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The Arrigo Recordati International Prize for Scientific Research

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 7/16/2018

2015 ARRIGO RECORDATI INTERNATIONAL PRIZE FOR SCIENTIFIC RESEARCH AWARDED TO JOHN JOSEPH VALENTINE MCMURRAY AND SALIM YUSUF

The Prize was awarded to the two scientists for their contribution in researching secondary prevention and risk reduction strategies for patients with cardiovascular diseases.

Milan, June 13, 2015

Today the Eighth Edition of the Arrigo Recordati International Prize for Scientific Research came to its conclusion with 100,000 Euros being awarded to Professor John Joseph Valentine McMurray, Professor of Medical Cardiology and convener for clinical research in the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, Scotland, UK and Professor Salim Yusuf, Professor of Medicine, Executive Director of the Population Health Research Institute (PHRI), McMaster University, Hamilton, Canada.

The ceremony took place during the 25th European Society of Hypertension (ESH) Annual Meeting in Milan.

The Arrigo Recordati International Prize for Scientific Research was established in 2000, in memory of the Italian pharmaceutical entrepreneur Arrigo Recordati, who led the homonymous company through a period of intense growth and development for 48 years until his premature death in February 1999. The Prize recognizes the seminal work of an individual who has demonstrated, through dedication to research, the values recognized by Arrigo Recordati, by granting every two years a prize of 100,000 Euros to a distinguished scientist, of any nationality, working in an institutional setting and not affiliated with pharmaceutical or medical device companies, for his/her commitment and accomplishments in the field of cardiovascular disease. Each edition of the Prize is devoted to a specific theme in this field.

For the 2015 Edition of the Prize, relevant International Societies and organizations specializing in the areas of Cardiology and Internal Medicine were invited to nominate candidates that they felt merited the Award for lifetime ARRIGO RECORDATI INTERNATIONAL PRIZE FOR SCIENTIFIC RESEARCH AWARDED TO JOHN JOSEPH VALENTINE MCMURRAY AND SALIM YUSUF achievement in researching secondary prevention and risk reduction strategies for patients with cardiovascular diseases.Self-nominations were not considered. The Jury panel of the 2015 Edition of the Prize, who announced the final decision, is composed of experts who have provided leadership throughout their long careers in the field of cardiology and secondary prevention and risk reduction strategies for patients with cardiovascular diseases.

The Jury is chaired by M. John Chapman B.Sc. (Hons), Ph.D., D.Sc., FESC, Research Professor, Medical Faculty of the Pierre and Marie Curie University (UPMC), Paris, Director Emeritus of the Dyslipidemia and Atherosclerosis Research Unit, (INSERM), Pitié-Salpêtrière University Hospital, Paris, France, Past-President of the European Atherosclerosis Society (EAS). Members of the Jury are Thomas F. Lüscher MD, FRCP, Professor and Chairman of Cardiology, University Heart Center, Zurich, Director of Center for Molecular Cardiology, University of Zurich, Switzerland and Chris J. Packard CBE, Ph.D., FRCPath, D.Sc. FRCP(Gla), FRSE, Director of Research and Development, NHS Greater Glasgow & Clyde, Honorary Professor of Vascular Biochemistry at the University of Glasgow, Consultant Clinical Scientist, Department of Biochemistry, NHS Greater Glasgow & Clyde, Scotland, UK. Professor Chapman, on behalf of the Jury, officially awarded the winners with the following motivation:

“Unique and exceptional contributions of each candidate to studies and clinical trials in secondary prevention, to the impact of their works on development of new strategies for risk reduction in subjects with CVD”. The winners of the Arrigo Recordati Prize, after expressing their satisfaction for the important Award, gave a brief lecture summarizing their research efforts and results in the study of the secondary prevention and risk reduction strategies for patients with cardiovascular diseases.

Over the last 3 decades, Professor Salim Yusuf has built capacity for clinical and population research across the world by establishing networks at over 1500 sites in 85 countries, spanning all inhabited continents of the world. He has trained over 100 researchers, many of whom are internationally renowned leaders in medical research. He has helped develop major research institutes or programs in Canada, India, Argentina, Brazil, South Africa, Saudi Arabia, Malaysia, and China. Throughout his professional career, Professor John Joseph Valentine McMurray has published approximately 700 original papers, reviews, and book chapters, including several in leading medical (e.g. Goldman Cecil’s) and cardiology textbooks (e.g. The ESC Textbook on Cardiovascular Medicine). He is the primary author or editor of thirteen books.

Professor McMurray was recently identified as one of the 400 most influential biomedical researchers in the world and the only cardiovascular researcher on this list from the UK (Boyack KW, Klavans R, Sorensen AA, Ioannidis JP. A list of highly influential biomedical researchers,1996-2011. Eur J Clin Invest. 2013;43:1339-65). He was also included in the new 2014 Highly Cited Researchers listing and one of The World’s Most Influential Scientific Minds.

The theme of the 2017 Edition of the Arrigo Recordati Prize will be: “Biological therapies for the treatment of diseases and conditions with high cardiovascular risk”.

Finally, Giovanni Recordati, Arrigo Recordati’s son and current Chairman and CEO of the Recordati pharmaceutical company, renewed the Company‘s strong commitment to research and officially announced that the theme chosen for the Nineth Edition of the Arrigo Recordati Prize is: “Biological therapies for the treatment of diseases and conditions with high cardiovascular risk”. A large body of evidence now indicates that several chronic diseases and conditions are associated with a high cardiovascular (CV) risk. This is largely documented also for autoimmune diseases such as rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus. Indeed, it is now well established that in rheumatoid arthritis (RA) the risk of CV morbidity and mortality is increased by almost 50%, as compared with the general population, and that CV disease is the leading cause of death in these patients. Large studies in RA patients have shown an almost 2-fold increase in their risk for myocardial infarction, to a level comparable to that observed in patients with type-2 diabetes. Recognized CV risk factors (such as hypertension, smoking and type-2 diabetes) certainly contribute to the increased CV risk level in RA patients, but do not fully explain it. Rather, growing evidence suggests that the chronic systemic inflammatory burden associated with RA is a key element of the increased CV risk. In the past decade, important new findings have emerged linking also psoriasis with chronic systemic inflammation and a subsequent increase in CV risk. High-need psoriatic patients show a high prevalence of CV risk factors, and may consequently be predisposed to CV diseases. A significantly higher prevalence of obesity, smoking, and hypertension was found for high-need psoriatic patients compared with controls. Striking differences were found with respect to body mass index and obesity (more than 35% of all high-need psoriatic patients were found to be obese). Furthermore, the associations between psoriasis and CV risk factors are reported to be stronger as psoriasis severity increases. As this is relevant for therapy management in everyday clinical practice, CV risk should be evaluated for each high-need psoriasis patient, before and during systemic treatment. All the above evidence indicates that the study and survey of the prevalence of CV risk factors in patients with chronic diseases and conditions, and in particular with autoimmune diseases, is highly relevant. It has been proposed that an effective control of inflammation could help reduce CV risk and illness in patients with autoimmune diseases. Growing clinical evidence has shown the increasing efficacy of therapies and therapeutic strategies, largely based on the use of biological products, in significantly reducing disease activity and the CV risk level in autoimmune diseases. On the other hand, it also has to be carefully assessed whether these biological therapies are safe for the treatment of diseases and conditions with high CV risk. At this point, it is encouraging that a recent meta-analysis evaluating a possible association between biological therapies for psoriasis and major adverse cardiovascular events (MACEs) did not show a significant increase in risk associated with the use of biological therapies.

