Selective NSAIDs Research Articles

Increase in Nonfatal Digestive Perforations and Haemorrhages following Introduction of Selective NSAIDs: a Public Health Concern

tion of selective NSAIDs on overall prescription patterns of NSAIDs and associated gastroprotective agents (GPAs), and on the rate of nonfatal digestive perforations and haemorrhages. Methods: A retrospective, closed cohort study was conducted using the Quebec Health Insurance Board databases, for a 3-year period overlapping the introduction of selective NSAIDs. All adult subjects who were continuously registered with the Public Prescription Drug Program (PPDP) between 1 January 1999 and 31 December 2001 (n = 2 052 231) were included. Prescriptions for NSAIDs (selective [celecoxib, rofecoxib and meloxicam] and nonselective), concomitant use of GPAs and nonfatal digestive perforations or haemorrhages diagnosed in hospital were compiled. Data were analysed on an annual basis according to age, sex and patient risk of gastrointestinal (GI) complications. Results: The listing of selective NSAIDs in the PPDP formulary was followed by a 28.2% increase in the prevalence of NSAID use from 19.5% in 1999 to 25% in 2001. The proportion of long-term users also evolved rapidly with a 135% increase over 3 years. From 1999 to 2001, there was a 75.9% increase in the rate of nonfatal digestive perforations and haemorrhages in the presence of NSAIDs. Conclusion: The introduction of selective NSAIDs stimulated NSAID use and coincided with an increased incidence of nonfatal digestive perforations and haemorrhages in the presence of NSAIDs. Selective NSAIDs should be prescribed with caution to persons at risk for GI complications.

30-Day Mortality After Peptic Ulcer Perforation Among Users of Newer Selective Cox-2 Inhibitors and Traditional NSAIDs: A Population-Based Study

30-Day Mortality After Peptic Ulcer Perforation Among Users of Newer Selective Cox-2 Inhibitors and Traditional NSAIDs: A Population-Based Study

Similar effects of rofecoxib and indomethacin on the incidence of heterotopic ossification after hip arthroplasty

Background Although indomethacin is effective in preventing heterotopic ossification (HO) after primary total hip arthroplasty, side effects are frequently observed. In the last decade a new class of drugs—the COX-2 selective nonsteroidal anti-inflammatory drugs—has been developed. To investigate the effect of these COX-2 selective NSAIDs on heterotopic ossification (HO) after primary total hip arthroplasty (THA), we conducted a randomized controlled trial using either indomethacin or rofecoxib for 7 days.Methods 186 patients received either indomethacin 3 times daily, or rofecoxib twice, and 1 placebo, daily for 7 days. HO was graded according to the 1-year postoperative radiographs according to the Brooker classification.Results 12 of the 186 patients included discontinued their medication before the end of the trial due to side effects. The remaining 174 patients were included in the analysis. In the indomethacin group (n = 89), 77 patients (87%) showed no HO, 9 showed HO of grade 1 and 3 showed HO of grade 2 according to the Brooker classification. In the rofecoxib group (n = 85) 73 patients (86%) showed no ossification, 9 showed grade 1, and 3 showed grade 2.Interpretation The prophylactic effect of rofecoxib for 7 days in preventing heteropic ossification after primary total hip arthroplasty is comparable to the effect of indomethacin given for 7 days. These results indicate that the development of HO follows a COX-2 pathway.

Etoricoxib: equipped with MEDAL-winning safety data?

According to data from the MEDAL program, results of which were presented at both the joint 70th Annual Scientific Meeting of the American College of Rheumatology and the 41st Annual Meeting of the Association of Rheumatology Health Professional (ACR/ARHP) [Washington, District of Columbia, US; November 2006], and the 79th Scientific Sessions of the American Heart Association (AHA) [Chicago, Illinois, US; November 2006], the COX-2 selective NSAID etoricoxib [Arcoxia] has a similar cardiovascular safety profile to the traditional non-selective NSAID, and most commonly used NSAID worldwide, diclofenac. The Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program pooled data from three randomised, double-blind, multinational trials conducted in more than 34,000 patients with rheumatoid arthritis or osteoarthritis. Etoricoxib and diclofenac were associated with a similar cumulative incidence of thrombotic cardiovascular events (the primary endpoint of the program). However, the COX-2 selective inhibitor had no significant benefit over the traditional NSAID with respect to complicated GI events, despite improved GI tolerability being the reason behind the development of the COX-2 drug class.

