxicity to humans. RAC hydrochloride is a β-adrenergic agonist drug used as a feed additive to (1) improve feed efficiency, (2) rate of weight gain, and (3) increase carcass leanness in animals raised for their meat. This drug is excreted by animals in urine and introduced into the environment affecting nontarget organisms including fish. In wastewater released from farms, RAC concentrations were detected from 0.124 µg/L to 30.1 µg/L, and in levels ranging from 1.3 × 10 -5 to 5.4 × 10 -4 μg/L in watersheds. The aim of this study was to examine the effects of exposure to RAC at 0.1, 0.2, 0.85, 8.5, or 85 µg/L dissolved in water on behavior and oxidative status in adult zebrafish. At 0.85 µg/L, RAC treatment increased exploratory behavior of zebrafish; while at 8.5 µg/L, decreased locomotor and exploratory activities were noted. With respect to oxidative stress biomarkers, results showed that RAC at 0.2 µg/L induced lipid peroxidation and elevated total thiol content in zebrafish brain. All drug tested concentrations produced a fall in nonprotein thiol content. Finally, RAC at 0.85, 8.5, or 85 µg/L increased catalase enzyme activity. Our results demonstrated that the exposure to RAC induced behavioral alterations and oxidative stress in zebrafish.

QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period). The above proarrhythmic parameters do not only result in TdP, but can also lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Note that QT prolongation (not listed as a causal factor) yields many false positives (potentially depriving patients from much needed drugs) and false negatives (potentially exposing patients to lethal arrhythmias). Thus, drug-induced QT prolongation is a bad surrogate for TdP, VT or VF; it is high time to move away from an oversimplified and erroneous surrogate.

Background: Although dofetilide labeling states that the drug must be initiated or reinitiated with continuous electrocardiographic monitoring and in the presence of trained personnel, the risks of dofetilide reloading justifying repeat hospitalization have not been investigated., Methods and Results: Patients admitted for dofetilide reloading for atrial arrhythmias were retrospectively reviewed. The need for dose adjustment and the incidence of torsades de pointes (TdP) were identified. The incidence of TdP in dofetilide reloading was compared with patients admitted for dofetilide initial loading. Of 138 patients admitted for dofetilide reloading for atrial arrhythmias, 102 were reloaded at a previously tolerated dose, 30 with a higher dose from a previously tolerated dose and 2 at a lower dose; prior dosage was unknown in 4 patients. Dose adjustment or discontinuation was required in 44 patients (31.9%). No TdP occurred in the same dose reloading group, but TdP occurred in 2 patients admitted to increase dofetilide dosage (0% versus 6.7%; P =0.050). Dofetilide dose adjustment or discontinuation was required in 30 of 102 patients (29.4%) reloaded at a previously tolerated dose and in 11 of 30 patients (36.7%) admitted for an increase in dose., Conclusions: Although no TdP occurred in patients admitted to reload dofetilide at the same dose as previously tolerated, dosage adjustments or discontinuation was frequent and support the need for hospitalization for dofetilide reloading. Patients admitted for reloading with a higher dose tended to be at higher risk for TdP than patients reloaded at a prior tolerated dose., (© 2017 American Heart Association, Inc.)

Dofetilide is a class III antiarrhythmic used for treating atrial dysrhythmias. Though its adverse effects are well described in routine use, very little is known about dofetilide toxicity in overdose. This is a retrospective case series of consecutive patients reported to our poison center after dofetilide overdose. Twenty-seven cases were included. Seventeen patients were treated at a healthcare facility, and of these, eight were admitted. Twenty-one patients took one extra capsule, four took someone else's medication, one took three extra capsules, and one had a large intentional overdose. Ten patients had co-ingestants reported, including three QT-prolonging agents. No one required cardioversion, defibrillation, CPR, or overdrive pacing. The patient who reported taking 90 times his usual dose in suicide attempt was the only patient to have significant clinical effects. He experienced an 8-beat run of non-sustained ventricular tachycardia, frequent multifocal PVCs, and ventricular bigeminy. He received magnesium sulfate and potassium chloride supplementation. In this series, unintentional small overdoses did not result in significant clinical effects and were often managed successfully at home, despite the fact that information showing a single capsule can cause torsades. This study is limited by its small sample size, retrospective design, and reliance on incomplete information.

