Intravenous Sotalol for the Treatment of Ventricular Dysrhythmias in an Infant on Extracorporeal Membrane Oxygenation.

Sotalol is a class III anti-arrhythmic agent with beta receptor blocking properties. Intravenous (IV) sotalol may be useful to treat refractory atrial and ventricular arrhythmias. A report on the efficacy and safety of IV sotalol in an infant on extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), who developed refractory ventricular arrhythmias following surgery for congenital heart disease. A 10-day old infant with severe pulmonary valve stenosis underwent surgical pulmonary valvectomy and enlargement of the main pulmonary artery. Post-operatively, the patient developed hemodynamically significant accelerated idioventricular rhythm which was not responsive to a combination of amiodarone, lidocaine, and procainamide leading to 2 cardiac arrest events and placement on ECMO. The amiodarone infusion was uptitrated to 20 mcg/kg/min, but episodes of the hemodynamically compromising arrhythmia continued. Amiodarone was discontinued and IV sotalol was initiated at 42 mg/m2/day, divided to 3 doses, and administered every 8 h, which completely suppressed the arrhythmia. The initial sotalol dose was calculated based on a daily dose of 90 mg/m2 and reduced by an age-related factor as recommended by the FDA approved prescribing information. Subsequently, acute kidney injury requiring CRRT developed. The patient remained on IV sotalol for 3 weeks and then transitioned to oral sotalol. The oral dose was increased to 44 mg/m2/day (3.5 mg every 8 h) to account for the difference in bioavailability between the IV and oral formulations. Serial sotalol levels during IV and PO therapy remained therapeutic on ECMO and CRRT. The patient maintained normal sinus rhythm on sotalol without adverse events. IV sotalol in the setting of ECMO and CRRT was safe and effective in controlling refractory hemodynamically compromising accelerated idioventricular rhythm unresponsive to amiodarone.

Intravenous Sotalol: An Under Used Treatment Strategy.

The pharmacologic treatment of arrhythmias has seen little advance over the past few years. Physicians treating life threatening or hemodynamically destabilizing arrhythmias depend almost entirely on intravenous (IV) amiodarone. This is regrettable due to the multiple toxicities of amiodarone and its long half-life. Once administered, it is a therapeutic commitment to long-term therapy. Given the very long terminal elimination half-life, treatment with amiodarone may interfere with baseline electrophysiologic studies and ablation procedures. Additionally, the side effect profile can be consequential, even with brief periods of treatment. Currently, sotalol, like amiodarone, is available in both IV and oral formulations, facilitating their use in emergency situations. IV sotalol has a rapid onset of action with linear pharmacokinetics. While sotalol's efficacy has mostly been evaluated in small clinical trials, 2 recent meta-analysis have been informative as to the utility of sotalol. Sotalol has similar efficacy as amiodarone, but has much more favorable adverse event profile. IV sotalol has been underutilized and could offer advantage in the treatment of AF for rate and rhythm control, as well in the pediatrics for treatment of supraventricular arrhythmias often resistant to other therapies.

The Use of Intravenous Sotalol in Cardiac Arrhythmias.

Sotalol is a non-selective beta-adrenergic blocking agent without intrinsic sympathomimetic activity. It has the additional unique property of producing pronounced prolongation of the cardiac action potential duration. Sotalol therapy has been indicated for the management of supraventricular arrhythmias, refractory life threatening ventricular arrhythmias and atrial fibrillation/flutter. Until recently, sotalol was only available in the oral form, however, it was approved for intravenous administration by the US Food & Drug Administration (FDA). The current recommendations are for sotalol 75-150mg to be administered intravenously over 5hours. This rate of administration does not reflect the majority of the research that has been performed with regards to intravenous sotalol. Also, the safety of intravenous bolus dosing of 100mg over 1 and 5minutes has previously been demonstrated. The antiarrhythmic action of sotalol depends on its ability to prolong refractoriness in the nodal and extra nodal tissue. Hence, by giving a lower dose over a long duration, patients may not necessarily benefit from its anti-arrhythmic potential. The purpose of this article is to review the research that has been conducted with regards to dosage and safety of intravenous sotalol, its electrophysiological effects and finally the spectrum of arrhythmias in which it has been used to date.

