Nonspecific NSAIDs Research Articles

Role of prostaglandins in colorectal tumorigenesis: Localization and expression of COX-1, COX-2, microsomal Prostaglandin E Synthase-1 and the EP2 receptor

Background: Prostaglandins, in particular prostaglandin E2 (PGE2), are elevated in adenomas and colorectal cancers (CRC). Experimental and epidemiological studies have demonstrated reduced incidence of adenomas and CRC by inhibitors of prostanoid synthesis (NSAIDs). This study aimed to characterize the expression and localization of key enzymes/receptors for PGE2 synthesis in adenomas and CRC in comparison to normal colon. Methods: Immunoblotting and immunohistochemistry were used for semi-quantitative and qualitative analysis of COX-1, COX-2, mPGES-1 and the EP2 receptor in biopsies from patients undergoing resection of adenomas or surgery for CRC (Dukes' A-C). Normal colon served as control for the corresponding tumor in each of the CRC patients. Results: COX-1 was decreased significantly in all groups of CRC (Dukes' A-C) compared to normal colon. In contrast, COX-2 was increased, but only in the combined group of CRC. Microsomal PGES-1 was increased in CRC (Duke's B), and EP2 was augmented in adenomas and CRC. The localization was predominantly epithelial in normal colon and in adenomas, while in CRC both epithelial- and stromal expression was demonstrated. Conclusions: The results support the PGE2- pathway, with epithelial- stromal interactions, in the evolvement of adenomas and in the progression of CRC. Co-expression of COX-1 and COX-2 is in line with the preventive effects of non-specific NSAIDs on adenoma formation. The decrease of COX-1, in combination with an increase of COX-2, favors the potential use of selective COX-2 inhibitors as an adjunct therapy in CRC.

Cause for concern in the use of non-steroidal anti-inflammatory medications in the community--a population-based study.

BackgroundNon-steroidal anti-inflammatory (NSAID) medications are a common cause of reported adverse drug side-effects. This study describes the prevalence of non-steroidal anti-inflammatory (NSAID) use (other than low-dose aspirin) and the presence of co-existing relative contraindications to NSAID use and chronic conditions in a representative population sample.MethodsData were analysed from 3,206 adults attending first follow-up of the North West Adelaide Health Study (NWAHS) in 2004 - 2006, a longitudinal representative population study. Medications were brought into study clinic visits by participants. Clinical assessment included measured blood pressure, kidney function, serum cholesterol, blood glucose. Questionnaires assessed demographics, lifestyle risk factors, physician-diagnosed chronic conditions. Data were weighted to census measures by region, age group, gender, and probability of selection in the household, to provide population representative estimates. Pearson's Chi-square tests determined significant differences in proportions. Multiple logistic regression was used to examine associations of socio-demographic characteristics with use of NSAIDs.ResultsOf 3,175 participants, 357 (11.2%), and 16% of those aged > 55 years, reported using either non-specific NSAIDs or COX-2 inhibitors, other than low-dose aspirin. Among people using NSAIDs, 60.8% had hypertension, 30.8% had Stage 3 or higher chronic kidney disease, 17.2% had a history of cardiovascular disease (CVD) and 20.7% had a > 15% 10-year CVD risk. The prevalence of NSAID use among people with hypertension was 16%, with kidney disease 15.9%, and a history of CVD 20.0%. Among people taking diuretics, 24.1% were also taking NSAIDs, and of those taking medications for gastro-esophageal reflux, 24.7% were on NSAIDs. Prescription-only COX-2 inhibitors, but not other NSAIDs, were used more by people > 75 years than by 35-54 year olds (OR 3.7, 95% CI 2.0, 6.7), and also were more commonly used by people with hypertension, cardiac and kidney disease.ConclusionsThere is a high prevalence of current NSAID use among groups at-risk for significant drug-related adverse events or who have major chronic conditions that are relative contraindications to NSAID use. Assessment of absolute risks regarding cardiovascular and kidney disease need to take into account use of medications such as NSAIDs. The potential to make a substantial impact on chronic disease burden via improved use of NSAIDs is considerable.

