Traditional NSAIDs Research Articles

Gastroprotection among new chronic users of non-steroidal anti-inflammatory drugs: a study of utilization and adherence in the Netherlands

ABSTRACTObjective: To describe the use of gastroprotection (GP) among new chronic users of NSAIDs in the Netherlands by gastrointestinal (GI) risk factor (RF) score.Methods: Data for this retrospective follow-up study were extracted from the PHARMO database. We selected new chronic users of COX-2 inhibitors (coxibs) or traditional NSAIDs (tNSAIDs) between 1st January 2000 and 31st December 2004. GP strategies were defined as: use of proton pump inhibitors (PPI), coxibs or both. GI RF score at index date was based on: history of GI drug use, high dose of NSAIDs, age > 60 years, use of corticosteroids/anticoagulants/SSRIs, rheumatoid arthritis, heart failure or diabetes, with each condition accounting for one factor. Switching was assessed among those with ≥ 1 GI RF during the first year of follow-up.Results: Among 58 770 new chronic NSAID users at index date, 80% used tNSAIDs alone, 8% used tNSAID + PPI, 10% used a coxib alone and 2% used coxib + PPI. Mean (SD) number of GI RF among these groups was 1.6 (2.1), 3.1 (1.3), 1.5 (1.5) and 2.8 (1.3), respectively. Among 48 390 patients (82.3%) with a GI RF score of ≥ 1, 20.9% used a GP strategy, this increased with number of GI RFs. Within the first year, 5.3% (n = 2067) and 4.8%(n = 1 843) of tNSAID users with ≥ 1 GI RF switched to tNSAID+PPI and coxib alone, respectively.Conclusions: Gastroprotection in users of tNSAIDs was inadequate. Over 80% of NSAID users with ≥ 1 GI RF did not receive any gastroprotection, and even when prescribed, a PPI is used only half the time. More research should show if gastroprotection was used for prevention.

NO‐sulindac inhibits the hypoxia response of PC‐3 prostate cancer cells via the Akt signalling pathway

Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.

Indomethacin: A NSAID sensitive to micro heterogeneity in alcohol–water mixtures

Photo physical behavior of indomethacin, a NSAID in binary water ethanol mixtures have been studied. Results reveal that indomethacin can sense the micro heterogeneity in the binary mixtures forming ground state complexes with two predominant types of clusters viz. ethanol self-association clusters and hydrogen bonded water clusters. UV–vis absorption, steady state and time resolved fluorescence studies on the photo physical behavior of indomethacin, a traditional NSAID in binary water ethanol mixtures have been presented. Our results reveal that indomethacin can sense the micro heterogeneity in the binary mixtures forming ground state fluorescent complex with two predominant types of clusters viz. ethanol self-association clusters and hydrogen bonded water clusters.

The balance between severe cardiovascular and gastrointestinal events among users of selective and non-selective non-steroidal anti-inflammatory drugs

Objective:To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors.Methods:Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data...

Cardiovascular risks of COX inhibition: current perspectives

Background: NSAIDs are among the most commonly used pharmacotherapeutic agents worldwide. As the long-term use of these drugs is associated with serious gastrointestinal side effects, a new subgroup of COX-2 selective NSAIDs was developed. It was thought that the therapeutic strategy underlying the development of these newer compounds would enable them to provide the same analgesic and anti-inflammatory benefits as those of their traditional counterparts but perhaps offer a much safer gastrointestinal profile. Much scientific data has accumulated over the last few years, however, raising concerns regarding the increased cardiovascular complications associated with the use of COX-2 selective NSAIDs, and perhaps of the traditional NSAIDs as well. Objective: To review current and emerging evidence related to the cardiovascular effects of COX inhibitors and examine the clinical implications. Method: We studied data from basic clinical research, non-randomized analyses, and randomized trials of COX inhibitors that investigated their cardiovascular effects. Conclusion: Both COX-2 selective and traditional NSAIDs are associated with a moderately increased risk of cardiovascular events.

