Endpoints in Heart Failure Drug Development: History and Future.

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.

Bloqueadores beta: perspectiva histórica y mecanismos de acción / Beta-blockers: historical perspective and mechanisms of action

Los bloqueadores beta son moléculas ampliamente utilizadas y capaces de antagonizar los receptores adrenérgicos (RA) beta, pertenecen a la familia de receptores acoplados a proteínas G y reciben el estímulo de las catecolaminas endógenas. Tras su estimulación, se activan cascadas intracelulares que en última instancia originan la contracción cardiaca o la dilatación vascular, según el subtipo y su ubicación. Se han descrito 3 subtipos, que se expresan de manera diferenciada en el organismo (RA-ß1, ß2 y ß3), y el subtipo ß1 es el más abundante en el corazón. Desde su descubrimiento, los RA-ß se han convertido en diana para combatir las enfermedades cardiovasculares. Desde su invención por James Black a finales de los años cincuenta, los bloqueadores beta han supuesto una revolución en la terapia cardiovascular. Hasta ahora se dispone de 3 generaciones: los bloqueadores beta no selectivos, los bloqueadores beta cardioselectivos (antagonista selectivo de ß1) y los bloqueadores beta vasodilatadores. Estos constituyen la tercera generación y son capaces de bloquear los ß1 además de tener actividad vasodilatadora, bien bloqueando los RA-alfa1 o activando los RA-ß3. Los bloqueadores beta todavía se utilizan ampliamente en la clínica tras más de 50 años desde la introducción del propranolol en el mercado por su capacidad para reducir la frecuencia cardiaca y, por lo tanto, la demanda miocárdica de oxígeno en el caso de una angina

Beta-blockers are widely used molecules that are able to antagonize ß-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon ß-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (ß1-, ß2- and ß3-ARs), ß1 being the most abundant subtype in the heart. Since their discovery, ß-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, ß-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective ß-blockers, cardioselective ß-blockers (selective ß1-antagonists), and a third generation of these drugs able to block ß1 together with extra vasodilation activity (also called vasodilating ß-blockers) either by blocking alfa1- or by activating ß3-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, ß-blockers are still widely used in clinics

The first 3500 years of aspirin history from its roots - A concise summary.

Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70 years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins.

The Beat Goes On: The Story of Five Ageless Cardiac Drugs.

This article traces the history of 5 cardiac drugs-Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine-that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy. Their present clinical status has evolved from long-term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.

Diagnosis and treatment of uncomplicated type B aortic dissection.

A type B dissection involves the aorta distal to the subclavian artery, and accounts for 25-40% of aortic dissections. Approximately 75% of these are uncomplicated with no malperfusion or ischemia. Multiple consensus statements recommend thoracic endovascular aortic repair (TEVAR) as the treatment of choice for acute complicated type B aortic dissections, while uncomplicated type B dissections are traditionally treated with medical management alone, including strict blood pressure control, as open repairs have a prohibitively high morbidity of up to 31%. However, with medical treatment alone, the morbidity, including aneurysm degeneration of the affected segment, is 30%, and mortality is 10% over 5 years. For both chronic and acute uncomplicated type B aortic dissections, emerging evidence supports the use of both best medical therapy and TEVAR. This paper reviews the current diagnosis and treatment of uncomplicated type B aortic dissections.

The ten advances that have defined modern cardiology.

Modern cardiology was born early in the twentieth century. Here I list and review what I believe to be the ten most important advances in the twentieth century in this field. They are as follows: electrocardiography, cholesterol-induced atherosclerosis, cardiac catheterization, cardiovascular surgery, coronary angiography and percutaneous coronary angioplasty, the coronary care unit, the development of new cardiovascular drugs, preventive cardiology, cardiac imaging, and implanted cardiac pacemakers/defibrillators.

Nitroglycerine and sodium trioxodinitrate: from the discovery to the preconditioning effect.

The history began in the 19th century with Ascanio Sobrero (1812-1888), the discoverer of glycerol trinitrate (nitroglycerine, NTG), and with Angelo Angeli (1864-1931), the discoverer of sodium trioxodinitrate (Angeli's salt). It is likely that Angeli and Sobrero never met, but their two histories will join each other more than a century later. In fact, it has been discovered that both NTG and Angeli's salt are able to induce a preconditioning effect. As NTG has a long history as an antianginal drug its newly discovered property as a preconditioning agent has also been tested in humans. Angeli's salt properties as a preconditioning and inotropic agent have only been tested in animals so far.

The cardiovascular polypill in high-risk patients.

