Use Of Selective Cyclooxygenase-2 Inhibitors Research Articles

Risk factor management matters more than pharmaceutical cyclooxygenase-2 inhibition in the prevention of de novo intracranial aneurysms.

Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2-PGE2-NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients. The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses. De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level. For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition.

Factors Associated with the Risk of Major Adverse Cardiovascular Events in Patients with Ankylosing Spondylitis: A Nationwide, Population-Based Case-Control Study.

Background: Potential risk factors for major adverse cardiovascular events (MACE) in patients with ankylosing spondylitis (AS) requiring medical therapy should be investigated. Methods: We identified newly diagnosed AS patients without previous MACE from 2004 to 2012 using the National Health Insurance Research Database, matched MACE cases with non-MACE controls at a 1:4 ratio for age, gender, AS duration, and index date, and included 947 AS patients with MACE and 3896 matched controls for final analyses. By using conditional logistic regression analyses, we examined the associations of MACE with low income, urbanisation, comorbidities, common extra-articular manifestations (EAM), and medications, including nonsteroidal anti-inflammatory drugs (NSAID) of three categories (traditional NSAIDs, selective cyclooxygenase-2 inhibitors (COX-2i), and preferential COX-2is) with their annual cumulative defined daily dose (cDDD) within a year before MACE development. Results: MACE development was associated with the use of selective COX-2is (especially with annual cDDD > 132) and corticosteroids, residence in rural regions, and well-known associated comorbidities, but not with the use of traditional NSAIDs, preferential COX-2i, biologics, methotrexate, sulfasalazine, and common EAMs. Conclusions: The risk factors of MACE in newly diagnosed AS patients include residence in rural regions, well-known associated comorbidities, and the use of corticosteroids and selective COX-2is. A major limitation was the lack of information on individual lifestyle patterns and disease activity.

Design, Synthesis and Biological Evaluation of New N-Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX-2 Inhibitors.

The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX-1 enzyme. Therefore, the use of COX-2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX-2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX-2 inhibitors remain necessary. It is important to develop new COX-2 inhibitors in the field of medicinal chemistry. Accordingly, novel N-acyl hydrazone derivatives were synthesized as new COX-2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX-2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a-3j) was characterized by spectroscopic methods. Evaluation of in vitro COX-1/COX-2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX-2 enzyme inhibition. Compound 3j showed important COX-2 inhibition with a value of IC50 =0.143 uM. Interaction modes between the COX-2 enzyme and compound 3j were investigated by docking studies.

Cardiovascular Safety of Celecoxib after Cardiac Surgery with Cardiopulmonary Bypass: A Retrospective Cohort Study.

Cardiac surgery is a highly invasive procedure resulting in hypercoagulability due to thoracotomy and cardiopulmonary bypass (CPB). The long-term use of selective cyclooxygenase-2 inhibitors has been shown to increase the risk of adverse cardiovascular (CV) events such as myocardial infarction. This study aimed to determine whether short-term prescription of celecoxib increases CV events in patients who have undergone cardiac surgery with CPB. This retrospective observational study included 16,141 patients (≥20 years) who had undergone cardiac surgery with CPB between April 1, 2008 and March 31, 2016. Patients who underwent coronary artery bypass grafting were excluded. Patients who received celecoxib (n = 904) and acetaminophen (n = 5,002) from postoperative day 0 to 30 were extracted and matched by propensity score (PS). The primary outcomes were all-cause death and CV events, defined as coronary artery disease, ischemic stroke, pulmonary embolism, and venous thrombosis, coded using International Classification of Diseases-10 within 30 days after the first postoperative prescription of either medication. Results were assessed using Kaplan-Meier survival analysis and multivariate Cox regression analysis. PS matching created 885 pairs. Multivariate Cox regression analysis showed that prescription of celecoxib after cardiac surgery was not associated with an increase in the primary outcomes when compared with prescription of acetaminophen (hazard ratio, 0.76; 95% confidence interval, 0.35-1.65). The prescription of celecoxib in patients who had undergone cardiac surgery with cardiopulmonary bypass was not statistically different from the prescription of acetaminophen in the incidence of CV events and death.

