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Inhibitors of the cyclooxygenases (COXs), the nonsteroidal antiinflammatory drugs (NSAIDs), relieve inflammatory pain, but are associated with gastrointestinal and cardiovascular complications. Given the widespread use of NSAIDs, there has been a longstanding interest in optimizing their risk-benefit ratio, for example by reducing their gastrointestinal risk. More recently, the focus has shifted toward the cardiovascular complications of NSAIDs and very large prospective studies have been performed to compare cardiovascular risk across distinct NSAIDs. Surprisingly, much less attention has been paid to the efficacy side of the risk-benefit ratio. There is marked variability in the degree of pain relief by NSAIDs due to the complex interplay of molecular mechanisms contributing to the pain sensation, variability in the disposition of NSAIDs, and imprecision in the quantification of human pain. Here we discuss how NSAIDs relieve pain, how molecular mechanisms relate to clinical efficacy, and how this may inform our interpretation of clinical trials. [ABSTRACT FROM AUTHOR]

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs-ibuprofen, naproxen, and celecoxib-to cause a drug-drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug-drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk. [ABSTRACT FROM AUTHOR]

The author discusses the limitations to the interpretation of randomized clinical trial Prospective Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen or PRECISION trial on the comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs). Noted is the analgesic efficacy of NSAIDs largely derived from suppressing cyclooxygenase 2 (COX-2)-derived prostaglandins, while their gastrointestinal adverse effects result from the inhibition of COX-1.

Inhibition of cyclooxygenase (COX) 2, which is associated with >40% of breast cancers, decreases the risk of tumorigenesis and breast cancer recurrence. To study the role of COX-2 in breast cancer, we engineered mice that lack selectively mammary epithelial cell (MEC) COX-2 (COX-2 KOMEC). Compared with wild type (WT), MEC from COX-2 KOMEC mice expressed >90% less COX-2 messenger RNA (mRNA) and protein and produced 90% less of the dominant pro-oncogenic COX-2 product, prostaglandin (PG) E2. We confirmed COX-2 as the principle source of PGE2 in MEC treated with selective COX-2 and COX-1 inhibitors. Tumors were induced in mice using medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene. Breast cancer onset was significantly delayed in COX-2 KOMEC compared with WT (P = 0.03), equivalent to the delay following systemic COX-2 inhibition with rofecoxib. Compared with WT, COX-2 KOMEC tumors showed increased mRNA for Caspase-3, Ki-67 and common markers for leukocytes (CD45) and macrophages (F4/80). Analysis of multiple markers/cytokines, namely CD86, inducible nitric oxide synthase (iNOS), interleukin-6, tumor necrosis factor α (TNFα) and Tim-3 indicated a shift toward antitumorigenic type 1 immune responses in COX-2 KOMEC tumors. Immunohistochemical analysis confirmed elevated expression of CD45, F4/80 and CD86 in COX-2 KOMEC tumors. Concordant with a role for COX-2 in restraining M1 macrophage polarization, CD86 and TNFα expression were offset by exogenous PGE2 in bone marrow-derived macrophages polarized in vitro to the M1 phenotype. Our data reveal the importance of epithelial COX-2 in tumor promotion and indicate that deletion of epithelial COX-2 may skew tumor immunity toward type 1 responses, coincident with delayed tumor development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the relative contribution of cyclooxygenase (COX) isoforms and prostaglandins (PG) species in the autoantibody-driven K/BxN serum-transfer arthritis. The study analyzed the prostanoid content of arthritic ankles in ankle homogenates and the presence of COX isoforms was assessed by Western blotting. It highlighted the potential pathogenic contribution of prostanoids synthesized via COX-1.