SOURCE

http://www.recordati.com/resources/Pubblicazione/___f62376e579e74cea87b51c3f84292263_/2015-arrigo-recordati-prize.pdf

THE PIVOTAL ROLE OF MICROCIRCULATION IN SYSTEMIC AND ORGAN DISEASES

The term “microcirculation” describes the network of small vessels embedded within the organs that are responsible for the distribution of blood and the fluid exchanges within the tissues. Thus, microcirculation differs from macrocirculation, which is formed by larger vessels that transport blood to and from the organs.

The vessels on the arterial side of the microcirculation, the arterioles (10-100 µm in diameter) are well innervated and surrounded by smooth muscle cells. Arterioles carry the blood to the capillaries (about 5-8 µm in diameter) which are not innervated and have no smooth muscle cells. Fluid exchange between the capillaries and the tissues takes place at the capillary bed. Blood then flows out of the capillaries into the venules (10-200 µm in diameter) which have little smooth muscle, and finally blood flows from the venules into the veins. In addition to these blood vessels, the microcirculation also includes lymphatic capillaries and collecting ducts. It is important to note that blood is supplied to all parts of the body at all times, but all capillary beds do not contain blood at all times. Blood is diverted to the parts of the body that need it most at a particular time.

The main functions of the microcirculation include the regulation of:
1. blood flow and tissue perfusion
2. blood pressure,
3. tissue fluid (swelling or edema),
4. delivery of oxygen and other nutrients and removal of CO2 and other metabolic waste products, and
5. body temperature.

Therefore, microcirculation is a complex system that plays an important role in the hemodynamics of the body, by regulating blood pressure and venous return to the heart. It regulates the balance between oxygen demand and supply of parenchymal cells. In addition, microcirculation interacts extensively with the immune system and the body’s defense mechanisms.

The pivotal role of microcirculation in many disease conditions is well established. Indeed, microcirculation abnormalities often occur in subjects with high blood pressure. Also, metabolic diseases such as dislipidemia and type-2 diabetes induce destructive changes in the microvascular system that feeds the heart, the retina and the kidneys. As a consequence, early symptoms affecting patients, often the first signs of an underlying and more serious disease, can be due to a disturbance of microcirculation. Thus, microcirculation is an essential factor, albeit often poorly recognized, in the pathogenesis of many disease conditions.

With the constant improvement of diagnostic tools, scientists and physicians have realized that many problems affecting patients may occur in the microcirculatory system. Novel techniques have made it possible for the microcirculation to be observed directly at the patient’s bedside. Currently, research using these new techniques is focusing at the central role of the microcirculation in critical diseases. Experimental studies have demonstrated differences in microvascular alterations between models of septic and hypovolemic shock. In human studies, the microcirculation has most extensively been investigated in septic syndromes and has revealed highly heterogeneous alterations with clear evidence of arteriolar-venular shunting. Until now, the microcirculation in acute heart failure syndromes such as cardiogenic shock has scarcely been investigated.

Recordati at a Glance

Recordati is an international pharmaceutical group dedicated to the research, development, manufacturing and marketing of pharmaceuticals for primary care as well as orphan drugs for the treatment of rare diseases. Headquartered in Milan, it has operations in the main European countries, in Russia and other Central and Eastern European countries, in Turkey and in the United States of America. Recordati has been listed on the Italian Stock Exchange since 1984.

Recordati offers a wide range of innovative pharmaceuticals, both proprietary and under license, in a number of therapeutic areas including a specialized segment dedicated to treatments for rare diseases. A field force of more than 1700 medical representatives promotes these products in all countries where subsidiaries have been established. The company’s leading products are drugs for the treatment of hypertension and other cardiovascular disorders as well as treatments for disorders of the lower urinary tract such as benign prostatic hyperplasia. Drugs for rare diseases are mainly treatments for metabolic deficiencies of a genetic nature. Recordati sells its proprietary pharmaceuticals directly to the market in the countries where it is present and through licensees elsewhere. Pharmaceutical production is based mainly in Italy (Milan), France (Montluçon) and Turkey (Esenyurt). Plants for the production of proprietary active ingredients are situated in Italy (Campoverde, Latina) and in Cork (Ireland).

Pharmaceutical research is focused on the discovery of new chemical entities for the treatment of urogenital conditions while development activities are concentrated on urology, on the area of rare diseases and on the cardiovascular therapeutic area.

Recordati also has a minor pharmaceutical chemicals business. Recordati produces active ingredients for both its own proprietary pharmaceuticals and for the generic drugs industry. Over 90% of third party production is for the export markets.

Key consolidated data

  • Consolidated revenue for 2012 is € 828.3 million.
  • Operating income for 2012 is € 167.0 million.
  • Net income for 2012 is € 118.5 million.

Strategy

  • Continue its commitment to research and development mainly in the urological and cardiovascular areas and in treatments for rare diseases. Special care is a priority in the product development pipeline.
  • Expand through organic development and through acquisitions.
  • Pursue geographical expansion by entering new markets characterized by high growth potential.
  • Develop sales of orphan drugs globally.

