Role of dofetilide in patients with ventricular arrhythmias.

BACKGROUND OR PURPOSE: To assess effectiveness of dofetilide in reducing the burden of ventricular arrhythmias (VAs). BACKGROUND: Prior small sample studies show that dofetilide has benefit in reducing VA. However, large sample investigations with long-term follow-up are lacking. METHODS: Two hundred seventeen consecutive patients admitted between January 2015 and December 2021 for dofetilide initiation for control of VA were assessed. Dofetilide was successfully started in 176 patients (81%) and had to be discontinued in the remaining 41 patients (19%). Dofetilide was initiated for control of ventricular tachycardia (VT) in 136 patients (77%), whereas 40 (23%) patients were initiated on dofetilide for reducing the burden of premature ventricular complexes (PVCs). RESULTS: The mean follow-up was 24 ± 7 months. In total, among the 136 VT patients, 33 (24%) died, 11 (8%) received a left ventricular assist device (LVAD), and 3 (2%) received a heart transplant during follow-up. Dofetilide was discontinued in 117 (86%) patients due to lack of sustained effectiveness during follow-up. Dofetilide use was associated with similar odds of the composite outcome of all-cause mortality/LVAD/heart transplant (OR: 0.97, 0.55-4.23) in patients with ischemic cardiomyopathy (ICM) compared to those with non-ischemic cardiomyopathy (NICM). Dofetilide did not reduce PVC burden during follow-up in the 40 patients with PVCs (mean baseline PVC burden: 15%, at 1-year follow-up: 14%). CONCLUSIONS: Dofetilide use was less effective in reducing VA burden in our cohort of patients. Randomized controlled studies are needed to confirm our findings.

Ractopamine residues in meat might reduce the risk of type 2 diabetes.

Background: The overall prevalence of diabetes in the world has risen substantially in the past several decades, so have complications and mortalities associated with it. Aim: Prevention strategies for diabetes thus become an urgent public health need for reducing the burden of diabetes. Methods: Ractopamine, a ß1/2-adrenergic receptor agonist, has been approved for use in finishing swine, cattle, and turkey in countries where meat exporting brings tremendous economic benefits. This leanness enhancer is recently found to be a full agonist at trace amine-associated receptor 1 also. A thorough literature review was performed to assess possible effects of ractopamine on glucose metabolism. Results: Activating ß-adrenoceptor could lead to glucose-lowering effects independent of insulin while activation on trace amine-associated receptor 1 induces an incretin-like signaling on insulin-secreting pancreatic ß-cells. Conclusion: Accordingly, it is hypothesized that long-term consuming meat containing ractopamine might lower the risk of type 2 diabetes.

Anti-rheumatic activity of pseudoephedrine (a substituted phenethylamine) in complete Freund's adjuvant-induced arthritic rats by down regulating IL-1ß, IL-6 and TNF-α as well as upregulating IL-4 and IL-10.

Pseudoephedrine (substituted phenethylamine) is well known as psychotic and bronchodilator. Numerous studies on phenethylamine derivatives indicated that these agents have the potential to abolish inflammatory responses in the non-biological and biological systems. These facts provided the basis to conduct a study on pseudoephedrine to explore its therapeutics in Complete Freund's Adjuvant (CFA)-induced arthritis. Furthermore, existing treatment approaches for RA associated with limited effect on chronic immunological models. Real-time polymerase chain reaction (q-PCR) was performed to execute the expression of pro and anti-inflammatory cytokines in treated and non-treated arthritic rats. These findings were further co investigate by histological observations. The paw volume, paw diameter, weight variations and arthritic score were determined at specific days throughout the experiment of 28 days. Pseudoephedrine at all doses significantly (p < 0.001) suppressed the expression of PGE2, TNF-α, IL-1ß and IL-6. Moreover, pseudoephedrine (20 and 40 mg/kg) caused significant augmentation of IL-4 and IL-10. Similarly, the drug expressed a significant anti-arthritic effect by reducing the paw volume, paw diameter and arthritic score. Similarly, it also reverts the reduction in body weight of arthritic rats at all above-mentioned doses. These findings supported the anti-arthritic potential of pseudoephedrine and recommended it for clinical trials.

Comparative evaluation of efficacy and safety of drotaverine versus mebeverine in irritable bowel syndrome: A randomized double-blind controlled study.