To use or not to use: the dilemma of NSAIDs and craniotomy

To use or not to use: the dilemma of NSAIDs and craniotomy

Non-specific NSAIDS modulate the proliferation/differentiation interplay on human bone marrow-derived osteoblasts

Non-specific NSAIDS modulate the proliferation/differentiation interplay on human bone marrow-derived osteoblasts

Performance Characteristics of the Suspected Blood Indicator Feature in Capsule Endoscopy According to Indication for Study

The suspected blood indicator (SBI) feature of wireless capsule endoscopy (WCE) was developed for rapid screening of intestinal lesions with bleeding potential. Our aim was to assess the accuracy and performance characteristics of the SBI according to the indications for study in a large cohort of patients. We reviewed collected data on all WCE studies performed at Johns Hopkins Hospital from January 2006 to June 2007. Study indications were as follows: anemia of unknown origin (n = 53), obscure gastrointestinal bleeding (n = 112), suspected Crohn's disease (n = 122), and other (n = 4). Concordant and discordant findings between gastroenterologists' readings and SBI were recorded for each patient. A total of 221 lesions with bleeding potential was detected. The overall sensitivity, specificity, positive predictive value, and negative predictive value for the SBI were 56.4%, 33.5%, 24.0%, and 67.3%, respectively. For actively bleeding lesions, the SBI sensitivity and positive predictive value were only 58.3% and 70%, respectively. The sensitivity was highest (64%) in patients undergoing WCE for suspected Crohn's disease, with a negative predictive value of 80.4%. The sensitivity was only 58.3% and 41.3%, respectively, in studies performed for obscure gastrointestinal bleeding and anemia. Performance characteristics of the currently available SBI feature in WCE are suboptimal and insufficient to screen for lesions with bleeding potential. Even in patients with active intestinal bleeding, the sensitivity of SBI was less than 60%, which is lower than previously reported. However, in patients with suspected Crohn's disease, the high sensitivity and negative predictive value of SBI may make it a useful tool for the detection of large areas of abnormal mucosa.

Update on the role of nonsteroidal anti-inflammatory drugs and coxibs in the management of acute pain

Although NSAIDs have been shown to reduce postoperative analgesics, their ability to reduce opioid-related adverse effects and improve functional outcomes is questioned. Further, perioperative NSAID use may contribute to cardiovascular toxicity and impaired bone healing. This review highlights recent advances in our understanding of the role perioperative NSAIDs have on modulating nociception, their benefits when utilized as components of a multimodal analgesic regimen, and potential deleterious cardiovascular and osteogenic effects. Recent research indicates that, in addition to peripheral blockade of prostaglandin synthesis, central inhibition of cyclooxygenase-2 may play an important role in modulating nociception. Although nonspecific NSAIDs provide analgesic efficacy similar to coxibs, their use has been limited in the perioperative setting because of platelet dysfunction and gastrointestinal toxicity. Coxibs may be a safer alternative in that setting. Both coxibs and traditional NSAIDs may contribute to a dose-dependent increase in cardiovascular toxicity and impaired osteogenesis. When used short term at the lowest effective dose, however, NSAIDs may provide for analgesic benefit without significant toxicity. When utilized as a component of a multimodal analgesic regimen for acute pain, short-term NSAID administration reduces opioid-related side effects and may contribute to improved functional outcomes without significant adverse effects.

How to Advise Aspirin Use in Patients Who Need NSAIDs

NSAIDs are widely used all over the world. NSAID use is rising due to increasing availability without a prescription, use of aspirin for prevention of thrombotic disorders and the ageing population. Aspirin is used as an analgesic drug in many countries, but the main current indication is low-dose aspirin for the prevention of cardiovascular events. However, NSAIDs and aspirin use account for approximately 20-25% of all reported drug adverse events. Most of those are gastrointestinal including dyspepsia, hemorrhage, perforation and even death. The COX-2- selective inhibitors (coxibs) have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain but have less gastrointestinal adverse events, although coxibs and probably all NSAIDs, significantly increase risk of serious thromboembolic events. Concomitant use of low-dose aspirin is present in more than 20% of all patients taking either NSAIDs or coxibs, thus increasing the risk of gastrointestinal side effects. Furthermore, at present, it is not known whether aspirin decreases the cardiovascular risks of COX-2 inhibitors or NSAIDs. Appropriate strategies for gastrointestinal risk reduction with NSAIDs and aspirin must consider the overall health status of our patients including the presence of cardiovascular and gastrointestinal risk factors. Use of the lowest possible dose of these drugs, gastroprotectants, especially proton pump inhibitors and Helicobacter pylori eradication will reduce the risk of gastrointestinal side effects in patients taking low-dose aspirin and NSAIDs or coxibs.

