Conventional Nonsteroidal Anti-inflammatory Drugs Research Articles

Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis.

Several new drugs have become available for the treatment of patients with osteoarthritis and rheumatoid arthritis (RA). These agents include selective cyclooxygenase (COX)-2 inhibitors, leflunomide and anti-tumour necrosis factor (TNF)-alpha antagonists. COX-2 inhibitors have a more favourable gastrointestinal adverse effect profile than conventional non-steroidal anti-inflammatory drugs (NSAIDs). However, the COX-2 inhibitors are also associated with hypertension, oedema and congestive heart failure, the well-known adverse effects of conventional NSAIDs. Patients with treated hypertension should be monitored regularly when conventional NSAIDs or COX-2 inhibitors are administered. At present, there is a considerable debate regarding the risk of cardiovascular events with the COX-2 inhibitors. The available literature gives no unequivocal answers. This matter can only be solved by an appropriate trial assessing the cardiovascular risk of these agents. Patients with RA appear to have an enhanced cardiovascular risk which might be related to an unfavourable lipid profile. Corticosteroids induce hypercholesterolaemia in patients other than those with RA. It was recently shown that total and high-density lipoprotein (HDL) cholesterol were low in patients with RA who had a high disease activity. Contrary to the expectation, combination therapy with prednisolone rapidly improved the atherogenic index (total/HDL cholesterol). Ongoing studies investigating this topic are underway. It is not known to what extent corticosteroids induce hypertension in patients with RA. Hence, we advocate blood pressure control for these patients. A small percentage of patients with RA develop hypertension when taking leflunomide, and no other serious cardiovascular adverse effects have been reported in the literature. Blood pressure monitoring is recommended especially in the first months of treatment. TNFalpha antagonists are contraindicated in patients with RA who have congestive heart failure. No specific cardiovascular adverse effects have been reported with the use of these agents in the non-cardiovascular compromised patient. TNFalpha antagonists are the most powerful anti-inflammatory drugs presently available. As inflammation plays an important role in RA as well as in cardiovascular disease and, in view of the increased cardiovascular risk in RA, it is tempting to expect that suppression of inflammation ultimately will lower the cardiovascular morbidity and mortality in patients with RA.

Nitric Oxide Releasing Aspirin Protects the Gastric Mucosa against Stress and Promotes Healing of Stress-Induced Gastric Mucosal Damage: Role of Heat Shock Protein 70

Background/Aim: Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs that induce such damage. We compared the effects of native aspirin (ASA) with those of NO-releasing ASA (NO-ASA) on the development and healing of acute gastric lesions induced by water immersion and restraint stress (WRS) and the mucosal expression of heat shock protein 70 (HSP70). Methods: Wistar rats received: (1) vehicle; (2) ASA (40 mg/kg i.g), and (3) NO-ASA (2.5–40 mg/kg i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate, the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was assessed 0–24 h after termination of WRS. Number of gastric lesions, gastric mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of HSP70 mRNA were determined. Results: WRS caused typical bleeding erosions that were aggravated by aspirin and this was accompanied by a fall in the GBF and a significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which raised significantly the luminal content of NO_x, reduced number of WRS lesions and mucosal MDA levels while increasing significantly the GBF. These protective and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased significantly the MDA content and induced overexpression of HSP70 mRNA during healing of WRS lesions.Conclusion: NO-ASA exhibits mucosal protective and healing effects against WRS-induced gastric lesions due to the release of NO, which induces gastric hyperemia, and the attenuation of lipid peroxidation and counteracts the inhibition of HSP70 expression induced by native ASA.

Cyclo-oxygenase-2 inhibitors and the kidney: a case for caution.

Cyclo-oxygenase (COX) is one of the key enzymes in the biosynthesis of prostaglandins. Two isoforms of this enzyme COX-1 and COX-2 are known to exist. Among other functions, prostaglandins play an important role in the protection of the gastric mucosa and maintenance of renal function in pathophysiological conditions which would otherwise threaten it. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis, resulting in gastric mucosal injury and renal dysfunction in susceptible individuals. The recent introduction of selective COX-2 inhibitors, celecoxib and rofecoxib, appear to induce less gastrointestinal morbidity. Although conclusive data are still lacking, there is evidence to suggest that COX-2 antagonists may be capable of causing some of the same renal syndromes seen in association with the older, less selective NSAIDs.