Peri-operative blood management in elective orthopaedic surgery. A critical review of the literature

Blood loss during orthopaedic procedures can be extensive and the need for allogeneic blood is a common requirement. However, blood transfusion conceals a number of well-recognised risks and complications and blood products have become more expensive because of their specific preparation procedure. Surgical technique, awareness of the problem and restriction of transfusion triggers are important factors affecting the management of blood loss. Several studies have additionally shown the efficacy of epoetin injections in increasing the pre-operative haemoglobin level. On the other hand, the true benefit of pre-operative autologous donation, acute normovolemic haemodilution and COX-2 selective NSAIDs remains under dispute. Regarding the role of platelet rich plasmapheresis, fibrin sealing and anti-fibinolytic drugs more data are needed. Hypotensive epidural anaesthesia seems to be an advantageous method in minimising peri-operative blood loss. However, this is not a widely performed technique in orthopaedic surgery. In addition, post-operative blood cell saving systems after total knee or hip arthroplasty have been reported to significantly minimise allogeneic blood transfusions when compared to control groups. It can be concluded that many interventions diminish more or less allogeneic blood transfusion in elective orthopaedic surgery. Nevertheless more prospective studies are needed and appropriate algorithms should be applied in peri-operative blood loss management. This review presents an overview of the available interventions which aim to diminish the use of allogeneic blood in elective orthopaedic surgery.

Use and costs of anti-secretory and cardiovascular co-medication in osteoarthritis patients treated with selective or non-selective NSAIDS

This study aims to compare use and costs of anti-secretory and cardiovascular co-medication in osteoarthritis patients treated with selective or non-selective NSAIDs. A retrospective study examined Belgian patients aged 65 years or more who suffer from osteoarthritis and are chronic users of selective NSAIDs (n=1,376) or non-selective NSAIDs (n=8,482). A before-and-after analysis compared drug use and costs between period 1 (first 6 months of 2002) and period 2 (several 1-year periods stretching over 2003-2004). A cohort analysis contrasted patients taking selective NSAIDs with patients taking non-selective NSAIDs. Anti-secretory co-medication included histamine H2-receptor antagonists and proton pump inhibitors. Cardiovascular co-medication referred to cardiac glycosides, anti-arrhythmics, anti-thrombotics, anti-angina drugs, anti-hypertensive drugs and serum-lipid-reducing drugs. Volume of drug use was expressed as number of packages and costs were computed in Euro. The volume of anti-secretory co-medication increased by 36% with selective NSAIDs and by 55% with non-selective NSAIDs between periods 1 and 2. Cardiovascular co-medication rose by 18% with selective NSAIDs and by 12% for non-selective NSAIDs. Focusing on patients who did not take anti-secretory co-medication in period 1, patients taking selective NSAIDs were just as likely to start anti-secretory co-medication in period 2 as patients taking non-selective NSAIDs (odds ratio: 1.05; 95% confidence interval: 0.90-1.23). Patients taking selective NSAIDs were just as likely to start cardiovascular co-medication as patients taking non-selective NSAIDs (odds ratio: 1.03; 95% confidence interval: 0.78-1.36). Annual costs of treating osteoarthritis in ambulatory care amounted to 756 <euro> with selective NSAIDs and 416 <euro> with non-selective NSAIDs. This originated from higher acquisition costs (278 <euro> vs. 24 <euro>) and higher costs of co-medication (477 <euro> vs. 392 <euro>) with selective NSAIDs. The use of selective and non-selective NSAIDs is accompanied by a higher use of co-medication over time. The increase in anti-secretory co-medication was more prominent with non-selective NSAIDs. The rise in cardiovascular co-medication was more pronounced with selective NSAIDs. Treatment of osteoarthritis with selective NSAIDs is more expensive than with non-selective NSAIDs in terms of acquisition costs and costs of co-medication.

