NSAIDS
COX-2 Inhibitors, their deadly mechanism
Home
ASPIRIN prevents MI, Cancer, and Alzheimer's disease
Celebrex and COX-2 inhibitors--American Heart Association Warnings
American Heart Association warns NSAIDs cause MI
COX-2 Inhibitors, their deadly mechanism
AHA on COX inhibitors
NSAIDs & Myocardial Infraction Risk--only ASPIRIN is safe
How VIOXX kills--jk
COX-2 INHIBITORS not as good as Ibuprofen
Continued Risk after taking VIOXX
HYDROCODONE--Opiates work for pain management
Acetaminophen, causes asthma, liver failure, & male infertility,
Acetaminophen causes male infertility
Liver failure Acetaminophen
Acetaminophen leading drug cause of liver damage
Acetaminophen increase ASTHMA risk 63%
Asthma risk and acetaminophen
Warfarin Number 1 Causes of Hospital Emergencies--WP
PLAVIX HAS SERIOUS SIDE EFFECTS--ASPIRIN PREFERRED

The COX-2 drugs (VIOXX et al) inhibit a substance that mediates the immune response that limits damage.  The end result is an acceleration of plaque formation, and thus more heart attacks and strokes.  The less pacific (effects both XOX-1 & COX-2  of NSAIDs cause this same problem, but at about half the rate.  The only exception is aspirin. 

 

Cyclooxygenase Inhibition and Cardiovascular Risk

Elliott M. Antman, MD; David DeMets, PhD; Joseph Loscalzo, MD, PhD

Circulation. 2005;112:759-770.)
© 2005 American Heart Association, Inc.

http://circ.ahajournals.org/cgi/content/full/112/5/759

 

BIOLOGY OF THE EICOSANOIDS

Eicosanoids are oxidized derivatives of the polyunsaturated long-chain fatty acids, arachidonic acid and eicosapentaenoic acid, that serve many roles in cardiovascular biology and disease. They are a class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid.  They are hormone like substances that act near the site of synthesis without altering functions throughout the body.  Eicosanoid biosynthesis can be initiated by release of arachidonic acid from membrane phospholipids by lipases (predominantly of the phospholipase A2 type) (Figure 1). Once mobilized, arachidonic acid is oxygenated into eicosanoids along the following 4 pathways: (1) prostaglandin (PG) endoperoxide synthase (cyclooxygenase [COX]), (2) lipoxygenase (LO), (3) P450 epoxygenase, and (4) (nonenzymatic) isoprostane synthesis. Details of the pharmacology of products of the LO, epoxygenase, and isoprostane pathways, as well as the lipoxins, are reviewed elsewhere.14–16 Here, we focus on products of the COX pathway. These derivatives of arachidonic acid are collectively referred to as prostanoids and comprise the PGs and thromboxanes. COX, a key enzyme in eicosanoid metabolism, converts arachidonic acid liberated from membrane phospholipids into PGG2 and PGH2.

 

WHY COX-2 INHIBITION CAUSES CARDIAC EVENTS:  Inhibition of COX-2 also has as a theoretical side effect an increase in the flux of arachidonate through the LO pathways, which may be especially important in the setting of inflammation in the atheromatous plaque. The 12-,15-, and 5-LOs all have key roles in inflammation, and the role of each in atherosclerosis has been examined.  [Inflammation’s role in development of atheromatous plaque was reported in Scientific American in 1978—jk]  Although 12-LO and 15-LO appear to contribute to LDL oxidation, the data supporting the proatherogenic role of these enzymes are inconsistent.39 Data suggest that 15-LO products may be antiinflammatory.40 Furthermore, work from Serhan’s group shows that acetylation of COX-2 by low-dose aspirin leads to its biosynthesis of 15R-hydroxyeicosatetraenoic acid.40 This intermediate is then converted by transcellular metabolism to the antiinflammatory lipoxin 15-epi-lipoxin A4 in leukocytes.41