Current Features of Peptic Ulcer Disease in Finland: Incidence of Surgery, Hospital Admissions and Mortality for the Disease During the Past Twenty-five Years

Background: Medical therapy of peptic ulcer disease (PUD) has improved dramatically during the past 20 years with the introduction of modern antisecretory drugs as well as eradication therapy of Helicobacter pylori. During the 1990s, there has been a 3-fold increase in the consumption of histamine2-receptor antagonists and proton-pump inhibitors, but also an 8-fold increase in the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) in Finland. Methods: The incidence of surgery, hospital admissions and mortality for PUD was analysed between 1972 and 1999; the data were collected from the National Research and Development Centre for Welfare and Health and from the National Centre for Statistics. In the analysis, the codes of the International Statistical Classification of Diseases 8-10 were used. Results: In 1987, 11.9 elective operations (per 10 5 inhabitants) were performed (mean of 2 consecutive years), but only 1.3 in 1997, a reduction of 89%. In 1987, 5.2 emergency operations for ulcer perforation or bleeding were performed, whereas there were 7.5 in 1997, an increase of 44%. The annual hospital admission rate increased from 38.3 admissions (per 10 5 inhabitants) in 1972 (mean ± s (standard deviation) of 5 consecutive years) to 68.7 in 1992. This 79% increase was mainly due to bleeding from gastric ulcer in elderly women. The overall annual mortality rate increased between 1972 and 1992 from 6.4 to 8.4 deaths (per 10 5 inhabitants), i.e. by 31%. The mortality rate from ulcer perforation and haemorrhage increased from 4.2 deaths in 1972 to 7.3 deaths in 1992, i.e. by 74%. Conclusions: The increasing incidence rates of emergency surgery, hospital admissions and mortality for PUD in the 1980s and 1990s have started to decrease in the most recent years in Finland. This epidemiologic change probably reflects both the demographic change and an increased consumption of NSAIDs, among the elderly people, in particular. The most recent epidemiologic change may reflect an increased consciousness about the harmful effects of conventional NSAIDs. Regardless of the constantly occurring emergency surgery, elective surgery for PUD is hardly ever required today.

Alteration of Gastric Ulcerogenic and Healing Responses in Rats With Adjuvant-Induced Arthritis

Gastroenteropathy is the most common among patients who use non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of inflammatory disorders. It is known that rheumatoid arthritic patients are more susceptible to NSAID-induced gastropathy than other NSAID users. This article reviewed our recent studies concerning the influence of arthritic conditions on gastric ulcerogenic response to NSAID and healing response of chronic gastric ulcers in rats. Gastric lesions induced by indomethacin, one of the conventional NSAIDs, were markedly aggravated in arthritic rats. This increased ulcerogenic response in arthritic rats was attributable to nitric oxide production due to up-regulation of inducible nitric oxide synthase. In arthritic rat stomachs, cyclooxygenase (COX)-2 was also up-regulated, where COX-2 selective inhibitors such as rofecoxib or celecoxib provoked gross lesions, although they caused no damage in normal rats. In addition, the healing of chronic gastric ulcers was also delayed in arthritic rats because of less expression of various growth factors such as basic fibroblast growth factors or insulin-like growth factors. Based on these findings, it is concluded that arthritic conditions alter the mucosal ulcerogenic and healing responses in the stomach. Especially, caution should be paid on the use of COX-2 selective inhibitors in rheumatoid arthritic patients.

Cyclooxygenase-2 selective inhibitors and the kidney

Cyclooxygenases (COX) are the target of non-steroidal anti-inflammatory drugs (NSAIDs) which exert their therapeutic effect by blocking COX's capacity to metabolize arachidonate to a series of biologically active fatty acids, designated prostaglandins. NSAID use is associated with two major tonicities: gastrointestinal bleeding and renal dysfunction. In the setting of significant physiologic stress, renal function becomes dependent upon prostaglandins and NSAID use may be associated with acute deterioration of renal function, including development of sodium retention, edema, hypertension, hyperkalemia, and or papillary necrosis. Two isoforms, COX1 and COX2, have been identified. They are products of distinct genes and their expression is under different regulatory control. Both COX1 and COX2 are highly expressed in the kidney and both are inhibited by conventional NSAIDs. Accumulating data using recently developed selective COX2 inhibitors suggest that while these agents spare the gastrointestinal tract they have similar renal effects as non-selective NSAIDs. Therefore, caution should be taken when prescribing selective COX2 inhibitor to patients, especially to patients with predisposed physiologic stress.