Vascular events with selective COX2 inhibitors and NSAIDs: analyzing the risks

Vascular events with selective COX2 inhibitors and NSAIDs: analyzing the risks

Cardiovascular events associated with the use of four nonselective NSAIDs (Etodolac, Nabumetone, Ibuprofen, or Naproxen) Versus a Cyclooxygenase-2 Inhibitor (Celecoxib): A population-based analysis in taiwanese adults

Background: Serious cardiovascular events (CVEs) have been linked to the use of cyclooxygenase (COX)-2 inhibitors, a category of selective NSAIDs. However, few studies are available that have compared the risk for CVEs between COX-2 inhibitors and nonselective NSAIDs in adults undergoing long-term treatment. Objectives: The present study assessed (1) whether long-term use of nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) is associated with an increased risk for treatment-related CVEs (acute myocardial infarction [AMI], angina, cerebrovascular attack [CVA], and/or transient ischemic attack [TIA]) compared with long-term use of celecoxib and (2) which factors are associated with the risk for treatment-related CVEs in long-term users of nonselective NSAIDs in Taiwan. Methods: This population-based analysis used data from the Taiwanese Bureau of National Health Insurance (Taipei, Taiwan) database. Eligible patients were aged ≥18 years and had been receiving etodolac, nabumetone, ibuprofen, naproxen, or celecoxib for ≥180 days between January 1, 2001, and December 31, 2003. The primary outcomes measure was the prevalence of serious CVEs (AMI, angina, CVA, and/or TIA requiring hospitalization) after initiation of treatment. Analyses were performed on data from all eligible patients; person-time exposures to the drugs and hazard ratios (HRs) were calculated to determine the risk for CVEs with long-term use. Results: A total of 16,326 patients (8166 men, 8160 women; mean [SD] age, 61.83 [20.23] years) who had received long-term treatment with etodolac (2014 [12.34%]), nabumetone (2262 [13.86%]), ibuprofen (5239 [32.09%]), naproxen (3049 [18.68%]), or celecoxib (3762 [23.04%]) were identified. The overall prevalences of AMI, angina, CVA, and TIA were higher in long-term users with a history of cardiovascular disease (CVD) than in those without (AMI, 4.76% vs 0.99%; angina, 4.11% vs 0.43%; CVA, 7.74% vs 1.51%; and TIA, 4.03% vs 0.52%) (all, P < 0.01). The HRs for AMI, angina, CVA, and TIA were not significantly different between the NSAID and celecoxib groups. History of CVD played a significant role in recurrence during the period studied; the HRs (95% CIs) were 2.29 (1.22–4.32) for AMI, 6.19 (3.56–10.78) for angina, 3.56 (2.80–4.52) for CVA, and 6.60 (3.72–11.73) for TIA. Preexisting medical conditions (hypertension, dyslipidemia, diabetes mellitus, congestive heart failure, chronic renal disease) also significantly affected the risk for CVEs. Conclusions: In this cohort study of long-term (≥180 days) use of NSAIDs in Taiwanese adults, no significant differences in the risk for treatment-related CVEs were observed between groups prescribed 1 of 4 nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) or celecoxib. History of CVD was the most significant determinant of CVE risk. Patients with preexisting medical conditions appeared to have a significantly higher risk for CVEs associated with the use of NSAIDs and celecoxib compared with patients without these conditions.

CV safety of non selective NSAIDs under review again in the EU

CV safety of non selective NSAIDs under review again in the EU

Efecto del tratamiento con AINE sobre la presión arterial en pacientes hipertensos con riesgo cardiovascular elevado

