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Unresolved Issues in the Role of Cyclooxygenase-2 in Normal Physiologic Processes and Disease
Peter E. Lipsky, MD;
Peter Brooks, MD;
Leslie J. Crofford, MD;
Raymond DuBois, MD, PhD;
David Graham, MD;
Lee S. Simon, MD;
Leo B. A. van de Putte, MD, PhD, FRCP;
Steven B. Abramson, MD
Arch Intern Med. 2000;160:913-920.
ABSTRACT
Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2–specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.
INTRODUCTION
Since the synthesis of aspirin 100 years ago, nonsteroidal anti-inflammatory drugs (NSAIDs) have become mainstays in the medical management of pain and inflammation.1 The common but perhaps not the only mechanism underlying NSAID activity, inhibition of the cyclooxygenase (COX) enzyme that catalyzes the initial step of arachidonic acid metabolism, became clear in the early 1970s,2 and served to encourage the development of an NSAID class that now includes over 30 compounds. Despite the capacity of these agents to suppress pain, inflammation, and fever,3 and the expansion of the use of these agents into one of the most widely used classes of drugs in the world, mechanism-based toxicity related to the suppression of the production of specific arachidonic acid metabolites in individual tissues and organs4 has limited unmitigated acceptance of these compounds. Moreover, this mechanism-based toxicity has stimulated research into the possibility that less toxic analgesic and anti-inflammatory agents could be developed.
Within the past 10 years, COX activity was found to be associated with 2 distinct isozymes, COX-1 and COX-2.1, 5-7 Initial evidence suggested that COX-1 was expressed constitutively within many tissues and was thought to be responsible for homeostatic production of arachidonic metabolites. In contrast, COX-2 was thought not to be expressed normally, but to be rapidly induced in response to inflammatory stimuli and to be responsible for the large amounts of prostaglandin E2 (PGE2)and other arachidonic acid metabolites produced at inflammatory sites. This generated the hypothesis that the functions of the COX isoforms were mutually exclusive, with COX-1 involved in maintenance of the physiologic function of a variety of organs and COX-2 involved in pathophysiologic processes, including inflammation, pain, and fever. This hypothesis was so compelling that before it was rigorously tested, it served as the rationale to develop specific COX-2 inhibitors (agents that at therapeutic doses block the activity of COX-2 but not COX-1) with the expectation that these agents would have all of the anti-inflammatory and analgesic properties of standard NSAIDs, but lack the well-recognized toxic effects related to COX-1 inhibition.8-9 Clinical trials with 2 of these agents (Figure 1) have produced results consistent with this general paradigm and have led to the approval of these agents for the treatment for osteoarthritis (celecoxib, rofecoxib), rheumatoid arthritis (celecoxib), and acute pain (rofecoxib).10-11 However, newly emerging information has challenged some aspects of the original model, documenting much wider physiologic roles for both COX-1 and COX-2. This information has altered some aspects of the anticipated outcome of treatment with specific COX-2 inhibitors, but also expanded their potential therapeutic indications.
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Figure 1. Cyclooxygenase-2 inhibitors.
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DISCOVERY OF COX-2
Although a multitude of NSAID actions have been proposed, the ability of NSAIDs to suppress inflammation and inflammatory pain results primarily from their inhibition of arachidonic acid metabolism and, specifically, PGE2 production.1-4,12-13 Because arachidonic acid metabolites also maintain gastric mucosal integrity (PGE2, prostacyclin) and platelet function (thromboxane A2), as well as renal blood flow, especially in the face of volume contraction, inhibition of arachidonic acid metabolism also explains the mechanism-based toxicity of NSAIDs, including gastrointestinal ulceration and bleeding and diminished renal function.4, 14-23
Also called prostaglandin H synthase, COX is the first enzyme in the prostanoid biosynthetic pathway catalyzing the conversion of arachidonic acid to prostaglandin G2 and then to prostaglandin H2.1-7 Subsequent activity by a variety of other specific enzymes results in the characteristic array of arachidonic acid metabolites produced by individual cells and tissues. It is the regulated production of those specific metabolites that determines the unique and often opposing dominant effects of arachidonic acid metabolites at specific tissue sites. For example, platelet derived thromboxane favors platelet aggregation and thrombosis that is opposed by the vasodilatory effects of endothelial cell–derived prostacyclin.
In the late 1980s, it was shown that expression of COX activity could be markedly stimulated by interleukin-1 in fibroblasts and monocytes and inhibited by corticosteroids.24-26 This was important because prostaglandin production was previously thought to be determined only by the amount of arachidonic acid substrate present. Based on this work, the existence of 2 distinct forms of COX was proposed, one constitutive and one inducible.25 Since that time, separate genes for the 2 isoenzymes have been cloned,27-29 and regulation and expression of the 2 proteins have been delineated, providing clues to their proposed distinct biological roles.1, 5-7
The genes for the 2 COX isoforms are approximately 65% homologous in their coding regions and, as a result, the proteins are quite similar, with comparable enzymatic activities and substrate specificities. One potential difference in the enzymatic activities of the 2 isoforms is the source of the arachidonic acid substrate, with COX-2 using intracellular arachidonic acid and COX-1 using extracellular substrate.5, 30-31 Soluble phospholipase A2, produced by a variety of cells, seems to be important in providing extracellular arachidonic acid substrate for COX-1.5, 30-31 As the amount of substrate might be an essential contributor of arachidonic acid metabolite production by COX-1, regulation of soluble phospholipase A2 rather than COX-1 itself may provide the crucial influence of the metabolic activity of the COX-1 isoform.