Transplacental treatment of fetal tachycardia: A systematic review and meta-analysis.

OBJECTIVE: Multiple transplacental medications can be used to treat fetal tachycardia. We sought to perform a systematic review and meta-analysis to determine whether digoxin, flecainide, or sotalol was the most efficacious therapy for converting fetal tachycardia to sinus rhythm. METHOD: We performed a systematic review and meta-analysis to compare digoxin, flecainide, or sotalol as first-line therapy for fetal tachycardia. Studies were identified by a search of PubMed (Medline), Web of Science, and Scopus. RESULTS: There were 21 studies included. Flecainide (OR: 1.4, 95% CI: 1.1-2.0, I2  = 60%, P = 0.03) and sotalol (OR:1.4, 95% CI:1.1-2.0, I2  = 30%, P = 0.02) were superior to digoxin for conversion of fetal tachycardia to sinus rhythm. In those with hydrops, the benefit over digoxin was more notable for both flecainide (OR: 5.0, 95% CI: 2.5-10.0, I2  = 0%, P < 0.001) and sotalol (OR: 2.5, 95% CI: 1.7-5.0, I2  = 0%, P < 0.001). When limited to atrioventricular reentrant tachycardia, flecainide was superior to digoxin (OR:1.7, 95% CI:1.1-3.3, I2  = 62%, P = 0.03) and sotalol (OR:1.3, 95% CI:1.1-1.7, I2  = 0%, P = 0.01). CONCLUSION: Digoxin should not be first-line therapy for fetal tachycardia, particularly in the presence of hydrops fetalis. Flecainide should be the first-line therapy of choice in atrioventricular reentrant tachycardia. Further study may identify further sub-populations responding differently.

Pediatric Dosing of Intravenous Sotalol Based on Body Surface Area in Patients with Arrhythmia.

In a recently published study, we evaluated the efficacy and safety of intravenous sotalol in pediatric patients with incessant tachyarrhythmias and we have found that intravenous sotalol is effective and safe. Our dosing regimen was based on the body weight of the patients. In the US, the recommendation for intravenous sotalol dosing in pediatric patients is based on body surface area (BSA) while taking into consideration the patients' age. The purpose of this paper is to show the correspondence of a body weight-based dosing regimen when expressed for BSA as mg/m2. We evaluated the similarity of a body weight-based dose to that calculated based on BSA using the US labeling recommendations. Of the 83 patients, 5 were newborns (age: 0-30 days), 39 infants and toddlers (age: 1-24 month), 26 young children (age: >2-6 years), 11 older children (age: 6-12 years), and 2 adolescents (age: 14 years). Each received a loading dose of 1 mg/kg intravenous sotalol administered over 10 min followed by a maintenance dose of 4.5 mg/kg/day. There was a close correlation between the sotalol loading doses calculated based on body weight and BSA across the entire age range (r = 0.977, p < 0.001). In most of the age groups, the body weight-based loading doses were lower or equal to the BSA-based doses. Only in the adolescents were the body weight-based doses higher. The maintenance doses given in our study were significantly higher than the BSA-based dose in newborns: 75 ± 6 versus 53 ± 8 mg/m2, p < 0.05; infants/toddlers: 88 ± 14 versus 77 ± 7 mg/m2, p < 0.001; younger children: 113 ± 12 versus 85 mg/m2, p < 0.001; older children: 123 ± 16 versus 85 mg/m2, p < 0.01; and adolescents 157 ± 30 versus 85.5 mg/m2. Despite the rapid administration of the loading dose and the increased maintenance doses, our body weight-based dosing regimen was safe. Only one newborn had significant adverse event (AV block) that resolved spontaneously after discontinuation of the infusion.

Influences of rapid pacing-induced electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits.

Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2-4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant.

Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk.

