1,721,140 research outputs found
Role of Clinical Pharmacology in the Development of Antiplatelet Drugs
No full textThis review discusses the role of clinical pharmacology in the development of low-dose aspirin and other antiplatelet agents during the past 30 years, emphasizing the main determinants of several success stories as well as of complete failures in the field
Aspirin Continues to Attract Research and Debate, 115 Years After Its Synthesis
No full textAcetylsalicylic acid, synthesized in an industrial environment in
1897, was introduced to the market as AspirinW in 1899. For about
70 years it represented the mainstay of analgesic/antiinflammatory
drug therapy and its pharmacologic actions provided the
template for the synthesis of novel nonsteroidal antiinflammatory
drugs. Following several fundamental discoveries on its mechanism
of action as an antiplatelet drug in the seventies, aspirin has
lived a second life as an antithrombotic agent, becoming a
fundamental component of cardiovascular prevention and treatment.
1 Making the jump from a largely over-the-counter analgesic
remedy to a life-saving prescription drug represents a success story
of independent translational research. Key components of success
were: a) mechanistic insight into the way in which aspirin inhibits
platelet function; b) careful studies of the clinical pharmacology of
its antiplatelet effect, establishing the unusual requirements of low
dose and long dosing interval for optimal platelet inhibition; and
c) a large number of adequately sized, placebo-controlled clinical
trials to demonstrate its efficacy and safety in a variety of
clinical settings characterized by high cardiovascular risk.
Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither?
No full textLow-dose aspirin has been shown to be effective in preventing about one-fifth of atherothrombotic vascular complications (non-fatal myocardial infarction, non-fatal stroke, or vascular death) in a meta-analysis of 16 secondary prevention trials in patients with previous myocardial infarction, stroke, or transient cerebral ischaemia. This corresponds to an absolute reduction of about 10-20 per 1000 patients in the yearly incidence of non-fatal events, and to a smaller, but still definite, reduction in vascular death. Against this benefit, the absolute increase in major extracranial bleeding complications [mostly, gastrointestinal (GI)] is 20- to 50-fold smaller, depending on age and sex. Hence, for secondary prevention, the benefits of antiplatelet therapy substantially exceed the risks. For primary prevention, the balance between vascular events avoided and major bleeds caused by aspirin is substantially uncertain because the risks without aspirin, and hence the absolute benefits of antiplatelet prophylaxis, are at least an order of magnitude lower than in secondary prevention. The aim of this article is to review the updated evidence for the efficacy and safety of low-dose aspirin in primary prevention and to discuss additional health benefits resulting from prolonged antiplatelet therapy in apparently healthy people at low average risk of vascular events
The Multifaceted Clinical Readouts of Platelet Inhibition by Low-Dose Aspirin
No full textInactivation of platelet cyclooxygenase (COX)-1 by low-dose aspirin leads to long-lasting suppression of thromboxane (TX) A2 production and TXA2-mediated platelet activation and aggregation. This effect is necessary and sufficient to explain aspirin's unique (among other COX-1 inhibitors) effectiveness in preventing atherothrombosis, as well as its shared (with other antiplatelet agents) bleeding liability. However, different mechanisms of action have been suggested to explain other beneficial effects of aspirin, such as prevention of venous thromboembolism, chemoprevention of colorectal (and other) cancers, and reduced risk of dementia. These mechanisms include acetylation of other proteins in blood coagulation, inhibition of COX-2 activity, and other COX-independent mechanisms. The intent of this review is to develop the concept that the multifaceted therapeutic effects of low-dose aspirin may reflect pleiotropic consequences of platelet inhibition on pathophysiological tissue repair processes. Furthermore, the clinical implications of this concept will be discussed in terms of current clinical practice and future research
Cyclooxygenase inhibitors: From pharmacology to clinical read-outs
No full textAcetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance.
