Showing papers by "Garret A. FitzGerald published in 2005"

Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities

Abstract: Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs--adverse effects attributed to suppression of COX-1-derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a "balance" between COX-2-derived PGI2 and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.

Bioinformatic analysis of circadian gene oscillation in mouse aorta

Abstract: Background— Circadian rhythmicity of many aspects of cardiovascular function—blood pressure, coagulation and contractile function—is well established, as is diurnal variation in important clinical events, such as myocardial infarction and stroke. Here, we undertake studies to globally assess circadian gene expression in murine aorta. Methods and Results— Aortae from mice were harvested at 4-hour intervals for 2 circadian cycles (48 hours). Gene expression was assessed by expression profiling and subjected to a gene ontology bioinformatics analysis. Three hundred thirty transcripts exhibited a circadian pattern of oscillation in mouse aorta, including those intrinsic to the function of the molecular clock. In addition, many genes relevant to protein folding, protein degradation, glucose and lipid metabolism, adipocyte maturation, vascular integrity, and the response to injury are also included in this subset of roughly 7000 genes screened for circadian oscillation. Conclusions— Detection of functional cass...

COX-2–Derived Prostacyclin Modulates Vascular Remodeling

Abstract: Suppression of prostacyclin (PGI 2 ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2–derived PGI 2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI 2 receptor (IP) or suppression of PGI 2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A 2 and the isoprostane, 8, 12 – iso iPF 2α -VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA 2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2–derived PGI 2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.

Parecoxib, Valdecoxib, and Cardiovascular Risk

Abstract: Selective inhibitors of cyclooxygenase (COX)-21 depress prostacyclin (PGI2) but not COX-1–derived thromboxane A2. The effects of thromboxane A2 would be exaggerated during treatment with COX-2 inhibitors, potentially predisposing patients to heart attack and stroke.2 A randomized controlled trial in patients undergoing coronary artery bypass graft (CABG) surgery and receiving either placebo or 40 mg parecoxib (Dynastat; Pfizer), the intravenously administered prodrug of valdecoxib (Bextra; Pfizer), followed by oral valdecoxib 40 mg BID for 14 days, revealed a cluster of cardiovascular events.3 In a second study, one group received parecoxib/valdecoxib, another …

Opinion: anticipating change in drug development: the emerging era of translational medicine and therapeutics.

Abstract: Despite the large investments made in drug discovery in the past decade, there is still a dearth of new drugs. This highlights the persistence of a model of drug development that has not adapted to changes in science, public perception of drug companies or the marketplace. A high profit margin in the United States has shielded drug development from the usual economic pressures that would ordinarily drive reform. The strategy of merger, pursued by many companies to compensate for the failure to develop new drugs, has, in most cases, compounded the problem, imposing geographic and cultural segregation on an already inefficient process.

Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition

Abstract: Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/Neo)) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/Neo) mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1(Neo/Neo) mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.

Peripheral clocks and the regulation of cardiovascular and metabolic function.

Abstract: Circadian rhythms generated by cell autonomous biological clocks allow for the appropriate temporal synchronization of physiology and behavior, optimizing the efficiency of biological systems. Circadian oscillators and functions have been uncovered in both central and peripheral tissues. This article describes methodology, experimental design, and technical challenges pertaining to studies of circadian rhythms in the periphery. Experimental approaches are focused upon revealing the role of peripheral clocks in cardiovascular and metabolic function using in vitro and in vivo techniques.

Assessment of cardiovascular risk

Abstract: The instant invention is drawn to methods and compositions useful for the assessment of cardiovascular risk in a mammal. The methods utilize biomarkers including prostanoid metabolites and isoprostanes as sensitive and stable markers of cardiovascular risk. The methods are particularly useful in a mammal that is contemplating undergoing coxib therapy, is undergoing coxib therapy, is undergoing antioxidant therapy, has ceased coxib therapy or has never undergone coxib therapy. The invention also includes kits useful for the assessment of cardiovascular risk in a mammal.

Pulmonary embolism in a woman taking oral contraceptives and valdecoxib.

Abstract: A 25-y-old woman, who had been on an oral contraceptive pill for 3 years, presented with pulmonary embolism. One month prior to presentation she had been started on valdecoxib for neck pain.

Cyclooxygenase-2-derived prostacyclin confers atheroprotection on female mice

Abstract: Before menopause, women are relatively protected against cardiovascular disease. Although estrogen (E 2 ) retards atherogenesis in animal models and improves endothelial function in women with hyperlipidemia, the mechanisms of atheroprotection remain to be defined completely. The prostaglandin PGI 2 inhibits platelet activation, vascular smooth muscle contraction, leukocyte-endothelial cell interactions, and cholesteryl ester hydrolase. PGI 2 analogs limit atherogenesis, and atherosclerotic lesions have a reduced ability to produce PGI 2 . Cyclooxygenase 2 (COX-2), expressed in vascular endothelial cells, catalyzes the formation of prostaglandin endoperoxide from arachidonic acid, and this subsequently is transformed to PgI 2 in endothelial cells by the action of PGI 2 synthase. Selective COX-2 inhibitors retard the excretion of PGI 2 metabolites. These mechanisms may be relevant to atheroprotection in women because E 2 increases the expression of COX-2 in vascular tissues and promotes the in vitro production of PGI 2 . Male mice lacking low-density lipoprotein receptor (LDLR) developed atherosclerosis more rapidly than did females, despite the lack of differences in total plasma cholesterol or high-density lipoprotein cholesterol. Female mice lacking both PGI 2 receptor and the LDLR developed more prominent aortic lesions than did LDLR-knockout females (ie, lacking the gene for the LDL receptor). This effect was not gene dose-dependent and was not apparent in male mice. Further observations indicated that PGI 2 decreases the platelet activation that characterizes early atherogenesis in female mice. It appears that PGI 2 serves as an antioxidant in female LDLR-knockout mice before atherogenesis and at its earliest stage. Adding hydrogen peroxide to cultured mouse aortic smooth muscle cells increased synthesis of PGI 2 and lipid peroxidation. There was no change in the expression of COX-2. Peroxide increased reactive oxygen species, and this effect was augmented by the lack of PGI 2 receptor expression. These observations suggest that the PGI 2 receptor modulates oxidant stress under baseline conditions. Importantly, E 2 stimulated COX-2 expression and PGI 2 formation. These findings suggest that E 2 receptor alpha-mediated COX-2 stimulation of PGI 2 makes a substantial contribution to atheroprotection in female LDLR-knockout mice. It is possible that ongoing treatment of patients with selective COX-2 inhibitors might undermine protection from cardiovascular disease in premenopausal females.

Targeting mPGES-1 as a treatment for inflammation which avoids cardiovascular risk

Abstract: The present invention relates to methods for the treatment of inflammation and pain without increasing cardiovascular risk by administration of an inhibitor of mPGES-1. The invention further is related to identifying inhibitors of mPGES-1 that do not increase cardiovascular risk when administered to an individual.

Assessment of cardiovascular risk using isoprostane biomarkers and COX-2 selective inhibitors

Abstract: The instant invention is drawn to methods and compositions useful for the assessment of cardiovascular risk in a mammal. The methods utilize biomarkers including prostanoid metabolites and isoprostanes as sensitive and stable markers of cardiovascular risk. The methods are particularly useful in a mammal that is contemplating undergoing coxib therapy, is undergoing coxib therapy, is undergoing antioxidant therapy, has ceased coxib therapy or has never undergone coxib therapy. The invention also includes kits useful for the assessment of cardiovascular risk in a mammal.