thromboxane-a2 and rofecoxib

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2 Inhibitors; Epoprostenol; Humans; Isoxazoles; Lactones; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Sulfones; Thromboxane A2

Even though non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for a long time, the search continues for anti-inflammatory drugs with few side-effects. COX-2 inhibitors are currently most debated, because they have less gastrointestinal side effects but have been linked to increased cardiovascular morbidity and mortality, presumably related to thrombotic events. This has brought about the withdrawal of rofecoxib and other COX-2 inhibitors from the market. Although the results of several large studies with prospective, randomized design and meta-analysis of different trials have led to the demise of many popular COX-2 inhibitors, yet the conclusion seems to be rather simplistic. This review presents evidence from basic biology and clinical studies with the expectation that a balanced position, particularly in relation to increase in cardiovascular events, may be elucidated.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diclofenac; Drug Labeling; Endothelium, Vascular; Epoprostenol; Humans; Lactones; Platelet Aggregation; Product Surveillance, Postmarketing; Pyrazoles; Randomized Controlled Trials as Topic; Risk Assessment; Sulfonamides; Sulfones; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Epoprostenol; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Thromboxane A2

Angiogenesis is required for multistage carcinogenesis. The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. COX-2 expression occurs in a wide range of preneoplastic and malignant conditions; and the enzyme has been localized to the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within tumors. The proangiogenic effects of COX-2 are mediated primarily by three products of arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)), and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these eicosanoid products include: (1) production of vascular endothelial growth factor; (2) promotion of vascular sprouting, migration, and tube formation; (3) enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4) induction of matrix metalloproteinases; (5) activation of epidermal growth factor receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production. Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in vitro and in vivo. Because these agents are safe and well tolerated, selective COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer prevention, as well as for intervention in established disease alone or in combination with chemotherapy, radiation, and biological therapies.

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Celecoxib; Cell Movement; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Epidermal Growth Factor; Epoprostenol; Humans; Interleukin-12; Isoenzymes; Lactones; Matrix Metalloproteinases; Membrane Proteins; Neoplasms; Neovascularization, Pathologic; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Signal Transduction; Sulfonamides; Sulfones; Thromboxane A2; Vascular Endothelial Growth Factor A

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cardiovascular Diseases; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Dinoprostone; Epoprostenol; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Incidence; Intestinal Mucosa; Isoenzymes; Lactones; Membrane Proteins; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Randomized Controlled Trials as Topic; Substrate Specificity; Sulfonamides; Sulfones; Thromboembolism; Thromboxane A2; Treatment Outcome

Cigarette smoking is highly pathogenic to the vasculature. In smokers, the biosynthesis of both thromboxane (Tx) A2 and prostacyclin is increased. We hypothesized that the excess in prostacyclin biosynthesis in smokers was derived from the inducible cyclooxygenase-2 (COX-2). We further hypothesized that if the overproduction of prostacyclin in smokers were restraining platelet activation, then inhibition of COX-2 would lead to an increase in the activation of platelets, with a corresponding increase in the biosynthesis of TxA2.. Smokers and nonsmokers received rofecoxib 25 mg twice daily or placebo for 1 week each in random sequence. The systemic biosynthesis of TxA2 and prostacyclin was assessed by analysis of their respective urinary metabolites, 11-dehydrothromboxane B2 (Tx-M) and 2'3-donor-6-keto-PGF(1alpha) (PGI-M). Serum TxB2 was measured as an indicator of platelet COX-1 activity. Results are expressed as mean+/-SE with median and range. The elevated PGI-M in smokers (189+/-25, median 174, range 85 to 390 pg/mg creatinine) was reduced by rofecoxib to 78+/-27, median 71.5, range 50 to 135 pg/mg creatinine (P=0.002), and in nonsmokers, PGI-M at baseline (115+/-10, median 107, range 67 to 198 pg/mg creatinine) fell to 56+/-15, median 50, range 34 to 125 pg/mg creatinine (P=0.001) with rofecoxib. The increased excretion of Tx-M in smokers (284+/-26, median 252, range 200 to 569 pg/mg creatinine) was reduced by 21% to 223+/-16, median 206, range 154 to 383 pg/mg creatinine by rofecoxib (P=0.04) but was not changed in nonsmokers. Levels of serum TxB2 were not different in smokers and nonsmokers and were unaffected by rofecoxib.. The increased prostacyclin biosynthesis in smokers is derived largely from the inducible COX-2. COX-2 also contributes to the increased biosynthesis of TxA2 in smokers, most likely from inflammatory cells.

Topics: Adult; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Double-Blind Method; Epoprostenol; Humans; Lactones; Male; Membrane Proteins; Platelet Activation; Prostaglandins; Reference Values; Smoking; Sulfones; Thromboxane A2

It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.