HISTORY OF THE AWARD

Arrigo Recordati Profile

“Research is the only true engine of growth for the pharmaceutical industry”
Arrigo Recordati

Arrigo Recordati believed research was the most powerful asset for the pharmaceutical industry. He became head of the family business in 1951, at the age of 23, and transformed the family pharmaceutical laboratory employing 325 people into an international company listed on the Italian Stock Exchange. Arrigo Recordati’s remarkable life came to a premature end at the age of 71, in 1999.

Under his direction, in 1953 the company’s headquarters and pharmaceutical plant moved from Correggio, a small town in the Emilia region of Italy, to Milan, the capital of Italian business. During this time Arrigo Recordati provided the company with a stronger competitive advantage by updating its research facilities with advanced pharmacological laboratories.

In the 1950s and 60s, Arrigo Recordati relied on two strong beliefs: scientific research and internationalization. To maximize the results of Recordati research, he established subsidiaries in Brazil and Mexico. Arrigo Recordati also fostered a close relationship with the United States, signing among other things a strategic partnership agreement with Syntex Corporation (acquired by Roche Corporation in 1990) – at that time a company involved in cutting-edge research on the synthesis of steroid hormones.

Arrigo Recordati strongly believed in the power of scientific research to drive the growth of the pharmaceutical industry and provide products beneficial to public health and individual well being. Efloxate (1955), a coronary vasodilator for the treatment of cardiovascular disease, was the first compound to originate from Recordati’s research laboratories during Arrigo Recordati’s leadership. Other original molecules developed and marketed during his leadership include: dimefline (1958), a respiratory analeptic, flavoxate (1957), a urinary anti-spasmodic, tibezonium iodide (1971), an oral antiseptic, fenticonazole (1978), an antimycotic and lercanidipine (1984), a calcium channel blocker for the treatment of hypertension. In particular, flavoxate was the first original New Chemical Entity developed by an Italian company to be approved by FDA.

Arrigo Recordati also believed that even small companies – if managed with vigor and imagination – can compete effectively in the pharmaceutical arena. In 1984 Recordati was listed on the Italian Stock Exchange, completing its transformation from a small, family-run operation to a modern, professional, publicly listed company.

Recordati continues to dedicate a substantial amount of its resources to research and development, specializing in urological and cardiovascular therapies as well as treatments for rare diseases.

After 48 years of intense and challenging leadership, Arrigo Recordati passed away, leaving a solid, international business projected into the future.

INFORMATION ON THE AWARD

Mission

The Arrigo Recordati International Prize for Scientific Research was established in the year 2000 in memory of the Italian pharmaceutical entrepreneur Arrigo Recordati and aims to promote scientific research in the field of cardiovascular disease.

The award is presented every two years to a scientist who has demonstrated dedication to the advancement of scientific knowledge in cardiology.

The Prize 2013

The seventh edition of the International Prize in 2013 was awarded to a clinical or basic science investigator who, through his work, has achieved distinction in the study of the pivotal role of microcirculation in systemic and organ diseases.

The Prize awarded 100,000 Euros to the winner.

Scientists of all nationalities who work in an institutional setting and are not affiliated with a pharmaceutical company or medical device company are eligible.

The winner of the Prize was announced during an awards ceremony on the 15th of June 2013 in Milan, Italy, during the 23rdESH (European Society of Hypertension) Annual Meeting.

Latest Press Release

2013 Arrigo Recordati International Prize for Scientific Research.
The pivotal role of microcirculation in systemic and organ diseases

Award Regulations

The Prize

The Arrigo Recordati International Prize for Scientific Research is awarded every two years to a scientist who has shown special distinction in the area of cardiovascular disease or the study of biochemical mechanisms of particular importance in the same therapeutic field.

Each edition is devoted to a specific theme in the cardiovascular therapeutic field. The Prize is open to researchers of all nationalities who are not in any case directly affiliated with a pharmaceutical company or medical device company.

The Prize winner receives a sum of 100,000 Euros.

The Theme

The seventh edition of the Prize in 2013 recognized a clinical or basic science investigator who has achieved distinction in the study of the pivotal role of microcirculation in systemic and organ diseases.

Selection Procedures

The candidates were selected on the basis of nominations from scientific societies around the world.

The nominees were evaluated and a winner selected by a Judging Panel of three world-renowned cardiologists.

Jury

Members of the Jury of the 2013 edition:

Mara Lorenzi, MD (Panel Chairman), Professor of Ophthalmology, Harvard Medical School, Senior Scientist and George and Frances Levin Scholar in Diabetic Retinopathy, Schepens Eye Research Institute Massachusetts Eye and Ear, Boston, MA, USA.

Dr Ignatios Ikonomidis, MD, Ph.D., FESC, Assistant Professor in Cardiology, Director of the Laboratory of Preventive Cardiology, 2nd Cardiology Department, National and Kapodistrian University of Athens Attikon University Hospital, Athens, Greece.

Can IncePh.D., Professor in Clinical Physiology, Dept. of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Dept. of Intensive Care Adults, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands.

Nomination Procedures
Nominations have to be decided and proposed by scientific societies and organizations invited to submit their candidates.

Each nominator is allowed to submit more than one nominee for the Award.

Self nominations will not be considered.

Nominations will be sent in electronic format, through the dedicated website www.recordati.com/prizewith the use of a password assigned to scientific societies invited to nominate.

The deadline for nominations for the 2013 award was February 28, 2013.

The information received is held strictly confidential. Only those involved in the Prize selection procedure have access to the material submitted. The Judging Panel requires the same discretion by those making nominations.

Announcement of the Winner

The winner was notified with an official letter following the Judging Panel decision and was invited to give a lecture during the awards Ceremony.

Award Ceremony

The winner of the Prize was announced during an awards ceremony on the 15th of June 2013 in Milan, Italy, during the 23rd ESH (European Society of Hypertension) Annual Meeting.

Prize Winners: 2001 – 2013

Filippo Crea, MD
2013 Prize Winner

The Prize was awarded to the scientist for his contribution in researching the pivotal role of microcirculation in systemic and organ diseases.

The theme of the 2015 Edition of the Arrigo Recordati Prize will be: “Secondary prevention and risk reduction strategies for patients with cardiovascular diseases”.

Milan, June 15, 2013

Today the seventh edition of the Arrigo Recordati International Prize for Scientific Research came to its conclusion with 100,000 Euros being awarded to Prof. Filippo Crea, Full Professor in Cardiology at Policlinico “Agostino Gemelli”, Rome, Italy. The ceremony took place during the 23rd ESH (European Society of Hypertension) Annual Meeting in Milan.