BACKGROUND: Recently a new risk marker for drug-induced arrhythmias called index of cardio-electrophysiological balance (iCEB), measured as QT interval divided by QRS duration, was evaluated in an animal model. It was hypothesized that iCEB is equivalent to the cardiac wavelength λ (λ = effective refractory period (ERP) x conduction velocity) and that an increased or decreased value of iCEB would potentially predict an increased susceptibility to TdP or non-TdP mediated VT/VF, respectively. METHODS: First, the correlation between QT interval and ERP was evaluated by invasively measuring ERP during a ventricular stimulation protocol in humans (N = 40). Then the effect of administration of sotalol and flecainide on iCEB was measured in 40 patients with supraventricular tachycardias. Finally iCEB was assessed in carriers of a long QT syndrome (LQTS, N = 70) or Brugada syndrome (BrS, N = 57) mutation and compared them with genotype negative family members (N = 65). RESULTS: The correlation between QT interval and ERP was established (Pearson R(2) = 0.25) which suggests that iCEB≈ERPxCV≈QT/QRS. Sotalol administration increased iCEB (+ 0.23; P = 0.01), while it decreased with the administration of flecainide (-0.21, P = 0.03). In the LQTS group iCEB was increased (5.22 ± 0.93, P < 0.0001) compared to genotype negative family members (4.24 ± 0.5), while it was decreased in the BrS group (3.52 ± 0.43, P < 0.0001). CONCLUSIONS: Our data suggest that iCEB (QT/QRS) is a simple but effective ECG surrogate of cardiac wavelength. iCEB is increased in situations that predispose to TdP and is decreased in situations that predispose to non-TdP mediated VT/VF. Therefore, iCEB might serve as a noninvasive and readily measurable marker to detect increased arrhythmic risk.

[A change in adrenal responsiveness in sotalol-treated patients with paroxysmal atrial fibrillation depending on autonomic nervous system tone].

AIM: To evaluate the efficacy of sotalol depending on the magnitude of changes in adrenal responsiveness and autonomic nervous system tone in patients with paroxysmal atrial fibrillation (AF). SUBJECTS AND METHODS: Twenty-six patients with paroxysmal AF in the presence of coronary heart disease (CHD) and hypertension were examined. Sinus rhythm variability and sympathicotonic and vagotonic disorders were studied in patients with paroxysmal AF before and during sotalol treatment. A commercial Beta-ARM-Agat kit was used to estimate the adrenal responsiveness of erythrocyte membranes (ß-APM), which can judge the body's individual sensitivity to ß-adrenoblockers. RESULTS: Sotalol used in the average therapeutic doses of 160-240 mg did not reduce ejection fraction or increase atrioventricular conduction up to abnormal values. In patients with borderline and mild hypertension, the drug lowered blood pressure statistically significantly (p=0.01) and was well tolerated. The drug increased the sensitivity of ß-adrenoblockers in patients with adrenergic AF. CONCLUSION: The effect of sotalol on the autonomic nervous system manifested in the higher power of a high-frequency spectral component of heart rate variability than in that of a low-frequency one. Long-term sotalol administration significantly reduced ß-APM, increasing the sensitivity of adrenoceptors.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

AIM: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS: Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 µg ml(-1) (range 1.1-2.8) vs. 1.4 µg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per µg ml(-1) vs. 23 ms per µg ml(-1) in men; P = 0.0135). CONCLUSIONS: The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

Combination drug therapy for patients with intractable ventricular tachycardia associated with right ventricular cardiomyopathy.

BACKGROUND: Drug therapy for patients with right ventricular (RV) cardiomyopathy refractory to single-drug therapy and ablation has not been well defined. METHODS: We reviewed our entire RV cardiomyopathy database (31 patients) and found four patients presenting with ventricular arrhythmias of RV origin refractory to single-drug therapy. These patients underwent complete evaluation for arrhythmogenic right ventricular cardiomyopathy (ARVC). RESULTS: Following the revised 2010 task force criteria, of these four patients, three were diagnosed with ARVC, and one with cardiac sarcoidosis. These patients proved to be refractory to drug monotherapy and either failed or deemed to not be candidates for endocardial ablation. Their arrhythmias were ultimately controlled with combinations of sotalol, flecainide, and mexiletine. CONCLUSIONS: In our experience, combination drug therapy is an effective treatment strategy for patients with ventricular tachycardia refractory to monotherapy and, in some cases, ablation. In addition, flecainide appears to be safe and effective for those with RV cardiomyopathy without significant left ventricular dysfunction.

