Follow-up of children or teenagers with paroxysmal supraventricular tachycardia, but without pre-excitation syndrome.

BACKGROUND: Paroxysmal supraventricular tachycardia (SVT) is considered benign in children if the electrocardiogram in sinus rhythm is normal, but causes anxiety in parents, children and doctors. AIMS: To report on the clinical and electrophysiological data from children with SVT, their follow-up and management. METHODS: Overall, 188 children/teenagers (mean age 15±2.8 years) with a normal electrocardiogram in sinus rhythm were studied for SVT, and followed for 2.3±4 years. RESULTS: SVT was poorly tolerated in 30/188 children (16.0%). SVT was related to atrioventricular nodal reentrant tachycardia (AVNRT) (n=133) or atrioventricular reentrant tachycardia (AVRT) over a concealed accessory pathway (n=55; 29.3%). Ablation of the slow pathway (n=66) or the accessory pathway (n=43) was performed without general anaesthesia, 2±3 years after initial evaluation. Failure or refusal to continue occurred in 18/109 (16.5%) children: 7/66 with AVNRT (10.6%), 11/43 with AVRT (25.6%) (P<0.001). Symptoms of SVT recurred in 20/91 children (22.0%) with apparently successful ablation: 6/91 (6.6%) had real SVT recurrence; 14/91 (15.4%) had only a sinus tachycardia, more frequent in AVNRT (11/59; 18.6%) than AVRT (3/32; 9.4%) (P<0.05). In 13 children treated with an antiarrhythmic drug (AAD), SVT recurred in four; two presented AAD-related syncope. In 66 untreated children, one death was noted after excessive AAD infusion to stop SVT; the others remained asymptomatic or had well-tolerated SVT. CONCLUSIONS: At the time of ablation, SVT management remains difficult in children. Indications for ablation are more common in AVRT than in AVNRT, but failures are frequent; 22.0% remained symptomatic after successful ablation, but false recurrences were frequent (15.4%). Without ablation, one third had a spontaneous favourable evolution.

Intravenous Dosing as an Alternate Approach to Safely Achieve Supratherapeutic Exposure for Assessments of Cardiac Repolarization: A Randomized Clinical Trial with Mavoglurant (AFQ056).

PURPOSE: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS: This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS: This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.

Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study.

The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects (N = 73) were randomized 1:1 to secukinumab 10 mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30 days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49 % (95 % CI -10 to 77 %; P = 0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67 % (31-84 %, P = 0.003). CUAL reductions were progressively greater from week 4 (1 %) to week 16 (49 %) and persisted until end-study (50 %). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49 %), although mild-to-moderate infection was somewhat more frequent (37 versus 23 %). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect.

Signal-regulated Pre-mRNA occupancy by the general splicing factor U2AF.

Alternative splicing of transcripts in a signal-dependent manner has emerged as an important concept to ensure appropriate expression of splice variants under different conditions. Binding of the general splicing factor U2AF to splice sites preceding alternatively spliced exons has been suggested to be an important step for splice site recognition. For splicing to proceed, U2AF has to be replaced by other factors. We show here that U2AF interacts with the signal-dependent splice regulator Sam68 and that forced expression of Sam68 results in enhanced binding of the U2AF65 subunit to an alternatively spliced pre-mRNA sequence in vivo. Conversely, the rapid signal-induced and phosphorylation-dependent interference with Sam68 binding to RNA was accompanied by reduced pre-mRNA occupancy of U2AF in vivo. Our data suggest that Sam68 can affect splice site occupancy by U2AF in signal-dependent splicing. We propose that the induced release of U2AF from pre-mRNA provides a regulatory step to control alternative splicing.