Role of nitric oxide in the gastrointestinal tract

Worldwide osteoarthritis (OA) affects more than 9.6% of men and 18% of women older that 60 years. Treatment for OA often requires chronic use of selective or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which have been associated with gastrointestinal and cardiovascular complications. An increased risk for upper gastrointestinal bleeding with NSAIDs alone and when combined with low-dose aspirin has been described in numerous studies. Although cyclo-oxygenase-2 inhibitors have been shown to carry a lower risk for gastrointestinal injury than nonselective NSAIDs, research continues to identify new treatments that not only are effective but also provide an improved benefit/risk profile, including better gastrointestinal tolerability. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract. In preclinical studies NO was shown to help maintain gastric mucosal integrity, to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Recent studies have shown that cyclo-oxygenase inhibiting NO-donating drugs (CINODs), in which a NO molecule is chemically linked to an NSAID, are effective anti-inflammatory agents and may result in less gastrointestinal damage than is associated with NSAID use. Therefore, these agents provide a potential therapeutic option for patients with arthritis who require long-term NSAID therapy.     

Non-steroidal anti-inflammatory drug use and cervical cancer risk: A case-control study using the Clinical Practice Research Datalink

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have many anticarcinogenic properties via the inhibition of cyclooxygenase 2 (COX-2). Only one study, a cohort study examining risk of all cancers, investigated their role in cervical cancer with inconsistent findings between non-aspirin NSAIDs and aspirin. The aim of this study was to further investigate NSAID/aspirin use and cervical cancer risk. Methods: Using the United Kingdom Clinical Practice Research Datalink, 724 women diagnosed with cervical cancer between 1 January, 1995 and December 2010 were compared to 3479 women (without cervical cancer) matched on year of birth and general practice. Conditional logistic regression analysis adjusted for smoking, sexually transmitted infections, HRT and contraceptive use, was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for cervical cancer risk among users of any oral NSAIDs, non-aspirin NSAIDs and aspirin, as assessed from primary care prescribing data. Results: Excluding the year prior to diagnosis, there was no association in adjusted analyses between ever vs. never use of an NSAID (OR 0.92, 95% CI 0.77–1.09), non-aspirin NSAID (OR 0.95, 95% CI 0.80–1.13) or low-dose aspirin (OR 1.07, 0.80–1.44) and cervical cancer risk. In analysis of daily defined doses, there was no association with cervical cancer risk comparing the highest users to non-users of NSAIDs (OR 0.98, 95% CI 0.69–1.39) or non-aspirin NSAIDs (OR 1.00, 95% CI 0.70–1.43) or low-dose aspirin (OR 1.04, 95% CI 0.59–1.81). Conclusion: This large historical cohort study found no evidence of an association between non-aspirin NSAID or aspirin use and cervical cancer risk.     

Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study

Objective To evaluate whether prenatal use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of miscarriage.Design Population based cohort study. Prenatal use of NSAIDs, aspirin, and paracetamol (acetaminophen) ascertained by in-person interview.Setting Kaiser Permanente Medical Care Program, a healthcare delivery system, in the San Francisco area of the United States.Participants 1055 pregnant women recruited and interviewed immediately after their positive pregnancy test. Median gestational age at entry to the study was 40 days.Main outcome measures Pregnancy outcomes up to 20 weeks of gestation.Results 53 women (5%) reported prenatal NSAID use around conception or during pregnancy. After adjustment for potential confounders, prenatal NSAID use was associated with an 80% increased risk of miscarriage (adjusted hazard ratio 1.8 (95% confidence interval 1.0 to 3.2)). The association was stronger if the initial NSAID use was around the time of conception or if NSAID use lasted more than a week. Prenatal aspirin use was similarly associated with an increased risk of miscarriage. However, prenatal use of paracetamol, pharmacologically different from NSAIDs and aspirin, was not associated with increased risk of miscarriage regardless of timing and duration of use.Conclusion Prenatal use of NSAIDs and aspirin increased the risk of miscarriage. These findings need confirmation in studies designed specifically to examine the apparent association.     