Expedited loading with intravenous sotalol is safe and feasible-primary results of the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry.

BACKGROUND: Loading of oral sotalol for atrial fibrillation requires 3 days, frequently in the hospital, to achieve steady state. The Food and Drug Administration approved loading with intravenous (IV) sotalol through model-informed development, without patient data. OBJECTIVE: We present results of the first multicenter evaluation of this recent labeling for IV sotalol. METHODS: The Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry was a multicenter observational registry of patients undergoing elective IV sotalol load for atrial arrhythmias. Outcomes, measured from hospital admission until first outpatient follow-up, included adverse arrhythmia events, efficacy, and length of stay. RESULTS: Of 167 consecutively enrolled patients, 23% were female; the median age was 68 (interquartile range, 61-74) years, and the median CHA2DS2-VASc score was 3 (interquartile range, 2-4). Overall, 99% were admitted for sotalol initiation (1% for dose escalation), with a target oral sotalol dose of either 80 mg twice daily (85 [51%]) or 120 mg twice daily (78 [47%]); 62 patients (37%) had an estimated creatinine clearance ≤90 mL/min. On presentation, 40% of patients were in sinus rhythm, whereas 26% underwent cardioversion before sotalol infusion. In 2 patients, sotalol infusion was stopped for bradycardia or hypotension. In 6 patients, sotalol was discontinued before discharge because of QTc prolongation (3), bradycardia (1), or recurrent atrial arrhythmia (2). The mean length of stay was 1.1 days, and 95% (n = 159) were discharged within 1 night. CONCLUSION: IV sotalol loading is safe and feasible for atrial arrhythmias, with low rates of adverse events, and yields shorter hospitalizations. More data are needed on the minimal duration required for monitoring in the hospital.

Sodium channel block by ranolazine in an experimental model of stretch-related atrial fibrillation: prolongation of interatrial conduction time and increase in post-repolarization refractoriness.

AIMS: In several clinical and pre-clinical studies, application of ranolazine (RAN) led to suppression of atrial fibrillation (AF). The aim of the present study was to investigate whether RAN can suppress AF in an experimental rabbit whole heart model, in which acute haemodynamic changes trigger AF. Ranolazine was compared with flecainide and sotalol as established antiarrhythmic agents. METHODS AND RESULTS: In 60 Langendorff-perfused, isolated rabbit hearts, AF episodes were evoked by burst pacing with a fixed number of stimuli at baseline and following acute atrial stretch. Data were obtained in the absence and presence of acute dilatation of the left atrium (20 mmHg) at baseline and after drug application (RAN 10 µM, n = 10; flecainide 2 µM, n = 10; sotalol 50 µM, n = 10). Application of sotalol, but not RAN or flecainide increased the atrial action potential duration at 90% repolarization (aAPD90); however, both RAN (+8 ms) and flecainide (+13 ms) increased interatrial conduction time. All three drugs caused a significant increase in atrial effective refractory period (aERP) and, thus, an increase in atrial post-repolarization refractoriness (aPRR: +11 ms each, P < 0.05). Acute dilatation of the left atrium reduced aAPD90 and aERP. The described drug effects were preserved in the setting of acute atrial dilatation. Acute atrial dilatation significantly increased the incidence of AF. Ranolazine and flecainide, but not sotalol, decreased the number of responses. CONCLUSION: Ranolazine-related sodium channel block is preserved upon acute atrial stretch. Ranolazine suppresses stretch-induced AF by increasing interatrial conduction time and aPRR. These results shed further evidence on the potential role of RAN in the prevention of AF. This might also apply to clinical conditions that are associated with haemodynamic or mechanical disorders, leading to acute dilatation of the atria.

Role of brain nitric oxide in the cardiovascular control of bullfrogs.