Prostacyclin is one of a number of lipid mediators elaborated from the metabolism of arachidonic acid by the cyclooxygenase (COX) enzymes. This prostanoid is a potent inhibitor of platelet aggregation, and its production by endothelial cells and protective role in the vasculature are well established. In contrast, much less is known regarding the function of this prostanoid in other disease processes. We show here that COX-2-dependent production of prostacyclin plays an important role in the development of fibrotic lung disease, limiting both the development of fibrosis and the consequential alterations in lung mechanics. In stark contrast, loss of prostaglandin E2 synthesis and signaling through the Gs-coupled EP2 and EP4 receptors had no effect on the development of disease. These findings suggest that prostacyclin analogs will protect against bleomycin-induced pulmonary fibrosis in COX-2-/- mice. If such protection is observed, investigation of these agents as a novel therapeutic approach to pulmonary fibrosis in humans may be warranted. [ABSTRACT FROM AUTHOR]

Background & Aims: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. Methods: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. Results: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9. Conclusions: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications. [Copyright &y& Elsevier]

Examines the developmental expression of cyclooxygenases (COX) in zebrafish. Role of COX in murine reproduction and renal organogenesis; Existence of phospholipase; Importance of cross-reacting antibodies in the expression of COX.

The relevance of cyclooxygenases (COX)-1 and -2 and their products to inflammation, thrombosis and gastroprotection are well known. Their importance in the immune response was first recognized more than 25 years ago, but has only gained widespread attention recently.In this review, we attempt to integrate information on prostanoids and both the innate and acquired immune responses, including effects on leukocytes, antigen presenting cells, dendritic cells, T and B lymphocytes. Prostanoids may be relevant to immunotolerance, autoimmune disorders, transplantation, immunologic defense against tumors, acquired immunodeficiencies and viral infections. Insight into the role of prostanoids in immune function may afford novel therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Studies the acceleration of atherogenesis by cyclooxygenase-1-dependent (COX-1) prostanoid formation in low density lipoprotein receptor in knockout mice. Effects of biochemically defined selective inhibition of COX-2 on atherogenesis; Assessment of the effects of combined inhibition of both COX isoenzymes on the process.

Describes how aspirin reduces the secondary incidence of stroke, myocardial infarction, and vascular death. How aspirin irreversibly inhibits cyclo-oxygenase by acetylation of a serine residue; Transformation of arachidonic acid to the unstable prostaglandin; Consideration of how ibuprofen and diclofenac are reversible inhibitors of cyclo-oxygenase; Clinical implications.

The article provides information on nonsteroidal antiinflammatory drugs (NSAIDs). Although they are effective for the treatment of arthritis, menstrual pain and headache, the long-term use of NSAIDs is limited by gastrointestinal effects such as dyspepsia and abdominal pain and less often, gastric or duodenal perforation or bleeding. Three broad classes of cyclooxygenase inhibitors have emerged which include aspirin synthesized from salicylic acid, indomethacin and other NSAIDs, whose chemical modifications were based largely on findings in models of inflammation and gastric mucosal damage

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). In low-density lipoprotein receptor-deficient (Ldlr-/-) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors. [ABSTRACT FROM AUTHOR]

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti- inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is probably the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin — thus, the drug-microbe interactions described here provide candidate mediators of individualized drug responses. [ABSTRACT FROM AUTHOR]

Background—Global deletion of microsomal prostaglandin E synthase 1 (mPGES-1) in mice attenuates the response to vascular injury without a predisposition to thrombogenesis or hypertension. However, enzyme deletion results in cell- specific differential use by prostaglandin synthases of the accumulated prostaglandin H2, substrate. Here, we generated mice deficient in mPGES-l in vascular smooth muscle cells, endothelial cells, and myeloid cells further to elucidate the cardiovascular function of this enzyme. Methods and Results—Vascular smooth muscle cell and endothelial cell mPGES-1 deletion did not alter blood pressure at baseline or in response to a high-salt diet. The propensity to evoked macrovascular and microvascular thrombogenesis was also unaltered. However, both vascular smooth muscle cell and endothelial cell mPGES-1-deficient mice exhibited a markedly exaggerated neointimal hyperplastic response to wire injury of the femoral artery in comparison to their littermate controls. The hyperplasia was associated with increased proliferating cell nuclear antigen and tenascin-C expression. In contrast, the response to injury was markedly suppressed by myeloid cell depletion of mPGES-1 with decreased hyperplasia, leukocyte infiltration, and expression of proliferating cell nuclear antigen and tenascin-C. Conditioned medium derived from mPGES-1-deficient macrophages less potently induced vascular smooth muscle cell proliferation and migration than that from wild-type macrophages. Conclusions—Deletion of mPGES-1 in the vasculature and myeloid cells differentially modulates the response to vascular injury, implicating macrophage mPGES-1 as a cardiovascular drug target. [ABSTRACT FROM AUTHOR]