An elevation in the risk of cardiovascular (CV) events and blood pressure (BP) levels in patients treated with COX-2 inhibitors compared to non selective NSAID has been shown previously. To compare the effects of NSAID (COX-2 inhibitors and non-selective) on BP levels and control of HT. To determine the association between NSAID use and coronary heart disease in HT patients with elevated CV risk. Cross sectional epidemiological study in 8126 ambulatory HT patients, older than 40, with a high CV risk. We obtained data on personal variables, CV risk factors, previous CV history, CV medication, analgesic and anti inflammatory drugs (AID). Control of HT was classified: optimal, suboptimal and no control. Absolute CV risk was calculated according to the WHO-ISH score. 44.2% of subjects took ASA and 3.7% another NSAID. SBP was 5.90 mmHg (95%CI: 2.53-9.27 mmHg) higher (p < 0.05) in patients treated with NSAID than in those with no AID medication. Patients having ASA, both SBP and DBP were 5.89 mmHg (p < 0.01) and 2.25 mm Hg (p < 0.05) respectively, lower than in patients with NSAID. However, mean SBP was similar in the ibuprofen group compared to without AID; 11.12 mmHg lower (95%CI: 3.66-18.58) than in the group on NSAID (p < 0.05) and 8.82 mmHg (95%CI: 0.27-17.38) (p < 0.05) lower than in those on COX-2 inhibitors. Among HT patients, NSAID therapy (selective or not) is associated with a higher level of SBP than in those without such medication. However, patients treated exclusively with Ibuprofen show similar levels of SBP than without NSAID treatment. Frequency of ischemic disease was significantly higher in the group treated with COX-2 inhibitors than in the non-selective NSAID treated group or in patients without NSAID treatment.

A Computational Protocol for the Integration of the Monotopic Protein Prostaglandin H2 Synthase into a Phospholipid Bilayer

Prostaglandin H2 synthase (PGHS) synthesizes PGH 2, a prostaglandin precursor, from arachidonic acid and was the first monotopic enzyme to have its structure experimentally determined. Both isozymes of PGHS are inhibited by nonsteroidal antiinflammatory drugs, an important class of drugs that are the primary means of relieving pain and inflammation. Selectively inhibiting the second isozyme, PGHS-2, minimizes the gastrointestinal side-effects. This had been achieved by the new PGHS-2 selective NSAIDs (i.e., COX-2 inhibitors) but it has been recently suggested that they suffer from additional side-effects. The design of these drugs only made use of static structures from x-ray crystallographic experiments. Investigating the dynamics of both PGHS-1 and PGHS-2 using classical molecular dynamics is expected to generate new insight into the differences in behavior between the isozymes, and therefore may allow improved PGHS-2 selective inhibitors to be designed. We describe a molecular dynamics protocol that integrates PGHS monomers into phospholipid bilayers, thereby producing in silico atomistic models of the PGHS system. Our protocol exploits the vacuum created beneath the protein when several lipids are removed from the top leaflet of the bilayer. The protein integrates into the bilayer during the first 5 ns in a repeatable process. The integrated PGHS monomer is stable and forms multiple hydrogen bonds between the phosphate groups of the lipids and conserved basic residues (Arg, Lys) on the protein. These interactions stabilize the system and are similar to interactions observed for transmembrane proteins.

Rheumatic-like syndrome as a symptom of underlying gastric cancer

Several observations imply that atypical rheumatic manifestations may be associated with occult neoplasia. A 71-year-old woman was admitted to the hospital three times in 2 years. Initially, she was admitted for investigation of an iron-deficient anemia associated with upper intestinal tract symptoms. Endoscopy revealed hiatus hernia, esophagitis, and duodenal ulcer with a Helicobacter pylori infection, but there were no signs of malignancy, and the patient received appropriate drug treatment. Two years later, she presented with arthralgias concerning the upper and lower limbs in an asymmetrical distribution, low fever, and persistence of the anemia, despite the treatment she had received and the fact that her gastrointestinal symptoms had long ceased. Immunological assays showed no specific rheumatic disorder, and the patient was discharged after showing significant improvement with the use of COX-2 selective NSAIDs. Finally, 4 months later, she was readmitted with worsening of the arthralgias, arthritis in the right radiocarpal joint, and severe anemia. Hematemesis that occurred during her hospital stay led to an emergency endoscopy and the diagnosis of gastric adenocarcinoma. Only a few cases have been reported so far concerning rheumatic manifestations as signs of an occult gastric cancer. Thus, there must be some degree of suspicion when dealing with patients with anemia and rheumatic symptoms that cannot be classified into a particular rheumatologic entity, because they might conceal a gastrointestinal malignancy not yet evident.

Do coxibs reduce prescription of gastroprotective agents? Results of a record linkage study.

