Showing papers by "Garret A. FitzGerald published in 2010"

Impact of Smokeless Tobacco Products on Cardiovascular Disease: Implications for Policy, Prevention, and Treatment. A Policy Statement From the American Heart Association

Abstract: Various forms of smokeless tobacco (ST) products (snuff, chewing tobacco) are used by individuals of all ages. Over the past several years, US tobacco companies have expanded marketing and promotion of ST products. A major aim of this statement is to review and summarize the scientific evidence regarding ST product use and the potential cardiovascular risks associated with ST product use that can be used to inform policy related to tobacco control and strategies related to tobacco harm reduction. A specific policy question is whether ST products should be recommended to smokers instead of cigarettes to reduce the morbidity and mortality associated with smoking and/or as an approach to enhance smoking cessation. Although evidence is consistent with the suggestion that the cardiovascular risks are lower with ST products compared with cigarette smoking, ST products are not without harm. As reviewed in this statement, there is evidence that long-term ST product use may be associated with a modest risk of fatal myocardial infarction (MI) and fatal stroke, suggesting that ST product use may complicate or reduce the chance for survival after a MI or stroke. In addition, there is inadequate evidence to support the use of ST products as a smoking cessation strategy. Based on the findings reviewed in this statement, clinicians should continue to discourage use of all tobacco products and emphasize prevention of smoking initiation and smoking cessation as primary goals for tobacco control. In the United States, various forms of ST products (snuff, chewing tobacco) are used by individuals of all ages, including adolescents and young adults.1 Over the past several years, US cigarette companies have been purchasing companies that only previously sold ST products.2 Consequently, there has been a proliferation of ST products such as moist snuff and snus that are sold under cigarette brand …

Emotion recollected in tranquility: lessons learned from the COX-2 saga.

Abstract: Nonsteroidal antinflammatory drugs (NSAIDs) inhibit prostaglandin formation by cyclooxygenases (COX) 1 and 2. NSAIDs selective for inhibition of COX-2 are less likely than traditional drugs to cause serious gastrointestinal adverse effects, but predispose to adverse cardiovascular events, such as heart failure, myocardial infarction, and stroke. Evidence from human pharmacology and genetics, genetically manipulated rodents, and other animal models and randomized trials indicates that this is consequent to suppression of COX-2-dependent cardioprotective prostagladins, particularly prostacyclin. Lessons drawn from how this saga unfolded are relevant to how we approach drug surveillance and regulation, integrate diversifed forms of information and might pursue a more personalized approach to drug efficacy and risk.

Circadian Clocks and Vascular Function

Abstract: The circadian clock regulates many aspects of physiology, including cardiovascular function. Internal oscillators exist in endothelial, smooth muscle cells, and fibroblasts of the vasculature. Vascular tone and thrombus formation, 2 key elements of vascular function with regard to adverse cardiovascular events, exhibit diurnal rhythmicity. In this review, we describe changes in vascular function that result from genetic disruption of discrete elements of the circadian clock.

The Role of Clock Genes in Pharmacology

Abstract: The physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.

Reengineering the national clinical and translational research enterprise: the strategic plan of the National Clinical and Translational Science Awards Consortium.

Abstract: Advances in human health require the efficient and rapid translation of scientific discoveries into effective clinical treatments; this process, in turn, depends on observational data gathered from patients, communities, and public health research that can be used to guide basic scientific investigation. Such bidirectional translational science, however, faces unprecedented challenges due to the rapid pace of scientific and technological development, as well as the difficulties of negotiating increasingly complex regulatory and commercial environments that overlap the research domain. Further, numerous barriers to translational science have emerged among the nation's academic research centers, including basic structural and cultural impediments to innovation and collaboration, shortages of trained investigators, and inadequate funding.To address these serious and systemic problems, in 2006 the National Institutes of Health created the Clinical and Translational Science Awards (CTSA) program, which aims to catalyze the transformation of biomedical research at a national level, speeding the discovery and development of therapies, fostering collaboration, engaging communities, and training succeeding generations of clinical and translational researchers. The authors report in detail on the planning process, begun in 2008, that was used to engage stakeholders and to identify, refine, and ultimately implement the CTSA program's overarching strategic goals. They also discuss the implications and likely impact of this strategic planning process as it is applied among the nation's academic health centers.