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD2 and PGE2 followed by COX-2-dependent production of PGE2. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD2 receptor DP1. NSAID-mediated suppression of COX-2-derived PGI2 has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD2. Here, we show that PGD2 biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD2 biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD2 was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD2, like PGI2, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy. [ABSTRACT FROM AUTHOR]

Prostaglandin D2 (PGD2) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15- Dioxo-9α-hydroxy-2,3,4,5-tetranorprostan- 1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD2 that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD2 metabolites, 11βPGF2α and 2,3-dinor-11β-PGF2α, in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD2 dose dependently increased urinary tetranor PGDM > 2,3-dinor-11β-PGF2α > 11β-PGF2α in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11β-PGF2α were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD2 has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11β-PGF2α in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11β-PGF2α in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD2 in humans and mice. [ABSTRACT FROM AUTHOR]

The prostaglandin G/H synthase enzymes, commonly termed COX-1 and COX-2, differ markedly in their responses to regulatory stimuli and their tissue expression patterns. COX- 1 is the dominant source of ‘housekeeping’ prostaglandins, whereas COX-2 synthesizes prostaglandins of relevance to pain, inflammation, and mitogenesis. Despite these distinctions, the two enzymes are remarkably conserved, and their subcellular distributions overlap considerably. To address the functional interchangeability of the two isozymes, mice in which COX-1 is expressed under COX-2 regulatory elements were created by a gene targeting ‘knock-in’ strategy. In macrophages from these mice, COX-1 was shown to be lipopolysaccharide-inducible in a manner analogous to COX-2 in wild-type macrophages However, COX-1 failed to substitute effectively for COX-2 in lipopolysaccharide-induced prostaglandin E2 synthesis at low concentrations of substrate and in the metabolism of the endocannabinoid 2-arachidonylglycerol. The marked depression of the major urinary metabolite of prostacyclin in COX-2 null mice was only partially rescued by COX-1 knock-in, whereas the main urinary metabolite of prostaglandin E2 was rescued totally. Replacement with COX-1 partially rescued the impact of COX-2 deletion on reproductive function, The renal pathology consequent to COX-2 deletion was delayed but not prevented, whereas the corresponding peritonitis was unaltered, Insertion of COX-1 under the regulatory sequences that drive COX-2 expression indicated that COX-1 can substitute for some COX-2 actions and rescue only some of the consequences of gene disruption. Manipulation of COX-2 also revealed a preference for coupling with distinct downstream prostaglandin synthases in vivo. These mice will provide a valuable reagent with which to elucidate the distinct roles of the COX enzymes in mammalian biology. [ABSTRACT FROM AUTHOR]

We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2–derived prostacyclin (PGI2) and PGE2. Therefore, the challenge remains to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2–derived PGI2, was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE2 expression, augmented PGI2 expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE2, while avoiding the adverse cardiovascular consequences associated with PGHS-2–mediated PGI2 suppression. [ABSTRACT FROM AUTHOR]

Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin, PGI[sub 2], by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PGI[sub 2] receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females. [ABSTRACT FROM AUTHOR]

Background: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies. Methods: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily). Results: Serum thromboxane B2 levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B2 formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin. Conclusions: The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. (N Engl J Med 2001;345:1809-17.) [ABSTRACT FROM AUTHOR]