Mehrabian and colleagues42 have demonstrated convincingly that 5-LO is a critical determinant of atherogenesis in mouse models of the disease, even in the setting of profound hypercholesterolemia. The inflammatory eicosanoids derived from increased 5-LO expression in plaque–leukotriene B4 and the cysteinyl-leukotrienes–are active in the atherothrombotic vasculature, having been shown to promote inflammatory cell activation, cell proliferation, and vasoconstriction. In human subjects, Dwyer and colleagues43 showed that variant 5-LO genotypes–tandem promoter repeats of Sp-1 binding motifs–identify a subpopulation of individuals with increased atherosclerosis (determined as carotid intima-media thickness). Helgadottir and colleagues44 showed that a promoter haplotype comprising 4 linked polymorphisms in the 5-LO activating peptide (an accessory protein that facilitates presentation of substrate arachidonate to 5-LO) confers an approximately 2-fold increased risk of myocardial infarction (MI) and stroke in an Icelandic population. Thus, the potential importance of shifting the flux of arachidonate through the LO pathway by inhibiting COX activity bears consideration as we attempt to dissect the vascular consequences of coxib use.

To appreciate the complexity of interactions among the small-molecule vascular mediators in the system, we also need to consider nitric oxide (NO) and superoxide anion. NO activates prostacyclin synthase and suppresses thromboxane synthase, likely by nitrosylating bound heme.45 In addition, NO potentiates the vascular effects of prostacyclin, likely via the cGMP-dependent inhibition of cAMP phosphodiesterase.46 This potentiation of prostacyclin by NO has also been demonstrated to account for the synergistic inhibition of platelets by these vascular effectors.47,48 Niwano and colleagues49 have shown that a stable prostacyclin analogue (beraprost) increases endothelial NO synthase (eNOS) expression by activating a cAMP-dependent transcriptional element in the eNOS promoter. In the setting of an inflammatory stimulus that induces expression of inducible NO synthase (iNOS) and a source of superoxide [such as NAD(P)H oxidase], peroxynitrite generation ensues and leads to 3-nitration of tyrosine 430 in prostacyclin synthase, inactivating the enzyme,50,51 and activation of the TxA2 receptor TP.50 TxA2, in turn, induces gp91phox expression and NAD(P)H oxidase–dependent superoxide generation,52 increasing oxidant stress in the inflamed vasculature. NO derived from iNOS also increases expression and activity of COX-2.53,28 In addition, other inflammatory mediators may modulate these interactions; eg, evidence suggests that C-reactive protein decreases prostacyclin release from endothelial cells.54

Consideration of these interactions is essential for understanding the full spectrum of activities of COX-2–dependent eicosanoid synthesis in the context of their interaction with NO. For example, COX-2 not only has been recognized as a key source of prostacyclin under normal laminar flow conditions in the vasculature but also is cardioprotective in ischemia-reperfusion injury55 and has antiproliferative effects toward vascular smooth muscle cells in conjunction with NO.56 NO can also inhibit 5-LO, likely by peroxynitrite-dependent S-nitrosation and/or 3-nitrotyrosination.57,58 Induction of iNOS by endotoxin leads to inhibition of 5-LO activity without an effect on expression,59 likely via a peroxynitrite-dependent mechanism.

The interrelationships among COX-2, 5-LO, and NO in the endothelium can best be analyzed when considered under 2 sets of conditions: in the normal state of laminar flow and in an inflammatory state (Figure 5). Under normal conditions, laminar flow induces COX-2 in the endothelial cell to promote the synthesis of prostacyclin, and stimulates elaboration of NO by eNOS. NO derived from eNOS, in turn, stimulates prostacyclin synthase activity and suppresses thromboxane synthase activity; NO also activates guanylyl cyclase to increase cGMP and acts synergistically with prostacyclin to increase cAMP levels in target cells (eg, platelets). Taken together, the net effect of these actions is to impair platelet activation, as summarized in Figure 4 (left) and Figure 5A.