The Arrigo Recordati International Prize for Scientific Research was established in 2000, in memory of the Italian pharmaceutical entrepreneur Arrigo Recordati, who led the homonymous company through a period of intense growth and development for 48 years until his premature death in February 1999. The Prize recognizes the seminal work of an individual who has demonstrated, through dedication to research, the values recognized by Arrigo Recordati, by granting every two years a prize of 100,000 Euros to a distinguished scientist, of any nationality, working in an institutional setting and not affiliated with pharmaceutical or medical device companies, for his/her commitment and accomplishments in the field of cardiovascular disease. Each edition of the Prize is devoted to a specific theme in this field.

For the 2013 edition of the Prize, relevant international societies and organizations were invited to nominate candidates that they felt merited the award for lifetime achievement in researching the pivotal role of microcirculation in systemic and organ diseases. Self-nominations were not considered.

The Jury panel of the 2013 edition of the Prize, who announced the final decision, is composed of experts who have provided leadership throughout their long careers in the field of cardiology and microcirculation. The jury is chaired by Mara Lorenzi, MD, Professor of Ophthalmology, Harvard Medical School, Senior Scientist and George and Frances Levin Scholar in Diabetic Retinopathy, Schepens Eye Research Institute Massachusetts Eye and Ear, Boston, MA, USA. Members of the Jury are Ignatios Ikonomidis, MD, Ph.D., FESC, Assistant Professor in Cardiology, Director of the Laboratory of Preventive Cardiology, 2nd Cardiology Department, National and Kapodistrian University of Athens Attikon University Hospital, Athens, Greece and Can Ince, Ph.D., Professor of Clinical Physiology, Dept. of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Dept. of Intensive Care Adults, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands.

Professor Lorenzi, on behalf of the Jury, officially awarded the winner with the following motivation: “The Recordati Prize recognizes Professor Filippo Crea for his outstanding contributions in researching the pivotal role of microcirculation in systemic and organ diseases”.

The winner of the Arrigo Recordati Prize, after expressing his satisfaction for the important award, gave a brief lecture summarizing his research efforts and results in the study of the pivotal role of microcirculation in systemic and organ diseases.

Throughout his professional career, Professor Filippo Crea has kept a consistent focus on clinical conditions related to dysfunction of the coronary microcirculation, identifying the clinical impact of events occurring in the coronary microcirculation, uncovering mechanisms, and pioneering therapeutic approaches.

Finally, Giovanni Recordati, Arrigo Recordati’s son and current Chairman and CEO of the Recordati pharmaceutical company, renewed the Company‘s strong commitment to research and officially announced that the theme chosen for the eighth edition of the Arrigo Recordati Prize is: “Secondary prevention and risk reduction strategies for patients with cardiovascular diseases”.

Every year, millions of people are admitted to hospitals and intensive care units following acute cardiovascular events. Most of these patients receive “state of the art” medical and interventional care during their hospitalization.

However, observational data suggest that, after discharge from the hospital, patients are neither properly followed nor receive appropriate evidence-based treatments, even though a large body of evidence supporting the value and effectiveness of secondary prevention of acute cardiovascular events is currently available.

Thus, it seems clear that secondary prevention is not fully implemented in many cases of acute cardiovascular events. Secondary prevention should aim to reduce the risk of these events, thus reducing the need for interventional procedures, improving quality of life and in the end, extend survival of the affected patients.

Important new evidence has emerged that further supports and broadens the merits of intensive and comprehensive risk-reduction therapies for patients with cardiovascular diseases, including atherosclerotic vascular disease and peripheral artery diseases. Evidence-based recommendations and guidelines for secondary cardiovascular prevention are available, and are the key reference for clinical intervention. Therapeutic lifestyle changes including identification and treatment of established risk factors (especially hypertension, smoking, dyslipidemia, diabetes, obesity or poor diet, and physical inactivity) are of proven benefit and are regarded as major strategies to improve outcomes and diminish premature morbidity and mortality from cardiovascular diseases (CVD). Adjunctive drug therapies (such as aspirin, statins, anti-hypertensive drugs) have proven benefits.

The great impact of innovative scientific and clinical research accomplished in the field of secondary prevention and risk reduction strategies for patients with cardiovascular diseases must be recognized and acknowledged.

The Arrigo Recordati Prize in its next edition of 2015 will seek to identify a leading contributor in this highly relevant area of medical research.

Filippo Crea was born in Cosenza, Italy on 19 September 1953. He graduated from Pisa Medical School with full honours in 1977 and passed the Postgraduate Boards in both Pulmonary and Cardiovascular Diseases, again with full honours, at Pisa Medical School in 1980 and 1983 respectively. During the whole of 1984 he was Research Fellow at the Division of Cardiology of the University of Florida, directed by Professor Richard C. Conti. From 1985 to 1991 he was Honorary Clinical Assistant and then Senior Lecturer and Honorary Consultant at the Cardiovascular Research Unit of the Hammersmith Hospital in London, directed by Professor Attilio Maseri. He returned to Italy upon his appointment as Chief of the Catheterization Laboratory at the Institute of Cardiology of the Catholic University in Rome. In 2000 he became Associate Professor of Cardiology and Chief of the Intensive and Sub-Intensive Care Units. In 2001 he became Professor of Cardiology, Director of the Institute of Cardiology and Director of the Postgraduate School in Cardiology at the Catholic University in Rome. Since October 2008 he has been Director of the Department of Cardiovascular Sciences.

He is a Fellow of the American College of Cardiology and of the European Society of Cardiology, Past Chairman of the Working Group on “Coronary Pathophysiology and Microcirculation” and Past Member of the Congress Programme Committee of the European Society of Cardiology.

He is Associate Editor of the “European Heart Journal”, member of the Editorial Board of “Circulation”, “Clinical Cardiology” and “Revista Espagñola de Cardiologia”, past Associate Editor of “Heart” and past Deputy Editor of the “Italian Heart Journal”.

In 1992 he received the Newburg Prize for his scientific contribution to cardiovascular research from Professor Rita Levi Montalcini.

His main fields of interest are coronary microvascular dysfunction, mechanisms of acute coronary syndromes and pathophysiology of stem cells in coronary artery disease.