A Methodological Approach to Adjust for Channeling Bias in Nonrandomized Observational Studies: Application to Cyclooxygenase-2 (COX-2) Specific Inhibitors

Background: Channeling bias may confound the interpretation of results of nonrandomized observational studies. We undertook this analysis to develop a methodology for examining potential channeling bias in the prescription of cyclooxygenase-2 specific inhibitors (COX-2 SIs) and to determine the effect of such bias on measured estimates of drug safety. Methods: The Protocare Sciences Propriety Research database, a managed care claims database that has integrated information on patient eligibility and claims, was used as the data source. Patients were identified based on dispensation of either COX-2 SIs (n 43,653) or nonspecific (ns) NSAIDs (n 492,831) between January 1, 1999 and December 31, 2001. Odds ratios were calculated to determine the association of health status and gastrointestinal (GI) history with COX-2 SI and ns NSAID dispensation. Propensity scores were derived from multivariate logistic regression analyses to adjust for risk factors associated with COX-2 SI and ns NSAID dispensation. Poisson regression accounting for duration of exposure was used in conjunction with propensity scores to examine the incidence of NSAID-related and ulcer specific hospitalizations during therapy. Results: Among patients with a history of GI hospitalization, the crude incidence rates were approximately 4-fold higher in the ns NSAID compared with the COX-2 SI cohort (incidence rate/100 pt-years: 4.06, 95% CI 3.10–5.32 and 0.88, 95% CI 0.33–2.34, respectively). Disease state severity based on advancing age and history of GI healthcare resource utilization or NSAID intolerance were strongly associated with COX-2 SI dispensation. After adjusting for these predictors of COX-2 prescribing or factors associated with selective COX-2 prescribing (channeling bias), the relative risk (RR) of both NSAID-related and ulcer-specific GI hospitalizations was reduced among COX-2 SI users compared with ns NSAID users (RR 0.61, 95% CI 0.48–0.78 and 0.68, 95% CI 0.48–0.96, respectively). Similar results were obtained regardless of exposure to gastroprotective agents (H2RAs, PPIs, or misoprostol) (RR 0.55, 95% CI 0.40–0.77 and 0.52, 95% CI 0.31–0.87 for NSAID-related and ulcer-specific hospitalizations, respectively). Conclusions: Managed care patients with a history of GI problems or ns NSAID intolerance are being channeled to COX-2 SIs. After adjusting for channeling bias, COX-2 SI therapy was associated with fewer GI events, even though these patients had a higher background risk of GI complications. 4 Flagellin Stimulates IL-8 Production in Native Human Colon and Enhances Ongoing Colonic Inflammation in Mice Sang Hoon Rhee, Martin Riegler, and Charalabos Pothoulakis

Celecoxib associated with lower rate of renal dysfunction compared to nonspecific inhibitor NSAIDs