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits

BACKGROUND: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case‐control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.g., gastroschisis/umbilical hernia, diaphragmatic hernia [DH]) when administered during sensitive windows of development. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenases (COXs) 1 and 2. Hence, the developmental toxicity seen in rats after exposure to aspirin may be due to the irreversible inhibition of COX‐1 and/or COX‐2. If so, other NSAIDs, which act through a reversible inhibition of COX, may produce a weak developmental toxicity signal or no developmental toxicity signal when tested in preclinical models. To investigate this relationship, a comprehensive analysis of the NSAID developmental toxicity literature was undertaken to determine whether NSAIDs other than aspirin induce developmental anomalies similar to those elicited by aspirin. METHODS: Developmental toxicity studies were identified through literature searches of PubMed and TOXNET, and pregnancy outcome data were extracted and tabulated. By using a set of defined criteria, each study was evaluated for quality and assigned to one of five tiers. The relation between certain malformations and NSAID treatment was analyzed for the best studies (tiers 1–4) by using concurrent control data (Mantel–Haenszel and permutation tests) and by combining the concurrent control data with historical control data (χ² test and permutation tests). RESULTS: A qualitative analysis of these data led to a focus on three types of malformations: DH, ventricular septal defects (VSDs), and midline defects (MDs). In rats, the incidences of VSD and MD were increased among fetuses treated with NSAIDs when compared with the concurrent controls. The extent of the increase was attenuated when the data from the aspirin studies were excluded from the analysis. There were no qualifying (i.e., tiers 1–4) aspirin studies conducted in rabbits, but the incidences of the three defects were increased over control incidences among non‐aspirin NSAID‐treated animals. Statistical analysis of these data was subsequently conducted. When tiers 1–4 were combined and compared with concurrent controls plus the most appropriate historical control database, the strongest associations were between NSAID treatment and VSD in rats, VSD in rabbits, and MD in rabbits. There also was some suggestion of an association between NSAID treatment and DH in rabbits. CONCLUSIONS: This analysis of the non‐clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non‐aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX‐1 and/or COX‐2 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization–compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low‐incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD. Birth Defects Research (Part B) 68:5–26, 2003. © 2003 Wiley‐Liss, Inc.     

The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage

NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.     

Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance

Conventional 'nonselective' nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation; however, the potential gastrointestinal risks associated with their use can be a cause for concern. In response to the adverse effects that can accompany nonselective NSAID use, selective cyclo-oxygenase (COX)-2 inhibitors were developed to target the COX-2 isoenzyme, thus providing anti-inflammatory and analgesic benefits while theoretically sparing the gastroprotective activity of the COX-1 isoenzyme. Data from large-scale clinical trials have confirmed that the COX-2 inhibitors are associated with substantial reductions in gastrointestinal risk in the majority of patients who do not receive aspirin. However, some or all of the gastrointestinal benefit of COX-2 inhibitors may be lost in patients who receive low, cardioprotective doses of aspirin, and recent evidence suggests that some of these agents, at some doses, may be associated with an increased risk for cardiovascular adverse events compared with no therapy. The risks and benefits of conventional NSAIDs and of COX-2 inhibitors must be weighed carefully; in clinical practice many patients who might benefit from NSAID or COX-2 therapy are likely to be elderly and at relatively high risk for gastrointestinal and cardiovascular adverse events. These patients are also more likely to be taking low-dose aspirin for cardiovascular prophylaxis and over-the-counter NSAIDs for pain. Identifying therapies that provide relief from arthritis related symptoms, confer optimum cardioprotection, and preserve the gastrointestinal mucosa is complex. Factors to consider include the interference of certain NSAIDs with the antiplatelet effects of aspirin, differences in the adverse gastrointestinal event rates among nonselective NSAIDs and selective COX-2 inhibitors, emerging data regarding the relative risks for cardiovascular events associated with these drugs, and the feasibility and cost of co-therapy with proton pump inhibitors.     

Development of affinity labeling agents based on nonsteroidal anti-inflammatory drugs: labeling of the nonsteroidal anti-inflammatory drug binding site of 3 alpha-hydroxysteroid dehydrogenase.