The multi-billion dollar dietary supplement industry is global in reach. The industry has been criticized for problems related to poor quality control, safety, misbranding, and adulteration. In this review, we describe how the US Food and Drug Administration (FDA) regulates dietary supplements within the framework of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The Dietary Supplement Health and Education Act of 1994 (DSHEA), which amended the FD&C Act, gave the FDA the authority to promulgate Good Manufacturing Practices for dietary supplements and required that manufacturers provide the FDA information supporting a conclusion that the ingredients are reasonably expected to be safe if the dietary ingredients were not marketed in the USA before 15 October 1994. Recent amendments to the FD&C Act require that serious dietary-supplement-related adverse events be reported to the FDA and provide the agency with mandatory recall authority. We discuss the presence of naturally occurring (e.g. Ephedra, Citrus aurantium, Acacia) and synthetic (e.g. β-methylphenethylamines, methylsynephrine, α-ethyl-phenethylamine) biologically active phenethylamines (PEAs) in dietary supplements and of PEA drugs (e.g. clenbuterol, fenfluramine, sibutramine, lorcaserin) in weight-loss products. Regulatory actions against manufacturers of products labelled as dietary supplements that contain the aliphatic amines 1,3-dimethylamine and 1,3-dimethylbutylamine, and PEAs such as β-methylphenethylamine, aegeline, and Dendrobium illustrate the FDA's use of its authority under the FD&C Act to promote dietary supplement safety. Published 2016. This article is a U.S. Government work and is in the public domain in the USA., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Over the past decade, monitoring systems have identified the rapid emergence of new psychoactive substances (NPS). While the use of many NPS is minimal and transitory, little is known about which products have potential for capturing the attention of significant proportions of the drug consuming market. The aim of this study was to explore self-reported experiences of three commonly used NPS classes within the Australian context (synthetic cathinones, hallucinogenic phenethylamines and hallucinogenic tryptamines) relative to traditional illicit drug counterparts., Methods: Frequent psychostimulant consumers interviewed for the Australian Ecstasy and related Drugs Reporting System (EDRS) (n=1208) provided subjective ratings of the pleasurable and negative (acute and longer-term) effects of substances used in the last six months on the last occasion of use, and the likelihood of future use., Results: Stimulant-type NPS (e.g., mephedrone, methylone) were rated less favourably than ecstasy and cocaine in terms of pleasurable effects and likelihood of future use. DMT (a hallucinogenic tryptamine) showed a similar profile to LSD in terms of pleasurable effects and the likelihood of future use, but negative effects (acute and comedown) were rated lower. Hallucinogenic phenethylamines (e.g., 2C-B) showed a similar negative profile to LSD, but were rated as less pleasurable and less likely to be used again., Conclusion: The potential for expanded use of stimulant-type NPS may be lower compared to commonly used stimulants such as ecstasy and cocaine. In contrast, the potential of DMT may be higher relative to LSD given the comparative absence of negative effects., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Limited studies have been published examining dofetilide's postmarketing use and its recommended monitoring., Objective: To evaluate the impact of a collaborative pharmacy-cardiology antiarrhythmic drug (AAD) monitoring program on dofetilide monitoring., Methods: This retrospective cohort study was performed to assess if a novel monitoring program improved compliance with dofetilide-specific monitoring parameters based on the Food and Drug Administration's Risk Evaluation and Mitigation Strategy., Results: A total of 30 patients were included in the analysis. The monitoring parameters evaluated included electrocardiogram, serum potassium, serum magnesium, and kidney function. The primary outcome evaluated was the composite of these dofetilide monitoring parameters obtained in each cohort. In the standard cohort, 245 of 352 (69.6%) monitoring parameters were completed versus 134 of 136 (98.5%) in the intervention group ( P < 0.05)., Conclusion: A collaborative pharmacy-cardiology AAD monitoring program was associated with a significant improvement in dofetilide monitoring. This improvement could potentially translate into enhanced patient safety outcomes, such as prevention of adverse drug reactions and decreased hospitalizations.

Over the last decade, the 'traditional' drug scene has been supplemented - but not replaced - by the emergence of a range of novel psychoactive substances (NPS), which are either newly created or existing drugs, including medications, now being used in novel ways. By the end of 2014, in excess of 500 NPS had been reported by a large number of countries in the world. Most recent data show, however, that synthetic cathinones, synthetic cannabinoids, and psychedelics/phenethylamines account for the largest number of NPS.The present chapter aims at providing an overview of the clinical and pharmacological issues relating to these most popular NPS categories. Given the vast range of medical and psychopathological issues associated with the molecules here described, it is crucial for health professionals to be aware of the effects and toxicity of NPS. A general overview of the acute management of NPS adverse events is provided as well, although further studies are required to identify a range of evidence-based, index molecule-focused, treatment strategies. The rapid pace of change in the NPS online market constitutes a major challenge to the provision of current and reliable scientific knowledge on these substances.