He is the author of more than 650 publications in peer-reviewed journals with an impact factor of more than 3900 and H-Index of 60. He has contributed to several multi-author textbooks. In particular, he is the author of the Chapter on Chronic Ischaemic Heart Disease of the ESC Textbook of Cardiovascular Medicine published in 2009 and author of a book entitled Coronary Microvascular Dysfunction (in press).

2011 Prize Winner

Lindsey D. Allan

Lindsey Allan is currently Professor of Fetal Cardiology at King’s College, London. She started her research in fetal cardiology in 1980 with a grant from the British Heart Foundation. Subsequent grant requests were also successful and led to the establishment of a BHF group under her direction, which continued until 1993. In 1992, she was awarded a personal chair by the Foundation. She then held an appointment as Professor of Pediatrics at Columbia University of New York between 1993 and 2000. She returned to London to her current post at King’s College Hospital, London in 2001.

She has published almost 200 peer-reviewed original articles on the subject of fetal cardiology, as well as many review articles. She is on the Editorial Board of several journals, including Ultrasound in Obstetrics and Gynecology, Prenatal Diagnosis and Cardiology in the Young. She has published 4 textbooks, “Manual of Fetal Echocardiography” in 1986, “Atlas of Fetal Cardiology” in 1992, “Fetal Cardiology” in 2000 and “A Practical guide to Fetal Echocardiography” in 2008, as well as contributing to several multi-author textbooks. She was awarded the Ian Donald Gold Medal for ultrasound in 1998 and is an honorary member of the American Society of Maternal-Fetal Medicine.

After receiving her medical degree from Glasgow University in 1969, she became a member of the Royal College of Physicians and Surgeons of Glasgow in 1972. A research year in Genetics in 1973 stimulated her interest in prenatal diagnosis, which later became focused on the heart when ultrasound technology advanced to a stage where real-time imaging of the heart became possible in 1980. She was a fellow in paediatric cardiology between 1980-82 at Guy’s Hospital in London, where she continued her research until 1993. She completed her MD thesis in 1983. She became a Fellow of the Royal College in 1986. She was an attending physician at Babies Hospital, Columbia Presbyterian Medical Center between 1993 and 2000 and has been a consultant at King’s College, London since 2001.

2009 Prize Winner

Valentin Fuster

Dr. Fuster serves The Mount Sinai Medical Center as Director of Mount Sinai Heart, the Zena and Michael A. Wiener Cardiovascular Institute and the Marie-Josée and Henry R. Kravis Center for Cardiovascular Health. He is the Richard Gorlin, MD/Heart Research Foundation Professor, Mount Sinai School of Medicine. Dr. Fuster is also the President of Science of the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in Madrid, Spain.

Among the seemingly countless positions of distinction that he holds are Past President of the American Heart Association, Immediate Past President of the World Heart Federation, a member of the Institute of Medicine of the National Academy of Sciences where he serves as Chair of the committee on Preventing the Global Epidemic of Cardiovascular Disease, a former member of the National Heart, Lung and Blood Institute Advisory Council, and former Chairman of the Fellowship Training Directors Program of the American College of Cardiology. Twenty-six distinguished universities throughout the world have granted him Doctor Honoris Causa.

Dr. Fuster is the recipient of one major ongoing NIH grant. He has published more than 750 articles on the subjects of coronary artery disease, atherosclerosis and thrombosis, and he has become the lead Editor of two major textbooks on cardiology, ‘The Heart’ (previously edited by Dr. J. Willis Hurst) and “Atherothrombosis and Coronary Artery Disease” (with Dr. Eric Topol and Dr. Elizabeth Nabel). Dr. Fuster has been appointed Editor-in-Chief of the Nature journal that focuses on cardiovascular medicine (Nature Reviews, Cardiology, April 2009) and he is the Editor of the new “AHA Guidelines and Scientific Statements Handbook”, which compiles all the latest information.

Dr. Fuster is the only cardiologist to receive the two highest gold medal awards and all four major research awards from the four major cardiovascular organizations: The Distinguished Researcher Award (Interamerican Society of Cardiology, 2005 and 2009), Andreas Gruntzig Scientific Award and Gold Medal Award (European Society of Cardiology, 1992 and 2007 respectively), Gold Medal Award and Distinguished Scientist (American Heart Association, 2001 and 2003 respectively), and the Distinguished Scientist Award (American College of Cardiology, 1993).

In addition, he has received the Lewis A. Conner Memorial Award by the American Heart Association, the James B. Herrick Achievement Award from the Council of Clinical Cardiology of the American Heart Association, and the 1996 Principe de Asturias Award of Science and Technology (the highest award given to Spanish-speaking scientists). In 2008, Dr. Fuster received the Kurt Polzer Cardiovascular Award from the European Academy of Science and Arts. In March 2009, he received the Distinguished Teacher Award of the American College of Cardiology.

After receiving his medical degree from Barcelona University and completing an internship at Hospital Clinic in Barcelona, Dr. Fuster spent several years at the Mayo Clinic, first as a resident and later as Professor of Medicine and Consultant in Cardiology. In 1981, he came to Mount Sinai School of Medicine as head of Cardiology. From 1991 to 1994, he was Mallinckrodt Professor of Medicine at Harvard Medical School and Chief of Cardiology at the Massachusetts General Hospital. He returned to Mount Sinai in 1994 as Director of the Zena and Michael A. Wiener Cardiovascular Institute and most recently, he has been named the Director of the Mount Sinai Heart.

2007 Prize Winner

Patrick W. Serruys

Dr. Serruys received the M.D. degree (1972) from the Catholic University of Louvain, Louvain, Belgium and his PhD degree (1986) from the Erasmus University, Rotterdam, The Netherlands. Patrick W. Serruys is Professor of Interventional Cardiology at the Interuniversity Cardiological Institute of the Netherlands (1988-1998), and the Erasmus University.

Since 1980 he has been Director of the Clinical Research Program of the Catheterization Laboratory, Thoraxcenter, Erasmus University, Rotterdam, The Netherlands and since 1997 the Head of the Interventional Department, Heartcenter Rotterdam. He is a Fellow of the American College of Cardiology and a Fellow of the European Society of Cardiology and scientific council of the International College of Angiology. He is the author or coauthor of over 1400 papers and editor or coeditor of 32 books, and a member of 14 Editorial Boards of Scientific Journals. He has been associate editor of Circulation for Europe for five years and he recently co-edited the Textbook of Cardiology of the European Society of Cardiology.