Efficacy and safety of etoricoxib in the treatment of osteoarthritis

Osteoarthritis is a progressive disease that affects millions of people worldwide, but for which there are no curative options and indeed a limited number of medical treatment options. The American College of Rheumatology recommendations suggest administering either a traditional NSAID or a COX-2-selective inhibitor for pain relief. Traditional NSAIDs, such as naproxen, may have a higher risk of gastrointestinal (GI) events, while COX-2-selective inhibitors may have a higher risk of thrombotic cardiovascular (CV) events (with traditional NSAIDs and COX-2-selective agents appearing to have a similar CV risk). Etoricoxib, introduced in 2002, has been approved in over 60 countries worldwide for osteoarthritis. Large-scale studies addressing the efficacy, GI tolerability and potential for CV events with etoricoxib have now been published. Several patient types appear to benefit from etoricoxib, including those with CV risk factors and those requiring gastroprotective agents. In patients with CV risk factors, the benefits and risks of all NSAIDs should be weighed carefully in each patient, balancing the potential risks of treatment against the potential relief for pain and disability.

T1298 Comparison of the Effects of a COX-2 Selective Inhibitor (Firocoxib) and a Traditional NSAID (Flunixin Meglumine) On Recovery of Ischemic-Injured Equine Jejunum

T1298 Comparison of the Effects of a COX-2 Selective Inhibitor (Firocoxib) and a Traditional NSAID (Flunixin Meglumine) On Recovery of Ischemic-Injured Equine Jejunum

Hospitalizations for Upper and Lower GI Events Associated With Traditional NSAIDs and Acetaminophen Among the Elderly in Quebec, Canada

The risk of upper/lower gastrointestinal (GI) adverse events associated with the concomitant use of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) with acetaminophen has not been assessed. Among users of these drugs, the concomitant use of proton pump inhibitors (PPIs) with tNSAIDs may reduce the risk of upper GI adverse events, but its effect on lower GI events is not clear. To compare the rates of GI hospitalization (ulceration, perforation, or bleeding in the upper or lower GI tract) among elderly patients taking tNSAIDs or the combination of a tNSAID and acetaminophen with and without a PPI versus those taking acetaminophen alone. We conducted a population-based retrospective cohort study using data obtained from the government of Quebec health insurance agency databases and the hospital discharge summary database. Patients of 65 yr of age or older who filled a prescription for acetaminophen or a tNSAID between January 1998 and December 2004 were entered in the cohort at the date of the first filled prescription from either of these medications (index date). Follow-up ended at the first date of a GI hospitalization, death, or the end of the study period. The cohort included 644,183 elderly patients. These patients received 1,778,541 prescriptions for tNSAIDs (315,222, 17.7% with a PPI), 158,711 for the combination of a tNSAID and acetaminophen (40,797, 25.7% with a PPI), 1,597,725 for acetaminophen (> 3 g/day) (504,939, 31.6% with a PPI), and 3,641,140 for acetaminophen (< or = 3 g/day) (1,031,939, 28.3% with a PPI). Using Cox regression models that adjusted for time-dependent variables (aspirin, anticoagulants, and clopidogrel) and other fixed patient baseline characteristics, we found similar risks of GI hospitalizations among time periods when patients were exposed to either a tNSAID with a PPI, acetaminophen (> 3 g/day) with a PPI, or acetaminophen (< or = 3 g/day) with a PPI. The risk of GI hospitalization among users of PPIs during exposure to the combination of acetaminophen with a tNSAID was twice as high as that of the reference category, acetaminophen (< or = 3 g/day) without a PPI (hazard ratio [HR] 2.15, 95% confidence interval [CI][1.35-3.40]). Among nonusers of PPIs, the risk of GI hospitalization was 1.20 (1.03-1.40) during exposure to acetaminophen (> 3 g/day), 1.63 (1.44-1.85) during exposure to tNSAIDs, and 2.55 (1.98-3.28) during exposure to the combination of a tNSAID and acetaminophen compared with the reference category. Among elderly patients requiring analgesic/anti-inflammatory treatment, use of the combination of a tNSAID and acetaminophen may increase the risk of GI bleeding compared with either agent alone.