The body of a 19-year-old male was found apparently concealed underneath bushes with recent head and facial trauma, and multiple superficial abrasions. Subsequently, it was discovered that the decedent had been running into objects and buildings following the ingestion the evening before of what was thought to be lysergic acid diethylamide (LSD). Blood staining of a nearby wall close to where the body was lying was in keeping with the described behavior. Toxicology revealed 3,4-methylenedioxymethamphetamine (Ecstasy), in addition to two only recently available drugs 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, (25B-NBOMe), and 1-(3,4-methylenedioxyphenyl)-2-(1-pyrrolidinyl)-1-butanone, (MDPBP). At autopsy, the skull was fractured with cerebral swelling, contusions, and subarachnoid hemorrhage. Death was due to blunt cranial trauma against a background of mixed drug toxicity. The case demonstrates a rare cause of death in a drug-induced acute delirium, as well as highlighting two new designer street drugs that may result in significant aberrant behavior., (© 2016 American Academy of Forensic Sciences.)

Background: Arrhythmia management has become the major treatment challenge in adult patients with congenital heart disease (ACHD)., Objective: We sought to investigate the utility and safety profile of dofetilide for atrial arrhythmias in ACHD., Methods: A retrospective chart review was performed. We included patients (age ≥18 years) with congenital heart disease who had atrial fibrillation (AF) or intra-atrial reentrant tachycardia treated with dofetilide., Results: We identified 64 patients with a mean age at initiation of 42 ± 14 years. ACHD type included single ventricle (n = 19, 30%), transposition of the great arteries (n = 14, 22%), atrial septal defect (n = 9, 14%), tetralogy of Fallot (n = 8, 12%), atrioventricular canal defect (n = 5, 8%), mitral/aortic stenosis (n = 7, 11%), and other (n = 2, 3%). Thirty-five (55%) had atrial fibrillation, and 29 (45%) had intra-atrial reentrant tachycardia. A total of 3 (4.7%) patients had major inpatient adverse events: torsades de pointes (n = 1, 1.5%), ventricular tachycardia (n = 1, 1.5%), and corrected QT prolongation requiring discontinuation (n = 1, 1.5%). Dofetilide was discontinued in 1 patient because of sinus node dysfunction, and another patient discontinued therapy before discharge because of persistent arrhythmia. Of the patients who were discharged on dofetilide (n = 59, 92%), 40 (68%) had adequate rhythm control and 19 (32%) had partial rhythm control. After a median follow-up of 3 years, 29 (49%) patients remained on dofetilide and 2 (3%) patients died. Reasons for discontinuation included waning effect (n = 16, 57%), side effects (n = 5, 18%), noncompliance (n = 2, 7%), successful ablation (n = 3, 11%), high cost (n = 1, 3.5%), and unknown (n = 1, 3.5%)., Conclusion: Dofetilide remains a viable antiarrhythmic drug option in this challenging population. At 3 years, 49% remained on dofetilide. Close monitoring of renal function, concomitant medications, and corrected QT interval is required., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Dofetilide is a class III antiarrhythmic drug approved for the treatment of atrial fibrillation (AF). Dofetilide-induced corrected QT (QTc) interval prolongation is a surrogate for the degree of drug effect, but the relationships between drug-induced QTc interval prolongation, pharmacological cardioversion (PCV), and freedom from recurrent AF are unclear., Objective: The purpose of this study was to assess associations between QTc interval change during dofetilide initiation and PCV and long-term AF recurrence., Methods: We performed retrospective analyses of a prospective cohort of patients with AF admitted for dofetilide initiation between 2001 and 2014. Clinical characteristics and electrocardiographic variables were assessed. We evaluated outcomes of successful PCV in patients with persistent AF and time to recurrence of AF in patients with paroxysmal and persistent AF., Results: During the study, 243 patients with persistent AF and 176 patients with paroxysmal AF initiated dofetilide. PCV occurred in 93/243 (41.7%) patients with persistent AF. After multivariable adjustment, QTc interval change was associated with PCV (adjusted odds ratio 1.21; P = .003 per 10-ms QTc increase). Inhospital QTc interval change was associated with long-term freedom from AF in patients with persistent AF (adjusted hazard ratio 0.92; P = .011 at 4 years per 10-ms QTc increase), but not in patients with paroxysmal AF. In patients with persistent AF, PCV was also associated with long-term freedom from recurrent AF (adjusted hazard ratio 0.62; P = .009 at 4 years)., Conclusion: The magnitude of QTc interval prolongation during dofetilide initiation is an independent predictor of successful PCV and long-term freedom from arrhythmia in patients with persistent AF. QTc interval change had no association with AF recurrence in patients with paroxysmal AF, suggesting that different mechanisms of arrhythmogenesis may be operant in different AF types., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy., Methods: This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation., Results: In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001)., Conclusion: This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630)., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Accumulated evidence demonstrated that Adenosine A2A receptor (A2AR) is involved in the inflammatory diseases. In the