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effect by inhibiting the target enzyme cyclooxygenase (prostaglandin H2 synthase); however, little is known about the peptides comprising its NSAID binding site. Hydroxyprostaglandin dehydrogenases also bind NSAIDs, but their NSAID binding sites have not been well characterized. Using existing synthetic strategies, we have incorporated the bromoacetoxy affinity labeling moiety around the perimeter of two potent NSAIDs, indomethacin and mefenamate, a N-phenylanthranilate. The compounds synthesized were 1-(4-(bromoacetamido)benzyl)-5-methoxy-2-methylindole-3-acetic acid (1), 3-(2-(2-bromoacetoxy)ethyl)-1-(4-chlorobenzyl)-5-methoxy-2-methylindole (2), 4-(bromoacetamido)-N-(2,3-dimethylphenyl)anthranilic acid (3), N-(3-(bromoacetamido)phenyl)-anthranilic acid (4), and N-(4-(bromoacetamido)phenyl)anthranilic acid (5). To access whether these compounds have general utility in labeling NSAID binding sites, the compounds were evaluated as affinity labeling agents for 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) from rat liver cytosol. This enzyme displays 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase activity, is inhibited potently by NSAIDs, and is homologous to bovine lung prostaglandin F synthase. Compounds 1-5 were shown to affinity label the NSAID binding site of 3 alpha-HSD. They inactivated 3 alpha-HSD through an E.I complex in a time- and concentration-dependent manner with t1/2 values ranging from seconds to hours. Ligands that compete for the active site of 3 alpha-HSD (NAD+ and indomethacin) afforded protection against inactivation, and the inactivators could demonstrate competitive kinetics against 3 alpha-hydroxysteroid substrates by forming an E.NAD+.I complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Balancing the gastrointestinal benefits and risks of nonselective NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of medications to treat pain and inflammation. However, gastrointestinal complications associated with NSAIDs are prevalent, largely due to the frequent use of these agents. Adverse events associated with NSAIDs include minor side effects, such as dyspepsia, as well as serious complications, such as bleeding and perforation. Although the probability that any given individual user of an NSAID will suffer a serious gastrointestinal complication is fairly low, widespread patient exposure can translate into a major national health burden. The increasing use of aspirin in the prevention of cardiovascular events and the availability of select over-the-counter NSAIDs represent additional challenges to clinicians in their efforts to make the most appropriate therapeutic decisions while minimizing the potential gastrointestinal risks associated with the use of these agents. Side effects such as dyspepsia do not provide adequate warning of gastrointestinal complications, because most complications occur without the presence of antecedent symptoms. Therefore, accurate risk assessment and the management of controllable risk factors are crucial to the safe administration of NSAIDs. This review focuses on the gastrointestinal effects of aspirin, acetaminophen, and other nonselective NSAIDs, and discusses those factors that are associated with increased risk for adverse gastrointestinal events in certain individuals.     

Prevention of alphaII(b)beta3 activation by non-steroidal antiinflammatory drugs

We have studied the effect of non-steroidal antiinflammatory drugs (NSAIDs) on alphaII(b)beta3 integrin activation and platelet aggregation. NSAIDs such as meloxicam, piroxicam, indomethacin and aspirin, but not aceclofenac or diclofenac interfered with the activation state of alphaII(b)beta3. NSAIDs that inhibited alphaII(b)beta3 activation were also able both to partially inhibit platelet primary aggregation and to accelerate platelet deaggregation. These effects of NSAIDs were not dependent on cyclooxygenase inhibition. The results obtained indicate that some NSAIDs exert a specific action on alphaII(b)beta3 activation, and provide an additional mechanism that accounts for their beneficial effects in diseases in which platelet activation is involved.     

Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.     

Efficacy,tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials

ObjectiveTo determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.DesignSystematic review of randomised trials that compared at least 12 weeks'' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.Participants15 187 patients with osteoarthritis or rheumatoid arthritis.ResultsNine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.ConclusionCelecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.

What is already known on this topic

Long term NSAID use is associated with the development of peptic and duodenal ulcersCOX 2 specific inhibitors are claimed to cause fewer gastrointestinal complicationsThe National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirin

What this study adds

Systematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritisCelecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDsAn improvement in gastrointestinal safety was still evident in patients who were also taking aspirin     

An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants.