In states of vascular inflammation, COX-2, iNOS, and NAD(P)H oxidase are induced in endothelial cells; these enzymes, together with 5-LO, are also expressed in inflammatory leukocytes. High-flux production of NO (from iNOS) together with superoxide anion [from NAD(P)H oxidase, COXs, LOs, and uncoupled NO synthases, among other sources] leads to the synthesis of peroxynitrite (OONO–), which inhibits prostacyclin synthase, activates TP-dependent signaling, and promotes additional COX-2 activity. The COX pathways also promote NAD(P)H oxidase activation via TxA2,33 whereas 5-LO promotes NAD(P)H oxidase activation via leukotriene B460 and the cysteinyl-leukotrienes. Moreover, PGE2, the synthesis of which is enhanced by COX2-derived PGH2 owing to kinetic selectivity and compartmentalization,61 promotes platelet activation by increasing intraplatelet calcium flux and decreasing cAMP via its interaction with the platelet surface EP3 receptor.62 (For a review of the effects of NO-derived reactive nitrogen species in inflammatory states on COXs, LOs, and peroxidases, see Coffey and colleagues.63) Taken together, the net effect of these actions is to promote platelet activation, as summarized in Figure 4 (right) and Figure 5B.

We can use the models shown in Figures 4 and 5 to construct working hypotheses about the use of coxibs in the normal state and in states of vascular inflammation. Central to this model is the balance between prostacyclin (PGI2) and thromboxane A2 in normal and diseased vessels.27,64,65 The use of a coxib under normal (ie, noninflammatory) conditions would be expected to have limited effects on platelet activation in that NO production by eNOS is relatively unimpaired, and COX-1–dependent generation of prostacyclin would still be maintained. In contrast, the use of a coxib in vascular inflammatory states would lead to a decrease in antithrombotic prostacyclin made by arachidonate flux through COX-2 and would, therefore, make available more arachidonate for leukotriene synthesis. Leukotrienes, especially leukotriene B4 and the cysteinyl-leukotrienes, would increase reactive oxygen species generation by leukocytes, especially superoxide, thereby consuming antithrombotic NO through the synthesis of peroxynitrite. Peroxynitrite, in turn, would further limit prostacyclin synthesis via synthase nitration.47 Coxibs may also increase reactive oxygen species generation via uncoupling of mitochondrial oxidative phosphorylation.66 Thus, the net result of coxib action in diseased vessels is an increase in the amount of TxA2 relative to PGI2 (see Figure 4).

In addition to the considerations at the molecular level discussed above, it should be noted that manipulation of the relative balance of COX-1 and COX-2 activity may alter important cardiorenal responses in patients.19 COX-1 and COX-2 are colocalized in the macula densa. In elderly patients or under conditions of sodium or fluid depletion, selective COX-2 inhibitors cause sodium retention and may result in edema formation.67 Administration of COX-2 inhibitors has also been associated with a reduction in glomerular filtration rate and exacerbation of hypertension.68–70 Increases in blood pressure have been proposed as a mechanism by which COX-2 inhibitors may promote an increased risk of cardiovascular events.71

{Given that the effects of the COX-2 would increase with time, since antheorsclorsis is accumulative, and COX-2 were often proscribed for chronic conditions such as arthritis, the risk increase for such long-term treatments would be much greater than the 1.5 increase of 340%. For the APC trail—jk]. 

Additional information bearing on the issue of cardiovascular risk comes from the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), which compared the most selective coxib, lumiracoxib (see Figure 2), 400 mg once daily with either naproxen 500 mg twice daily or ibuprofen 800 mg 3 times daily for 1 year in 18 000 patients with osteoarthritis.86 Low-dose aspirin (75 to 100 mg daily) was permitted in TARGET. There were only 109 cardiovascular or cerebrovascular events reported, of which 59 (0.65%) occurred in the lumiracoxib group and 50 (0.55%) occurred in the NSAID groups (hazard ratio, 1.14; 95% CI, 0.78 to 1.66; P=0.51). Although these findings might be interpreted as showing that lumiracoxib is as safe as either naproxen or ibuprofen, in the absence of a placebo group, the results are also consistent with the possibility that all 3 drugs are associated with increased risk of events with little difference among them.