BackgroundCoxibs are claimed to be cost-effective drugs and reduced prescription of gastroprotective agents is assumed to be one of their major benefits. Real life prescription of these drugs may be substantially different than that considered in pharmacoeconomic analyses or claimed by drug companies, yet. Our objective was to evaluate whether coxibs were associated with reduced prescription of gastro-protective agents (GPAs, specifically proton pump inhibitors, H2 blockers and misoprostol) compared to non selective NSAIDs.MethodsA record-linkage study was performed using 2001 outpatient prescription data from the province of Modena (about 632,000 inhabitants, in Northern Italy). Logistic regression was used to calculate the odds ratio of GPA prescription for coxib and non-selective NSAID adult users (> 14 years). Three categories of users were further investigated: "acute", "chronic and "incident or new". Main outcome measures were same-day co-prescription and 30 days prescription of GPAs in coxibs and non selective NSAIDs users. To limit selection bias, data were adjusted for age, sex, DDD of coxibs and non selective NSAIDs received during 2001, DDD of GPAs and (for non-incident users) DDD of NSAIDs received during the previous 4 yearsResultsSame day co-prescription rates were similar considering the overall population and "acute" users. Chronic coxibs users instead showed higher co-prescription rates than chronic NSAIDs users (OR = 1.2, p < 0.05). GPA prescription within thirty days was also higher among all subgroups of coxibs users (OR ranging from 1.6 to 2.0, p < 0.001).ConclusionAssumptions made in pharmacoeconomic analyses on coxibs (lower GPA prescription associated with coxibs use) may be overly optimistic. Claims made through cost-effectiveness data should be carefully interpreted, and mechanisms for attributing drug prices revised accordingly.

Chronic Osteoarthritis

Chronic Osteoarthritis

Treatment of Patients With Osteoarthritis With Rofecoxib Compared With Nabumetone

Rofecoxib and nabumetone were developed to provide gastrointestinal benefits over traditional nonsteroidal antiinflammatory drugs (NSAIDs). However, there is limited comparative information relating to these 2 drugs. The objective of this study was to compare rofecoxib and nabumetone, at their lower, recommended doses, in patients with osteoarthritis (OA). Nine hundred seventy-eight patients with knee OA and a positive history of NSAID response were randomized to 12.5 mg rofecoxib per day (N=390), nabumetone 500 mg twice a day (N=392), or placebo (N=196) for 6 weeks. The primary efficacy end point was percent of patients with a "good" or "excellent" Patient Global Assessment of Response to Therapy (PGART) at week 6; PGART was also evaluated over days 1 to 6. Additional end points included investigator assessment of response, pain walking over 6 days and 6 weeks, joint tenderness, discontinuation as a result of lack of efficacy, and quality of life. Adverse experiences (AEs) were collected. Significantly more rofecoxib (50.4%) than nabumetone (43.3%, P=0.043) or placebo (29.5%, P<0.001) patients had a good or excellent PGART at week 6. Median time to a good or excellent PGART was significantly shorter with rofecoxib (52 hours) than nabumetone (100 hours, P=0.001) or placebo (>124 hours, P<0.001). Results for rofecoxib and nabumetone were similar in all additional end points except pain in walking over 6 days and 6 weeks, in both of which the rofecoxib treatment group demonstrated better results. There were significantly (P<0.050) more overall and serious AEs and discontinuations resulting from AEs with rofecoxib than nabumetone. Five rofecoxib and one nabumetone patients had confirmed thrombotic cardiovascular events (P=0.123). Information on thrombotic cardiovascular events from this study was included in a published, prespecified pooled analysis and is included here for completeness. At their recommended starting doses for OA, both agents were more effective than placebo. Rofecoxib at a dosage of 12.5 mg demonstrated significantly better efficacy in PGART than 1000 mg nabumetone in these patients known to be NSAID responders. Significantly more AEs occurred with rofecoxib than nabumetone. Considering these data and other recent safety information regarding cyclooxygenase-2 selective and nonselective NSAIDS, physicians must make risk/benefit assessments for each individual patient when considering the use of these agents, as recommended by the U.S. Food and Drug Administration.

