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.

A critical reappraisal of aspirin for secondary prevention in patients with ischemic heart disease.

Aspirin was established more than a quarter century ago as an evidence-based therapy to reduce recurrent cardiovascular events in patients with coronary artery disease based on limited data by contemporary standards. Indeed it is unclear how regulatory agencies would define the optimal dose or duration of aspirin therapy if assessed in the current era. Subsequent clinical investigation has focused on the addition of antithrombotic agents on top of baseline aspirin therapy in the acute and chronic setting to reduce patient's risk of further ischemic events, at the cost of increased bleeding complications. The current armamentarium of potent and predictable antiplatelet and antithrombotic agents has ushered in a new era where clinicians and scientists are contemplating withdrawal of previously established agents to minimize bleeding risk while sustaining efficacy; indeed, subtraction may lead to the next advance in the treatment of acute and chronic ischemic vascular disease.

The History of Antithrombotic Therapy: The Discovery of Heparin, the Vitamin K Antagonists, and the Utility of Aspirin.

The administration of intravenous heparin to postoperative patients by Barritt and Jordan reduced the incidence of fatal and nonfatal pulmonary embolism and established heparin as the standard for parenteral anticoagulation. The coumarin family of vitamin K antagonists quickly became the standard for long-term oral anticoagulation. Aspirin became a widely used antithrombotic agent after the discovery that chronic oral administration reduced the incidence of secondary strokes and myocardial infarction. This article gives a brief history of antithrombotic therapy, including the discovery of heparin, the vitamin k antagonists, and the utility of aspirin.

How an aspirin, a throat swab from a chicken, and four Guinea pigs changed thoracic surgery.

The development of antituberculous drugs changed thoracic surgery and also markedly lowered the morbidity and mortality of a disease that had epidemic proportions. This article summarizes aspects from 3 important articles that led to the discovery of these drugs.

Aspirin: a history, a love story.

Most pharmacists know that aspirin's origins lie with willow bark, but they may be unaware of its role in the development of the pharmaceutical industry. Evolving from salacin (the active ingredient in many plant remedies) to salicylic acid (an analgesic in its own right) to the more effective, less toxic acetylsalicylic acid, this pain reliever cornered the nonsteroidal anti-inflammatory market for more than 70 years. It helped the dye industry branch into pharmaceuticals, and is now used in multiple indications.

Current evidence and clinical implications of aspirin resistance.

Atherothrombosis, characterized by atherosclerotic plaque rupture and subsequent occlusive or subocclusive thrombus formation is the primary cause of acute ischemic syndromes involving all vascular beds and accounts for more than one-third of all deaths in the developed world. Platelet activation and aggregation constitute the most critical component in the pathophysiology of atherothrombotic disease. Aspirin is currently the most commonly used antiplatelet agent and one of the most frequently prescribed drugs, with as many as 30 million Americans on chronic aspirin regimens. Multiple well-designed prospective randomized clinical trials have demonstrated aspirin's efficacy in both primary and secondary prevention of a wide variety of entities that the atherothrombotic disease spectrum encompasses, such as cerebrovascular, coronary artery, and peripheral vascular disease. Despite its proven benefit, however, a growing body of evidence suggests that up to 70% of aspirin-takers may still be at risk for atherothrombotic complications due to resistance. Patients with laboratory-confirmed aspirin resistance seem to have an almost fourfold increase in their risk for acute thrombotic episodes, which underlines the magnitude of the problem for the vascular specialist. In this article, we review the physiology of platelet activation and the role of aspirin as an antiplatelet agent; the various laboratory assays used in assessing aspirin effectiveness; and current data on aspirin resistance and its clinical implications in patients with cardiovascular disease. We also review the studies that explore this phenomenon in patients with peripheral arterial disease and discuss the optimal management options in aspirin-resistant individuals. Suggestions are advanced for the direction of future trials evaluating aspirin resistance in patients with vascular disease.

