Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years

Seeding uniformity for vacuum precision seeders Uniformidade de semeaduras para semeadeiras de precisão a vácuo

The performance of three vacuum precision seeders was investigated in a field study. Seeding uniformity was determined in three different within-row distances: 14, 18 and 21 cm. The seeders were operated at 1.8, 3.6, 5.4 and 7.2 km h-1. Successive seed spacing along of 3 m of row was measured in three replications on each row. For evaluating the seeding uniformity of seeders, seed spacings were analyzed using the methods (MISS, MULT, QFI and PREC). There were no differences between seeders. For P < 0.01, operating speed affected MISS and QFI values, and the within-row seed spacing affected MULT and PREC values. The best operating speed was 1.8 km h-1 because of the highest QFI value (88.5%). There was no difference between 1.8 and 3.6 km h-1. The speeds, 1.8 and 3.6 km h-1, were different from 5.4 and 7.2 km h-1. The best within-row distance was 18 cm because the QFI value was higher than those of 14 and 20 cm, 86.9%, 82.0% and 81.8%, respectively. The best PREC value was obtained for 21 cm within-row distance (17.4%). PREC values were acceptable for precision seeding in all trials.<br>O comportamento de três semeadeiras de precisão a vácuo foi investigado em um estudo de campo. A uniformidade de semeadura foi determinada para três distâncias de entrelinha: 14, 18 e 21 cm. As semeadeiras operaram nas velocidades de 1,8; 3,6; 5,4 e 7,2 km h-1. O espaçamento entre sementes sucessivas foi feito ao longo de 3 m de linha, com três repetições em cada linha. Para avaliar a uniformidade, os espaçamentos entre sementes foram analisados usando os métodos (MISS, MULT, QFI e PREC) e nos resultados não foi achada diferença entre semeadeiras. Para P < 0,001 a velocidade de operação afetou MISS e QFI e o espaçamento entre linhas afetou MULT e PREC. A melhor velocidade de operação foi de 1,8 km h-1 devido ao seu mais alto valor de QFI (88,5%). Não houve diferença entre as velocidades de 1,8 e 3,6 km h-1, mas elas foram diferentes das velocidades 5,4 e 7,2 km h-1. A melhor distância entre linhas foi de 18 cm, pois seu QFI foi maior em relação à 14 e 20 cm, 86,9%, 82,0% e 81,8%, respectivamente. O melhor PREC foi obtido para 21 cm de entrelinha (17,4) e os valores de PREC foram aceitáveis para todos experimentos

HyMeX, un programme multi-disciplinaire de 10 ans sur le cycle de l'eau en Méditerranée

International audienceThe Mediterranean countries are experiencing important challenges related to the water cycle including water shortages and floods, extreme winds and ice/snow storms that impact critically the socioeconomic vitality in the area (causing damage to property; threatening lives; affecting the energy and transportation sectors, etc.). There are gaps in our understanding of the Mediterranean water cycle and its dynamics, which include the variability of the Mediterranean Sea water budget and its feedback on the variability of the continental precipitation through air/sea interactions, the impact of precipitation variability on aquifer recharge, river discharge, soil water content and vegetation characteristics specific of the Mediterranean basin and the mechanisms that control the location and intensity of heavy precipitating systems which often produce floods. The HyMeX (Hydrological cycle in the Mediterranean Experiment) programme is a 10-year concerted experimental effort at the international level aiming at advancing the scientific knowledge of the water cycle variability in all compartments (land, sea and atmosphere) and at various time and spatial scales. It also aims at improving the processes-based models needed for forecasting hydro-meteorological extremes and the models of the regional climate system for predicting regional climate variability and evolution. It finally aims at assessing the social and economic vulnerability to hydrometeorological natural hazards in the Mediterranean and the adaptation capacity of the territories and populations therein to provide support to policy makers to cope with water related problems under the influence of climate change, by linking scientific outcomes with related policy requirements

Short-term therapies for treatment of acute and advanced heart failure—why so few drugs available in clinical use, why even fewer in the pipeline?

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but—per definition—causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio-and vasoactive drugs used in the hospitalization phase to stabilize the patient’s hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

HyMeX, a 10-year multidisciplinary program on the Mediterranean water cycle

The Mediterranean countries are experiencing important challenges related to the water cycle, including water shortages and floods, extreme winds, and ice/snow storms, that impact critically the socioeconomic vitality in the area (causing damage to property, threatening lives, affecting the energy and transportation sectors, etc.). There are gaps in our understanding of the Mediterranean water cycle and its dynamics that include the variability of the Mediterranean Sea water budget and its feedback on the variability of the continental precipitation through air–sea interactions, the impact of precipitation variability on aquifer recharge, river discharge, and soil water content and vegetation characteristics specific to the Mediterranean basin and the mechanisms that control the location and intensity of heavy precipitating systems that often produce floods. The Hydrological Cycle in Mediterranean Experiment (HyMeX) program is a 10-yr concerted experimental effort at the international level that aims to advance the scientific knowledge of the water cycle variability in all compartments (land, sea, and atmosphere) and at various time and spatial scales. It also aims to improve the processes-based models needed for forecasting hydrometeorological extremes and the models of the regional climate system for predicting regional climate variability and evolution. Finally, it aims to assess the social and economic vulnerability to hydrometeorological natural hazards in the Mediterranean and the adaptation capacity of the territories and populations therein to provide support to policy makers to cope with water-related problems under the influence of climate change, by linking scientific outcomes with related policy requirements

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps. © 2016 The Author