Impact of Prescriber Nonresponse on Patient Representativeness

In pharmacoepidemiology studies where patients are selected by prescribers, there is concern that the patients of responding prescribers are not necessarily an unbiased sample of all patients. However, this usually cannot be explored. In the CADEUS study, patients and prescribers were independently contacted so that data are available for patients irrespective of whether their prescriber responded or not. Our objective was to compare the characteristics of patients whose prescriber did or did not respond. The CADEUS study included patients treated with COX-2 inhibitors (celecoxib, rofecoxib) or traditional NSAIDs from September 2003 to August 2004. Redeemed prescriptions were randomly sampled on a monthly basis within the database of the French national healthcare insurance system for salaried persons during 1 year. Patients and prescribers were questioned independently. Data from patients and from the database were used to compare patients whose prescriber responded and those whose prescriber did not. Of 45,217 patients, 26,618 had prescriber data. Patients whose prescriber responded were similar to patients whose prescriber did not respond for the main study outcomes: age (56.8 +/- 16.3 years vs. 56.1 +/- 16.3 years), sex (66.0% female vs. 64.8%), cardiovascular disease history (52.2% vs. 52.0%), gastrointestinal disease history (39.5% vs. 39.4%), concomitant prescription of gastroprotective agents (22.4% vs. 23.7%), and NSAID indication, prescription type, use, and duration. We found no evidence for a difference between patients whose prescriber responded and patients whose prescriber did not participate in the study.

Are NSAIDs and selective cyclo-oxygenase 2 inhibitors associated with increased risk of myocardial infarction?

Scott et al. conducted a systematic review to evaluate the risk of myocardial infarction (MI) associated with cyclo-oxygenase-2 (COX2) inhibitors and traditional NSAIDs. The review found a small increased risk of MI associated with COX2 inhibitors, particularly rofecoxib. Although a fixed-effects model of 14 case-control studies suggested a slightly increased risk of MI with NSAID use, a random-effects model of the same data and analysis of 6 cohort studies found no such link. An increased risk of MI was found in four RCTs of NSAID use in colonic adenoma. In an analysis of 14 RCTs that compared COX2 inhibitors with traditional NSAIDs in patients with arthritis, the odds ratio for MI with COX2 inhibitors was 1.6 (95% CI 1.1-2.4), although most of this risk was accounted for by rofecoxib. COX2 inhibitors were, however, associated with a reduced risk of serious gastrointestinal events. An analysis of previous systematic reviews showed increased risks of MI associated with rofecoxib and celecoxib.

A Comparison of Cardiovascular Biomarkers in Patients Treated for Three Months with Etoricoxib, Celecoxib, Ibuprofen, and Placebo.

ObjectivesSelective cyclooxygenase (COX)-2 inhibitors are effective analgesic and anti-inflammatory agents with improved gastrointestinal safety and tolerability compared with traditional NSAIDs. However, data from long-term, placebo-controlled studies have shown an increased risk of thrombotic cardiovascular (CV) events for COX-2 inhibitors. Changes in levels of CV biomarkers are potentially useful surrogate measures of pathologic changes associated with CV risk.MethodsWe randomized 433 patients with osteoarthritis to etoricoxib 90 mg once daily, celecoxib 200 mg twice daily, ibuprofen 800 mg three times daily, or placebo for 12 weeks. The hypothesis was that etoricoxib would be non-inferior or superior to placebo in effect on C-reactive protein (CRP), LDL-cholesterol, homocysteine, and fibrinogen.ResultsRelative to placebo, etoricoxib was noninferior for effect on CRP (decreased 7.8% vs. placebo; 97.5% CI of the difference: −30.5, 22.4), LDL-C (−4.0% vs. placebo; 97.5% CI: −10.6, 3.2), homocysteine (−3.9% vs. placebo; 97.5% CI: −11.6, 4.6), and fibrinogen (−3.7% vs. placebo; 97.5% CI: −9.4, 2.3). Etoricoxib was not different from placebo, celecoxib, or ibuprofen for any biomarker.ConclusionEtoricoxib was comparable to placebo, celecoxib, and ibuprofen for effects on the CV risk markers measured.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Etoricoxib