One additional difference between COX-1 and COX-2 emerged from analysis of the 3-dimensional structures of the molecules.32-35 A subtle difference in the structures of the hydrophobic channel leading to the active site of the COX-2 molecule has been identified, with a somewhat larger orifice and an additional pocket pointing away from the catalytic site. This has permitted the development of inhibitors that block the activity of COX-2, specifically at concentrations that have only minimal effects on COX-1.8-9 In general, COX-2 inhibitors differ from classic competitive inhibitors in that they require time to fit into the active site of the enzyme, after which their inhibitory effects may become persistent. Of note, the same compound may function as a competitive inhibitor of COX-1 at high concentrations and as a "timed inhibitor" of COX-2 at markedly lower concentrations owing to the unique configuration of the hydrophobic channel leading to the active site of the COX-2 isoform. Of importance, the differences between the mechanisms of inhibition of COX-1 and COX-2 can influence the estimation of the activity of a putative inhibitor when analyzed with only isolated enzymes or intact or broken cells.
THE HOMEOSTATIC VS PROINFLAMMATORY THEORY OF COX ACTIONS
Analysis of the expression of COX-1 using monoclonal antibodies and molecular probes has documented that this isoform is expressed constitutively in many cells and tissues.36 Of importance, in certain tissues and cells such as the normal gastric mucosa and the platelet, COX-1 is the only isoform expressed. In the gastric antrum, local production of PGE2 and endothelial cell–derived prostacyclin synthesized via the action of COX-1 promotes vasodilatation, thereby promoting the maintenance of mucosal integrity.21-23 Similarly, in the kidney, COX-1 is important in producing vasodilatory prostaglandins that maintain renal blood flow and the glomerular filtration rate, especially during periods of systemic vasoconstriction.37-38 Finally, in platelets, the action of COX-1 is essential for the production of thromboxane A2 that promotes platelet aggregation.39 These findings stimulated the concept that the major, if not the only, function of COX-1 was to maintain homeostasis and promote specific physiologic activities.
In contrast to the constitutive expression of COX-1 and its putative role in homeostatic regulation of physiologic processes, the COX-2 enzyme was initially noted to be undetectable in most normal tissues and cells.5-7,36 However, when a variety of cells such as macrophages and endothelial cells were challenged with various inflammatory mediators, COX-2 expression was rapidly induced. Moreover, at sites of inflammation such as the rheumatoid synovium, COX-2 was dramatically up-regulated.40-42 Finally, in animal models of inflammation, COX-2 messenger RNA and protein, but not COX-1, were dramatically up-regulated at the inflammatory site by the evoking stimulus and just before the marked increase in local prostaglandin production and clinical manifestation of inflammation.43 This evidence suggested the hypothesis that COX-2 was an inducible enzyme that was markedly up-regulated at sites of inflammation and accounted for the increased production of arachidonic acid metabolites locally and the resultant vasodilitation, edema, and pain.
This information provided the basis for the hypothesis that COX-1 was involved in cellular "housekeeping functions" necessary for normal physiologic activity, whereas COX-2 acted primarily at sites of inflammation to amplify pain and proinflammatory manifestations. The clinical corollary to this hypothesis was that highly specific inhibition of COX-2 would exert beneficial anti-inflammatory and analgesic effects without influencing the important physiologic functions of COX-1. Since all currently available NSAIDs inhibit both COX-1 and COX-2 to varying degrees16-17 by competing with arachidonate for binding to the active site of the enzyme, this line of reasoning suggested that the toxicity of these agents might be related to their capacity to inhibit COX-1, whereas their analgesic, anti-inflammatory and antipyretic effects might depend on their ability to inhibit COX-2. The potential of segregating the "good" from the "bad" actions of NSAIDs stimulated the search for agents that inhibited COX-2 specifically.
Evolving knowledge of the biologic function of COX-1 and COX-2 has suggested that the initial paradigm is an oversimplification. Although COX-2 is induced at sites of inflammation, a critical role for COX-2 in a number of other physiologic processes has emerged. Moreover, in certain circumstances COX-1 has been shown to be induced44-46 and to play a protective function,47 or to contribute to inflammatory responses.48 Thus, a more complex interplay of COX-1 and COX-2 in physiologic and pathophysiologic processes has emerged with certain unexpected outcomes resulting from targeted disruption or inhibition of specific COX isoforms. Moreover, a role for COX isoforms in unanticipated physiologic or pathophysiologic processes has emerged, suggesting unexpected therapeutic opportunities or consequences of specific COX-2 inhibition.
EMERGING COMPLEXITY: DIVERSE PHYSIOLOGIC AND PATHOPHYSIOLOGIC ROLES FOR COX-1 AND COX-2
Emerging information suggests that both COX-1 and COX-2 play broad and complex physiologic and pathophysiologic roles. Animal data, for example, demonstrate that COX-2 is expressed constitutively in the kidney49-50 and brain51-53 and can be induced by physiologic stimuli in the kidney, brain, ovary, uterus, cartilage, and bone.49, 54-66 Conversely, COX-1 can be induced in response to injury, for example in the crypt cells of the small intestine after radiation injury, and play a role in regeneration.47 Cyclooxygenase-2 seems to play an important role in a number of essential physiologic functions such as ovulation and implantation,55, 57 whereas COX-1 may play a critical role in inflammation, especially when it is induced by extracellular arachidonic acid or when it occurs in the skin.48 These findings have provided a more complex model of the interplay of COX-1 and COX-2 in both normal physiologic processes and in pathophysiologic conditions than the homeostasis vs inflammation paradigm of COX-1 and COX-2 action originally suggested.