Evolución de los conocimientos sobre el Ácido Acetil Salicílico / Evolution of the knowledge about the acetil salicilic acid

El saber popular, empírico, desde tiempos inmemoriales incorporó a la "terapéutica" mèdica diversos productos vegetales de los que hoy son conocidos como salicáceas, muy ùtiles remedios para las fiebres y dolores, que el tiempo fue consagrando. Hoy es sorprendente, luego de siglos, de experiencias de triunfos, de fracasos y luego nuevos triunfos, la vigencia y ventajas de las propiedades terapéuticas de las salicilinas, o mejor dicho, de sus derivados sintéticos: primero el Ácido Salicílico y posteriormente el Ácido Acetil Salicílico y sorprende aún más la variedad de patologìas médicas en las cuales estos fármacos pueden ser utilizados con éxito, no obstante conocidos efectos nocivos. El trabajo que se presenta intenta con brevedad ofrecer una visiòn de la evoluciòn de los conocimientos, principalmente históricos y terapéuticos, del Ácido Acetil Salicílico.

Popular, empiric knowledge, from immemorial times added to medical therapeutic different vegetable products known nowadays as salicaceas, very useful medications against fevers and pains that time has sanctioned. Nowadays, after centuries, after triumphal experiences, after failures, and successes again, it still surprises the effectiveness and advantages of the salicylins´ therapeutic properties, or better, of their synthetic derivates: firstly, the salicylic acid and the acetyl salicylic acid; it is still more surprising the variety of medical pathologies against which these drugs can be successfully used, even though some noxious effects are known. This work is aimed to briefly offer a vision of the evolution of the knowledge, mainly therapeutic and historical, of the acetyl salicylic acid.

My health: whose responsibility? Low-dose aspirin and older people.

The benefit of aspirin as a prophylactic after a thrombotic event was first observed 30 years ago. Its use after coronary or cerebral thrombosis, and in patients judged to be at increased risk of a thrombotic event, is now virtually mandatory, unless there are signs of intolerance. The present policy in the UK for cardiovascular protection by low-dose aspirin is dependent upon the identification of people at high vascular risk. The policy has had only very limited success, partly owing to the fact that only a relatively small proportion of people with levels of vascular risk factors that would justify aspirin prophylaxis are identified. In fact, it has been demonstrated that the application of accepted guidelines for aspirin prophylaxis to risk factor data in representative UK population samples gives a cost-effective evidence-base for a reasonable extension of prophylaxis to all people aged over approximately 50 years. It is possible that reductions in both dementia and cancer incidence could also follow the wider use of low-dose aspirin but further research on these outcomes is urgently required. The evidence on possible benefits and harm from low-dose aspirin should therefore be publicized widely, and everything possible should be done to stimulate discussion involving the general public. In the end, however, the preservation of health is one's own responsibility and, therefore, people should generally be encouraged to evaluate the evidence on health-promotion measures, including low-dose aspirin, and take responsibility for their own health.

Anagrelide: what was new in 2004 and 2005?

Anagrelide is an established platelet-reducing drug. Although there are gaps in the understanding of its mechanism of action, two randomized comparisons with other drugs used for therapy of patients with essential thrombocythemia (ET) have been performed. Recent progress has been made in this field with the development of better determination techniques, with the characterization of metabolites, and with studies of their mechanism of action on megakaryocytes and platelets. More data are now available from various noncomparative clinical trials on its clinical efficacy and safety. Only few investigations are available that document its long-term effects. Although the drug should not be used during pregnancy, there are a few studies that report that pregnant women have taken this drug without harm to the newborn. Studies have also investigated the effects of anagrelide on platelets, indicating that platelet function is as important as platelet counts in ET. Preliminary analyses of the mechanism of action of anagrelide have revealed that the drug interferes with the signal transduction of the thrombopoietin receptor. Results of the first phase III trial (PT1) that compared anagrelide/aspirin with hydroxyurea/aspirin have sparked an intense discussion, given that the combination of anagrelide and aspirin causes more bleeding complications in the gastrointestinal tract. It has been speculated that the higher number of transient ischemic attacks in this study arm is not caused by thrombotic events but by small bleedings that would be responsible for transient hemorrhagic attacks. More insights are expected from the recently completed ANAHYDRET trial that compared monotherapy with hydroxyurea and anagrelide.

The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential.