The NSAID etoricoxib is a selective inhibitor of cyclo-oxygenase 2 (COX-2), approved for treatment of patients with chronic arthropathies and musculoskeletal and dental pain. The rate of absorption of etoricoxib is moderate when given orally (the maximum plasma drug concentration occurs after approximately 1 hour), and the extent of absorption is similar with oral and intravenous doses. Etoricoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 120 L in humans. The area under the plasma concentration-time curve (AUC) of etoricoxib increases in proportion to increasing oral doses between 5 and 120 mg. The elimination half-life of approximately 20 hours in healthy subjects enables once-daily dosing. Etoricoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little of the drug (<1%) being eliminated unchanged in the urine. Etoricoxib is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Plasma concentrations (AUC) of etoricoxib appear not to be different in patients with chronic renal insufficiency compared with individuals who have normal renal function. Compared with healthy subjects, it has been reported that the AUC is increased by approximately 40% in patients with moderate hepatic impairment. No inhibitory effects on CYP2C9, 2C19, 2D6, 2E1 or 3A4 are expected to occur with etoricoxib. Coadministration of etoricoxib with other drugs has been examined only to a limited extent, thus further assessment is necessary. Etoricoxib has been assessed for the management of several specific disease states, including pain, osteoarthritis, and rheumatoid arthritis, and has shown similar efficacy in comparison with traditional NSAIDs (including naproxen, diclofenac and ibuprofen) in these conditions. Etoricoxib has demonstrated a significant reduction in gastrointestinal toxicity compared with many traditional NSAIDs. The renal adverse effects of etoricoxib appear to be similar to those of other NSAIDs, and the cardiovascular adverse effects of this selective COX-2 inhibitor require further clinical scrutiny. Further study is necessary to delineate the relevance of the pharmacokinetic disposition in terms of the clinical benefits and risks of etoricoxib compared with other options in the clinical arsenal.

Risk-Benefit Perspectives in COX-2 Blockade

The withdrawal of the celebrity arthritis drug, rofecoxib (Vioxx) has sparked an intense discussion and controversy about the safety of the selective COX-2 inhibitors. Laboratory, epidemiological, and clinical studies have surged and continued to evaluate and understand the safety of coxibs and traditional NSAIDs. This paper reviews the scientific and clinical basis of not only the risks, but also the benefits surrounding the use COX-2 inhibitors and NSAIDs. Discussion, debate, opinions, regulatory and clinical recommendations have evolved since the unexpected emergence of cardiac thrombotic events from the use of these drugs. The evidence by which coxibs and NSAIDs can potentially attenuate or exacerbate cardiovascular disease by affecting endothelial function is assessed; and how NSAIDs and coxibs affect renal function and blood pressure is revisited. Several investigations provide insight into their mechanism and clinical application.

NSAID Use in Individuals at Risk of Renal Adverse Events

Cyclo-oxygenase (COX)-2 inhibitors were introduced to world markets with claims of improved gastrointestinal safety compared with traditional NSAIDs. Randomized clinical trials had demonstrated fewer adverse gastrointestinal events with COX-2 inhibitors, but no difference with other adverse events, including adverse renal events. There was a rapid uptake of these medicines. To compare uptake rates of NSAIDs, including COX-2 inhibitors, in a reference population with those in two high-risk populations: a population taking medicines affecting the renin-angiotensin system and loop diuretics, and a population taking medicines for diabetes mellitus. An observational study was undertaken in which the Department of Veterans' Affairs claims dataset was used to identify: veterans dispensed ACE inhibitors (ACEIs) or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and furosemide (ACEI-ARB/furosemide cohort); veterans dispensed medicines for diabetes (diabetes cohort); and all other veterans (reference cohort) from July 1999 to July 2007. Concurrent dispensing of NSAIDs was assessed. Prior to celecoxib becoming subsidized in Australia, the baseline level of NSAID use was 19.5% in the reference cohort, 15.3% in the diabetes cohort and 15.6% in the ACEI-ARB/furosemide cohort. After the listing of celecoxib, utilization of NSAIDs increased by 42.2% in the reference cohort, with similar increases in the diabetes cohort (40.8%; p = 0.88 compared with the reference cohort) and the ACEI-ARB/furosemide cohort (49.6%; p = 0.09 compared with the reference cohort). With the withdrawal of rofecoxib, utilization of NSAIDs in the reference cohort fell by 25.3%, with similar falls in the diabetes cohort (24%; p = 0.28 compared with the reference cohort) and the ACEI-ARB/furosemide cohort (26.1%; p = 0.43 compared with the reference cohort). Despite the increased vulnerability of veterans receiving ACEI-ARB/furosemide or diabetes medicines to adverse events of NSAIDs, uptake rates of COX inhibitors were equivalent to the rest of the veteran population. This suggests the gastrointestinal safety messages were interpreted broadly by prescribers and the adverse renal effects were not considered.

