Foreword

This remarkable edition of “Frontiers in Drug Discovery" aims to revisit the “Erythropoietic-Stimulating Agents (ESAs)” under different and interesting perspectives. It seems imperative to introduce this excellent compilation of papers by highlighting briefly the discovery of the central theme - erythropoietin. Indeed, its discovery was one of the most extraordinary advances in Medicine, perfectly demonstrating the importance of the relationship between basic research and clinical practice what we at present call Translational Medicine. Since the observations in the early nineteenth century by Carnot and Deflandre, and later confirmed by Ersley in 1953, surrounding the erythropoietic properties of serum in anemic animals, a long road has been traveled. It was then, in the second half of the twentieth century, with Goldwasser et al., that the kidney was identified as the main site of endogenous synthesis. It took roughly 20 years to isolate erythropoietin from urine in patients with aplastic anemia, and then in 1985, gene cloning opened the way for large scale erythropoietin production. Erythropoietin was finally approved in 1989 by the U.S. Food and Drug Administration (FDA) for the treatment of anemia in patients with chronic renal failure on dialysis. Its use was subsequently extended in 1990 to chronic kidney disease patients not on dialysis, and other groups of patients, such as carriers of the human immunodeficiency virus and patients undergoing major orthopedic surgery or chemotherapy. Consequently, today we can safely say that those approximately 80 years of hard work and dedication have been entirely successful. This is confirmed by about 25 years of experience in different patient populations, especially those suffering from chronic kidney disease. In this regard, it is important to remember that for over twenty years, until the systematic use of erythropoietin in clinical practice, many patients on dialysis often needed blood transfusions to maintain a relatively normal life, with all the adverse consequences resulting therefrom. However, the story of stimulating agents does not end here, since the clinical use of a recombinant molecule has opened up new challenges in the research. The biotechnological engineering of the original molecule sought to optimize its power and increase its half-life, enabling the creation of new analogues. While the primary goal focused on the correction of hemoglobin levels, numerous investigations have sought to evaluate the positive and negative effects of the use of ESAs in different organ systems. Particular controversy has been raised by the high target hemoglobin levels to achieve, especially since an association with mortality was found in patients with chronic renal failure. Moreover, many investigations have produced surprising discoveries concerning the ESAs pleotrophic effects, allowing for new and effective alternatives to the use of those molecules. Those studies are essentially based on the effects at a cellular and molecular level through anti-apoptotic and immuno-modulatory mechanisms.

Over the following pages, I have the privilege to present the knowledge and experience of notable researchers who have dedicated themselves to thoroughly studying the effects of ESAs. From clinical to basic research, the focus is on topics as diverse as cardiovascular disease, oncology, degenerative diseases, regenerative medicine and infection. Erythropoietin, “the mother molecule”, remains at the center of them all.