In 1996 he received the TCT Career Achievement Award and in 1997 he was awarded the Wenkebach Prize of the Dutch Heart Foundation. In 2000 he was awarded the Gruentzig Award of the European Society of Cardiology. In 2001 he held the Paul Dudley White Lecture at the American Heart Association in the USA. In 2004 he held the 4th International Lecture at the AHA and Mikamo Lecture at the Japanese heart Association. In 2006 he received the highest award of the Clinical Council of the American Heart Association: the James Herrick Award.

Summary of Achievements

Patrick Washington Serruys was born on April 27, 1947 (current age 63 years) in Belgium. He graduated from the University of Leuven (MD 1972) and was trained in Cardiology at the same hospital. In 1976 doctor Serruys moved to the Thoraxcenter Erasmus University Rotterdam, which was led at that time by Paul Hugenholtz. He was appointed senior cardiology staff member in 1977 and became director of the clinical research programme in diagnostic and interventional cardiology in 1980. In 1986 he obtained his PhD-degree (cum laude) after defending his thesis on « transluminal coronary angioplasty : an investigational tool of acute myocardial ischemia ». In 1988 doctor Serruys was appointed as Professor of Interventional Cardiology at Erasmus University in Rotterdam and the Inter Cardiology Institute of the Netherlands (ICIN), an institute of the Royal Netherlands Academy of Science (KNAW). Today, professor Serruys is the director of Interventional Cardiology at the Thoraxcenter, Erasmus University Medical Center.

Professor Serruys is fellow, member and/or honorary member of a number of medical organisations and societies, including the European Society of Cardiology, the American Heart Association, and the American College of Cardiology. He has been associate editor of Circulation (2001- 2004) and is a member of the editorial boards of 14 scientific journals. In 2002 he was invited to edit a textbook of cardiology, which will be published by the European Society of Cardiology in the second half of 2005. He has received six significant international awards: the Career Achievement Award (TCT Washington 1996), the Wenckebach Price from the Dutch Heart Foundation (1997), the Andreas Gruentzig Award (European Society of Cardiology, 2000), the Kurt Polzer Price (Austria, 2001), and the Paul Dudley White Award from the American Heart Association (2001).

The research interests of professor Serruys are coronary artery disease and interventional cardiology, ranging from basic science to clinical trials. He has used clinical investigation and interventions as a method for research of coronary pathology and pathophysiology, employing different imaging and measurement techniques including quantitative coronary angiography, intravascular ultrasound, Doppler flow measurements, and more recently palpography as well as optical coherence tomography. Recently a combination of intracoronary imaging and proteomic research has led to increased insight in the pathophysiology of the vulnerable plaque.

Three major developments in interventional cardiology can largely be attributed to Patrick Serruys. First, in the early years of interventional cardiology (1984) he has described the process of restenosis, using a systematic quantitative approach. He systematically studied by quantitative angiography patients at different intervals after balloon angioplasty, and concluded that the restenosis process appeared between 2 and 4 months after the intervention. Therefore, quantitative angiography after 6 months became the world standard for studies of the restenosis process, and of interventions to reduce restenosis. In different animal models, different drugs seemed to be effective to reduce the restenosis process. However, clinical trials, part of which were led by professor Serruys failed to show a systematic reduction of restenosis by antithrombotic therapy, inflammatory therapy, ACE inhibitors and other medication.

Second, professor Serruys was the initiator of the first study comparing stents with balloon angioplasty (Benestent I) and subsequent studies with improved stent design (Benestent II). These studies demonstrated a significant reduction in restenosis using stents. Together with a parallel study in the USA this resulted in the general application of stents in clinical practice, and approval by the regulator authorities (FDA).

Third, in 2000, a new concept has been introduced: drug-eluting stents. These stents are covered with drugs inhibiting the cell cycle, which are slowly released and prevent proliferation of the intima, which is responsible for restenosis. Professor Serruys was the driving force of the concept of the drug eluting stent, assisted in the preclinicial evaluation, the first in man studies, and initiated clinical trials to test the concept. These trials demonstrated that drug eluting stents almost abolish in stent restenosis.

Over the years, the research led by professor Serruys, has been conducted in collaboration with other academic centers in the Netherlands (Inter University Cardiology Institute of the Netherlands), in Europe and in North and South America. He has established close collaboration with different pharmaceutical and medical device companies. Professor Serruys has coached 38 PhD-students who defended their thesis between 1991 and 2005, 24 of these came from abroad, exemplifying his strong international network of research collaboration.

Since 2002, research conducted at the Thoraxcenter has been brought under the newly established cardiovascular research school at the Erasmus University Rotterdam (CŒUR). In CŒUR research is organised in six teams. Professor Serruys is the leader of theme 4: surgical, interventional and device therapy in cardiovascular diseases. Within this context professor Serruys continues to stimulate and lead preclinical and clinical studies of atherosclerosis, the vulnerable plaque, neoangiogenesis and implantation of stam cells or skeletal muscle cells to improve cardiac function after myocardial function. The multidisciplinary interest of professor Serruys has stimulated several technical innovations and the introduction into clinical practice of different technologies developed by engineers at the Thoraxcenter and other institutions, including quantitative coronary angiography, intravascular ultrasound and elastography. The same multidisciplinary approach is evident from the series of meetings organised in 2003, 2004 and 2005 to coordinate worldwide research on the “vulnerable plaque”.

Professor Serruys has been editor or (co) editor of 32 books and he has published over 1.400 papers (up to end 2005) most in international peer reviewed journals. He has been invited to edit the new prestigious Textbook by the European Society of Cardiology. The scope and quality of these papers is outstanding with 10 original articles in the New England Journal of Medicine, 1 in JAMA, 4 in Lancet, 131 in Circulation, 95 in the European Heart Journal and 73 in the Journal of the American College of Cardiology.

His colleagues have enjoyed working with Professor Serruys at the Thoraxcenter for more than 30 years and to share his enthusiasm and energy. He is indeed a creative, imaginative and visionary scientist, a champion for basic and applied research and an active mentor for fellows in training to become an interventional cardiologist as well as PhD-students. While professor Serruys strives for the best research, and high quality patient care, he also has an enthusiastic and warm personality. Professor Serruys is fluent in French, his native language and he is member honoraire de la Societe Francaise de Cardiologie.