The next major event in this rapidly evolving story occurred on April 7, 2005.87 The FDA concluded that the overall risk-to-benefit profile for valdecoxib was unfavorable and that valdecoxib lacked any demonstrable advantage compared with other NSAIDs. The agency requested that Pfizer voluntarily withdraw valdecoxib from the market, which Pfizer agreed to do. While permitting celecoxib to remain on the market, the FDA requested revision to the labeling of celecoxib and 18 other nonselective NSAIDs to highlight the increased risk for cardiovascular events and stated that all NSAID prescriptions must be accompanied by a medication guide to inform patients. In support of this decision by the FDA is a report from a registry experience in Denmark of 10 280 cases of first-time hospitalization for MI and 102 797 controls.88 Current and new users of all classes of non-aspirin NSAIDs had elevated RR estimates for MI.   [Only aspirin has been shown to lower cardiac risk, which is why it has been widely proscribed for years in low doses for exactly that prupose—jk]

REFERENCES:

 

  1. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005; 352: 1092–102.[Abstract/Free Full Text]

  1. Pratico D, Dogne J. Selective COX-2 inhibitors development in cardiovascular medicine. Circulation. In press.

  1. Brophy J. Hot Topic: Cyclooxygenase-2 inhibition and coronary risk. Available at: McGraw-Hill’s AccessMedicine, Harrison’s Online Updates, 2005. Accessed March 25, 2005.

  1. Statement of Sandra Kweder, MD, Deputy Director, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration. Washington, DC: Committee on Finance, United States Senate; November 18, 2004. Available at: http://www.fda/gov/ola/2004/vioxx1118.html. Accessed December 31, 2004.

  1. US Food and Drug Administration, Center for Drug Evaluation and Research, Public Health Advisory. Non-steroidal anti-inflammatory drug products (NSAIDS). Available at: http://www.fda.gov/cder/drug/advisory/nsaids.htm. Accessed January 19, 2005.

  1. American College of Rheumatology. American College of Rheumatology offers guidance for assessing arthritis pain medication usage. Press release, 2005. Available at: http://www.rheumatology.org/press/2004/cox_2_news.asp. Accessed January 23, 2005.

  1. Bennett JS, Daugherty A, Herrington D, et al. The use of nonsteroidal anti-inflammatory drugs (NSAIDs): a science advisory from the American Heart Association. Circulation. 2005; 111: 1713–1716.[Free Full Text]

  1. Crawford L. Letter to FDA revealing heart dangers in an unpublished clinical trial of Celebrex (HRG Publication #1721). Public Citizen, citizen.org, 2005. Available at: http://www.citizen.org/publications/release,cfm?ID=7359. Accessed on February 1, 2005.

  1. Summary of Prepared Testimony, Raymond V. Gilmartin, President, Chairman and Chief Executive Officer, Merck and Co, Inc, before the US Senate Committee on Finance, November 18, 2004. Merck News Item, 2005. Available at: http://www.merck.com/newsroom/vioxx_withdrawal/11182004.html. Accessed April 12, 2005.

  1. Rubin R. Painkillers hang in the balance. USATODAY.com, 2005. http://www.usatoday.com/news/health/2005–02–10-painkillers_x.htm. Accessed February 11, 2005.

  1. Schmid R. FDA scientist warns of COX-2 drug dangers. USA TODAY. February 18, 2005: 4A.

  1. Hla T. A balanced look at COX-2 drugs. Boston Globe. March 25, 2005.

  1. Henderson D, Rowland C. Once "too slow," FDA approvals called "too fast." Boston Globe. Available at: http://www.boston.com/business/articles/2005/04/10/fda_criticized_as_too_quick_to_ok_drugs/. Accessed on April 10, 2005.

  1. Foegh M, Ramwell P. The eicosanoids: prostaglandins, thromboxanes, leukotrienes, and related compounds. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2004.