Comparative Efficacy and Safety of Celecoxib and Naproxen in the Treatment of Osteoarthritis of the Hip

Osteoarthritis (OA) is responsible for more disability of the lower extremities in the elderly than any other disease in the US. The pain associated with OA is the primary symptom leading to disability in these patients. Current ACR guidelines recommend consideration of acetaminophen for mild-to-moderate pain and conventional non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 specific inhibitors for moderate-to-severe OA symptoms. The aim of this study was to compare the efficacy and safety of the COX-1 sparing, COX-2 specific inhibitor, celecoxib, with the conventional NSAID naproxen, and placebo, in the treatment of OA of the hip. In this multicenter, randomized, placebo-controlled trial, 1061 patients with symptomatic OA of the hip were randomized to receive celecoxib at doses of 100 mg, 200 mg, or 400 mg/day; naproxen 1000 mg/day; or placebo, for 12 weeks. Patients were evaluated using standard measures of efficacy at baseline, 2-4 days after discontinuing previous NSAID or analgesic therapy, and after 2, 6, and 12 weeks of treatment. All doses of celecoxib and naproxen significantly improved the symptoms of OA, at all time points compared with placebo. This sustained treatment effect of celecoxib was dose dependent. In terms of pain relief and improvement in functional capacity, celecoxib 200 mg/day and 400 mg/day were similarly efficacious and were comparable to naproxen. Both drugs were generally well tolerated. Celecoxib at a dose of 200 mg/day is as effective as a standard therapeutic dose of the conventional NSAID, naproxen, in reducing the pain associated with OA of the hip.

Treatment of spondyloarthropathies. Recent advances and prospects in 2001

The management of patients with spondyloarthropathy is undergoing radical changes in several areas and for several reasons. The main reason seems to be improved awareness of the fairly high prevalence of this group of disorders, which is close to that of rheumatoid arthritis. Evaluation of the various treatment modalities has benefited from work by the international Assessment in Ankylosing Spondylitis group (ASAS) group aimed at developing standardized evaluation criteria. Controlled treatment trials have provided useful information on non-pharmacological treatments such as physical exercise programs and patient information. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of the pharmacological treatment. Recent studies have shown that NSAIDs capable of selectively inhibiting type 2 cyclooxygenase have a better gastrointestinal safety profile and are as effective in relieving clinical symptoms as conventional NSAIDs. Importantly, maintenance treatment seems effective not only on peripheral joint manifestations but also on axial manifestations that fail to respond to NSAIDs. Thalidomide and TNF antagonists are promising maintenance agents.

Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition

Prostanoid products of the cyclo-oxygenase (COX) pathway of arachidonic acid metabolism modulate blood pressure (BP) and sodium homeostasis. Conventional non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit both COX isoforms (COX-1 and -2), cause sodium retention, exacerbate hypertension, and interfere with the efficacy of certain anti-hypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors. While a new class of NSAIDs that specifically inhibit COX-2 is now widely used, the relative contribution of the individual COX isoforms to these untoward effects is not clear. To address this question, we studied mice with targeted disruption of the COX-1 (Ptgs1) gene. Blood pressure, renin mRNA expression, and aldosterone were measured while dietary sodium was varied. To study interactions with the renin-angiotensin system, ACE inhibitors were administered and mice with combined deficiency of COX-1 and the angiotensin II subtype 1A (AT1A) receptor were generated. On a regular diet, BP in COX-1-/- mice was near normal. However, during low salt feeding, BP values were reduced in COX-1-/- compared to +/+ animals, and this reduction in BP was associated with abnormal natriuresis despite appropriate stimulation of renin and aldosterone. Compared to COX-1+/+ mice, the actions of ACE inhibition were markedly accentuated in COX-1-/- mice. Sodium sensitivity and BP lowering also were enhanced in mice with combined deficiency of COX-1 and AT1A receptor. The absence of COX-1 is associated with sodium loss and enhanced sensitivity to ACE inhibition, suggesting that COX-1 inhibition does not cause hypertension and abnormal sodium handling associated with NSAID use.