Celecoxib versus indomethacin as prevention of arthrofibrosis. A perspective case-control study

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly utilised prophylaxis to reduce arthrofibrosis (AF) related to the inflammatory response which leads to a pathological condition called arthrofibrosis. Several NSAIDs have shown to be effective, although postoperative indomethacin has been the historical gold standard. More recently, credit has been given to the use of COX-2 selective inhibitors, due to concerns over gastrointestinal effects, as peptic ulcers, with non-selective COX. However, to date, few studies have compared the therapeutic effects of the two drugs. The aim of this study is to compare the postoperative administration of indomethacin and celecoxib in patients with diagnosis of AF treated with arthroscopic lysis and evaluate joint recovery. In this prospective study, 42 patients were diagnosed with hip, knee and elbow residual AF. The inclusion criteria were age > 18 years and a diagnosis of residual AF, following exposure to a previous traumatic event or surgical treatment; exclusion criteria were patients with 35 or < 18 kg/m2, affected by peripherical neuropathies and presence of heavy functional limitations, active infection, complex regional pain syndrome diagnoses. All patients underwent to arthroscopy, operated by a single surgeon with the same team in the same clinic and postoperatively were randomly divided into two groups, one treated with indomethacin, and the other with celecoxib. Of the patients examined, the following parameter was considered: joint range of motion (ROM) preintervention and post-intervention at 3 months and after 12 months. ROM was analysed with Student t test. The comparison of the ROM between both the 3 months postoperative groups has been shown to be not statistically significant. On the other hand, after 1 year, t-Student test referred to preoperative condition was significantly in favour of the group treated with celecoxib (p = 0.02). Lastly, neither celecoxib nor indomethacin showed any gastrointestinal side effects.

Selective cyclooxygenase-2 inhibitor use and progression of renal function in patients with chronic kidney disease: a single-center retrospective cohort study.

BackgroundThe use of selective COX-2 (sCOX-2) inhibitors with acute kidney injury, salt water retention, and cardiovascular events have been correlated in subjects with normal kidney function, but sCOX-2 inhibitor use concerning the progression of chronic kidney disease (CKD) remains uncertain.ObjectivesTo determine the progression of renal function and electrolyte abnormalities among CKD patients after using sCOX-2 inhibitors during short- and long-term periods.MethodsThe study employed a retrospective cohort design comprising all types of CKD patients with and without sCOX-2 inhibitors (celecoxib and etoricoxib). Data collected included medical data, estimated glomerular filtration rate (eGFR), and serum electrolytes at 3 and 6 months between January 2009 and January 2014. Subjects attended the outpatient clinic and were then followed up until discontinuation of the drugs at years 1 and 2 until May 2016.ResultsNinety-two CKD patients on sCOX-2 inhibitors and 92 CKD patients without sCOX-2 inhibitors were included. The sCOX-2 inhibitor group showed more decline in eGFR than the control group at 3 and 6 months of follow-up (–8.27±9.75 vs –1.64±6.05 mL/min/1.73 m2, P<0.001 and –12.36±6.48 vs –4.31±5.11 mL/min/1.73 m2, P=0.001, respectively) and at 1 and 2 years of follow-up after subjects discontinued sCOX-2 (–6.84±10.34 vs –1.61±8.93 mL/min/1.73 m2, P=0.004 and –10.26±10.19 vs –5.12±8.61 mL/min/1.73 m2, P=0.005, respectively). In addition, the sCOX-2 inhibitor group had significantly more increased serum potassium during the study follow-up than the control group.ConclusionThe sCOX-2 inhibitors are associated with an increased risk for rapid eGFR decline and hyperkalemia in both the short term and in the long term after sCOX-2 inhibitors were terminated in the setting of a community-based CKD population. For CKD patients, these results suggest that sCOX-2 inhibitors should be closely monitored and chronic exposure to any sCOX-2 inhibitors should be avoided.