Renal Function
Cyclooxygenase-1, expressed in the vasculature, glomeruli, and collecting ducts of the kidney, seems to produce vasodilating prostaglandins that maintain renal plasma flow and glomerular filtration rate especially during conditions of angiotensin-stimulated systemic vasoconstriction.37-38 The NSAIDs, known to have multiple clinical effects on kidney function37, 67 are thought to block this COX-1 protective response and lead to renal ischemia and functional damage in some individuals.37-38
Recent studies have suggested that COX-2 may also play a role in the development of the renal cortex and in maintaining kidney function. Mice that do not express COX-2 because of targeted gene disruption (COX-2–null mice) show severe disruption of kidney development.68-70 Cyclooxygenase-2 is expressed in the interstitial cells of the medulla of the rabbit kidney50 and in the macula densa and the thick ascending loop of Henle in the rat kidney.49 Moreover, recent work suggests that COX-2 is also expressed in the human kidney—not in the macula densa, but rather in the podocytes of the glomerulus and the endothelial cells of arteries and veins.71-72
Chronic sodium deprivation or experimental hyperfiltration states increase COX-2 expression in the rat kidney, suggesting that the prostaglandin produced by COX-2 may function to increase sodium reabsorption in response to volume contraction or hyperfiltration that may occur with progressive renal failure.49 Renal COX-2 is also up-regulated in the rat by long-term administration of angiotensin-converting enzyme inhibitors or type 1 angiotensin 2 receptor antagonists, suggesting feedback inhibition of COX-2 expression by the renin-angiotensin system. Moreover, a specific COX-2 inhibitor blocked the increase in plasma and kidney renin levels induced by captopril and also in a model of renovascular hypertension. As shown in Figure 2, these results suggest that COX-2 plays a role in the regulation of renin production. Thus, in the rat, angiotensin 2 appears to down-regulate COX-2 expression, whereas COX-2 is involved in the increased production of renin in response to inhibition of angiotensin 2 production.
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Figure 2. The role of cyclooxygenase-2 (COX-2) in renin angiotensin physiologic processes. The minus sign in parentheses (-) indicates a negative or inhibitory effect.
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In normal humans, specific COX-2 inhibitors induce a transient sodium retention associated with a marked decrease in 6-keto prostaglandin F1 excretion, a measure of renal prostacyclin production, but no alteration in glomerular filtration rate.73 These results are consistent with the conclusion that a major fraction of renal prostacyclin production is dependent on COX-2 activity, presumably in the renal vasculature, and that this may contribute to renal sodium balance independent of an effect on renal hemodynamics. Of importance, glomerular filtration rate in normal subjects, even the normal elderly, does not seem to depend on renal COX-2 function. Whether this is also the case in individuals with intrinsic renal disease or those with hypertension or volume contraction remains to be determined.
Gastrointestinal Tract Integrity
Cyclooxygenase-1 is the only COX isoform identified in the gastric mucosa of normal animals, including humans, and is intimately involved in protecting the stomach from erosions and ulceration.21-23,74 As a result of inhibiting COX-1, all currently available traditional NSAIDs impose a risk of gastric ulceration and the major complications of gastrointestinal bleeding, perforation, and obstruction.16-23 Gastrointestinal bleeding caused by NSAIDs seems to relate to 2 events: inhibition of platelet COX-1 activity that increases the tendency to bleed75-76 and inhibition of gastric COX-1 that increases the likelihood of ulceration.16, 21 The net result is a relative risk for gastrointestinal bleeding of approximately 4 for currently available NSAIDs.18-19 Since COX-2 is not detectable in the normal gastric mucosa nor in the platelet,36, 74 inhibition of COX-2 would not be expected to impose a risk of gastric ulceration or bleeding. However, COX-2 is expressed during the acute stages of gastric erosion and ulceration in animal models and might play a role in facilitating ulcer healing.77 Therefore, COX-2–specific inhibitors may increase the risk of major gastrointestinal adverse effects not by increasing the likelihood of developing an ulcer or bleeding, but by decreasing ulcer healing induced by other stimuli such as Helicobacter pylori or concomitant aspirin administration. The potential clinical impact of this effect of specific COX-2 inhibition has not yet been reported in clinical trials and, therefore, the relative risk of gastrointestinal bleeding associated with these agents is not certain.
Cyclooxygenase-2 may also play an important physiologic role in other parts of the gastrointestinal tract. In response to invasion by pathogenic microorganisms, epithelial cells express COX-2, which leads to increased prostaglandin production. This seems to play a protective role in the stimulation of the chloride and fluid flux that flushes bacteria from the intestine.78 Thus, COX inhibitors block the rapid intestinal secretion of fluid that accompanies the Salmonella infection of rhesus monkeys.79 Moreover, antibodies to PGE2 block the accelerated production of chloride from bacterially infected intestinal cells.78 Together, the data indicate that invasion by pathogenic microorganisms leads to the production of COX-2 by intestinal cells, which catalyzes the production of PGE2, which governs the chloride and fluid secretion involved in expelling the intestinal pathogen. The potential protective role of COX-2 in the intestine is emphasized by the fact that COX-2 levels are increased in inflammatory diseases such as ulcerative colitis, whereas selective inhibition of COX-2 may exacerbate inflammation in animal models of colitis.80 The exact role of COX-2 in maintaining intestinal integrity in humans remains unresolved, but specific COX-2 inhibitors could limit intestinal healing or diminish resistance to invasive microorganisms.