Both the COX-1 and COX-2 isoforms are expressed by the human kidney and vasculature. Therefore, it is important to evaluate the renovascular effects of COX-2 specific inhibitors and NSAIDs, particularly in patients with preexisting renal dysfunction. The Celecoxib Long-term Arthritis Safety Study (CLASS) assessed gastrointestinal outcomes associated with supratherapeutic doses of the COX-2 specific inhibitor celecoxib (400mg bid), and standard doses of NSAIDs, ibuprofen (800mg tid) and diclofenac (75mg bid), in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). The trial's full database provided a large cardiorenal database for studying renal-related adverse events associated with nonspecific NSAIDs and celecoxib. Complete methods and gastrointestinal and cardiovascular results are published elsewhere. Enrolled patients had a serum creatinine ≤1.5mg/dL reflecting normal renal function. Renal function was assessed in all patients including those with mild prerenal azotemia defined by a baseline blood urea nitrogen (BUN) level of >20mg/dL. The renovascular effects measured in these patients were clinically important reductions in renal function (defined as an increase in serum creatinine >0.5mg/dL from baseline) and mean serum creatinine/estimated creatinine clearance. In patients with mild prerenal azotemia significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.4%) compared with either diclofenac (8.3%;P ≤0.05) or ibuprofen (7.7%;P ≤0.05). In patients with mild renal compromise, celecoxib was associated with a significantly lower rate of renal dysfunction at supratherapeutic doses compared with diclofenac and ibuprofen at standard doses. These data suggest that celecoxib may be a more suitable alternative to treat chronic pain and inflammation than nonspecific NSAIDs in patients with compromised renovascular function. (See Table) *P ≤ 0.05; ANCOVA, Fisher's exact test *P ≤ 0.05; ANCOVA, Fisher's exact test

Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo

Data indicate that cyclooxygenase-2-specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n = 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n = 118), or placebo (n = 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were 2.99 +/- 0.51, 55% for naproxen/omeprazole compared to 0.32 +/- 0.10, 16% for celecoxib and 0.11 +/- 0.04, 7% for placebo (P < .001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P = .04). Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE.

Selective Cyclooxygenase-2 Inhibition and Cardiovascular Effects

The differential effects of selective cyclooxygenase-2 (COX-2) inhibitors compared with nonspecific nonsteroidal anti-inflammatory agents (NSAIDs) on platelet aggregation and prostacyclin/thromboxane balance have led to concerns that COX-2 inhibitors may increase the risk for cardiovascular thrombotic events. Empirical studies have generally been limited to analyses of secondary end points with low event rates in clinical trials and single event rates in observational studies, all of which have come to conflicting conclusions. This observational cohort study examines the cardiovascular risk of COX-2 inhibitors compared with nonspecific NSAIDs in Maryland Medicaid enrollees, a high-risk population. Medical and prescription claims were analyzed for noninstitutionalized Medicaid enrollees who received at least a 60-day supply of a COX-2 inhibitor or other prescription NSAID between June 2000 and June 2002 and who did not use these drugs for at least 6 months prior. Naproxen users were excluded. We developed a logistic model of propensity for treatment with COX-2 inhibitors and stratified patients by quintiles of their propensity score. The model adjusted for demographics, indications for COX-2 inhibitors, and cardiovascular risk factors. The study population comprised 1005 patients using COX-2 inhibitors and 5245 patients using a nonnaproxen NSAID. Of the 6250 patients, 70% were female, 50% were African American, and 30% were older than 50 years. Overall, 12% of the patients had at least 1 cardiovascular thrombotic event after treatment within the follow-up period. The propensity-adjusted odds ratio showed no significant effect of COX-2 inhibitor use on this percentage of patients (odds ratio, 1.09; 95% confidence interval, 0.90-1.33). We did not find that COX-2 inhibitors increased cardiovascular risk over nonnaproxen NSAIDs in a high-risk Medicaid population.

Is there an inhibitory effect of COX-2 inhibitors on bone healing?

The use of the new selective cyclooxygenase-2 (COX-2) inhibitors (such as celecoxib and rofecoxib) for the treatment of pain and inflammation caused by fractures, cementless total joint replacements, soft tissue healing to bone, and spinal fusion surgeries has been controversial due to the convincing data collected from nonspecific NSAIDs such as indomethacin and naproxen regarding their inhibitory effects on bone healing and the similar effects of COX-2 specific NSAIDs in animal models. Is there a significant inhibitory effect of COX-2 inhibitors on bone healing in humans? To answer this question, we reviewed existing scientific evidence (based mainly on a MedLine search) of the potential effects of COX-2 inhibitors on bone healing. The literature shows that COX-2 inhibitors do have inhibitory effects on bone healing in animal models, but the effects of COX-2 inhibitors on similar processes in humans remain largely unknown.