Use of Selective Cyclooxygenase-2 Inhibitors, Other Analgesics, and Risk of Glioma.

BackgroundSelective cyclooxygenase-2 (COX-2) inhibitors are analgesic, antipyretic, and anti-inflammatory drugs. They have been found to inhibit the development of glioma in laboratory investigations. Whether these drugs reduce the risk of glioma incidence in humans is unknown.MethodsWe conducted a matched case-control analysis using the U.K.-based Clinical Practice Research Datalink (CPRD). We identified 2,469 cases matched to 24,690 controls on age, sex, calendar time, general practice, and number of years of active history in the CPRD prior to the index date. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) of glioma in relation to use of selective COX-2 inhibitors, adjusted for several confounding variables.ResultsUse of selective COX-2 inhibitors was unrelated to risk of glioma (adjusted OR for 1–9 versus 0 prescriptions = 1.02; 95% CI = 0.92–1.13, 10–29 versus 0 prescriptions = 1.01; 95% CI = 0.80–1.28, ≥30 versus 0 prescriptions = 1.16; 95% CI = 0.86–1.55). Trends for increasing numbers of prescriptions for other non-steroidal anti-inflammatory drugs (NSAIDs), and non-NSAID analgesics were also not associated with glioma risk.ConclusionFurther epidemiologic studies are needed to confirm the null relation of use of selective COX-2 inhibitors to glioma risk and to explain the discrepancy between laboratory investigations and our observational study. Impact: Use of selective COX-2 inhibitors is unrelated to glioma risk.

Fractals and self-organized criticality in anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective inhibitors. Extensive structural studies of the biology of prostaglandin synthesis and inhibition have explained some of the differences between COX-1 and COX-2 functionality, but others are still unexplained. Notably these include molecular differences that cause COX-1 inhibitors to produce a slight decrease, and COX-2 inhibitors to induce a significant increase, in heart attacks and strokes. These differences were unexpected because of the 60% overall COX-1 and COX-2 sequence similarity and the 1–2 conservation of catalytic sites. Hydropathic analysis shows important bicyclic differences between COX-1 and COX-2 on a large scale outside the catalytic pocket. These differences involve much stronger amphiphilic interactions in COX-2 than in COX-1, and may explain the selective antiplatelet effectiveness of COX-2. Success of the non-Euclidean structural analysis is the result of using the new Brazilian hydropathicity scale based on self-organized criticality (SOC) of universal protein modules.

SAT0117 Reduction of Nsaid-Induced Small Intestinal Damage in Rheumatoid Arthritis Patients Receiving Sulfasalazine

BackgroundRecent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) often cause damage to the small intestine, and NSAID-induced enteropathy is mediated by different inflammatory cytokines. Sulfasalazine is being widely used...

Inhibition of cyclooxygenase-2 activity impairs antibody production in human B cells and in mice infected with vaccinia virus (84.8)

Abstract Generation of protective humoral immune responses against vaccines depends on optimal production of antibodies by B lymphocytes. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to curb undesirable symptoms of vaccination, including pain, fever and swelling. We previously demonstrated in B cells that cyclooxygenase-2 (Cox-2) is induced in response to both T-dependent and T-independent stimuli, including the TLR9 ligand CpG DNA, and that Cox-2 is crucial for antibody production. Expression of plasma cell transcriptional regulatory factors, including Blimp-1 and Xbp-1, were dependent on Cox-2 activity. Significantly fewer antibody secreting plasma cell precursors were generated in the presence of Cox-2 selective inhibitors, indicating that Cox-2 is essential for human B cell terminal differentiation. Cox-2 selective inhibitors were administered in vivo to determine the role of Cox-2 in a humoral immune response to live infection with vaccinia virus. Mice chronically treated with Cox-2 selective inhibitors produced less viral neutralizing IgG following live virus infection. Inhibition of Cox-2 resulted in a reduced frequency of IFN-γ producing T cells, indicating that T cell priming of B cells was attenuated. These data support the idea that impaired humoral immunity in the absence of Cox-2 activity can be dependent on both B cells and T cells and that the use of Cox-2 selective inhibitors have the potential to dampen humoral immunity to live virus infection and vaccines.