LBOVI-A-4Short-term gastrointestinal and cardiovascular safety of selective COX-2 inhibitors and non-selective nsaids: An instrumental variable analysis

BACKGROUND A direct comparison of the gastrointestinal (GI) and cardiac safety of NSAIDs in elderly patients is not possible based on randomized trials since different trials employed non-overlapping patient populations and comparison exposures. We sought to estimate the risk reduction of GI complications and risk increase in acute myocardial infarction (MI) by celecoxib and rofecoxib compared with several non-selective NSAIDs addressing confounding by using instrumental variable methods. METHODS We identified 49,731 Medicare beneficiaries who initiated non-selective NSAIDs or selective COX2 inhibitors between 1/1/99 and 7/31/03. Risk increase of GI complications and MI in 180 days after initiation of NSAID therapy (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) was assessed using instrumental variable analysis adjusting un/measured confounders. RESULTS Compared with celecoxib, a tendency for increased risk of GI complications was observed for ibuprofen (risk difference = 0.93 events per 100 patients; −1.88; 3.73) and diclofenac (RD=5.20; −1.07;11.5). We found a clear increase in the risk of MI for rofecoxib (RD=2.17; 0.12;4.21) and diclofenac (RD=7.63; 0.24;15.0), while naproxen had the lowest risk (RD = −1.59; −4.62;1.44). CONCLUSIONS Diclofenac appears to have the least favorable safety profile among NSAIDs, while naproxen has the lowest risk of MI with no meaningful increase in risk for GI complications, making it a viable alternative to celecoxib. Clinical Pharmacology & Therapeutics (2005) 79, P83–P83; doi: 10.1016/j.clpt.2005.12.296

NSAID-Associated Adverse Effects and Acid Control Aids to Prevent Them

NSAIDs are central to the clinical management of a wide range of conditions. However, NSAIDs in combination with gastric acid, which has been shown to play a central role in upper gastrointestinal (GI) events, can damage the gastroduodenal mucosa and result in dyspeptic symptoms and peptic lesions such as ulceration.NSAID-associated GI mucosal injury is an important clinical problem. Gastroduodenal ulcers or ulcer complications occur in up to 25% of patients receiving NSAIDs. However, these toxicities are often not preceded by indicative symptoms. Data obtained from the Arthritis, Rheumatism, and Aging Medical Information System have shown that 50-60% of NSAID-associated peptic ulcer cases can remain clinically silent and do not present until complications occur. Therefore, prophylactic treatment to prevent GI complications may be necessary in a substantial proportion of NSAID users, especially those in groups associated with a high risk of developing these complications. Use of cyclo-oxygenase (COX)-2 selective NSAIDs, also known as 'coxibs', substantially reduces the incidence of upper GI toxicities seen with non-selective NSAIDs. However, there are concerns regarding the cardiovascular safety of coxibs. For this reason, the US FDA recommends minimal use of coxibs and only when strictly necessary. Additionally, rofecoxib has been removed from the US market and sales of valdecoxib have been suspended. Furthermore, upper GI toxicities still occur in patients receiving coxibs. Therefore, cotherapies are required to prevent and/or heal upper GI effects associated with NSAID use. Effective prophylactic and treatment strategies include misoprostol, histamine H(2) receptor antagonists and proton pump inhibitors (PPIs). The key role that gastric acid plays in upper GI adverse events among NSAID users suggests that it is important to choose the most effective agent for acid control to alleviate symptoms, heal mucosal erosions and improve the reduced quality of life in this patient population. PPIs provide effective acid suppression, which is essential to avoid GI mucosal injury, and they are, therefore, capable of dramatically decreasing the morbidity and mortality associated with this disorder. Since many serious GI complications are not heralded by any previous symptoms, physicians need to be aware of risk factor profiles that predispose patients to serious GI problems. Physicians also need to initiate the appropriate preventative acid suppressive therapy to minimise the burden of NSAID-associated GI adverse effects.

Increase in Nonfatal Digestive Perforations and Haemorrhages Following Introduction of Selective NSAIDs

Background and objective: This article documents the impact of the introduction of selective NSAIDs on overall prescription patterns of NSAIDs and associated gastroprotective agents (GPAs), and on the rate of nonfatal digestive perforations and haemorrhages.