Topics: Aspirin; Blood Platelets; Blood Proteins; Calcimycin; Calcium; Celecoxib; Cell Line; Cerebrospinal Fluid Proteins; Cyclooxygenase 1; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Humans; Indomethacin; Ionophores; Lactones; Meloxicam; Naproxen; Organ Specificity; Organic Chemicals; Protein Binding; Pyrazoles; Sodium Salicylate; Sulfonamides; Sulfones; Synovial Fluid; Thiazines; Thiazoles; Thromboxane A2

Licofelone is an analogue of arachidonic acid that inhibits 5-lipoxygenase (LOX), cyclooxygenase (COX)-1 and COX-2. We investigated the effects of licofelone on cardiovascular derangements and production of thromboxane (Tx)A(2) induced by the inflammatory agonist n-formyl-methionyl-leucyl-phenylalanine (fMLP) in the rabbit, in comparison with those of aspirin or rofecoxib, inhibitors of COX-1 and COX-2, respectively. In control rabbits, injection of fMLP (30 nmol/kg) in the jugular vein evokes ischemic electrocardiographic (ECG) changes in the first 1-5 min, i.e. a profound depression of the ST segment and inversion of the T wave. Simultaneously, fMLP induces bradycardia and hypotension and increases TxB(2) blood levels. All changes are transient. Licofelone (60 mg/kg/5 days, p.os) prevented fMLP-induced ECG ischemic changes in all treated animals, reverted bradycardia and hypotension, and significantly reduced TxB(2). Aspirin (10 mg/kg/5 days, p.os) prevented ischemic ECG alterations in 2 out of 5 treated animals and did not modify either bradycardia or hypotension. One rabbit died two min after fMLP. In 2 rabbits, aspirin reduced TxB(2) levels by more than 80% respect to mean control values; the remaining two rabbits produced an amount of TxB(2) similar to controls. These two rabbits also showed ischemic ECG changes. Rofecoxib (10 mg/kg/5 days, p.os) did not prevent fMLP-induced ischemic ECG alteration, bradycardia and hypotension, and did not significantly modify the increase of TxB(2). These results indicate that the capacity of licofelone to efficiently suppress TxA(2) production, is responsible for the protection from the cardiovascular derangement triggered by an inflammatory stimulus.

Topics: Acetates; Animals; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Electrocardiography; Heart Rate; Inflammation; Lactones; Leukotriene B4; Lipoxygenase Inhibitors; Male; Myocardial Ischemia; N-Formylmethionine Leucyl-Phenylalanine; Pyrroles; Rabbits; Sulfones; Thromboxane A2; Time Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiovascular System; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension; Lactones; Sulfones; Thromboxane A2

Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Approval; Drug Industry; Epoprostenol; Gastrointestinal Diseases; Humans; Isoenzymes; Isoxazoles; Lactones; Membrane Proteins; Naproxen; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Risk; Sulfonamides; Sulfones; Thromboxane A2; United States; United States Food and Drug Administration

The study was undertaken to determine the effects of a cyclo-oxygenase II inhibitor on fetoplacental artery production of prostacyclin and thromboxane A(2).. Eight placentas were obtained from normal parturients at delivery and four chorionic plate arteries were dissected from each placenta. Arteries were incubated in media alone, media plus angiotensin II (1x10(-10) mol), media plus rofecoxib (300 ng/mL), or media plus angiotensin II and rofecoxib. Serial samples were assayed for metabolites of thromboxane B(2) and prostacyclin by enzyme-linked immunosorbent assay. Results were compared by analysis of variance, and P<.05 was considered significant.. At 24 hours, 6-keto-prostaglandin F(1alpha) levels in the rofecoxib group (1.74+/-1.39 ng/mg tissue, P<.01) and the rofecoxib plus angiotensin II group (2.15+/-1.85 ng/mg tissue, P<.01) were significantly lower than levels in the control group (4.25+/-2.03 ng/mg tissue). Thromboxane B(2) levels were lower in the angiotensin II group (0.65+/-0.33 ng/mg tissue) than the control group (1.22+/-0.70 ng/mg tissue, P<.05).. Cyclo-oxygenase II inhibition decreases the production of prostacyclin in fetoplacental arteries and alters the normal ratio of thromboxane A(2) to prostacyclin.

Topics: Angiotensin II; Arteries; Culture Media; Culture Techniques; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; Female; Humans; Isoenzymes; Lactones; Membrane Proteins; Placenta; Pregnancy; Prostaglandin-Endoperoxide Synthases; Sulfones; Thromboxane A2

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carotid Artery Injuries; Cell Division; Clinical Trials as Topic; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Epoprostenol; Homeostasis; Humans; Isoenzymes; Lactones; Membrane Proteins; Mice; Muscle, Smooth, Vascular; Myocardial Infarction; Naproxen; Platelet Activation; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfones; Thromboxane A2

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carotid Artery Injuries; Carotid Artery, Common; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Endothelium, Vascular; Epoprostenol; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Naphthalenes; Platelet Activation; Platelet Aggregation; Propionates; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfones; Tetrahydronaphthalenes; Thromboxane A2; Tunica Intima

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Lactones; Membrane Proteins; Mice; Myocardial Infarction; Naproxen; Prostaglandin-Endoperoxide Synthases; Sulfones; Thromboxane A2