present study, we showed that a selective A2AR agonist, CGS21680, exacerbated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin. The exacerbation was accompanied with reduced CD4(+)Foxp3(+) T cells, increased CD4(+)CXCR5(+) T cells, B cells, dendritic cells and antigen-specific autoantibodies, which is possibly due to the inhibition of IL-2 induced by CGS21680. Combined with previous studies, our data indicate that the effects of A2AR stimulation in vivo are variable in different diseases. Caution should be taken in the use of A2AR agonists., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To examine the rates and patterns of new psychoactive substance (NPS) use amongst regular psychostimulant users (RPU) in Australia., Method: Data were obtained from the 2010-2015 Ecstasy and related Drugs Reporting System (EDRS), which comprised a total cross-sectional sample of 4122RPU., Results: Recent use of 'any' NPS increased from 33% in 2010 to 40% in 2015, although trends of use differed significantly across NPS classes. The correlates associated with NPS use also varied across NPS classes: frequent (i.e. weekly or more) ecstasy users were more likely to report recent phenethylamine use; LSD users were more likely to report recent phenethylamine and tryptamine use; and daily cannabis users were more likely to report recent synthetic cannabinoid use than RPU who had not used NPS. 'Poly' NPS consumers were found to be a particularly high risk group and were significantly more likely to be younger, male, report daily cannabis use, report weekly or more ecstasy use, report recent LSD use, have higher levels of poly drug use, have overdosed on any drug in the past year, and to have engaged in past month criminal activity., Conclusion: NPS use has been established as a significant and ongoing practice amongst our sample of RPU. It appears that RPU seek out NPS with similar properties to the illicit drugs that they are already consuming, with poly NPS consumers found to be a particularly high risk group., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: New psychoactive substances (NPSs) are substitutes for classical drugs of abuse and there are now compounds available from all groups of classical drugs of abuse. During 2014, the number of synthetic cathinones increased dramatically and, together with phenylethylamines, they dominate the NPS markets in the European Union. In total, 31 cathinones and 9 phenylethylamines were encountered in 2014. The aim of this article was to summarize the existing knowledge about the basic pharmacology, metabolism, and human toxicology of relevant synthetic cathinones and phenylethylamines. Compared with existing reviews, we have also compiled the existing case reports from both fatal and nonfatal intoxications., Methods: We performed a comprehensive literature search using bibliographic databases PubMed and Web of Science, complemented with Google Scholar. The focus of the literature search was on original articles, case reports, and previously published review articles published in 2014 or earlier., Results: The rapid increase of NPSs is a growing concern and sets new challenges not only for societies in drug prevention and legislation but also in clinical and forensic toxicology. In vivo and in vitro studies have demonstrated that the pharmacodynamic profile of cathinones is similar to that of other psychomotor stimulants. Metabolism studies show that cathinones and phenylethylamines are extensively metabolized; however, the parent compound is usually detectable in human urine. In vitro studies have shown that many cathinones and phenylethylamines are metabolized by CYP2D6 enzymes. This indicates that these drugs may have many possible drug-drug interactions and that genetic polymorphism may influence their toxicity. However, the clinical and toxicological relevance of CYP2D6 in adverse effects of cathinones and phenylethylamines is questionable, because these compounds are metabolized by other enzymes as well. The toxidromes commonly encountered after ingestion of cathinones and phenylethylamines are mainly of sympathomimetic and hallucinogenic character with a risk of excited delirium and life-threatening cardiovascular effects., Conclusions: The acute and chronic toxicity of many NPSs is unknown or very sparsely investigated. There is a need for evidence-based-treatment recommendations for acute intoxications and a demand for new strategies to analyze these compounds in clinical and forensic cases.

Effects of sex class (physically castrated, PC or immunologically castrated, IC) and diet (0 or 5mg/kg ractopamine hydrochloride, RAC) on characteristics of ham and bellies were determined from pigs slaughtered in three groups with similar ending live weights. One carcass per pen per marketing group (n=8) was selected to evaluate further processing characteristics. Data were analyzed as a 2×2 factorial design with a split plot in time and fixed effects of sex, diet, marketing group, and their interactions. IC fresh bellies were thinner (P<0.01) and softer (P<0.01) than PC bellies. IC hams and bellies were leaner (P<0.05) than those from PC pigs. RAC feeding did not affect (P>0.05) fresh ham or belly characteristics but decreased (P<0.01) fat in cured PC bellies. Marketing group affected (P<0.05) fresh quality, processing characteristics, and composition of hams and bellies. Immunological castration and RAC produced leaner finished products but did not alter processing yield of hams or bacon., (Copyright © 2015 Elsevier Ltd. All rights reserved.)