2005 Prize Winner

Leonard A. Cobb, MD, Hemeritus Professor, American College of Cardiology, Seattle WA, USA; Peter J. Schwartz, MD, Professor and Chairman, Department of Cardiology, Policlinico San Matteo IRCCS, Pavia, Italy and Hein J.J. Wellens, MD, Honoré Retired Professor, University of Maastricht; Director of Arrhythmology, Interventional Electrophysiology and Cardiology, University of Maastricht, Maastricht, The Netherlands, were the winners of the 2005 Edition of the Arrigo Recordati International Prize.

2003 Prize Winner

Jay N. Cohn , MD, Professor of Medicine, Cardiovascular Division, Departement of Medicine, University of Minnesota Medical School, Minneapolis and John K. Kjekshus, MD, PhD, Professor of Medicine, Department of Cardiology, Rikshospitalet, University of Oslo, Oslo have been selected by the judging panel as the winners of the 2003 edition of the Prize.

2001 Prize Winner

Giuseppe Mancia, PhD

Giuseppe Mancia is Professor of medicine and chairman of the department of clinical medicine, prevention and applied biotechnologies of the University of Milan – Bicocca. He is also chairman of the department of medicine at the S. Gerardo Hospital, Monza, Milan, Italy.

Giuseppe Mancia has been honored for his scientific contributions many times and was the recipient of the Heymans lecture and award from the International Society of Pharmacology, the International Merck Sharp & Dohme Award from the International Society of Hypertension, and the Folkow award from the European Society of Hypertension.

Professor Mancia is president of the European Society of Hypertension and member of the Executive Scientific Council of the American Society of Hypertension. He is also past-president and secretary of the International Society of Hypertension (ISH) and chairman of the World Health Organization-ISH liaison committee for the guidelines on hypertension.

Giuseppe Mancia’s special research interest concerns pathophysiology, diagnosis and therapy of hypertension, heart failure, coronary and other cardiovascular diseases. His expertise includes ambulatory blood pressure monitoring, neural control of the circulation, large artery mechanics and clinical trials.

In addition to publishing hundreds of scientific papers in peer-reviewed journals and a book on hypertension, Professor Mancia is deputy editor of the Journal of Hypertension, past-editor of various international journals on hypertension, and he serves on the editorial board of more than 30 international journals on cardiology, hypertension and internal medicine.

Professor Mancia graduated from the University of Siena, Medical School where he earned his Ph.D. in Physiology. After graduation he spent 3 years in the United States as a postdoctoral fellow at Mayo Clinic and Foundation, and as a resident in cardiology at Virginia Commonwealth University before being appointed professor of medicine at the University of Milan.

 SOURCE

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Predicting Drug Toxicity for Acute Cardiac Events

Reporter: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/?p=10679/Predicting Drug Toxicity for Acute Cardiac Events

Pharmaceuticals Dilemma

The pharmaceutical industry has, as the clinical diagnostics industry, consolidated, and seen new entries that are at some time merged into an established giant, needing resources to grow.  In the past, it was considered essential for a scientific commercial entity to invest at least 8 percent of budget to R&D.   However, the cost of manufacturing has gone down, but a large part of the budget outside of manufacture has to be taken up with, maybe a few exceptions, development, validation in clinical trials, and marketing.  This leaves the situation precarious without a basic research base, and has lead to consortia between academic centers, the federal governmant, and the industries.  I can’t venture into the role of Wall Street Investment and Venture Capital in the process of innovation, proprietary rights to discoveries, and viability.  A large problem they encounter really comes down to complexity of the biomedical reality, that keeps peeling off layers like an onion, exposing new problems to deal with.  As a result, we have seen repeated recalls of drugs that were blockbusters, over the last 2 decades.  To date, every “miracle” drug to manage sepsis and the several cardiac related drugs have  resulted in unexpected toxicities.
One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program

  • would produce significant benefits for pharmaceutical companies and, ultimately, public health, but
    • the reduction of therapeutic toxicities will not be easy and depends on the
    • emergence of genomic-based personalized medicine.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example,

  • the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation)
  • can be used to screen a series of related new chemical entities (NCE)

in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm.
Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess

  • effects of NCEs on a range of acute hemodynamic and cardiac parameters such as
    • heart rate,
    • blood pressure,
    • electrocardiogram (ECG),
    • ventricular contractility,
    • vascular resistance,
    • cardiac output, etc.

These studies employ small numbers of animals, but may allow termination of research into NCEs with obvious cardiovascular side effects. These preparations also provide information on the involvement of the

  • autonomic nervous system in the cardiovascular responses of the NCE.

Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.
But what if there are dangers that are not predictable in the short term because of the time span under which the effects can be viewed? The effects themselves are a result of interactions between

  • the drug,
  • endothelial cell receptors,
  • and/or imbalance in oxidative stress promoters and suppressors,
  • and involve signaling pathways.

That is a difficult challenge that may only be realized

  • by rapidly advancing knowledge at the molecular cell level.

The ICH S7A and ICH S7B guidelines provide

  • guidance on important physiological systems and
  • assessment of pharmaceuticals on
    • ventricular repolarization and
    • proarrhythmic risk.

The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively,

  • cardiac safety study designs have been realigned
  • to identify potential concerns prior to administering the first dose to humans.

It is now routine for all NCEs to be evaluated using an

  • in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for
    • the potential for QT interval prolongation.

Systems have evolved to screen large numbers of compounds

  • using automated high-throughput patch clamp systems early in the lead
  • optimization/drug discovery phase.

This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to

  • the development phase, it can once again be assessed with the hERG assay
  • utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then

  • pharmacological characterization should occur
  • early in the lead development process.

In addition to the techniques just discussed,

  • a variety of “disease models” are available to help determine
    • whether the NCE will be efficacious in a clinical setting.

However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies),

  • NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model)
  • have a higher likelihood of clinical success.

Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.
The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of

  1. heart rate,
  2. blood pressure, and
  3. ECG data
    • using an appropriate species
    • at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to

  • utilize animals surgically instrumented with telemetry devices that
  • can acquire the required parameters.

The advantage of using instrumented animals over anesthetized animals is that

  • data can be acquired from freely moving animals over greater periods of time
  • without anesthetic in the test system,
    • which has the potential to confound and perturb results interpretation.

Appropriate dose selection relative to those used in the clinic provides valuable information about

  • potential acute cardiac events and
  • how they may impact trial participants.

The obvious limitation here is that the method of observation is essentially

  • the same or less than that which is used in clinical practice,
  • relying mainly on classical physiology to detect
    • inherently deep seated processes.