Selective cyclo-oxygenase-2 inhibitors: cardiovascular and gastrointestinal toxicity

The introduction of selective inhibitors of cyclo-oxygenase-2 to the marketplace has been much anticipated for several years. It would appear that these compounds have lived up to the expectations of having reduced gastrointestinal toxicity and, at least for some indications, of efficacy similar to that of conventional non-steroidal anti-inflammatory drugs. However, there is a growing body of evidence suggesting that cyclo-oxygenase-2 plays a very important role in gastrointestinal mucosal defence, particularly in situations in which the mucosa is damaged or inflamed. Moreover, physiological roles for cyclo-oxygenase-2 both in the renal and cardiovascular systems are becoming better recognized. Inhibition of cyclo-oxygenase-2 can lead to peripheral oedema and hypertension, and may promote thrombosis. Indeed, there is recent evidence of increased rates of myocardial infarction in arthritis patients taking a selective cyclo-oxygenase-2 inhibitor. Use of low-dose aspirin concurrently with use of a selective cyclo-oxygenase-2 inhibitor may provide some degree of protection against the potential cardiovascular toxicity of the latter, but both laboratory and clinical studies suggest that the concomitant use of these two types of drugs results in gastrointestinal ulceration comparable to what is seen with conventional non-steroidal anti-inflammatory drugs. These recent results suggest that care must be exercised in the use of selective cyclo-oxygenase-2 inhibitors by individuals who are at increased risk of myocardial infarction and stroke, and the use of low-dose aspirin by these patients may place them at increased risk of gastrointestinal complications.

Renal and cardiovascular effects of selective cyclooxygenase-2 inhibitors

Selective inhibition of cyclooxygenase-2 (COX-2) was proposed as a novel anti-inflammatory and analgesic treatment with a reduced profile of gastrointestinal side effects compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Although perceived as an inducible enzyme by inflammatory and other stimuli, COX-2 is constitutively expressed in the kidney. In this review, we focus on renal and cardiovascular (CV) physiological and pathophysiological characteristics of COX-2 and renal and CV aspects of treatment with selective COX-2 inhibitors. Both clinical and experimental studies have shown that renal and CV effects of COX-2 inhibitors are similar to those of NSAIDs. These effects include sodium, potassium, and water retention and decreases in renal function, as well as mild to modest increases in blood pressure (BP) and edema. These deleterious effects are amplified in patients with volume and/or sodium depletion. The concomitant administration of COX-2 inhibitors may destabilize BP control in hypertensive patients treated with antihypertensive agents. In contrast to the normal kidney, which could constitute a target for adverse actions of COX-2 inhibitors, recent experimental studies showed increased renal COX-2 expression in several models of renal injury, such as the remnant kidney, renovascular hypertension, and diabetes, and implicated COX-2 in the progression of renal failure. This suggests that COX-2 inhibitors may confer a renoprotective effect in diverse renal disorders. These intriguing formulations must be delineated further in appropriately designed prospective clinical trials. © 2001 by the National Kidney Foundation, Inc.

Pharmacological therapies for the treatment of osteoarthritis.

Non-pharmacological interventions are the first-line therapy for osteoarthritis. If non-pharmacological therapy fails, paracetamol (up to 4 g daily) should be added. If paracetamol fails, the patient's risk factors for gastrointestinal and renal disease should be assessed. In patients with gastrointestinal risk factors, a COX-2-specific inhibitor (CSI) would be used in preference to a conventional non-steroidal anti-inflammatory drug (NSAID). In patients with renal risk factors, NSAIDs and CSIs should be used with care. In patients who continue to have problems, other treatments should be considered; these might include intra-articular hyaluronan or depot corticosteroid, analgesia or glucosamine.

Are cyclooxygenase 2 inhibitors free of gastrointestinal side effects?