Nitronaproxen

Nitronaproxen [AZD 3582, HCT 3012, naproxen nitroxybutylester, NO-naproxen] is a naproxen derivative with similar anti-inflammatory activity to the parent compound, but with less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-inhibiting nitric oxide donators (CINODs), which are under development by NicOx. The better gastrointestinal tolerability of nitronaproxen appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity. Nitronaproxen is in phase III clinical development for the treatment of osteoarthritis and is available for licensing. AstraZeneca had been a worldwide licensee for nitronaproxen and other CINODs. However, the results of phase II clinical trials of nitronaproxen did not fulfill AstraZeneca's strategic commercial criteria for further investment and NicOx reacquired rights following AstraZeneca's decision to discontinue its involvement in 2003. NicOx was surprised by AstraZeneca's decision, and remained fully convinced of the potential of nitronaproxen. NicOx is seeking new partners for development of compounds of the CINOD class. Nitronaproxen is in a phase III clinical trial for the treatment of osteoarthritis (OA) of the knee. The 13-week trial completed enrolment of 820 patients from 120 clinical sites in the US in May 2006. The study is designed to confirm that nitronaproxen is superior to placebo and is as effective as naproxen in relieving signs and symptoms of OA. The study will also seek to show that nitronaproxen has no adverse effect on blood pressure. An additional trial has begun that is employing ambulatory blood pressure monitoring to provide a description of the blood pressure effect of nitronaproxen over a 24-hour period in hypertensive subjects. This US trial will enrol approximately 120 volunteers with stable essential hypertension. The volunteers will not have osteoarthritis but will be between the ages of 50 and 75 years (representative of the osteoarthritis population). Results from both trials are expected in the fourth quarter of 2006. The phase II clinical programme for nitronaproxen, which included 2709 patients in five separate clinical studies, showed that the drug is a potent, safe anti-inflammatory agent, with potential for improved cardiovascular safety over NSAIDs and COX-2 selective NSAIDs. An independent advisory board recommended further development of nitronaproxen in the treatment of osteoarthritis in 2004 based on an evaluation of the full results of the phase II clinical programme.A clinical study had begun in September 2004 at the University of Pennsylvania in patients with mild essential hypertension, in which the effects of nitronaproxen and rofecoxib on arterial blood pressure would be compared. However, rofecoxib was withdrawn worldwide on 1 October 2004. It is unclear if the trial was completed. The STAR Multinational Study Group has conducted a phase II gastrointestinal safety and efficacy study of nitronaproxen versus naproxen in 970 patients with osteoarthritis at 80 sites in the following countries: Argentina, Brazil, Hungary, Mexico, Norway, Poland, South Africa and the UK. The study was completed in November 2002. AstraZeneca conducted a randomised, phase II trial evaluating the efficacy and safety of nitronaproxen among 672 subjects with symptomatic knee osteoarthritis. Results have been presented. Certain phase II trial data from 2003 had been somewhat disappointing. However, an underpowered trial and failures and deficiencies in a trial meant that it was not possible to draw conclusions from this data.

Risks of Hospitalization for Myocardial Infarction Among Users of Rofecoxib, Celecoxib, and Other NSAIDs

corticocoids,andhormonetherapybeforethedateofadmission for MI. Results: Current users of rofecoxib had an elevated risk estimate for hospitalization for MI compared with nonusers of any category of nonaspirin NSAIDs (adjusted relative risk [ARR], 1.80; 95% confidence interval [CI], 1.47-2.21). Increased risk estimates were also found among current users of celecoxib (ARR,1.25; 95% CI, 0.97-1.62), other cyclooxygenase-2 selective inhibitors (ARR, 1.45; 95% CI, 1.09-1.93), naproxen (ARR, 1.50; 95% CI, 0.99-2.29), and other conventional nonaspirin NSAIDs (ARR, 1.68; 95% CI, 1.52-1.85). The highest ARRs were found among new users of all examined drug categories. Conclusions:Currentandnewusersofallclassesofnonaspirin NSAIDs had elevated relative risk estimates for MI. Although the increased risk estimates may partly reflect unmeasured bias, they indicate the need for further examination of the cardiovascular safety of all nonaspirin NSAIDs. Arch Intern Med. 2005;165:978-984