Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies

Copyright ª 2019 by The Author(s) The anabolic effects of b2-adrenoceptor (b2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of b2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived b2-AR agonist in comparison with formoterol as a representative b2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human b2-AR and selectivity over the b1-AR and b3-AR. 5-HOB also shows potent agonistic activity at the b2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue–derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional b2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects

L'évaluation des effets externes du transport sur l'environnement

International audienceThe use of energy in the transport sector is the cause of many pollutions. The resulting environmental effects are various and often complex. However it seems possible for some effects to quantify the relationship between an increase in the pollutant concentration in the environment and the effect induced on receptors. The paper give examples of such exposure-response functions relating to impacts on the built environment, atmospheric visibility, vegetation, human health. The monetary value of these impacts can be estimated as an economic cost or by contingent valuation method. Evaluation of the external costs associated with the transport energy use raises methodological questions and involves large uncertainties. Such studies could nevertheless enlighten decisionmakers on the magnitude of some external effects. They are in any case interesting by the underlying system analysisLa consommation d'énergie par les transports est source de nombreuses pollutions. Les effets sur l'environnement qui en résultent sont très divers et souvent complexes. Pour certains d'entre eux, (impacts sur le cadre bâti, sur la visibilité, sur la végétation, sur la santé) il apparaît cependant possible de donner des éléments de quantification en termes physiques. La valorisation monétaire de ces effets peut se référer à leur coût économique ou bien à une "évaluation contingente" ; elle soulève certaines difficultés méthodologiques

Efficiency of the Wang-Landau Algorithm: A Simple Test Case

International audienceWe analyze the convergence properties of the Wang-Landau algorithm. This sampling method belongs to the general class of adaptive importance sampling strategies which use the free energy along a chosen reaction coordinate as a bias. Such algorithms are very helpful to enhance the sampling properties of Markov Chain Monte Carlo algorithms, when the dynamics is metastable. We prove the convergence of the Wang-Landau algorithm and an associated central limit theorem

Convergence of the Wang-Landau algorithm

International audienceWe analyze the convergence properties of the Wang-Landau algorithm. This sampling method belongs to the general class of adaptive importance sampling strategies which use the free energy along a chosen reaction coordinate as a bias. Such algorithms are very helpful to enhance the sampling properties of Markov Chain Monte Carlo algorithms, when the dynamics is metastable. We prove the convergence of the Wang-Landau algorithm and an associated central limit theorem

ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments

Background Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. Methods In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the Activin receptor type II (ActRII) preventing binding of ligands such as myostatin and Activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian Target of Rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Results Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. Conclusions Anti ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients

Tentative d'évaluation monétaire des coûts externes liés à la pollution automobile : difficultés méthodologiques et étude de cas: Cahiers du CEG, n° 29

La consommation d'énergie par les transports est source de nombreuses pollutions. Leseffets sur l'environnement qui en résultent sont très divers et souvent complexes. Pourcertains d'entre eux (impacts sur le cadre bâti, sur la visibilité, sur la végétation, sur la santé),il apparaît cependant possible de donner des éléments de quantification en termesphysiques. La valorisation monétaire de ces effets peut se référer à leur coût économique oubien à une "évaluation contingente" ; elle soulève certaines difficultés méthodologiques.Nous présentons des estimations des coûts externes liés à la pollution atmosphériqued'origine automobile, pour l'exemple d'un trajet allant de Paris à Lyon. Laméthodologie est une analyse des "Impact Pathways", approche pluridisciplinairedéveloppée par la DG12 de la Commission Européenne dans le cadre du projeteuropéen ExternE. Les principales étapes du calcul sont : les émissions, la dispersionatmosphérique, les fonctions dose-réponse, et l'évaluation monétaire. La dispersionest calculée en combinant deux logiciels : pour la zone locale <50 km ROADPOL (unmodèle de plume gaussienne) et au-delà de 50 km le Harwell Trajectory Model (dansla version utilisée dans le logiciel ECOSENSE du projet ExternE). Les fonctions doseréponseet l'évaluation monétaire sont également basées sur ExternE