The discovery of cyclooxygenase 2 (COX-2) a decade ago heralded one of the most rapid and expensive development and marketing of a new class of drug that we have witnessed. This has resulted in the publication of an interesting mixture of exceptionally high-quality basic and clinical research. Based on the COX dogma, that COX-1 is good and COX-2 is bad, we were promised equal therapeutic efficacy to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with the COX-2 selective inhibitors and the absence of gastrointestinal side effects that otherwise represent a significant public health problem. Have these promises come to fruition? The semantic problem about the term COX-2 selective agents is acknowledged,1,2,3 but for our purpose (accepting that nimesulide and etodolac, at least, have a case for using this label) our discussion relates to celecoxib and rofecoxib because data on these agents are now abundant. Gastroenterologists are usually unconcerned about therapeutic efficacy of anti-inflammatory analgesic drugs, but the COX-2 selective agents have equivalent efficacy to conventional NSAIDs, and no new unexpected side effects have been encountered. Curiously, the prevalence of dyspeptic symptoms is similar to that with the use of conventional NSAIDs.4 The COX-2 selective agents have otherwise come through the conventional gastroduodenal safety assessments with flying colors. Equivalent short-term endoscopy damage to placebo in volunteers, even at high doses.5 Equivalent long-term endoscopy damage to placebo in patients.6 Significant reduction (about 60%) in serious outcomes (perforation, hemorrhages) in patients taking the drugs long term (reported at Digestive Disease Week, San Diego, California). Also, nimesulide and rofecoxib cause no short-term small bowel damage in healthy volunteers, which is a good predictor of long-term tolerability.7,8 Is this the proof to the COX dogma, or are there still some concerns? Of special note is the high (3%-11%) prevalence of gastric damage in the placebo arms of the long-term endoscopy studies. Some of this damage may be due to concomitant ingestion of aspirin, used for cardiovascular prophylaxis. Interestingly, the normal intestinal appearances in COX-1 knockout (genetically engineered) animals rang warning bells for the COX dogma for some of us. It is, therefore, particularly interesting that in the absence of a “topical” effect (Peter Isakson, oral communication, 1999, and widely confirmed at the Digestive Disease Week, 2000), selective COX-1 inhibition (SC-560) is not associated with gastrointestinal damage. Rather, it is the dual inhibition of COX-1 and COX-2 that is important. These deviations from the COX dogma pose potential problems because even minidoses of aspirin inhibit gastric COX-1 almost completely. The precise importance of concomitant aspirin ingestion and COX-2 inhibitory agents demands further study, but these findings should also be a stimulus to develop selective COX-1 inhibitors that may be devoid of the gastric toxicity of aspirin. Selective COX-2 inhibition does not, therefore, appear to cause significant new gastrointestinal damage in humans. Their possible detrimental effect on preexisting intestinal disease,9 however, requires further clarification. COX-2 selective agents delay healing of experimental gastric ulcers in animals and, if substantiated in humans, may have implications for patients with Helicobacter pylori-driven gastroduodenal ulcer diathesis. Second, COX-2 inhibitors may exacerbate10 or ameliorate11 the severity of experimental colitis in rodents. This needs to be studied in humans because NSAIDs may cause relapse of inflammatory bowel disease, and many of these patients require anti-inflammatory analgesics for arthritis, metabolic bone disease, and the like. NSAIDs play a detrimental role in some other intestinal diseases, and it is also possible that selective COX-2 inhibitors may perpetuate NSAID-induced damage. This should not, however, deter from the fact that on current evidence, it is likely that selective COX-2 inhibitors will transform the care of arthritic patients. For many, this development has not come too soon.

Changes in ulcerogenic response to non-steroidal anti-inflammatory drugs (NSAIDs) in adjuvant arthritic rats

Gastroenteropathy is the most common among patients who use non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory disorders. It is known that rheumatoid arthritic (RA) patients are more susceptible to NSAID-induced gastropathy than other NSAID users. This article reviewed our recent studies concerning the influence of arthritis on gastric mucosal integrity in adjuvant-induced arthritic rats. The gastric mucosal lesions induced by indomethacin, one of conventional NSAIDs, were markedly aggravated in arthritic rats. Likewise, the healing of chronic gastric ulcers induced by thermal cauterization was significantly delayed in arthritic rats. The underlying mechanisms of these phenomena observed in arthritic rats may be attributable to the enhancement of iNOS/NO pathway in the former and the less expression of various growth factors in the ulcerated mucosa, such as basic fibroblast growth factors (bFGF) or insulin-like growth factors (IGF-1) in the latter. In addition, we recently found that cyclooxygenase-2 (COX-2) selective inhibitors, such as rofecoxib or celecoxib, induced apparent gastric lesions in arthritic rats, suggesting that a caution should be paid on the use of COX-2 selective inhibitors in RA patients.