Atherosclerotic cardiovascular diseases remain the leading cause of morbidity and mortality in both developed and developing countries. Adequate treatment of vascular risk factors, such as low-density lipoprotein cholesterol and systolic blood pressure are known to reduce the future risk of cardiovascular disease in these patients. However currently, large treatment gaps exist among high-risk individuals, in whom the guidelines recommend concomitant treatment with aspirin, statin, and blood-pressure lowering agents. Combining aspirin, cholesterol, and blood-pressure lowering agents into a single pill called the cardiovascular polypill has been proposed as complementary care in the prevention of cardiovascular diseases in both intermediate- and high-risk patient populations. It is now a decade since the first recommendations to develop and trial cardiovascular polypills. The major scientific debate has been about the appropriate initial target population. This review article focuses on the potential role of fixed-dose combination therapy in different patient populations, outlines the pros and cons of combination therapy, and emphasizes the rationale for trialing their use. Current and planned future cardiovascular polypill trials are summarized and the pre-requisites for implementation of the polypill strategy in both primary and secondary prevention are described. The recent development of combination pills containing off-patent medications holds promise for highly affordable and effective treatment and evidence is emerging on the use of this strategy in high-risk populations.

Uncomplicated type B dissection: are there any indications for early intervention?

Currently thoracic endovascular repair (TEVAR) has a limited role in uncomplicated type B aortic dissection. Aggressive medical therapy is deemed appropriate for most of these patients allowing one-year survival rate of 80-90%. Outcomes are less than optimal in the long term, however, since aorta related complications (disease progression, rapid deterioration, acute rupture and elevated mortality) may occur in up to 50% of patients at five years. Subgroups of patients with uncomplicated type B dissection may benefit from early stent-graft placement, but identification of these remains difficult. Only future studies, especially randomized trials, will clarify the utility of early TEVAR in the setting of uncomplicated acute type B dissection.

[On the history of heart failure]. / Zur Geschichte der Herzinsuffizienz.

The heart is by far the organ that is best known and has been identified for a long time. Myogenic weakness of the heart muscle pump with left-ventricular dysfunction remains the cardiac disease with the poorest prognosis while increasing in prevalence and incidence. Aside from all sorts of mystic treatment attempts and dubious herbal medicine, bloodletting was established early on as a superior remedy, which was applied in response to almost all cardiac illnesses. The first and perhaps most important cardiac drug was digitalis, the glycoside of the red and even more so of the white foxglove, described in 1552 by Leonhart Fuchs. In the 1980s, vasodilators and inotropic drugs supplemented the classical medications digitalis and diuretics. ACE inhibitors and beta-receptor blockers were added in the 1990s; at the turn of the millennium, the cardiac resynchronization therapy (CRT) and left-heart assist systems were developed; lately, there have been cellular and genetic approaches as well as xenotransplants. Preliminary results with stem cell technology are encouraging; however, it will be years until a clinical application-if it will happen at all.

Where are we with probucol: a new life for an old drug?

Probucol has a long history of clinical application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that has been in clinical use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacology, clinical benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacological properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacologic actions at the molecular level has recently been elucidated with the new concept of HDL metabolism associated with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C reduction may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-density lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk reduction has been recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.

Cardiogenic shock: a historical perspective.

Significant progress has been made over the past 60 years in defining and recognizing cardiogenic shock (CS), and there have been tremendous advances in the care of patients who have this illness. Although there are many causes of this condition, acute myocardial infarction with loss of a large amount of functioning myocardium is the most frequent cause. It was recognized early in the study of CS that prompt diagnosis and rapid initiation of therapy could improve the prognosis, and this remains true today. Although the mortality from CS remains high, especially in elderly populations, modern therapies improve the chance of survival from this critical illness.

Exploiting race in drug development: BiDil's interim model of pharmacogenomics.

This paper explores events surrounding the US Food and Drug Administration's formal approval of the heart failure drug BiDil in 2005. BiDil is the first drug ever to be approved with a race-specific indication, in this case to treat heart failure in 'self-identified black patients'. BiDil has been cast by many as a step toward the promised land of individualized pharmacogenomic therapies. This paper argues, however, that when examined in context, the approval of BiDil emerges as a new model of how a pharmaceutical company may exploit race in the marketplace by literally capitalizing on the racial identity of minority populations and leveraging the disproportionate risk of adverse health outcomes they suffer into a cheaper, more efficient way to gain the US Food and Drug Administration's approval for drugs. Discussions of BiDil in both popular media and professional journals have repeatedly elided the difference between pharmacogenomic and race-based medicine. In fact, broad-based true pharmacogenomic therapies remain years-perhaps decades-in the future. The story of BiDil's development elucidates an alternative model to developing tailored therapies that promises to fill in the gap between the promise and reality of pharmacogenomic medicine. It is a model that exploits race to gain regulatory and commercial advantage, while ignoring its power to promote a regeneticization of racial categories in society at large.