Nerve and Brain Function
Prostaglandin production plays a central role in the fever response and is thought to play a role in certain specific manifestations of brain function. The mechanism underlying the fever response seems to involve the COX-2 enzyme. In rats, intraperitoneal injection of lipopolysaccharide causes a marked fever response that temporally parallels COX-2 induction in the endothelial cells of the brain vasculature.81-82 This is thought to be mediated by interleukin-1 and perhaps other cytokines produced in response to lipopolysaccharides that stimulate brain endothelium.83 The resulting prostaglandins then act on temperature-sensing neurons in the preoptic area to produce the fever response. Cyclooxygenase-2–specific inhibition effectively blocks the fever response.84 Moreover, pyrexia in response to lipopolysaccharide stimulation does not occur in mice rendered COX-2 deficient by targeted gene disruption. By contrast, COX-1–deficient mice have a normal fever response.85
Cyclooxygenase-2 also seems to play an essential role in neural development and adaptation. While early-stage brain formation seems to be internally crafted by developmentally induced neural genes and proteins, the final stages of brain maturation are more environmentally imprinted by neural responses and synaptic activity and coincide with the local expression of COX-2 activity.86 Cyclooxygenase-2 is expressed most notably during ontogeny in the cortex and hippocampus. Throughout adult life, COX-2 may remain an important modulator of specific neural responses. Seizures, for example, strongly induce COX-2 in the postsynaptic dendritic arborization of excitatory neurons in major processing centers of the brain.51-52 Associations between COX-2 induction and neural degeneration following stresses such as glutamate stimulation,53 seizures, and spreading depressive waves54 suggest that the role of COX-2 and arachidonic acid metabolites produced may be involved in selective loss, but not formation, of neural connections. The role of COX-2 in human brain function and the potential impact of specific COX-2 inhibitors is unknown and requires evaluation, especially in view of the well-known negative impact of nonspecific COX inhibitors on cognitive function in the elderly.87
Cyclooxygenase-2 may also play a specific role in local inflammation in the brain. In this regard COX-2 can be up-regulated by specific stimuli in microglial cells, the tissue-specific macrophages that reside in the brain in a dormant condition until activated during host defense or tissue remodeling.88 Unlike other inflammatory cells, the microglial cell up-regulates COX-2 only in response to direct lipopolysaccharide exposure and not to cytokines, a rare event linked with direct bacterial infection of the brain. Thus, the microglial defense is usually not part of the systemic response to inflammation, but may play a critical role during brain infection.
Ovarian and Uterine Function
Although classically associated with parturition,89 prostaglandins and COX-2 have now been implicated as mediators of other stages of pregnancy, including ovulation and implantation. Studies with COX-2–null mice have documented reproductive failures at ovulation, fertilization, implantation, and deciduation,55 indicating the essential role of COX-2 at each of these stages.
When the induction of COX-2 was first observed immediately following the luteinizing hormone surge, research suggested that this COX isoform may play a role in normal physiologic events.90 This COX-2 induction accompanies normal oocyte development and seems to be necessary to produce the proteolytic enzymes that rupture the follicles.91 The inductive trigger for COX-2 during ovulation may involve luteinizing hormone and follicle-stimulating hormone, transforming growth factor ,92 or interleukin-1,56 leading to increased COX-2 gene transcription.58 Inhibition of COX-2 by NSAIDs may explain the infertility secondary to delayed or blocked follicular rupture associated with their use.93-96
Following fertilization in the mouse, COX-2 also plays a role in embryo implantation in the uterine myometrium. Whereas COX-1 and specific prostaglandin receptors apparently prepare the wall for interaction with the embryo,59-60 the COX-2 enzyme, leading to the production of prostacyclin, seems to be necessary for the implantation event itself.59, 97
Thrombosis
Maintenance of normal blood flow and the appropriate thrombogenic response to injury requires a delicate balance between the activities of platelet-produced thromboxane A2 and endothelial cell–derived prostacyclin (Table 1). After activation, platelets produce thromboxane A2 via the action of COX-1, the only COX isoform they contain.39, 75-76 Thromboxane A2 plays an essential role in the aggregation of platelets. The release of eicosanoids by activated platelets is thought to provide a substrate and a stimulus for the production of prostacyclin by endothelial cells.75 Prostacyclin stimulates vasodilatation, thereby counteracting the vasoconstrictive action of thromboxane A2.3 It has recently been shown that shear stress induces COX-2 expression in endothelial cells and that substantial amounts of eicosanoid production by endothelial cells results from the action of COX-2.98 In fact, recent studies have shown that excretion of 2,3 dinor 6-keto prostaglandin F1, a metabolite of prostacyclin that is indicative of systemic prostacyclin production in humans, was significantly inhibited by the administration of a specific COX-2 inhibitor.73, 99 These results indicate that a substantial proportion of systemic prostacyclin production derives from the action of COX-2. These data are all consistent with the conclusion that platelet thromboxane A2 production is uniquely regulated by the action of COX-1, whereas a substantial portion of endothelial cell–derived prostacyclin may be produced as a result of the action of COX-2. Since currently available NSAIDs inhibit both COX-1 and COX-2, a balanced impact on these prothrombotic and antithrombotic activities is expected. However, specific COX-2 inhibitors may limit the production of prostacyclin by endothelial cells while having no effect on the production of thromboxane A2 by platelets. The resulting imbalance may then favor platelet aggregation and vasoconstriction with a resulting increase in the tendency for vascular occlusion and tissue ischemia. The potential clinical impact of this imbalance has not been explored, but should be examined, especially in patients at risk for ischemic events.