  1. Wagner W, Khanna P, Furst DE. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2004.

  1. Samuelsson B, Dahlen SE, Lindgren JA, et al. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987; 237: 1171–1186.[Medline] [Order article via Infotrieve]

  1. Marcus AJ. Transcellular metabolism of eicosanoids. Prog Hemost Thromb. 1986; 8: 127–142.[Medline] [Order article via Infotrieve]

  1. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353: 307–314.[CrossRef][Medline] [Order article via Infotrieve]

  1. Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004; 18: 790–804.[Abstract/Free Full Text]

  1. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002; 359: 14–22.[CrossRef][Medline] [Order article via Infotrieve]

  1. Ofman JJ, MacLean CH, Straus WL, et al. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol. 2002; 29: 804–812.[Medline] [Order article via Infotrieve]

  1. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998; 105: 31S–38S.[CrossRef][Medline] [Order article via Infotrieve]

  1. Kaufman DW, Kelly JP, Rosenberg L, et al. Are cyclooxygenase-2 inhibitors being taken only by those who need them? Arch Intern Med. 2005; 165: 1066–1067.[Free Full Text]

  1. Gimbrone MA, Jr., Topper JN, Nagel T, et al. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci. 2000; 902: 230–239;discussion 239–240.

  1. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96: 272–277.[Abstract/Free Full Text]

  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.[Free Full Text]

  1. Belton O, Byrne D, Kearney D, et al. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation. 2000; 102: 840–845.[Abstract/Free Full Text]

  1. Schonbeck U, Sukhova GK, Graber P, et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155: 1281–1291.[Abstract/Free Full Text]

  1. Monobe H, Yamanari H, Nakamura K, et al. Effects of low-dose aspirin on endothelial function in hypertensive patients. Clin Cardiol. 2001; 24: 705–709.[Medline] [Order article via Infotrieve]

  1. Widlansky ME, Price DT, Gokce N, et al. Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension. Hypertension. 2003; 42: 310–315.[Abstract/Free Full Text]

  1. Bulut D, Liaghat S, Hanefeld C, et al. Selective cyclo-oxygenase-2 inhibition with parecoxib acutely impairs endothelium-dependent vasodilatation in patients with essential hypertension. J Hypertens. 2003; 21: 1663–1667.[CrossRef][Medline] [Order article via Infotrieve]

  1. Cipollone F, Prontera C, Pini B, et al. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability. Circulation. 2001; 104: 921–927.[Abstract/Free Full Text]

  1. Burleigh ME, Babaev VR, Oates JA, et al. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.[Abstract/Free Full Text]

  1. Olesen M, Kwong E, Meztli A, et al. No effect of cyclooxygenase inhibition on plaque size in atherosclerosis-prone mice. Scand Cardiovasc J. 2002; 36: 362–367.[CrossRef][Medline] [Order article via Infotrieve]

  1. Rott D, Zhu J, Burnett MS, et al. Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice. J Am Coll Cardiol. 2003; 41: 1812–1819.[Abstract/Free Full Text]

  1. Egan KM, Lawson JA, Fries S, et al. COX-2-derived prostacyclin confers atheroprotection on female mice. Science. 2004; 306: 1954–1957.[Abstract/Free Full Text]

  1. Takayama K, Garcia-Cardena G, Sukhova GK, et al. Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem. 2002; 277: 44147–44154.[Abstract/Free Full Text]

  1. Cayatte AJ, Du Y, Oliver-Krasinski J, et al. The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol. 2000; 20: 1724–1728.[Abstract/Free Full Text]

  1. Funk CD, Cyrus T. 12/15-lipoxygenase, oxidative modification of LDL and atherogenesis. Trends Cardiovasc Med. 2001; 11: 116–124.[CrossRef][Medline] [Order article via Infotrieve]

  1. Serhan CN, Jain A, Marleau S, et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol. 2003; 171: 6856–6865.[Abstract/Free Full Text]

  1. Chiang N, Bermudez EA, Ridker PM, et al. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci U S A. 2004; 101: 15178–15183.[Abstract/Free Full Text]

  1. Mehrabian M, Allayee H, Wong J, et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002; 91: 120–126.[Abstract/Free Full Text]