But it is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events,

the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on

  • clinical history,
  • physical examination,
  • effective use of the laboratory, and
  • increasingly helpful imaging technology.

and age, sex, diet, and ability to carry out the activities of daily living before treatment and 6 months to a year after discharge are relevant.

The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. There will be more to say about this.
Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period,
provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals

  • coupled with
  • recent advances in software-analysis systems allow for rapid data turnaround,
    • enables scientists to quickly determine if there are any potentially unwanted signals.

If any effects are detected on, for example, blood pressure or QT interval, then the decision to

  • either shelve the drug or
  • conduct additional studies

can be made before advancing any further in the developmental phase.   While this is very good for observing large effects, is it really sufficient for avoidance of late phase failure?

Interestingly, the experience that has been acquired since the approval of the ICH guidelines

  • has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal.
  • Rather than permanently shelve libraries of compounds that, for example, were
  • found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—
    • companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like

left ventricular pressure.
These experiments can be utilized to further assess their potential clinical impact
by examining effects on
myocardial contractility,
relaxation, and
conduction velocity.
These techniques primarily address acute effects: those following a single exposure.
Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies,
are conducted non-clinically during Phase 1 and 2 of the development process.

  • ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. It is recommended that
    • JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—
    • but not blood pressure—

be applied in freely moving animals. If chronic effects are discovered,

  • follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach

  • to determine best practices for conducting key preclinical cardiovascular assessments in drug development.
  •  to provide sensitive preclinical assays that can detect high-probability safety concerns.

Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into

  • clinical outcomes and
  • to encourage collaborations
    • between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together

  • industrial,
  • academic, and
  • government scientists
    • to discuss and determine what steps are necessary
    • to establish an integrated cardiovascular safety assessment program.

The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.
http://www.dddmag.com/articles/2012/08/predicting-potential-cardiac-events?et_cid=2816494&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fpredicting-potential-cardiac-events.

A recent poster presentation I think makes a good statement of advances that should move us forward:

http://www.biotechniques.com/multimedia/archive/00178/BTN_0311-March_Post_178205a.pdf

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is

  • a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes.
  •  it creates an algorrhytm-based score that determines the likelihood that a patient has obstructive coronary artery disease.

https://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/
“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.
This discussion will be followed with a discussion of the evaluation of the patient acutely presenting with symptoms and signs that are suggestive of either acute pulmonary or cardiac disease, or both, that may be suggestive of a non ST elevation AMI. It becomes more difficult if ST depression or T-wave inversion is not detected.
Related articles
Obstructive Coronary Artery Disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic Diagnostics
https://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/

English: QT interval corrected by heart rate.

English: QT interval corrected by heart rate. (Photo credit: Wikipedia)

Schematic diagram of normal sinus rhythm for a...

Schematic diagram of normal sinus rhythm for a human heart as seen on ECG (with English labels). (Photo credit: Wikipedia)

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Reported & Curated by: Dr. Venkat S. Karra, Ph.D.

Predicting Potential Cardiac Events

One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program would produce significant benefits for pharmaceutical companies and, ultimately, public health.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example, the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation) can be used to screen a series of related new chemical entities (NCE) in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm. Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess effects of NCEs on a range of acute hemodynamic and cardiac parameters such as heart rate, blood pressure, electrocardiogram (ECG), ventricular contractility, vascular resistance, cardiac output, etc. These studies employ small numbers of animals, but by allowing scientists to terminate research into NCEs with obvious cardiovascular side effects, they can eliminate the need for larger animal studies later in the development process. These preparations also provide information on the involvement of the autonomic nervous system in the cardiovascular responses of the NCE. Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.

The ICH S7A and ICH S7B guidelines provide guidance on important physiological systems and assessment of pharmaceuticals on ventricular repolarization and proarrhythmic risk. The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively, cardiac safety study designs have been realigned to identify potential concerns prior to administering the first dose to humans. It is now routine for all NCEs to be evaluated using an in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for the potential for QT interval prolongation. Systems have evolved to screen large numbers of compounds using automated high-throughput patch clamp systems early in the lead optimization/drug discovery phase. This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to the development phase, it can once again be assessed with the hERG assay utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then pharmacological characterization should also occur early in the lead development process. In addition to some of the techniques already discussed, a variety of disease models are available to help determine if the NCE will be efficacious in a clinical setting. However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies), NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model) have a higher likelihood of clinical success. Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.

The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of heart rate, blood pressure, and ECG data using an appropriate species at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to utilize animals surgically instrumented with telemetry devices that can acquire the required parameters. The advantage of using instrumented animals over anesthetized animals is that data can be acquired from freely moving animals over greater periods of time without anesthetic in the test system, which has the potential to confound and perturb results interpretation. Appropriate dose selection relative to those used in the clinic provides valuable information about potential acute cardiac events and how they may impact trial participants.

Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period, provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals coupled with recent advances in software-analysis systems allow for rapid data turnaround, which enables scientists to quickly determine if there are any potentially unwanted signals. If any effects are detected on, for example, blood pressure or QT interval, then the decision to either shelve the drug or conduct additional studies can be made before advancing any further in the developmental phase.

Interestingly, the experience that has been acquired since the approval of the ICH guidelines has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal. Rather than permanently shelve libraries of compounds that, for example, were found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like left ventricular pressure. These experiments can be utilized to further assess their potential clinical impact by examining effects on myocardial contractility, relaxation, and conduction velocity.

These techniques primarily address acute effects: those following a single exposure. Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies, which are conducted non-clinically during Phase 1 and 2 of the development process. ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. While traditional ECGs can be taken, it is recommended that JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—but not blood pressure—in freely moving animals, be applied. If chronic effects are discovered, follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach to determine best practices for conducting key preclinical cardiovascular assessments in drug development. From this, the hope is to provide sensitive preclinical assays that can detect high-probability safety concerns. Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into clinical outcomes and to encourage collaborations between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together industrial, academic, and government scientists to discuss and determine what steps are necessary to establish an integrated cardiovascular safety assessment program. The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.

http://www.dddmag.com/articles/2012/08/predicting-potential-cardiac-events?et_cid=2816494&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fpredicting-potential-cardiac-events.

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes. Using an algorithm, it then creates a score that determines the likelihood that a patient has obstructive coronary artery disease.

“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.

https://pharmaceuticalintelligence.wordpress.com/wp-admin/post.php?post=2272&action=edit

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