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Cyclooxygenase Activity and Thrombosis*
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SUMMARY
A full awareness of the physiologic and pathophysiologic roles of COX-1 and COX-2 continues to emerge. Although the initial paradigm that COX-1 was homeostatic and COX-2 was proinflammatory provides a general conceptual framework, more recent investigation has clearly indicated more complex roles for these isoforms in both health and disease. As specific COX-2 inhibitors progress to market, attention should be given to potential adverse effects related to the kidney, gastrointestinal tract, bone, and brain as well as a potential negative impact on pregnancy and thrombogenic potential. On the other hand, new potential therapeutic targets for specific COX-2 inhibitors have emerged as a role for COX-2 in the development and progression of adenomatous polyposis and colon cancer. 100-113 Moreover, the possibility that COX-2 may play a role in the progression of Alzheimer disease has also been suggested.114-120 Thus, developing information about the biologic function of COX-2 has presented the clinician with new challenges as well as new opportunities.
AUTHOR INFORMATION
Accepted for publication September 15, 1999.
The authors are members of the International COX-2 Study Group that has received unrestricted educational grants from G. D. Searle (Skokie, Ill), Pfizer Inc (New York, NY), Merck & Co Inc (Whitehouse Station, NJ), Johnson & Johnson (New Brunswick, NJ), and Roche Bioscience (Palo Alto, Calif).
Reprints: Peter E. Lipsky, MD, Rheumatic Diseases Division, Arthritis Research Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-8884 (e-mail: peter.lipsky{at}email.swmed.edu).
From the University of Texas Southwestern Medical Center, Dallas (Dr Lipsky); The University of Queensland, Brisbane, Australia (Dr Brooks); University of Michigan Medical Center, Ann Arbor (Dr Crofford); Vanderbilt University Medical Center, Nashville, Tenn (Dr DuBois); Veterans Affairs Medical Center Houston, Houston, Tex (Dr Graham); Harvard Medical School, Boston, Mass (Dr Simon); University Hospital Nijmegen, Nijmegen, the Netherlands (Dr van de Putte); and New York University School of Medicine, New York, NY (Dr Abramson).
REFERENCES
| |
1. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J. 1998;12:1063-1073.
FREE FULL TEXT
2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature. 1971;231:232-235.
3. Davies P, Bailey PJ, Goldenberg MM, Ford-Hutchinson AW. The role of arachidonic oxygenation products in pain and inflammation. Annu Rev Immunol. 1984;2:335-357.
FULL TEXT
|
ISI
| PUBMED
4. Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum. 1997;26:2-10.
FULL TEXT
|
ISI
| PUBMED
5. Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta. 1996;1299:125-140.
PUBMED
6. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem. 1996;271:33157-33160.
FREE FULL TEXT
7. Jouzeau J-Y, Terlain B, Abid A, Nédélec E, Netter P. Cyclo-oxygenase isoenzymes. Drugs. 1997;53:563-582.
ISI
| PUBMED
8. Masferrer JL, Isakson PC, Seibert K. Cyclooxygenase-2 inhibitors. Gastroenterol Clin North Am. 1996;25:363-372.
FULL TEXT
|
ISI
| PUBMED
9. van Ryn J, Pairet M. Selective cyclooxygenase-2 inhibitors: pharmacology, clinical effects and therapeutic potential. Exp Opin Invest Drugs. 1997;6:609-614.
FULL TEXT
10. Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor. Arthritis Rheum. 1998;41:1591-1602.
FULL TEXT
|
ISI
| PUBMED
11. Ehrich E, Schnitzer T, Kivitz A, et al. MK-966, a highly selective cox-2 inhibitor, was effective in the treatment of osteoarthritis (OA) of the knee and hip in a 6-week placebo controlled study. Arthritis Rheum. 1997;40(supp):S85.
12. Zhang Y, Shaffer A, Portanova J, Seibert K, Isakson PC. Inhibition of cycloocygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. J Pharmacol Exp Ther. 1997;283:1069-1075.
FREE FULL TEXT
13. Portanova JP, Zhang Y, Anderson GD, et al. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J Exp Med. 1996;184:883-891.
FREE FULL TEXT
14. Davies N. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995;38:1311-1321.
FULL TEXT
|
ISI
| PUBMED
15. Gutthann SP. Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure. Arch Intern Med. 1996;156:2433-2439.
FREE FULL TEXT
16. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104:413-421.
FULL TEXT
|
ISI
| PUBMED
17. Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol. 1996;62:167-215.
ISI
| PUBMED
18. García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:769-772.
FULL TEXT
|
ISI
| PUBMED
19. García Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med. 1998;158:33-39.
FREE FULL TEXT
20. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. Arch Intern Med. 1996;156:1530-1536.
FREE FULL TEXT
21. Scheiman JM. NSAIDs, gastrointestinal injury, and cytoprotection. Gastroenterol Clin North Am. 1996;25:279-299.
FULL TEXT
|
ISI
| PUBMED
22. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to the use of nonsteroidal antiinflammatory drugs: a meta-analysis. Ann Intern Med. 1991;115:787-796.
23. Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:1075-1078.