  1. Dwyer JH, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004; 350: 29–37.[Abstract/Free Full Text]

  1. Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004; 36: 233–239.[CrossRef][Medline] [Order article via Infotrieve]

  1. Wade ML, Fitzpatrick FA. Nitric oxide modulates the activity of the hemoproteins prostaglandin I2 synthase and thromboxane A2 synthase. Arch Biochem Biophys. 1997; 347: 174–180.[CrossRef][Medline] [Order article via Infotrieve]

  1. Zellers TM, Wu YQ, McCormick J, et al. Prostacyclin-induced relaxations of small porcine pulmonary arteries are enhanced by the basal release of endothelium-derived nitric oxide through an effect on cyclic GMP-inhibited-cyclic AMP phosphodiesterase. Acta Pharmacol Sin. 2000; 21: 131–138.[Medline] [Order article via Infotrieve]

  1. Koga T, Az-ma T, Yuge O. Prostaglandin E1 at clinically relevant concentrations inhibits aggregation of platelets under synergic interaction with endothelial cells. Acta Anaesthesiol Scand. 2002; 46: 987–993.[CrossRef][Medline] [Order article via Infotrieve]

  1. Stamler JS, Vaughan DE, Loscalzo J. Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. Circ Res. 1989; 65: 796–804.[Abstract]

  1. Niwano K, Arai M, Tomaru K, et al. Transcriptional stimulation of the eNOS gene by the stable prostacyclin analogue beraprost is mediated through cAMP-responsive element in vascular endothelial cells: close link between PGI2 signal and NO pathways. Circ Res. 2003; 93: 523–530.[Abstract/Free Full Text]

  1. Bachschmid M, Thurau S, Zou MH, et al. Endothelial cell activation by endotoxin involves superoxide/NO-mediated nitration of prostacyclin synthase and thromboxane receptor stimulation. FASEB J. 2003; 17: 914–916.[Free Full Text]

  1. Schmidt P, Youhnovski N, Daiber A, et al. Specific nitration at tyrosine 430 revealed by high resolution mass spectrometry as basis for redox regulation of bovine prostacyclin synthase. J Biol Chem. 2003; 278: 12813–12819.[Abstract/Free Full Text]

  1. Muzaffar S, Shukla N, Lobo C, et al. Iloprost inhibits superoxide formation and gp91phox expression induced by the thromboxane A2 analogue U46619, 8-isoprostane F2 , prostaglandin F2 , cytokines and endotoxin in the pig pulmonary artery. Br J Pharmacol. 2004; 141: 488–496.[CrossRef][Medline] [Order article via Infotrieve]

  1. Perez-Sala D, Lamas S. Regulation of cyclooxygenase-2 expression by nitric oxide in cells. Antioxid Redox Signal. 2001; 3: 231–248.[CrossRef][Medline] [Order article via Infotrieve]

  1. Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin release from human aortic endothelial cells. Circulation. 2003; 108: 1676–1678.[Abstract/Free Full Text]

  1. Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res. 2002; 55: 506–519.[CrossRef][Medline] [Order article via Infotrieve]

  1. Haider A, Lee I, Grabarek J, et al. Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G1 shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation. Circulation. 2003; 108: 1015–1021.[Abstract/Free Full Text]

  1. Coffey MJ, Phare SM, Peters-Golden M. Interaction between nitric oxide, reactive oxygen intermediates, and peroxynitrite in the regulation of 5-lipoxygenase metabolism. Biochim Biophys Acta. 2002; 1584: 81–90.[Medline] [Order article via Infotrieve]

  1. Velardez MO, Ogando D, Franchi AM, et al. Role of nitric oxide in the metabolism of arachidonic acid in the rat anterior pituitary gland. Mol Cell Endocrinol. 2001; 172: 7–12.[CrossRef][Medline] [Order article via Infotrieve]

  1. Coffey MJ, Phare SM, Peters-Golden M. Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis. J Immunol. 2000; 165: 3592–3598.[Abstract/Free Full Text]

  1. Luchtefeld M, Drexler H, Schieffer B. 5-Lipoxygenase is involved in the angiotensin II–induced NAD(P)H-oxidase activation. Biochem Biophys Res Commun. 2003; 308: 668–672.[CrossRef][Medline] [Order article via Infotrieve]