OBJECTIVE. To make recommendations for the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) in primary care practice, particularly for patients at high risk for NSAID-induced complications. OPTIONS. The use of misoprostol to prevent gastrointestinal ulceration and other unwanted NSAIDs effects was considered. The role of cyclooxygenase-2 (COX-2) versus COX-1 inhibiting agents was also examined. OUTCOMES. Reduction of complications associated with long-term use of NSAIDs. EVIDENCE. Evidence was gathered in late 1995 from published research studies and reviews. Position papers were prepared by faculty and advisory board members and discussed at the Canadian NSAID Consensus Symposium in Cambridge, Ont., Jan. 26 and 27, 1996. VALUES. Recommendations were based on randomized, placebo-controlled clinical trials (level I evidence) and case-control studies (level II evidence) involving NSAID use when such evidence was available. When the scientific literature was incomplete or inconsistent in a particular area, recommendations reflect the consensus of the participants at the symposium (level III evidence). Physicians were recruited from across Canada for their expertise in rheumatology, gastroenterology, epidemiology, gerontology, family practice, and clinical and basic scientific research. BENEFITS, HARMS AND COSTS. Although a reduction in complications due to inappropriate NSAID use should reduce costs of additional investigations, admissions to hospital and time lost from work, definitive cost analysis studies are not yet available. RECOMMENDATIONS. Currently, no NSAID is available that lacks potential for serious toxicity; therefore, long-term use of NSAIDs should be avoided whenever possible, particularly in high-risk patients (e.g., those who are elderly, suffer from hypertension, congestive heart failure, renal or hepatic impairment or volume depletion, take certain concomitant medications or have a history of peptic ulcer disease) (level I evidence). If NSAIDs are to be used in patients with gastric or nephrotoxic risk factors, the lowest effective dose of NSAID should be used (level III evidence); NSAIDs that are weak COX-1 inhibitors may be preferred (level II evidence). In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications (level I evidence). However, the clinical judgement of the practising clinician must always be part of any therapeutic decision. VALIDATION. These recommendations are based on the consensus of Canadian experts in rheumatology, gastroenterology and epidemiology, and have been subjected to external peer review.     

COX-2: Where are we in 2003? - Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients

Cyclooxygenase (COX)-2 selective inhibitors have been shown to have comparable efficacy to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Large outcome studies have shown that patients with OA and RA not taking low-dose aspirin have fewer symptomatic and complicated upper GI events when treated with COX-2 selective inhibitors than with nonselective NSAIDs. When used in recommended dosages, there is no convincing evidence that patients treated with COX-2 selective inhibitors have an increased incidence of cardiovascular thrombotic events, including non-fatal myocardial infarction, than patients treated with either placebo or nonselective NSAIDs other than naproxen. Co-therapy with low-dose aspirin is recommended in patients with OA and RA at increased risk for cardiovascular events; the need for gastroprotective therapy in such patients is controversial.     

COX-2: Where are we in 2003? - Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients

Cyclooxygenase (COX)-2 selective inhibitors have been shown to have comparable efficacy to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Large outcome studies have shown that patients with OA and RA not taking low-dose aspirin have fewer symptomatic and complicated upper GI events when treated with COX-2 selective inhibitors than with nonselective NSAIDs. When used in recommended dosages, there is no convincing evidence that patients treated with COX-2 selective inhibitors have an increased incidence of cardiovascular thrombotic events, including non-fatal myocardial infarction, than patients treated with either placebo or nonselective NSAIDs other than naproxen. Co-therapy with low-dose aspirin is recommended in patients with OA and RA at increased risk for cardiovascular events; the need for gastroprotective therapy in such patients is controversial.     

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer''s Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B₂ (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F₂-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F₂-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F₂-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.     

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.     

Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective in treating the pain and inflammation associated with osteoarthritis and rheumatoid arthritis, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Treatment guidelines suggest that patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment. However, well over 80% of such patients may not receive an appropriate therapeutic intervention. Multiple strategies are available to reduce the risk for NSAID associated gastrointestinal complications. First, risk may be reduced by using non-NSAID analgesics. Second, use of the minimum effective dose of the NSAID may reduce risk. Third, co-therapy with a proton pump inhibitor or misoprostol may be desirable in at-risk patients. Use of cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although this benefit is eliminated in patients who receive aspirin, and cyclo-oxygenase-2 inhibitors may increase cardiovascular adverse events. The optimal management of NSAID related gastrointestinal complications must be based on the individual patient's risk factors for gastrointestinal and cardiovascular disease, as well as on the efficacy and tolerability of both the NSAID and accompanying gastroprotective agent.     

On the mode of action and biochemical properties of anti-inflammatory drugs-II.

The inhibition of prostaglandin (PG) synthetase by nonsteroidal anti-inflammatory drugs (NSAID) is not well understood. Co-factors (glutathione and hydroquinone) are needed for maximum enzymatic activity in vitro, and we suggest that NSAID might inhibit PG synthetase partly by interfering with co-factor induced stimulation of the enzyme. This hypothesis was tested by: A) Examining the effect of glutathione, noradrenaline and hydroquinone on bull seminal vesicle (BSV) PG synthetase in vitro. The stimulatory effects were concentration-dependent. B) Three structurally distinct NSAID, indomethacin, aspirin and paracetamol, inhibited the stimulation by each co-factor in a concentration-related manner. Drug effectiveness also depended on the concentration of co-factor.