FULL TEXT
|
ISI
| PUBMED
24. Raz A, Wyche A, Siegel N, Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988;263:3022-3028.
FREE FULL TEXT
25. Raz A, Wyche A, Siegel N, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci U S A. 1989;86:1657-1661.
FREE FULL TEXT
26. Fu J, Masferrer J, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Clin Invest. 1990;86:1375-1379.
27. Kraemer SA, Meade SA, Dewitt DL Arch Biochem Biophys. 1992;293:391-400.
FULL TEXT
|
ISI
| PUBMED
28. Kujubu DA, Fletcher BS, Varnum BC, Lim FW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991;266:12866-12872.
FREE FULL TEXT
29. Jones DA, Carlton DD, McIntyre TM, Zimmerman GA, Prescott SM. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expiation in response to cytokines. J Biol Chem. 1993;268:9049-9054.
FREE FULL TEXT
30. Muakami M, Matsumoto R, Austen KF, Arm JP. Prostaglandin endoperoxide synthase-1 and -2 couple to different transmembrane stimuli to generate prostaglandin D2 in mouse bone marrow-derived mast cells. J Biol Chem. 1994;269:22269-22275.
FREE FULL TEXT
31. Kawata R, Reddy ST, Wolner B, Herschman HR. Prostaglandin synthase I and prostaglandin synthase II both participate in activation-induced prostaglandin D2 production in mast cell. J Immunol. 1995;155:818-825.
ABSTRACT
32. Karim S, Habib A, Levy-Toledano S, Maclouf J. Cyclooxygenases-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem. 1996;271:12042-12048.
FREE FULL TEXT
33. Kurumbail RG, Stevens AM, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384:644-648.
FULL TEXT
| PUBMED
34. Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat Struct Biol. 1996;3:927-933.
FULL TEXT
|
ISI
| PUBMED
35. Picot D, Loll PJ, Garavito M. The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994;367:243-249.
FULL TEXT
| PUBMED
36. Crofford L. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol. 1997;24:15-19.
37. Zambraski EJ. The effects of nonsteroidal anti-inflammatory drugs on renal function: experimental studies in animals. Semin Nephrol. 1995;15:205-213.
ISI
| PUBMED
38. Breyer MD, Jacobson HR, Breyer RM. Functional and molecular aspects of renal prostaglandin receptors. J Am Soc Nephrol. 1996;7:8-17.
ABSTRACT
39. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978;61:314-319.
40. Crofford LJ. Expression and regulation of cyclooxygenase-2 in synovial tissues of arthritic patients. In: Bazan N, Botting J, Vane J, eds. New Targets in Inflammation: Inhibitors of COX-2 or Adhesion Molecules. Boston, Mass: Kluwer Academic Publishers, William Harvey Press; 1996:83-91.
41. Kang RY, Freire-Moar J, Sigal E, Chu C-Q. Expression of cyclooxygenase-2 in human and and animal models of rheumatoid arthritis. Br J Rheumatol. 1996;35:711-718.
FREE FULL TEXT
42. Crofford LJ, Wilder RL, Ristimaki AD, Remmers EF, Epps HR, Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1, phorbol ester, and corticosteroids. J Clin Invest. 1994;93:1095-1101.
43. Anderson GD, Hauser SD, Bremer ME, McGarity KL, Isakson PC, Gregory SA. Selective inhibition of cyclooxygenase-2 reverses inflammation and expression of COX-2 and IL-6 in rat adjuvant arthritis. J Clin Invest. 1996;97:2672-2679.
ISI
| PUBMED
44. Brannon TS, North AJ, Wells LB, Shaul PW. Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression. J Clin Invest. 1994;93:2230-2235.
45. Hla T, Maciag T. Cyclooxygenase gene expression is down-regulated by heparin-binding (acid fibroblast) growth factor-1 in human endothelial cells. J Biol Chem. 1991;266:24059-24063.
FREE FULL TEXT
46. Samet JM, Fasano MB, Fonteh AN, Chilton FH. Selective induction of prostaglandin G/H synthase I by stem cell factor and dexamethasone in mast cells. J Biol Chem. 1995;270:8044-8049.
FREE FULL TEXT
47. Cohn SM, Schloemann S, Tessner T, Seibert K, Stenson WF. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J Clin Invest. 1997;99:1367-1379.
ISI
| PUBMED
48. Langenbach R, Morham SG, Tirano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid–induced inflammation and indomethacin-induced gastric ulceration. Cell. 1995;83:483-492.
FULL TEXT
|
ISI
| PUBMED
49. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;94:2504-2510.
50. Guan Y, Chang M, Cho W, et al. Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol. 1997;273:F18-F26.
51. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993;11:371-386.
FULL TEXT
|
ISI
| PUBMED
52. Kaufmann WE, Worley P, Pegg J, Bremer M, Isakson PC. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996;93:2317-2321.
FREE FULL TEXT
53. Tocco G, Freire-Moar J, Schreiber SS, Sakhi SH, Aisen PS, Pasinetti GM. Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer's disease. Exp Neurol. 1997;144:339-349.
FULL TEXT
|
ISI
| PUBMED
54. Miettinen S, Fusco F, Yrjanheikki J, et al. Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci U S A. 1997;94:6500-6505.
FREE FULL TEXT
55. Lim H, Paria B, Das SK, et al. Multiple female reproductive failures in cyclooxygenase-2 deficient mice. Cell. 1997;91:197-208.
FULL TEXT
|
ISI
| PUBMED
56. Narko K, Ritvos O, Ristimaki A. Induction of cyclooxygenase-2 and prostaglandin F2 alpha receptor expression by interleukin-1 beta in cultured human granulosa-luteal cells. Endocrinology. 1997;138:3638-3644.
FREE FULL TEXT
57. Chakraborty I, Das SK, Wang J, Dey SK. Developmental expression of the cyclo-oxygenase-1 and cyclo-oxygenase-2 genes in the peri-implantation mouse uterus and their differential regulation by the blastocyst and ovarian steroids. J Mol Endocrinol. 1996;16:107-122.