Drug switching patterns among patients with rheumatoid arthritis and osteoarthritis using COX-2 specific inhibitors and non-specific NSAIDs.

To compare RA and OA patients' time-to-switch after newly initiating treatment with three most commonly used non-specific (NS)-NSAIDs and two COX-2 inhibitors, celecoxib and rofecoxib. Managed care enrollees newly prescribed celecoxib, rofecoxib, ibuprofen, naproxen or diclofenac were identified. Time to switch to a different NS-NSAID or COX-2 specific inhibitor was determined using time-to-event analysis and Cox proportional hazards models were used to estimate the odds ratio (OR) after controlling for potential confounders. The time to 25% of the cohort switching was longer for rofecoxib and celecoxib (159 and 205 days respectively) compared to the three NS-NSAIDs (49-78 days). Patients were at the highest risk of switching within the first 100 days of therapy. After adjusting for potential confounding factors, the OR for switching to another NS-NSAID or COX-2 specific inhibitor ranged from 1.74 to 2.35 for the three NS-NSAIDs compared to celecoxib (all comparisons, p < 0.01). Similar findings were obtained when comparing rofecoxib to each of the three NS-NSAIDS (all comparisons, p < 0.01). When COX-2 inhibitors combined were compared to NS-NSAIDS combined, the OR for switching was 1.53 (95% confidence interval = 1.42-1.65; p < 0.01) after adjusting for potential confounders. Patients on the COX-2 specific inhibitors (celecoxib and rofecoxib) were significantly less likely to switch their therapy than patients on NS-NSAIDS (ibuprofen, naproxen and diclofenac). These results suggest that COX-2 specific inhibitors may be a more effective treatment option when compared with NS-NSAIDs in usual clinical practice.

Upper gastrointestinal (UGI) tolerability of valdecoxib a cox-2 specific inhibitor, compared with nonspecific (NS) NSAIDs, among patients with osteoarthritis (OA) and rheumatoid arthritis (RA)

Upper gastrointestinal (UGI) tolerability of valdecoxib a cox-2 specific inhibitor, compared with nonspecific (NS) NSAIDs, among patients with osteoarthritis (OA) and rheumatoid arthritis (RA)

Do NSAIDs induce esophagitis? The effect of non-specific NSAIDs and COX-2 specific inhibitors±low-dose aspirin in prospective, randomized, double-blind, placebo-controlled endoscopic trials

Do NSAIDs induce esophagitis? The effect of non-specific NSAIDs and COX-2 specific inhibitors±low-dose aspirin in prospective, randomized, double-blind, placebo-controlled endoscopic trials

COX-2 Specific Inhibitors Offer Improved Advantages Over Traditional NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications worldwide and are often the first choice of treatment for acute myalgias, orthopedic injuries, postoperative pain, chronic rheumatoid arthritis, and osteoarthritis. The mechanism through which NSAIDs provide analgesia and suppress inflammation is the inhibition of the enzyme cyclooxygenase, resulting in decreased prostaglandin synthesis. The suppression of prostaglandin synthesis can also produce gastric and renal toxicity, as well as impair normal platelet function. Thus, NSAIDs are associated with potentially harmful side effects. Cyclooxygenase exists in two isoenzymatic forms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 appears to be constitutively expressed in many tissues and produces prostaglandins, which regulate normal cellular functions. However, COX-2 activity is induced by proinflammatory cytokines and produces prostaglandins that mediate the inflammatory response and pain signaling transmission. Traditional nonspecific NSAIDs inhibit both COX-1 and COX-2, and in doing so, not only decrease inflammation and pain, but also promote gastrointestinal tract damage and bleeding. The potential clinical benefit of COX-2 inhibitors is significant due to the number of patients chronically treated with NSAIDs and the three- to ten-fold higher risk of gastrointestinal injury and death associated with traditional NSAIDs. Recently, a class of anti-inflammatory medications has been developed that primarily inhibits COX-2 while sparing the enzymatic activity of COX-1 at therapeutic dosages. Two medications that predominantly inhibit only COX-2, rofecoxib and celecoxib, are currently available by prescription in the United States.