Concomitant Use of Gastroprotective Drugs among Elderly NSAID/COX-2 Selective Inhibitor Users

NSAIDs and cyclo-oxgenase (COX)-2-selective inhibitors have been associated with gastrointestinal (GI) complications among the elderly. It is recommended that gastroprotective drugs (i.e. misoprostol, proton pump inhibitors or high doses of histamine H2 receptor antagonists) be taken concomitantly to prevent NSAID-induced GI complications among older people. However, there are concerns that the rate of concomitant use of gastroprotective drugs in elderly NSAID users is too low. This study aimed to investigate the extent to which elderly users of NSAIDs/COX-2-selective inhibitors are concurrently taking gastroprotective drugs, and to determine the factors associated with concomitant use of gastroprotective drugs and NSAIDs/COX-2-selective inhibitors in a nationwide population of older people. We analysed data on age, sex and dispensed drugs for people>or=75 years of age registered in the Swedish Prescribed Drug Register from October to December 2005 (n=732,230) and located 41,626 NSAID/COX-2-selective inhibitor users. Logistic regression analysis was used for analysing the association between the use of different NSAIDs/COX-2-selective inhibitors and gastroprotective drugs, and between individual characteristics and use of gastroprotective drugs. Gastroprotective drugs were used by 22% of NSAID/COX-2-selective inhibitor users. Celecoxib, ketoprofen, meloxicam and etoricoxib were most commonly used concomitantly with gastroprotective drugs. Meloxicam and celecoxib were most strongly associated with gastroprotective drugs, after adjustment for age, sex and number of other drugs. Furthermore, NSAID/COX-2-selective inhibitor+oral corticosteroid users, NSAID/COX-2-selective inhibitor+selective serotonin reuptake inhibitor users and users of two or more NSAIDs/COX-2-selective inhibitors were more likely to concomitantly use gastroprotective drugs compared with NSAID/COX-2-selective inhibitor only users, after adjustment for age, sex and number of other drugs. However, users of NSAIDs/COX-2-selective inhibitors+anticoagulants (both warfarin and low-dose aspirin [acetylsalicylic acid]) did not show an increased likelihood of concomitant use of gastroprotective drugs, after adjustment for age, sex and number of other drugs. Our results indicate that gastroprotective drugs are not prescribed to elderly NSAID users according to guidelines. Furthermore, COX-2-selective inhibitors were used with gastroprotective drugs more often than were traditional NSAIDs. Greater awareness of factors contributing to NSAID/COX-2-selective inhibitor-induced GI complications is warranted, particularly with respect to advanced age and concurrent use of anticoagulants.

Cardiovascular effects of valdecoxib: transducing human pharmacology results into clinical read-outs

Valdecoxib is an NSAID that is selective for COX-2 (commonly named coxibs). It exhibits anti-inflammatory, analgesic and antipyretic properties in animal models and humans due to inhibition of prostanoid synthesis primarily by affecting COX-2. In this review, the clinical results of cardiovascular effects of valdecoxib and its prodrug parecoxib were analyzed and the information from animal models and clinical pharmacology was exploited, that is, pharmacodynamic and pharmacokinetic data, to give a mechanistic interpretation. Similarly to other coxibs and some traditional (t)NSAIDs less selective for COX-2, such as diclofenac, valdecoxib may increase the risk of thrombotic events through a prostacyclin-based mechanism. The rapid and elevated thrombotic risk detected in two coronary artery bypass graft surgery trials with parecoxib and valdecoxib is coherent with almost complete suppression of COX-2 by supratherapeutic doses (particularly parecoxib), which plausibly translates into a deep suppression of prostacyclin. Drug potency, that is, the degree of suppression of COX-2-dependent prostacyclin, is proposed to represent a strong determinant in the increased incidence of thrombotic events associated with the use of COX-2 inhibitors and some tNSAIDs.