FREE FULL TEXT
58. Morris JK, Richards JS. An E-box region within the prostaglandin endoperoxide synthase-2 (PGS-2) promoter is required for transcription in rat ovarian granulosa cells. J Biol Chem. 1996;271:16633-16643.
FREE FULL TEXT
59. Chakraborty I, Das S, Wang J, Dey SK. Developmental expression of the cyclo-oxygenase-1 and cyclo-oxygenase-2 genes in the peri-implantation mouse uterus and their differential regulation by the blastocyst and ovarian steroids. J Mol Endocrinol. 1996;16:107-122.
60. Yang ZM, Das S, Wang J, Sugimoto Y, Ichikawa A, Dey SK. Potential sites of prostaglandin actions in the periimplantation mouse uterus: differential expression and regulation of prostaglandin receptor genes. Biol Reprod. 1997;56:368-379.
ABSTRACT
61. Bergmann P, Schoutens A. Prostaglandins and bone. Bone. 1995;16:485-488.
PUBMED
62. Pilbeam CC, Fall PM, Alander CB, Raisz LG. Differential effects of nonsteroidal anti-inflammatory drugs on constitutive and inducible prostaglandin G/H synthase in cultured bone cells. J Bone Miner Res. 1997;12:1198-1203.
FULL TEXT
|
ISI
| PUBMED
63. Tai H, Miyaura C, Pilbeam CC, et al. Transcriptional induction of cyclooxygenase-2 in osteoblasts is involved in interleukin-6-induced osteoclast formation. Endocrinology. 1997;138:2372-2379.
FREE FULL TEXT
64. Sato T, Morita I, Sakaguchi K, Nakahama K, Murota S. Involvement of cyclooxygenase-2 in bone loss induced by interleukin-1 beta. Adv Prostaglandin Thromboxane Leukotriene Res. 1995;23:445-447.
ISI
| PUBMED
65. Onoe Y, Miyaura C, Kaminakayashiki T, et al. IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts. J Immunol. 1996;156:758-764.
ABSTRACT
66. Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. J Clin Invest. 1997;99:1231-1237.
ISI
| PUBMED
67. Palmer BF, Henrich WL. Clinical acute renal failure with nonsteroidal anti-inflammatory drugs. Semin Nephrol. 1995;15:214-227.
ISI
| PUBMED
68. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 1995;378:406-409.
FULL TEXT
| PUBMED
69. Morham SG, Langenbach R, Loftin CD. Prostaglandin synthase-2 gene disruption causes severe renal pathology in the mouse. Cell. 1995;83:473-482.
FULL TEXT
|
ISI
| PUBMED
70. Zhang M-Z, Wang J-L, Cheng H-F, Harris RC, McKanna JA. Cyclooxygenase-2 in rat nephron development. Am J Physiol. 1997;273:F994-F1002.
71. Komhoff M, Grone JJ, Klein T, Seyerth HW, Nusing RM. Localization of cyclooxygenase-1 and cyclooxygenase-2 in adult and fetal human kidney: implication for renal function. Am J Physiol. 1997;272:F460-F468.
72. Khan KNM, Venturini CM, Bunch RT, et al. Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Path. 1998;26:612-620.
FULL TEXT
|
ISI
| PUBMED
73. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase 2 on sodium balance, hemodynamics and vasoactive eicosanoids. J Pharmacol Exp Ther. 1999;289:735-741.
FREE FULL TEXT
74. Kargman S, Charleson S, Cartwright M, et al. Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology. 1996;111:445-454.
FULL TEXT
|
ISI
| PUBMED
75. Schafter AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol. 1995;35:209-219.
ABSTRACT
76. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994;330:1237-1294.
FREE FULL TEXT
77. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997;112:387-397.
FULL TEXT
|
ISI
| PUBMED
78. Eckmann L, Stenson WF, Savidge TC, et al. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria: bacterial entry induces epithelial prostaglandin H synthase-2 expression and prostaglandin E2 and F2a production. J Clin Invest. 1997;100:296-269.
ISI
| PUBMED
79. Gianella RA, Formal SB, Dammin GJ, Collins H. Pathogenesis of salmonellosis: studies of fluid secretion, mucosal invasion, and morphologic reactions in the rabbit ileum. J Clin Invest. 1973;52:441-453.
80. Wallace JL, Keenan CM, Gale D, Shoupe TS. Exacerbation of experimental colitis by nonsteroidal antiinflammatory drugs is not related to elevated leukotriene B4 synthesis. Gastroenterology. 1992;102:18-27.
ISI
| PUBMED
81. Cao C, Matsumura K, Yamagata K, Watanabe Y. Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain. Am J Physiol. 1997;272:R1712-R1725.
82. Matsumura K, Cao C, Watanabe Y. Possible role of cyclooxygenase-2 in the brain vasculature in febrile response. Ann N Y Acad Sci. 1997;813:302-306.
PUBMED
83. Cao C, Matsumura K, Watanabe Y. Induction of cyclooxygenase-2 in the brain by cytokines. Ann N Y Acad Sci. 1997;813:307-309.
PUBMED
84. Taniguchi Y, Yokoyama K, Inui K, Deguchi Y, Furukawa K, Noda K. Inhibition of brain cyclooxygenase-2 activity and the antipyretic action of nimesulide. Eur J Pharmacol. 1997;330:221-229.