  1. Penglis PS, Cleland LG, Demasi M, et al. Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors. J Immunol. 2000; 165: 1605–1611.[Abstract/Free Full Text]

  1. Ma H, Hara A, Xiao CY, et al. Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP(3). Circulation. 2001; 104: 1176–1180.[Abstract/Free Full Text]

  1. Coffey MJ, Coles B, O’Donnell VB. Interactions of nitric oxide-derived reactive nitrogen species with peroxidases and lipoxygenases. Free Radic Res. 2001; 35: 447–464.[Medline] [Order article via Infotrieve]

  1. Kobayashi T, Tahara Y, Matsumoto M, et al. Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest. 2004; 114: 784–794.[Abstract/Free Full Text]

  1. FitzGerald GA, Smith B, Pedersen AK, et al. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med. 1984; 310: 1065–1068.[Abstract]

  1. Moreno-Sanchez R, Bravo C, Vasquez C, et al. Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs: study in mitochondria, submitochondrial particles, cells, and whole heart. Biochem Pharmacol. 1999; 57: 743–752.[CrossRef][Medline] [Order article via Infotrieve]

  1. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther. 1999; 66: 76–84.[Medline] [Order article via Infotrieve]

  1. Aw TJ, Haas SJ, Liew D, et al. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005; 165: 490–496.[Abstract/Free Full Text]

  1. Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005; 165: 161–168.[Abstract/Free Full Text]

  1. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet: a randomized, controlled trial. Ann Intern Med. 2000; 133: 1–9.[Free Full Text]

  1. Singh G, Miller JD, Huse DM, et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol. 2003; 30: 714–719.[Medline] [Order article via Infotrieve]

  1. Pfizer Inc. Protocol No. IQ5–97–02–001: a double-blind, randomized, placebo-controlled, comparative study of Celecoxib (SC–58635) for the inhibition of progression of Alzheimer’s disease; Protocol No. EQ5–98–02–002: a placebo-controlled evaluation of the long-term efficacy and safety of Celecoxib (SC-58635) in Alzheimer’s disease. ClinicalStudyResults.org, Available at: http://www.clinicalstudyresults.org/drugdetails/?inn_name_id=55&sort=c.company_name&. Accessed February 1, 2005.

  1. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004; 364: 2021–2029.[CrossRef][Medline] [Order article via Infotrieve]

  1. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005; 352: 1071–1080.[Abstract/Free Full Text]

  1. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR Study Group. N Engl J Med. 2000; 343: 1520–1528.[Abstract/Free Full Text]

  1. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286: 954–959.[Abstract/Free Full Text]

  1. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004; 109: 2068–2073.[Abstract/Free Full Text]

  1. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. 2005; 142: 157–164.[Abstract/Free Full Text]

  1. Levesque LE, Brophy JM, Zhang B The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005; 142: 481–489.[Abstract/Free Full Text]

  1. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005; 365: 475–481.[CrossRef][Medline] [Order article via Infotrieve]

  1. Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib, and cardiovascular risk. Circulation. 2005; 111: 249.[Free Full Text]

  1. US Food and Drug Administration. FDA issues Public Health Advisory recommending limited use of Cox-2 inhibitors: agency requires evaluation of prevention studies involving Cox-2 selective agents. FDA Talk Paper, 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01336.html. Accessed January 19, 2005.

  1. National Institutes of Health, NIH Office of Communications and Public Liaison. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer’s disease prevention trial. Available at: http://www.nih.gov/news/or/dec2004/od-20.htm. Accessed April 12, 2005.

  1. Whalen J. Stronger warnings are ordered for Cox-2 inhibitors in Europe. The Wall Street Journal Europe. February 18–February 20, 2005:A4.

  1. Adetunji L, Bowe C Watchdog imposes curbs on dosages of Cox-2 pain drugs. London Financial Times. February 18, 2005:15.