Targeted Deletions of Cyclooxygenase-2 and Atherogenesis in Mice

Abstract: Background— Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI2), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis. Methods and Results— Deletion of macrophage–COX-2 (Mac–COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by ≈30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac–COX-2 appeared to remove a restraint on COX-2 expression in l...

Cyclooxygenase-2–Dependent Prostacyclin Formation and Blood Pressure Homeostasis. Targeted Exchange of Cyclooxygenase Isoforms in Mice

Abstract: Rationale: Cyclooxygenase (COX)-derived prostanoids (PGs) are involved in blood pressure homeostasis. Both traditional nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX-1 and COX-2 and NSAIDs designed to be selective for inhibition of COX-2 cause sodium retention and elevate blood pressure. Objective: To elucidate the role of COX-2 in blood pressure homeostasis using COX-1>COX-2 mice, in which the COX-1 expression is controlled by COX-2 regulatory elements. Methods and Results: COX-1>COX-2 mice developed systolic hypertension relative to wild types (WTs) on a high-salt diet (HSD); this was attenuated by a PGI 2 receptor agonist. HSD increased expression of COX-2 in WT mice and of COX-1 in COX-1>COX-2 mice in the inner renal medulla. The HSD augmented in all strains urinary prostanoid metabolite excretion, with the exception of the major PGI 2 metabolite that was suppressed on regular chow and unaltered by the HSD in both mutants. Furthermore, inner renal medullary expression of the receptor for PGI 2 , but not for other prostanoids, was depressed by HSD in WT and even more so in both mutant strains. Increasing osmolarity augmented expression of COX-2 in WT renal medullary interstitial cells and again the increase in formation of PGI 2 observed in WTs was suppressed in cells derived from both mutants. Intramedullary infusion of the PGI 2 receptor agonist increased urine volume and sodium excretion in mice. Conclusions: These studies suggest that dysregulated expression of the COX-2 dependent, PGI 2 biosynthesis/response pathway in the renal inner renal medulla undermines the homeostatic response to a HSD. Inhibition of this pathway may contribute directly to the hypertensive response to NSAIDs.

Training translators for smart drug discovery

Abstract: To achieve advances in clinical medicine, we need investigators with a sophisticated understanding of medicine and pharmacology who are capable of projecting their preclinical research across the translational divide. Such expertise in translational medicine and therapeutics has become scant in academia, industry, and regulatory bodies. Here we discuss strategies for addressing this deficit in human capital.

Drug development needs a new brand of science.

Abstract: We need to break with the past to develop new medicines, says Garret FitzGerald. An interdisciplinary NIH centre points the way.

Perestroika in pharma: evolution or revolution in drug development?

Abstract: New-drug approvals have remained roughly constant since 1950, while the cost of drug development has soared. It seems likely that a more modular approach to drug discovery and development will evolve, deriving some features from the not-for-profit sector. For this to occur, we must address the deficit in human capital with expertise in both translational medicine and therapeutics and also in regulatory science; utilize regulatory reform to incentivize innovation and the expansion of the precompetitive space; and develop an informatics infrastructure that permits the global, secure, and compliant sharing of heterogeneous data across academic and industry sectors. These developments, likely prompted by the perception of crisis rather than opportunity, will require linked initiatives among academia, the pharmaceutical industry, the US National Institutes of Health, and the US Food and Drug Administration, along with a more adventurous role for venture capital. A failure to respond threatens the United States' lead in biomedical science and in the development and regulation of novel therapeutics.