Evaluation of Risk Profiles for Gastrointestinal and Cardiovascular Adverse Effects in Nonselective NSAID and COX-2 Inhibitor Users

Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (>/=18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselective NSAID users as the reference cohort. The effect of calendar time was examined by plotting mean CV or GI risk score by quarter-year. Correlation between GI and CV scores was examined using the Pearson correlation coefficient (R). Data were stratified by patients' history of switching. The four cohorts comprised patients using: first-line nonselective NSAIDs (n = 42 750); second-line nonselective NSAIDs (n = 1771); COX-2 preferential NSAIDs (n = 3661) and coxibs (n = 4861) patients. New coxib users were most likely to have high GI and CV risk scores (OR 5.3 [95% CI 5.0, 5.6] and OR 2.2 [95% CI 2.1, 2.4], respectively). At the individual patient level, GI and CV risk profiles were moderately well correlated for all NSAID cohorts (R range 0.48 to 0.62). There was no remarkable change in mean GI or CV risk profile of patients over calendar time since the market introduction of coxibs. Of the four NSAID cohorts, new coxib users tended to have the highest numbers of GI and CV risk factors, with no obvious change over calendar time. There was also evidence of correlation between GI and CV risk scores. Thus, selective prescribing of coxibs applies to people with co-existing CV as well as GI risk factors. This is important when comparing the safety and/or efficacy of new therapies to existing therapies, and emphasizes the difficulties encountered by prescribers in assessing levels of risk when initiating coxib treatment.

Risk of Upper Gastrointestinal Complications Among Users of Traditional NSAIDs and COXIBs in the General Population

Risk of Upper Gastrointestinal Complications Among Users of Traditional NSAIDs and COXIBs in the General Population

The problem with NSAIDs: What data to believe?

Patients with rheumatoid arthritis and osteoarthritis have relied upon NSAIDs as a cornerstone of their analgesic regime for decades. The choice of anti-inflammatory agents broadened for this group of patients when the selective inhibitors of cyclooxygenase-2 enzyme were developed. Much has been published in the past few years regarding the superior gastrointestinal safety of this class of drugs when compared with traditional NSAIDs. Their triumphant debut was swiftly followed by the emergence of data detailing their associated increased serious cardiovascular risks. This also led to a reevaluation of data concerning more traditional NSAIDs, and surprisingly, a similar trend was seen. The US Food and Drug Administration has recommended that both classes of drugs carry a black box warning with regard to gastrointestinal and cardiovascular risks.

Design, Synthesis and Evaluation of Antiinflammatory, Analgesic and Ulcerogenicity studies of Novel S-Substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of Diclofenac acid as Nonulcerogenic Derivatives

Diclofenac sodium is being used for its anti-inflammatory actions since 28 years, but as all the NSAIDs are suffering from the deadlier GI toxicities, diclofenac sodium is also not an exception to these toxicities. The free –COOH group is thought to be responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main motto was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. In this paper, the results of synthesis and pharmacological screening of a series of S-substituted phenacyl 1,3,4-oxadiazoles and Schiff bases derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid (diclofenac acid) are described. The 1,3,4-oxadiazoles and diclofenac moieties are important because of their versatile biological actions. In the present studies, the oxadiazole system has been functionalized onto the diclofenac acid moiety and 18 compounds in this series were synthesized. The structures of new compounds are characterized by TLC, FTIR, 1H NMR and Mass spectral data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds, which showed significant activity (comparable to the standard drug diclofenac sodium), were screened for their analgesic activity and to check their ability to induce ulcers by ulcerogenicity and histopathology studies. Eight new compounds, out of 18, were found to have significant anti-inflammatory activity in the carrageenan induced rat paw oedema model, with significant analgesic activity in the acetic acid induced writhing model with no ulcerogenicity. The compounds, which showed negligible ulcerogenic action, also showed promising results in histopathology studies, that is, they were found to be causing no mucosal injury.