  1. Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004; 364: 675–684.[CrossRef][Medline] [Order article via Infotrieve]

  1. US Food and Drug Administration. FDA announces series of changes to the class of marketed non-steroidal anti-inflammatory drugs (NSAIDS). FDA News. Available at: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed April 7, 2005.

  1. Johnsen SP, Larsson H, Tarone RE, et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med. 2005; 165: 978–984.[Abstract/Free Full Text]

  1. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001; 345: 1809–1817.[Abstract/Free Full Text]

  1. Weksler BB, Pett SB, Alonso D, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983; 308: 800–805.[Abstract]

  1. Okie S. What ails the FDA? N Engl J Med. 2005; 352: 1063–1066.[Free Full Text]

  1. Hawthorne F. How powerful is industry? In: Inside the FDA: The Business and Politics Behind the Drugs We Take and the Food We Eat. Hoboken, NJ: John Wiley & Sons; 2005: 143–177.

  1. Hawthorne F. The FDA meets Madison Avenue. In: Inside the FDA: The Business and the Politics Behind the Drugs We Take and the Food We Eat. Hoboken, NJ: John Wiley & Sons; 2005: 253–272.

  1. Coronary Drug Project Research Group. Practical aspects of decision making in clinical trials: the coronary drug project as a case study. Control Clin Trials. 1981; 1: 363–376.[CrossRef][Medline] [Order article via Infotrieve]

  1. US Department of Health and Human Services. Reforms will improve oversight and openness at FDA: Secretary Leavitt meets with employees and announces a new day at FDA. FDA Press Office, 2/15/05. Available at: www.fda.gov/cder/drugsafety.htm, http://www.hhs.gov/news. Accessed April 12, 2005.

  1. Hawthorne F. The next 100 years. In: Inside the FDA: The Business and Politics Behind the Drugs We Take and the Food We Eat. Hoboken, NJ: John Wiley & Sons; 2005: 285–308.

  1. Bennett CL, Nebeker JR, Lyons EA, et al. The Research on Adverse Drug Events and Reports (RADAR) project. JAMA. 2005; 293: 2131–2140.[Abstract/Free Full Text]

  1. Roden DM, Temple R. The US Food and Drug Administration Cardiorenal Advisory Panel and the drug approval process. Circulation. 2005; 111: 1697–1702.[Free Full Text]

  1. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. Br Med J. 2005; 330: 1366–1343.[Abstract/Free Full Text]

  1. Waxman HA. The lessons of Vioxx: drug safety and sales. N Engl J Med. 2005; 352: 2576–2578.[Free Full Text]

 

Blood Clots the second cause of increased heart attacks

 

Goodman & Gilman, 11th Ed.(684):  “Selective inhibition of COX-2 depress PGI­­-2 formation by endothelial cells without concomitant inhibition of platelet thromboxane.  Experiments in mice suggest that PGI-2 restrains the cardiovascular effects of TXA-2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis (McAdam et al, 19999, Catella-Lawson et al., 1999).  This mechanism should pertain to individuals otherwise at risk of thrombosis, such as those with rheumatoid arthritis, as the relative risk of myocardial infraction is increased in these patients compared to patients with osteoarthritis or no arthritis.”  {Patients who would be taking long-term COX-2 inhibitors.  However, the study, which took theory into reality, was not of that group, but rather a test to see if it reduced the risk of Alzheimer’s disease.  At 16 months the study was stopped because of a 2.5 increase in myocardial infraction, and 3.4 at the higher dose.}

 

 

and from

Medical Journal of Australia, MJA 2004; 181 (10): 524-525

Journal of the Australian Medial Association, Established 1914

 

The coxibs (COX-2-selective NSAIDs) do not inhibit production of platelet thromboxane (a potent platelet agonist and vasoconstrictor), but selectively suppress endothelial prostacyclin (an intrinsic vasodilator and platelet inhibitor).  It has been hypothesised that selective inhibition of prostacyclin production by coxibs without concomitant platelet inhibition leads to thrombosis in at-risk individuals

 

Enter supporting content here

INTERNAL SITE SEARCH ENGINE by Google

Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.