The CADEUS study: burden of nonsteroidal anti‐inflammatory drug (NSAID) utilization for musculoskeletal disorders in blue collar workers

The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population. This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as 'over four dispensations in one year with less than two months between any two'. Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6-1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5-2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5-2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2-1.6). Blue collar workers also had a 20% higher prevalence of 5-year history of dyspepsia. No difference was observed between sexes or in the use of COX-2 selective inhibitors between occupations. Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.

Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

N-Terminal Pro–B-Type Natriuretic Peptide Concentrations Predict the Risk of Cardiovascular Adverse Events from Antiinflammatory Drugs: A Pilot Trial

we investigated whether higher concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular adverse events (CV-AEs) in patients with osteoarthritis treated with antiinflammatory drugs. NT-proBNP was measured in baseline samples from 433 patients enrolled in a prospective randomized study designed to test the therapeutic effect of a novel metalloproteinase inhibitor. We monitored CV-AEs and retrospectively investigated their relationship to the concomitant use of selective cyclooxygenase-2 inhibitors (coxibs), traditional nonsteroidal antiinflammatory drugs (tNSAIDs), and glucocorticoids. CV-AEs included myocardial infarction, stroke, new or worsening of preexisting arterial hypertension, congestive heart failure, and several less severe CV-AEs. we observed 82 mild to serious CV-AEs during an observational period of 200 days. The risk of such events was 1.95-fold higher in patients who were taking tNSAIDs, glucocorticoids, or coxibs (i.e., any inhibitor) and who had NT-proBNP concentrations > or = 100 ng/L than in patients taking any inhibitor who had NT-proBNP values <100 ng/L (P < 0.05). Patients taking coxibs (alone or in addition to tNSAIDs or glucocorticoids) with baseline NT-proBNP values > or = 100 ng/L had a 7.41-fold higher risk for CV-AEs than those with baseline values <100 ng/L (P < 0.01). Patients who were taking 2 or more antiinflammatory drugs and had NT-proBNP values > or = 100 ng/L had a 3.74-fold higher risk for CV-AEs than those with NT-proBNP values <100 ng/L (P < 0.05). An NT-proBNP value <100 ng/L was associated with negative predictive values of >85% across all treatment groups. NT-proBNP may be a useful marker for anticipating cardiovascular risk associated with the use of antiinflammatory drugs for osteoarthritis.

Cardiovascular thromboembolic adverse effects associated with cyclooxygenase-2 selective inhibitors and nonselective antiinflammatory drugs

Background Concerns of increased cardiovascular (CV) thromboembolic adverse effects from nonsteroidal antiinflammatory drugs (NSAIDs, both nonselective [NS]-NSAIDs and cyclooxygenase [COX]-2 selective inhibitors) have prevented their use despite numerous benefits. Methods In this descriptive review, we critically examine the randomized, active- and placebo-controlled studies, observational trials, and meta-analyses evaluating the CV adverse effects associated with long-term and short-term use of COX-2 selective inhibitors and NS-NSAIDs. The potential mechanisms for these CV effects are also presented. Results Although the studies evaluating the CV risks have limitations, there appears to be an increased CV risk with both COX-2 selective inhibitors and NS-NSAIDs, particularly in high-risk patients. Therefore, the United States Food and Drug Administration has given a similar boxed warning highlighting the potential for increased risk of CV events associated with their use. Nevertheless, there are differences in the CV risks between COX-2 selective inhibitors (e.g., higher CV risk with rofecoxib than celecoxib) as well as differences in the CV risks between individual NS-NSAIDs (e.g., higher CV risks with diclofenac than naproxen). Conclusions Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations have been completed, the CV risks associated with the use of NSAIDs, especially in high-risk patients, will likely continue to be controversial. Nevertheless, the benefits of their short-term (e.g., perioperative) use in patients without CV risks probably outweigh their potential CV adverse effects. Finally, careful risk/benefit assessment should be undertaken and both COX-2 selective inhibitors and NS-NSAIDs should be used with caution in patients with CV risk factors.

Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs in High Doses Increases Mortality and Risk of Reinfarction in Patients With Prior Myocardial Infarction

The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. In the present study, we analyzed the risk of rehospitalization for acute myocardial infarction (re-MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with a prior myocardial infarction (MI). We included 58,432 patients discharged alive after a first MI, and subsequent use of all NSAIDs was identified from a nationwide register of drug dispensing from pharmacies. We found a dose-dependent increase in risk of death for both the selective COX-2 inhibitors and the nonselective NSAIDs (all of the drugs tested). There were trends for increased risk of re-MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs (high dosages). Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages should be used with particular caution in patients with a prior MI.

Cardiovascular Thromboembolic Adverse Effects Associated with Cyclooxygenase-2 Selective Inhibitors and Nonselective Antiinflammatory Drugs

Concerns of increased cardiovascular (CV) thromboembolic adverse effects from nonsteroidal antiinflammatory drugs (NSAIDs, both nonselective [NS]-NSAIDs and cyclooxygenase [COX]-2 selective inhibitors) have prevented their use despite numerous benefits. In this descriptive review, we critically examine the randomized, active- and placebo-controlled studies, observational trials, and meta-analyses evaluating the CV adverse effects associated with long-term and short-term use of COX-2 selective inhibitors and NS-NSAIDs. The potential mechanisms for these CV effects are also presented. Although the studies evaluating the CV risks have limitations, there appears to be an increased CV risk with both COX-2 selective inhibitors and NS-NSAIDs, particularly in high-risk patients. Therefore, the United States Food and Drug Administration has given a similar "boxed" warning highlighting the potential for increased risk of CV events associated with their use. Nevertheless, there are differences in the CV risks between COX-2 selective inhibitors (e.g., higher CV risk with rofecoxib than celecoxib) as well as differences in the CV risks between individual NS-NSAIDs (e.g., higher CV risks with diclofenac than naproxen). Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations have been completed, the CV risks associated with the use of NSAIDs, especially in high-risk patients, will likely continue to be controversial. Nevertheless, the benefits of their short-term (e.g., perioperative) use in patients without CV risks probably outweigh their potential CV adverse effects. Finally, careful risk/benefit assessment should be undertaken and both COX-2 selective inhibitors and NS-NSAIDs should be used with caution in patients with CV risk factors.

Back to the Future: COX-2 Inhibitors for Chemoprevention and Cancer Therapy

For more than a century, inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) has been achieved by non-steroidal anti-inflammatory drugs (NSAIDs), which targets both COX-1 and COX-2 and as such could be responsible for causing gastrointestinal (GI) toxicity. COX-2 is an inducible enzyme produced by many cell types in response to multiple stimuli. Recently, COX-2 over-expression has been found in several types of human cancers such as colon, breast, prostate and pancreas and appears to control many cellular processes. Because of its role in carcinogenesis, apoptosis, and angiogenesis, it is an excellent target for developing new drugs with selectivity for prevention and/or treatment of human cancers. Development of selective COX-2 inhibitors has been successfully documented and as such showed less toxicity to GI tract as compared to conventional NSAIDs. However, the long term use of COX-2 selective inhibitors showed cardiovascular toxicity, and thus their utilization for cancer prevention and therapy is currently questionable, suggesting that further development of novel COX-2 selective agents are needed. Among many solid tumors, pancreatic cancer has the worst prognosis, and inflammation has been identified as a significant factor in the development of pancreatic malignancy. Several cytokines, reactive oxygen species (ROS) and mediators of inflammatory pathway such as activation of nuclear factor-kappaB (NF-kappaB) and COX-2 leads to an increase in cell proliferation, survival, and inhibition of pro-apoptotic pathway, ultimately resulting in tumor angiogenesis, invasion and metastasis. In this brief review, we summarize the role of COX-2 and discuss some of the experimental data linking inflammation with the development of pancreatic cancer. In addition, we provide further evidence regarding the state of our knowledge toward the development of novel COX-2 targeting agents for the prevention and/or treatment of human cancers especially pancreatic cancer.