Una prima valutazione economica dell’impiego di rofecoxib versus FANS convenzionali nell’artrosi

Randomised clinical trials have demonstrated that rofecoxib has a better gastrointestinal tolerability profile than conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis, which results in a reduced utilisation of gastroprotective agents (GPA). The aim of this study was to estimate, from the national healthcare system perspective, the total drug costs in patients switched from NSAIDs plus GPAs to rofecoxib. In this longitudinal, observational study, drug prescriptions for symptomatic treatment of osteoarthritis were recorded. A decision tree was used to compare the mean daily drug cost of the following therapeutic options for ostheoarthritis: conventional NSAIDs and rofecoxib/conventional NSAIDs. Azienda Unita Sanitaria Locale 110, Ravenna, Italy. 56,827 patients affected by osteoarthritis were monitored from January 1997 to December 1999. Of this group, we considered the first 2,935 patients who were examined by 21 General Practitioners in the period July 2000-October 2000, in order to point out changes in GPAs co-prescription after the introduction of rofecoxib in the Italian market. Alternative treatments compared were: NSAIDs either alone or combined with GPAs (NSAIDs option), and just after the introduction of rofecoxib, NSAIDs or rofecoxib alone and NSAIDs or rofecoxib combined with GPAs (rofecoxib/NSAIDs option). 27,511 out of 56,827 patients (48.4%; IC 95%: 48.0–48.8%) treated with NSAIDs also received a GPA co-medication. In the aforementioned subgroup of 2,935 patients, 1,814 (62%) received multiple prescriptions of NSAIDs or rofecoxib. In this subgroup, rofecoxib was associated with a statistically significant reduction of GPAs utilisation of 58.8% (IC 95%: 30.7–80.1; p = 0.012) compared with what was recorded during treatment with NSAIDs. In fact, the mean daily cost per patient of the NSAIDs option was € 1.66 versus € 1.55 of the rofecoxib/NSAIDs option (6.6% lower). Our preliminary results suggest that the use of rofecoxib is associated with cost savings in terms of total drug costs compared with conventional NSAIDs.

Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increase in upper gastrointestinal complications. There is no agreement, however, on whether all conventional NSAIDs have a similar relative risk (RR), and epidemiologic data are limited on acetaminophen. We studied the association between these medications and the risk of upper gastrointestinal bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. Our nested case-control analysis included 2,105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper gastrointestinal bleed/perforation. Compared with non-users, users of acetaminophen at doses less than 2 gm did not have an increased risk of upper gastrointestinal complications. The adjusted RR for acetaminophen at doses greater than 2 gm was 3.6 [95% confidence interval (95% CI) = 2.6-5.1]. The corresponding RRs for low/medium and high doses of NSAIDs were 2.4 (95% CI = 1.9-3.1) and 4.9 (95% CI = 4.1-5.8). The RR was 3.1 (95% CI = 2.5, 3.8) for short plasma half-life, 4.5 (95% CI = 3.5-5.9) for long half-life, and 5.4 (95% CI = 4.0-7.1) for slow-release formulations of NSAIDs. After adjusting for daily dose, the differences in RR between individual NSAIDs tended to diminish except for apazone. Users of H2 receptor antagonists, omeprazole, and misoprostol had RRs of 1.4 (95% CI = 1.2-1.8), 0.6 (95% CI = 0.4-0.9), and 0.6 (95% CI = 0.4-1.0), respectively. Among NSAID users, use of nitrates was associated with an RR of 0.6 (95% CI = 0.4-1.0).

Vascular biology of thrombosis: platelet-vessel wall interactions and aspirin effects.

The antithrombotic effect of aspirin has long been recognized, and administration of low doses (80-160 mg/day) for the prevention of ischemic events in patients with coronary artery disease (CAD) is now generally considered to be routine practice. The action of aspirin derives mostly from the selective inhibition of cyclo-oxygenases (Cox). These enzymes (Cox-1 and Cox-2) catalyze the synthesis of eicosanoids, which play an important part in platelet-vessel wall interactions. Cox-1 catalyzes the synthesis of thromboxane A2 (Tx-A2), which causes platelet activation, vasoconstriction, and smooth muscle proliferation. Tx-A2 levels are elevated in conditions associated with platelet activation, including unstable angina and cerebral ischemia. Conversely, Cox-2 controls the synthesis of prostacyclin (PGI2), a local platelet regulator with an effect opposite to that of Tx-A2. PGI2 is produced as a compensatory response to increases in Tx-A2 during ischemic events. Aspirin is a more potent inhibitor of Cox-1 than of Cox-2, unlike other non-steroidal anti-inflammatory drugs (NSAIDs), which have limited selectivity. Aspirin at low doses selectively inhibits the formation of Tx-A2 without inhibiting the basal biosynthesis of cardioprotective PGI2. Furthermore, aspirin causes complete enzyme inhibition, without the recovery of enzyme activity at trough drug levels associated with conventional NSAIDs. The effect of aspirin in the prevention of ischemic events has been well documented in many recent clinical trials involving more than 50,000 patients with CAD. It is clear from these studies that aspirin, alone or in combination with other antithrombotics, significantly reduces the incidence of cardiovascular death, stroke, and myocardial infarction.

Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2—specific inhibitor, compared with ketorolac, naproxen, and placebo

Background: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2—specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. Objective: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. Methods: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive IV parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by IV ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. Results: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4 4 subjects; naproxen, 2 4 subjects; and placebo, 2 5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. Conclusion: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

COX-2 Specific Inhibitors in the Management of Osteoarthritis of the Knee: A Placebo-Controlled, Randomized, Double-Blind Study

COX-2 specific inhibitors have demonstrated significant safety advantages and comparable efficacy in osteoarthritis (OA) compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs), but no direct comparative trials between COX-2 specific inhibitors have been published. In this double-blind, placebo-controlled, parallel group, multicenter study, 182 patients (> or =40 years old) with OA of the knee were randomly assigned to treatment with celecoxib 200 mg q.d. (n = 63), rofecoxib 25 mg q.d. (n = 59), or placebo (n = 60) for 6 weeks. Arthritis assessments were performed at baseline and Weeks 3 and 6, or at early termination. At Week 6, celecoxib and rofecoxib treatment resulted in similar mean changes from baseline (p > 0.55) in arthritis pain visual analogue scale, patient's global assessment, and total score for WOMAC; all changes were superior to placebo (p < 0.05). In the patient's global assessment of arthritis pain at Week 6, 79% of celecoxib-treated and 78% of rofecoxib-treated patients improved by > or =1 grade, compared with 50% of placebo patients (celecoxib, p = 0.025; rofecoxib, p = 0.020). Adverse event incidences were similar among the active comparators; however, celecoxib-treated patients had significantly fewer adverse gastrointestinal symptoms compared with rofecoxib-treated patients, which suggests that celecoxib may have a better gastrointestinal tolerability profile than rofecoxib at these doses. Adverse events that prompted withdrawal occurred in fewer than 7% of patients, and the overall incidences were similar between the active agents. Once-daily doses of celecoxib 200 mg and rofecoxib 25 mg offer comparable efficacy and are an effective alternative to conventional NSAIDs in the management of OA.

EFFICACY OF CELECOXIB VS NAPROXEN IN THE TREATMENT OF ANKLE SPRAIN

Active adults commonly experience ankle sprain, resulting in pain, inflammation, ecchymosis, and swelling. Physicians often prescribe conventional nonsteroidal anti-inflammatory drugs to treat ankle sprain and accelerate return to activity. In a recent clinical trial, celecoxib, a COX-2 specific inhibitor with platelet-sparing properties, was as effective as ibuprofen and better than placebo in reducing ankle sprain signs and symptoms. We hypothesized that celecoxib would be as effective as naproxen in ankle sprain. In an 8-day, multicenter, randomized, double-blind, parallel group trial, 396 adults with first or second degree inversion ankle sprain were treated with celecoxib 200 mg BID (n = 198) or naproxen 500 mg BID (n = 198). At baseline, patients had moderate-to-severe ankle pain on weight bearing [at least 45 mm on 100-mm visual analog scale (VAS)]. Patients were mostly male (67%) with a mean age of 30 years. Injuries were sports- (54%) or non-sports-related and occurred within 48 hours of the first dose of study medication (mean duration, 23.2 hours). Covariate-adjusted analyses of the primary end points (Patient's Global Assessment and VAS) at Day 4 demonstrated that celecoxib was as effective as naproxen in improving signs and symptoms of ankle sprain. Both groups had a median of 5 days to return to normal function/activity or function improvement by at least 2 grades (5-point categorical scale).Table1Responders improved by ≥ 1 grade on 5-pt scale from 1 (very good) to 5 (very poor); †p ≥ 0.51; ‡cel vs napr within 95% CI limits for noninferiority. Celecoxib is as effective as the maximum recommended dose of naproxen in treating pain of ankle sprains. Celecoxib, with its platelet-sparing properties and superior gastrointestinal tolerability, may offer an advantage over naproxen in managing ankle sprain injuries. Sponsored by Pharmacia Corp.