BACKGROUND: Drotaverine and Mebeverine are used for alleviating the pain of IBS, but the evidence for their efficacy is scarce. In this randomised control study, we evaluated and compared their efficacy in improving severity, frequency of pain and its associated symptoms. METHODS: Patients fulfilling the ROME III criteria of IBS were evaluated in this randomised control trial during 4 weeks of treatment. Group A (n = 100) received 80 mg Drotaverine and Group B (n = 100) received 135 mg Mebeverine three times a day, 1 hour before meals. Primary outcome measure was, the reduction in severity of pain (>30% reduction) assessed by VAS (0 to 10 scale) & PSS (patient symptoms scores). RESULTS: The pain severity score fell from 6.02 to 4.8 on day 3 in Group A as compared to decrease from 6.72 to 6.62 in Group B (p < 0.01). This significant reduction in pain severity was observed till the end of the study, reducing from 6.02 to 1.78 (74% reduction) in Group A compared to 6.72 to 3.62 (46.1% reduction) in Group B (p < 0.05). There was a significant reduction in pain frequency, straining on stool, a change in one score in Bristol stool chart (BSC), achievement of complete spontaneous smooth bowel movement in Group A, compared to Group B patients. A significant improvement in Patient's evaluation of Global Assessment of Symptoms (p < 0.05) and Patient Assessment of Constipation - Quality Of Life (PAC-QOL) (p < 0.01) was observed in Group A compared to Group B. CONCLUSION: Drotaverine was significantly superior in efficacy as compared to Mebeverine in alleviating pain severity (starting from day 3), frequency and stools-elated symptoms of IBS.

Acute lead poisoning: a diagnostic challenge in the emergency department.

Acute abdominal pain is a common presentation to the emergency department (ED). Ruling out life-threatening causes and giving pain relief are the most important tasks in ED. We describe a 32-year-old man who presented to ED with abdominal pain and vomiting which was unrelieved by usual doses of analgesic. Extensive investigations revealed no significant abnormalities. On further probing, he admitted taking traditional medications for infertility. The toxicological panel revealed a high blood lead level, leading to a diagnosis of acute lead toxicity. Chelation therapy with D-penicillamine was initiated and the patient's abdominal pain resolved within 4 days.

Different effects of amiodarone and dofetilide on the dispersion of repolarization between well-coupled ventricular and Purkinje fibers1.

Increased transmural dispersion of repolarization is an established contributing factor to ventricular tachyarrhythmias. In this study, we evaluated the effect of chronic amiodarone treatment and acute administration of dofetilide in canine cardiac preparations containing electrotonically coupled Purkinje fibers (PFs) and ventricular muscle (VM) and compared the effects to those in uncoupled PF and VM preparations using the conventional microelectrode technique. Dispersion between PFs and VM was inferred from the difference in the respective action potential durations (APDs). In coupled preparations, amiodarone decreased the difference in APDs between PFs and VM, thus decreasing dispersion. In the same preparations, dofetilide increased the dispersion by causing a more pronounced prolongation in PFs. This prolongation was even more emphasized in uncoupled PF preparations, while the effect in VM was the same. In uncoupled preparations, amiodarone elicited no change on the difference in APDs. In conclusion, amiodarone decreased the dispersion between PFs and VM, while dofetilide increased it. The measured difference in APD between cardiac regions may be the affected by electrotonic coupling; thus, studying PFs and VM separately may lead to an over- or underestimation of dispersion.

A Randomized Trial to Examine the Utility of Mebeverine on the Early Return of Continence Following Orthotopic Bladder Substitution.

PURPOSE: We assessed the effect of mebeverine in the enhancement of the orthotopic bladder substitute continence. MATERIALS AND METHODS: A randomized trial was carried out for incontinent adult male patients during the first year post-orthotopic bladder substitute surgery. Patients were allocated to receive mebeverine 135 mg or placebo 3 times a day for only 3 months. The primary outcome was to compare the continence improvement between groups, assessed by the urinary domain of the Bladder Cancer Index and sanitary pad use. The secondary outcomes were to assess the safety of the drugs used. RESULTS: In placebo group 47 and in mebeverine group 52 patients completed followup. The median (range) interval time between orthotopic bladder substitute surgery and starting treatment was 7 (3-10) months and 6.5 (3-10) months in the placebo and mebeverine group, respectively (p=0.3). Compared to the baseline evaluation, the 3-month urinary domain of Bladder Cancer Index scores improved in both groups with significant improvement in the mebeverine group. The mean±SD 3-month urinary domain of Bladder Cancer Index was 67.79±13.05 and 83.27±12.21 in the placebo and mebeverine group, respectively (p <0.001). Also, the 3-month patient pad use decreased to 30 (63.8%) and 19 (36.5%) patients in the placebo and mebeverine group, respectively (p=0.007). Constipation occurred in 1 (2.1%) and 3 (5.8%) patients in the placebo and mebeverine group, respectively; abdominal distention occurred in 2 (3.8%) in the mebeverine group (p=0.25). CONCLUSIONS: Mebeverine accelerated continence development in male patients with ileal orthotopic bladder substitute during the first year post-orthotopic bladder substitute construction.

Clinical Outcomes and Characteristics With Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator.

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.

Novel Phenethylamines and Their Potential Interactions With Prescription Drugs: A Systematic Critical Review.

BACKGROUND: The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed. METHODS: The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals. RESULTS: Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication. CONCLUSIONS: A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.

Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury.