FULL TEXT
|
ISI
| PUBMED
85. Li S, Wang Y, Matsumura K, Ballou L, Morham SG, Blatteis CM. The febrile response to lipopoly-saccharide (LPS) is blocked in COX-2-/- but not in COX-1-/- mice. Brain Res. 1999;825:86-94.
FULL TEXT
|
ISI
| PUBMED
86. Kaufmann WE, Worley P, Taylor CV, Bremer M, Isakson PC. Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome. Brain Dev. 1997;19:25-34.
FULL TEXT
|
ISI
| PUBMED
87. Saag KG, Rubenstein LM, Chrischilles EA, Wallace RB. Nonsteroidal antiinflammatory drugs and cognitive decline in the elderly. J Rheumatol. 1995;22:2142-2147.
ISI
| PUBMED
88. Bauer MK, Lieb K, Schulze-Osthoff K, et al. Expression and regulation of cyclooxygenase-2 in rat microglia. Eur J Biochem. 1997;243:726-731.
ISI
| PUBMED
89. Sugimoto Y, Yamasaki A, Segi E, et al. Failure of parturition in mice lacking the prostaglandin F receptor. Science. 1997;277:681-683.
FREE FULL TEXT
90. Richards JS, Fitzpatrick S, Clemens JW, Morris JK, Alliston T, Sirois J. Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes. Recent Prog Horm Res. 1995;50:223-254.
91. Tsafriri A. Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. Adv Exp Med Biol. 1995;377:121-140.
PUBMED
92. Li J, Simmons D, Tsang BK. Regulation of hen granulosa cell prostaglandin production by transforming growth factors during follicular development: involvement of cyclooxygenase II. Endocrinology. 1996;137:2522-2529.
ABSTRACT
93. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol. 1996;35:76-78.
FREE FULL TEXT
94. Thylan S. NSAIDs and fertility. Br J Rheumatol. 1996;36:145-146.
95. Athanasiou S, Bourne TG, Kalid A, et al. Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women. Fertil Steril. 1996;65:556-560.
ISI
| PUBMED
96. Roberts R, Smith GW, Hall C, Nuke G. Leteinised unreputed follicles in women with inflammatory arthritis taking NSAIDs [abstract]. Br J Rheumatol. 1995;34(suppl 2):22.
97. Lim H, Dey S. Prostaglandin E-2 receptor subtype EP2 gene expression in the mouse uterus coincides with differentiation of the luminal epithelium for implantation. Endocrinology. 1997;138:4599-4606.
FREE FULL TEXT
98. Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996;93:10417-10422.
FREE FULL TEXT
99. McAdam BF, Catella-Lawson F, Mardini LA, Kapoor S, Lawson JA, Fitzgerald GA. 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.
FREE FULL TEXT
100. Oshima M, Dinchuk J, Kargman SL, et al. Suppression of intestinal polyposis in APC  716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2). Cell. 1996;87:803-809.
FULL TEXT
|
ISI
| PUBMED
101. Jacoby RF, Marshall DJ, Newton MA, et al. Chemoprevention of spontaneous intestinal adenomas in the Apc Minmouse model by the nonsteroidal anti-inflammatory drug piroxicam. Cancer Res. 1996;56:710-714.
FREE FULL TEXT
102. Thun MJ, Namboodiri MM, Heath CWJ. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325:1593-1596.
ABSTRACT
103. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328:1313-1316.
FREE FULL TEXT
104. Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr. Aspirin use and risk of fatal cancer. Cancer Res. 1993;53:1322-1327.
FREE FULL TEXT
105. Thun MJ. NSAID use and decreased risk of gastrointestinal cancers. Gastroenterol Clin North Am. 1996;25:333-348.
FULL TEXT
|
ISI
| PUBMED
106. Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med. 1994;121:241-246.
FREE FULL TEXT
107. Giovannucci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med. 1995;333:609-614.
FREE FULL TEXT
108. Williams CS, Smalley W, DuBois RN. Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest. 1997;100:1325-1329.
ISI
| PUBMED
109. Smalley WE, DuBois RN. Colorectal cancer and nonsteroidal antiinflammatory drugs. Adv Pharmacol. 1997;39:1-20.
110. Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res. 1995;55:2556-2559.
FREE FULL TEXT
111. Hanif R, Pittras A, Feng Y, et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharm. 1996;52:237-245.
FULL TEXT
|
ISI
| PUBMED
112. Sheng H, Shao J, Kirkland SC, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest. 1997;99:2254-2259.
ISI
| PUBMED
113. Sheng H, Shao J, Morrow JD, Beuchamp RD, DuBois RN. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998;58:362-366.
FREE FULL TEXT
114. Breitner JC, Welsh KA, Helms MJ, et al. Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16:523-530.
FULL TEXT
|
ISI
| PUBMED
115. Breitner JC. Inflammatory processes and antiinflammatory drugs in Alzheimer's disease: a current appraisal. Neurobiol Aging. 1996;17:789-794.
FULL TEXT
|
ISI
| PUBMED
116. Breitner JCS, Welsh KA, Helms MJ, et al. Delayed onset on Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16:523-530.
117. Steward WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology. 1997;48:626-632.
FREE FULL TEXT
118. Andersen K, Launer LJ, Ott A, Hoes AW, Breteler MMB, Hofman A. Do nonsteroidal anti-inflammatory drugs decrease the risk of Alzheimer's disease? The Rotterdam Study. Neurology. 1995;45:1441-1445.
FREE FULL TEXT
119. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. 1996;47:425-432.
FREE FULL TEXT
120. de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology. 1997;43:26-43.
ISI
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