Deletion of Microsomal Prostaglandin E Synthase-1 Does Not Alter Ozone-induced Airway Hyper-responsiveness

Abstract: Nonsteroidal anti-inflammatory drugs ameliorate pain and fever by inhibiting cyclooxygenase (COX) and suppressing prostanoid formation. Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes formation of PGE2 from the COX product PGH2 and has emerged as a therapeutic target. Inhibition of mPGES-1, however, renders the PGH2 substrate available for diversion to other PG synthases. To address the possibility that substrate diversion augments formation of PGs that might modulate bronchial tone, we assessed the impact of mPGES-1 deletion in a mouse model of ozone-induced airway hyper-responsiveness. Ozone exposure increased total lung resistance to inhaled methacholine in wild-type mice. Deletion of mPGES-1 had little effect on total lung resistance in either naive or ozone-exposed animals. The carbachol-induced narrowing of luminal diameter in intrapulmonary airways of lung slices from acute ozone-exposed mice was also unaltered by mPGES-1 deletion. Likewise, although concentrations of PGE2 were reduced in bronchoalveolar lavage fluid, whereas 6-keto-PGF1α, PGD2, and PGF2α, all were increased, deletion of mPGES-1 failed to influence cell trafficking into the airways of either naive or ozone-exposed animals. Despite biochemical evidence of PGH2 substrate diversion to potential bronchomodulator PGs, deletion of mPGES-1 had little effect on ozone-induced airway inflammation or airway hyper-responsiveness. Pharmacologically targeting mPGES-1 may not predispose patients at risk to airway dysfunction.

Biological clocks: a cardiovascular perspective

Abstract: Many aspects of cardiovascular physiology are subject to diurnal variation, and serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, occur with a frequency conditioned by the time of day. Over the last decades, growing evidence has revealed the existence of an endogenous oscillator intrinsic to the cell—called the molecular clock—that orchestrates the physiology of such time-dependent oscillatory patterns of events. In the present review, we first provide a short overview of the molecular basis of the oscillator. Then, we explain the organization of the clock at the level of the organism. We discuss the current understanding of the role of clocks in cardiovascular physiology and summarize potential entraining signals of relevance to cardiovascular function. Finally, we consider the interaction between the clock and metabolic function, which can also impinge on the propensity to cardiovascular disease.

Chapter 150 – Prostaglandin Mediators

Abstract: Publisher Summary Arachidonic acid (AA), a 20-carbon unsaturated fatty acid containing four double bonds, circulates in plasma in both free and esterified forms and is a natural constituent of the phospholipid domain of cell membranes. AA is mobilized for release by phospholipases (PLs) A2, particularly type IV cytosolic (c) PLA2, following its calcium-dependent translocation to the nuclear membrane and the endoplasmic reticulum. Three major groups of enzymes, prostaglandin G/H synthase (PGHS), lipoxygenase, or cytochrome p450, then catalyze the formation of the prostaglandins (PGs) and thromboxane A2 (TxA2), the leukotrienes, or the epoxyeicosatrienoic acids, respectively. Collectively, these products are known as eicosanoids. This chapter focuses on the PGs and TxA2, collectively termed the prostanoids. It begins by describing the cyclooxygenase pathway, which includes COX deletion. Following this, it discusses thromboxane A2 (TxA2), which is a potent vasoconstrictor, mitogen, and platelet activator. Inhibition of platelet TxA2 formation accounts for cardioprotection from aspirin, reflecting the importance of TxA2 as an amplification signal for more potent agonists, such as thrombin and ADP. Analogous to its role in vascular proliferation, TxA2 may also mediate cellular hypertrophy. The cyclooxygenase pathway of arachidonic acid metabolism generates a family of evanescent mediators with wide and varied physiological and pathophysiological actions. Understanding the biological role of the prostanoids requires examination of the biosynthetic pathways that lead to their temporal and tissue-specific generation, together with the array of signaling pathways activated by their multiple receptors.

Abstract 16834: Assessment of The Pharmacological Response to Aspirin by Quantitation of Platelet Cyclooxygenase Acetylation.

Abstract: Aspirin inhibits platelet activity irreversibly by covalent acetylation of cyclooxygenase-1 (COX-1). Variable non-responsiveness to aspirin has been reported based on clinical outcome measures, pla...