In OA chondrocytes, there is diminished mitochondrial production of ATP and diminished extracellular adenosine resulting in diminished adenosine A2A receptor (A2AR) stimulation and altered chondrocyte homeostasis which contributes to the pathogenesis of OA. We tested the hypothesis that A2AR stimulation maintains or enhances mitochondrial function in chondrocytes. The effect of A2AR signaling on mitochondrial health and function was determined in primary murine chondrocytes, a human chondrocytic cell line (T/C-28a2), primary human chondrocytes, and a murine model of OA by transmission electron microscopy analysis, mitochondrial stress testing, confocal live imaging for mitochondrial inner membrane polarity, and immunohistochemistry. In primary murine chondrocytes from A2AR-/- null mice, which develop spontaneous OA by 16 weeks, there is mitochondrial swelling, dysfunction, and reduced mitochondrial content with increased reactive oxygen species (ROS) burden and diminished mitophagy, as compared to chondrocytes from WT animals. IL-1-stimulated T/C-28a2 cells treated with an A2AR agonist had reduced ROS burden with increased mitochondrial dynamic stability and function, findings which were recapitulated in primary human chondrocytes. In an obesity-induced OA mouse model, there was a marked increase in mitochondrial oxidized material which was markedly improved after intraarticular injections of liposomal A2AR agonist. These results are consistent with the hypothesis that A2AR ligation is mitoprotective in OA.

A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm.

RATIONALE: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. OBJECTIVE: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. METHODS AND RESULTS: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. CONCLUSIONS: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease.

BACKGROUND: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-ß protein (Aß) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aß 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.

Activation of adenosine A2A receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients.

BACKGROUND: Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A2A adenosine receptor (A2AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients. METHODS: Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of A2AAR. Analysis of ADORA2A, TNFA, and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits. RESULTS: Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, A2AAR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals. CONCLUSION: According to our results, it appears that A2AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of A2AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

BACKGROUND: Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs. OBJECTIVE: The purpose of this study was to characterize acute effects of AADs on GEH measurements. METHODS: We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models. RESULTS: Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women. CONCLUSION: AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects.

Computational chemoproteomics to understand the role of selected psychoactives in treating mental health indications.

We have developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform to infer homology of drug behaviour at a proteomic level by constructing and analysing structural compound-proteome interaction signatures of 3,733 compounds with 48,278 proteins in a shotgun manner. We applied the CANDO platform to predict putative therapeutic properties of 428 psychoactive compounds that belong to the phenylethylamine, tryptamine, and cannabinoid chemical classes for treating mental health indications. Our findings indicate that these 428 psychoactives are among the top-ranked predictions for a significant fraction of mental health indications, demonstrating a significant preference for treating such indications over non-mental health indications, relative to randomized controls. Also, we analysed the use of specific tryptamines for the treatment of sleeping disorders, bupropion for substance abuse disorders, and cannabinoids for epilepsy. Our innovative use of the CANDO platform may guide the identification and development of novel therapies for mental health indications and provide an understanding of their causal basis on a detailed mechanistic level. These predictions can be used to provide new leads for preclinical drug development for mental health and other neurological disorders.

The A2A receptor agonist CGS 21680 has beneficial and adverse effects on disease development in a humanised mouse model of graft-versus-host disease.

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 A2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γnull (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A2A 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 A2A 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 A2A 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.

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice.

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Reduction in Blood Glutamate Levels Combined With the Genetic Inactivation of A2AR Significantly Alleviate Traumatic Brain Injury-Induced Acute Lung Injury.

Traumatic brain injury-induced acute lung injury (TBI-ALI) is a serious complication of traumatic brain injury (TBI). Our previous clinical study found that high levels of blood glutamate after TBI were closely related to the occurrence and severity of TBI-ALI, while it remains unknown whether a high concentration of blood glutamate directly causes or aggravates TBI-ALI. We found that inhibition of the adenosine A2A receptor (A2AR) after brain injury alleviated the TBI-ALI; however, it is unknown whether lowering blood glutamate levels in combination with inhibiting the A2AR would lead to better effects. Using mouse models of moderate and severe TBI, we found that intravenous administration of L-glutamate greatly increased the lung water content, lung-body index, level of inflammatory markers in bronchoalveolar lavage fluid and acute lung injury score and significantly decreased the PaO2/FiO2 ratio. Moreover, the incidence of TBI-ALI and the mortality rate were significantly increased, and the combined administration of A2AR activator and exogenous glutamate further exacerbated the above damaging effects. Conversely, lowering the blood glutamate level through peritoneal dialysis or intravenous administration of oxaloacetate notably improved the above parameters, and a further improvement was seen with concurrent A2AR genetic inactivation. These data suggest that A2AR activation aggravates the damaging effect of high blood glutamate concentrations on the lung and that combined treatment targeting both A2AR and blood glutamate may be an effective way to prevent and treat TBI-ALI.

A Quarter of a Century Later: What is Dofetilide's Clinical Role Today?

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.

Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation.

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.