Platelet activation and atherothrombosis
No full textPlatelets are essential for primary hemostasis and repair of the endothelium, but they also play a key role in the development of acute coronary syndromes and contribute to cerebrovascular events. In addition, they participate in the process of forming and extending atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process,1 and inflammation is an important component of acute coronary syndromes.2 The relation between chronic and acute vascular inflammation is unclear, but platelets are a source of inflammatory mediators,3 and the activation of platelets by inflammatory triggers may be a critical component of atherothrombosis.4 This review article describes the role of platelets in atherothrombosis by integrating our knowledge of basic mechanisms with the results of mechanistic studies in humans and clinical trials of inhibitors of platelet function
Aspirin and Cancer
No full textThe place of aspirin in primary prevention remains controversial, with North American and European organizations issuing contradictory treatment guidelines. More recently, the U.S. Preventive Services Task Force recommended “initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.” This recommendation reflects increasing evidence for a chemopreventive effect of low-dose aspirin against colorectal (and other) cancer. The intent of this paper is to review the evidence supporting a chemopreventive effect of aspirin, discuss its potential mechanism(s) of action, and provide a conceptual framework for assessing current guidelines in the light of ongoing studies
The coxibs, selective inhibitors of cyclooxygenase-2
No full textDrug TherapyALASTAIR J.J. WOOD, M.D., EditorDRUG THERAPYN Engl J Med, Vol. 345, No. 6·August 9, 2001·www.nejm.org·433THE COXIBS, SELECTIVE INHIBITORSOF CYCLOOXYGENASE-2GARRET A. FITZGERALD, M.D., AND CARLO PATRONO, M.D.From the Center for Experimental Therapeutics, University of Pennsyl-vania, Philadelphia (G.A.F.); and the Department of Medicine and Centerof Excellence on Aging, University of Chieti, Chieti, Italy (C.P.). Addressreprint requests to Dr. FitzGerald at the Department of Pharmacology, 153Johnson Pavilion, 3620 Hamilton Walk, University of Pennsylvania, Phila-delphia, PA 19104-6084, or at [email protected] antiinflammatory drugs(NSAIDs) are widely used to treat arthritis,menstrual pain, and headache. Although theyare effective, their long-term use is limited by gas-trointestinal effects such as dyspepsia and abdominalpain and, less often, gastric or duodenal perforationor bleeding. Development of the coxibs, a new groupof antiinflammatory drugs, represents a response tothe unsatisfactory therapeutic profile of NSAIDs. Bothgroups of drugs inhibit prostaglandin G/H synthase,the enzyme that catalyzes the transformation of arach-idonic acid to a range of lipid mediators, termedprostaglandins and thromboxanes (Fig. 1). However,whereas NSAIDs inhibit the two recognized forms ofthe enzyme, also referred to as cyclooxygenase-1 andcyclooxygenase-2, the coxibs are selective inhibitorsof cyclooxygenase-2. The inhibition of cyclooxygen-ase-2 has been more directly implicated in ameliorat-ing inflammation, whereas the inhibition of cycloox-ygenase-1 has been related to adverse effects in thegastrointestinal tract. Therefore, it was hoped thatcoxibs would be better tolerated than nonselectiveNSAIDs but equally efficacious. This review will as-sess the evidence that has emerged in suppor
The P2Y12 receptor: no active metabolite, no party
No full textPoor responders to clopidogrel have low levels of circulating active metabolite. However, in vitro experiments have shown that blood platelets from poor responders are fully inhibited by the active metabolite of this prodrug. Impaired platelet inhibition reflects inadequate plasma levels of active metabolites, and not differences in platelet P2Y12 receptor function
Diabetes: Does aspirin increase the risk of major bleeds?
No full textA new, observational study suggests that aspirin only marginally increases the bleeding risk in patients with diabetes mellitus, perhaps reflecting impaired platelet inhibition. Inconclusive evidence from small, randomized trials and mechanistic studies reinforces the need for larger trials to determine the relative cardioprotective benefits and bleeding risks of aspirin in these patients
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