Enhanced Activation of Cyclooxygenase‐2 Downregulates Th1 Signaling Pathway in Helicobacter pylori‐infected Human Gastric Mucosa

Evidence suggests that an impaired T-cell response against Helicobacter pylori plays a role in the pathogenesis of H. pylori-related diseases. Cyclooxygenase (COX) 2 has been shown to inhibit the production of T-helper (Th) 1 cytokines. This study aimed to ascertain whether COX-2 downregulates Th1 signaling pathway in human gastric mucosa colonized by H. pylori. COX-2 expression and prostaglandin E(2) (PGE(2)) production were determined in total proteins extracted from freshly obtained gastric biopsies of H. pylori-infected and uninfected patients by Western blotting and enzyme-linked immunosorbent assay (ELISA). Phosphorylated (p)STAT4, pSTAT1, T-bet, and pSTAT6 expression and interleukin (IL)-12, interferon (IFN)-gamma, and IL-4 production were also determined by Western blotting and ELISA, respectively, in total protein extracts from gastric biopsy cultures of H. pylori-infected patients treated without and with COX-2 inhibitor NS-398. Enhanced expression of COX-2 and production of PGE(2) was found in H. pylori-infected compared to uninfected patients. COX-2 inhibition significantly increased expression of Th1 transcription factors along with production of IL-12 and IFN-gamma. By contrast, no changes in the expression of STAT6 and production of IL-4 were found. This study provides a mechanism by which H. pylori may actually interfere with normal T-cell activation in human gastric mucosa, possibly enhancing its pathogenicity. The use of COX-2 selective inhibitors as immunomodulators in the course of H. pylori infection deserves investigations.

Adherence to Gastroprotective Therapy Limits NSAID-Associated Ulcer Complications

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) increase risk for peptic-ulcer complications. Use of selective cyclooxygenase-2 inhibitors

Peptic Ulcer and Bleeding Events Associated With Rofecoxib in a 3-Year Colorectal Adenoma Chemoprevention Trial

Our aim was to establish the incidence of symptomatic upper gastrointestinal ulcers, ulcer perforation, ulcer obstruction, or bleeding episodes (PUBs) associated with the use of selective cyclooxygenase-2 inhibitors at standard clinical doses compared with placebo. We report here on the PUB outcomes associated with the use of rofecoxib 25 mg in a 3-year, multicenter, double-blind, placebo-controlled trial designed to determine the effect of rofecoxib on the risk of recurrent neoplastic polyps of the colon. A total of 2587 patients with a history of colorectal adenomas underwent randomization to 25 mg/day of rofecoxib or to placebo. Investigator-reported PUBs were adjudicated by an external blinded committee. Kaplan-Meier and Cox proportional hazards techniques were used to estimate incidence and relative risks of PUBs in an intention-to-treat analysis. Patients assigned to rofecoxib had a higher incidence of confirmed PUBs than those randomized to placebo (.88 vs .18 events per 100 patient-years; relative risk, 4.9; 95% confidence interval, 1.98-14.54). The incidence of confirmed complicated PUBs (ulcer perforation, obstruction, or bleeds) was low, but was numerically higher in the rofecoxib than in the placebo group (.23 vs .06 events per 100 patient-years; relative risk, 3.8; 95% confidence interval, .72-37.46; P = .14). Rofecoxib increased the incidence of confirmed PUBs vs placebo in both low-dose aspirin users and nonusers. Among patients with a history of colorectal adenomas, the long-term use of 25 mg/day of rofecoxib was associated with an increased risk of clinically relevant upper gastrointestinal events when compared with placebo.