For several millennia, the willow tree and salicin have been associated with salicylic acid, the key precursor molecule that has contributed to the discovery of acetylsalicylic acid, traded as aspirin. These molecules have been shown to possess phyto- and chemotherapeutic activities as analgesic drugs. In recent decades, aspirin has become the focus of extensive investigation into antiproliferative and anticancer activities. The historical steps that led to the discovery of aspirin, and its antiproliferative and anticancer potential are highlighted in this review.

Aspirin: past, present and future.

Many folk remedies used since pre-historic times have depended upon salicylates for their effect. One hundred years ago aspirin was formulated from salicylic and acetic acids. It was the first drug to be synthesised and its formulation is regarded as the foundation of the modern pharmaceutical industry. The benefit of low-dose aspirin as a prophylactic after a thrombotic event was first reported 25 years ago. Its use after coronary or cerebral thrombosis is virtually mandatory, unless there are signs of intolerance. A 'loading dose' of soluble aspirin should be given on first contact with a patient who may be suffering from myocardial infarction. Patients considered to be at increased risk of a vascular event should also be advised to carry their own aspirin and, if they experience sudden severe chest pain, to chew and swallow a 300 mg tablet or a soluble preparation immediately. The current phase of the aspirin story is, however, not over, and its possible value in a variety of conditions, including dementia and certain cancers, seems likely to ensure that it will long continue to play a remarkable part in clinical practice.

El tratamiento con bajas dosis de aspirina mejora la respuesta ovárica, la tasa de implantación y de embarazo en pacientes que realizan procedimientos de FIV / Treatment with low-doses of aspirin improves ovaric response, implantation and pregnancy rate in patients of in-vitro fertilization

Objetivo: Determinar los efectos del tratamiento con bajas dosis de aspirina en la respuesta ovárica, las tasas de implementación y de embarazo en pacientes que realizan procedimientos de FIV. Diseño: Estudio prospectivo, randomizado, a doble ciego. Pacientes: Setenta y cuatro pacientes infértiles con una edad promedio de 35,6 años que realizaron 74 ciclos de FIV. Intervenciones: Grupo estudio: 39 pacientes que recibieron una hiperestimulación ovárica controlada (HOC) en asociación con 100 mg/día de aspirina. Grupo control: 35 pacientes que recibieron HOC en asociación con placebo. Determinaciones: Se evaluaron el número de folículos, número de ovocitos recuperados, niveles de estradiol plasmático, número de embriones transferidos, tasa de cancelación, tasa de implantación y tasa de embarazo. Resultados: Se hallaron diferencias estadísticamente significativas en el número de folículos, número de ovocitos recuperados, niveles plasmáticos de estradiol, tasa de implantación y tasa de embarazo en el grupo tratado con aspirina. Conclusiones: El tratamiento con bajas dosis de aspirina mejora la respuesta ovárica, la tasa de implantación y la tasa de embarazo en pacientes que realizan procedimientos de FIV

Polycythemia vera: a retrospective and reprise.

This article, by two of the late John H. Lawrence's fellows of the 1940s, traces the development of the knowledge of polycythemia vera from Vaquez, who wrote the first description of this disease, and Osler, who recognized it as "a new clinical entity," through John H. Lawrence and the use of 32P as a treatment for polycythemia vera, to the formation of French and Italian polycythemia study groups. In particular, the history of polycythemia vera after the Second World War, and its more recent history, can be traced through the development of an algorithm for evaluating an elevated hematocrit and the development of the first (O1) protocol of the Polycythemia Vera Study Group (PVSG), a randomized trial of the efficacy of 32P, chlorambucil, and phlebotomy for treating polycythemia vera. It was in 1948, only 9 years after the first use of 32P for treating polycythemia vera, that Byron Hall reported the occurrence of acute leukemia following this use of the isotope. This led to the formation of the PVSG. After completing enrollment of patients in the first protocol of the PVSG, an attempt to find a replacement for 32P as a myelosuppressive agent led to the testing of hydroxyurea as a putative non-leukemogenic drug for this purpose. However, the use of hydroxyurea for treating polycythemia vera is coming into question, as is the ability to maintain patients with phlebotomy alone. The PVSG as such no longer exists as an operational group; its files are maintained at the Mount Sinai School of Medicine in New York City. However, the French group created for the study of polycythemia vera has had a consensus conference, and the Italian group has developed a low-dose aspirin protocol for treating the disease.