INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology.

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.

QT interval correction assessment in the anesthetized guinea pig.

INTRODUCTION: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. METHODS: Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula.

Can shoulder muscle coordination during the support scale at ring height be replicated during training exercises in gymnastics?

The support scale at ring height, the swallow, is a difficult strength element, usually performed in gymnastics. Coaches try to simulate the swallow position during training to strengthen muscles, specifically in the position used for competition. However, the real effect of this position's simulation on muscle force and coordination and consequently on the muscle activity has not been determined. The purpose of the study was to compare muscle activity and coordination during a swallow performed on the rings, using a counterweight and during 2 training exercises using dumbbells or barbells, respectively. Six top-level gymnasts participated in the study. Electromyograms from the biceps brachii, triceps brachii, deltoideus (clavicular part), pectoralis major, serratus anterior, infraspinatus, trapezius (middle part), and latissimus dorsi in the right shoulder were collected during the 4 exercises and analyzed using root mean square (RMS) and mean power frequency (MPF). The RMS were normalized to the maximal voluntary contraction, and a co-activation index was also determined between biceps and triceps brachii. Our results show specific shoulder muscle coordination for each exercise. As compared with the swallow on the rings, the pectoralis major participates less in shoulder flexion during the counterweight exercise, whereas the deltoideus is more activated during the dumbbells exercise (p < 0.05). The barbell exercise reduces the participation of the serratus anterior in stabilizing the scapula (p < 0.05). Training exercises must therefore be chosen with knowledge of the specific muscle coordination induced by each. The counterweight exercise preserves the pectoralis major. The barbell exercise reduces participation of the serratus anterior. The dumbbells exercise may be useful to prepare the rotator cuff muscles carefully for use.

Is the VO2 slow component in heavy arm-cranking exercise associated with recruitment of type II muscle fibers as assessed by an increase in surface EMG?

The recruitment of additional type II muscle fibers is one mechanism often suggested to be responsible for the slow component of oxygen uptake (VO2 (SC)). We hypothesized that surface electromyogram (EMG) of the biceps brachii, triceps brachii, anterior deltoid, and infraspinatus muscles could be related to the VO2 (SC) amplitude during arm-cranking exercises above ventilatory threshold (VT). Eight healthy subjects performed transitions from rest to 6-min heavy exercise at a constant power output of approximately 40% between VT and peak VO2. A 2-component exponential model was used to fit the VO2 response. EMG were recorded the last 15 s of each minute to obtain root mean square (RMS) and mean power frequency (MPF). Mean EMG responses for RMS and MPF were calculated by averaging EMG responses of the 4 muscles. The VO2 (SC) amplitude was of 530 +/- 166 mL/min and occurred after 134 +/- 31 s of exercise onset. Significant correlations were found for most of the subjects between EMG parameters and the VO2 SC amplitude as determined between the 2nd and the 6th minute. For all muscles, RMS values significantly increased over time during the VO2 (SC), whereas MPF decreased significantly. These results suggest a relation between the recruitment of additional type II muscle fibers and the VO2 (SC) in arm-cranking exercises.

Effects of two devices on the surface electromyography responses of eleven shoulder muscles during Azarian in gymnastics.

Difficult elements of strength such as Azarian must be presented on the rings. Specific-muscles training may be realized with 2 devices, the Herdos and the Belt, both of which reproduce the competitive situation and allow many repetitions. The purpose of this study was therefore to compare the shoulder muscle activity during the performance of Azarian with each device. Our results show that muscles rhomboid, supraspinatus, deltoid (anterior, middle, and posterior parts), biceps brachii, and triceps brachii have significant (p < 0.05) higher root mean square value when gymnasts use the Belt compared with the Herdos. Although the Herdos and the Belt reproduce competitive movement, their muscle activities are quite different. The Herdos reduces the stress on the shoulder and elbow joints, whereas the Belt induces higher muscle activity and probably provides closer muscle synergisms to the rings.