The goal of the present study was to determine if nitric oxide (NO) acting on the brain of bullfrog (Lithobates catesbeianus) is involved in arterial pressure and heart rate (HR) control by influencing sympathetic activity. We investigated the effect of intracerebroventricular injections of L-NMMA (a nonselective NO synthase inhibitor) on mean arterial blood pressure (MAP), HR and cutaneous vascular conductance (CVC) of pelvic skin after intravenous injection of α or ß adrenergic blockers, prazosin or sotalol, respectively. Arterial pressure was directly measured by a telemetry sensor inserted in the aortic arch of animals. L-NMMA increased MAP, but did not change HR. This hypertensive response was inhibited by the pre-treatment with prazosin, but accentuated by sotalol. The effect of L-NMMA on MAP was also inhibited by i.v. injections of the ganglionic blocker, hexamethonium. Thus, NO acting on the brain of bullfrog seems to present a hypotensive effect influencing the sympathetic activity dependent on α and ß adrenergic receptors in the periphery.

Electrophysiologic profile of dronedarone on the ventricular level: beneficial effect on postrepolarization refractoriness in the presence of rapid phase 3 repolarization.

BACKGROUND: Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. METHODS AND RESULTS: Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 µM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 µM), +56 milliseconds (100 µM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. CONCLUSIONS: Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

Cardiac sarcoidosis masquerading as arrhythmogenic right ventricular cardiomyopathy.

We present a case of ventricular tachycardia with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy. However, endomyocardial biopsy revealed non-caseating granulomas diagnostic of cardiac sarcoidosis.

High-dose sotalol is safe and effective in neonates and infants with refractory supraventricular tachyarrhythmias.

Our objective was to assess the efficacy and safety of high-dose sotalol in neonates and infants with refractory supraventricular tachycardia (SVT). SVT in neonates and infants can be refractory to primary therapies; therefore, secondary agents, e.g., sotalol, are often required to obtain control of SVT. Age-factor nomogram dosing of sotalol is widely used; however, our institution uses greater doses based on body surface area (approximately 150-200 mg/m(2)/d). A retrospective review of 78 inpatients receiving sotalol, after failing another antiarrthymic medication, at our institution from 2001 to 2008 was performed. Corrected QT intervals (QTc), 24-h Holter-monitoring results, and outpatient records were reviewed to assess safety and efficacy for patients ≤ 2 years of age. Median patient age at the time of initiation of therapy was 24 days (range 3-728). Forty-eight patients (62%) were neonates, and 36 (46%) had congenital heart disease. The median sotalol dosage was 152 mg/m(2)/day (range 65-244). The SVT of 70 patients (90%) was controlled with sotalol. No patients experienced significant QTc prolongation or proarrhythmia. Mean duration of follow-up was 3.3 ± 0.24 years. High-dose sotalol allows for safe and rapid control of refractory tachyarrhythmias in this young age group.

Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

Ameliorating effects of histamine H3 receptor antagonist E177 on acute pentylenetetrazole-induced memory impairments in rats.

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on acute pentylenetetrazole (PTZ)-induced memory impairments, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (Glu), acetylcholine esterase (AChE) activity, and c-fos protein expression in rats. E177 (5 and 10 mg/kg, i.p.) significantly prolonged step-through latency (STL) time in single-trial passive avoidance paradigm (STPAP), and shortened transfer latency time (TLT) in elevated plus maze paradigm (EPMP) (all P < 0.05). Moreover, and in the hippocampus of PTZ-treated animals, E177 mitigated abnormal levels of AChE activity, ACh and HA (all P < 0.05), but failed to modify brain levels of GABA and Glu. Furthermore, E177 alleviated hippocampal oxidative stress by significantly decreasing the elevated levels of MDA, and increasing the abnormally decreased level of GSH (all P < 0.05). Furthermore, E177 reduced elevated levels of hippocampal c-fos protein expression in hippocampal tissues of PTZ-treated animals (all P < 0.05). The observed results propose the potential of H3R antagonist E177 with an added advantage of avoiding cognitive impairment, emphasizing the H3Rs as a prospective target for future pharmacological management of epilepsy with associated memory impairments.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice.

BACKGROUND: Due to blocking ß-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. MATERIALS AND METHODS: As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography-mass spectrometry. RESULTS: Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80-100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. CONCLUSION: Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.