Risk Of Serious Gastrointestinal Complications Research Articles

Poly(lactic acid)-aspirin microspheres prepared via the traditional and improved solvent evaporation methods and its application performances

Drug-loaded microspheres are significant for the development of modern pharmaceutical products. It is well known that the taken of aspirin for long-term increases the risk of serious gastrointestinal complications, therefore a controllable delivery of aspirin is of importance to lighten those side effects. In this work, poly(lactic acid) (PLA) was chosen as the carrier to prepare PLA-aspirin microspheres by using the traditional and the improved solvent evaporation methods. It was found that no matter which experimental condition was, the encapsulation efficiency of aspirin was higher by using the improved method than that of the traditional method. Specifically, when the concentration of polyvinyl alcohol = 1% (mass), the polymer concentration = 1:20, the oil/water rate = 1:2.5, PLA-aspirin microspheres were obtained via the improved method with a high yield of 82.83% (mass) and an encapsulation efficiency of 44.09%. PLA-aspirin microspheres were then prepared continuously using the improved method, which further enhanced the encapsulation efficiency to 54.56%. Approximate 85% aspirin released from microspheres within 7 days. Obvious degradation which was represented by reduction on hardness was observed by soaking microspheres in PBS for 60 days. This work is of interest because it provides a continuous route to prepare PLA-aspirin microspheres continuously with a high drug encapsulation efficiency.

Rebamipide as a Potential Alternative Gastroprotective Agent to Proton Pump Inhibitor in Elderly Chronic Nonsteroidal Anti-Inflammatory Drug Users without Risk Factors.

PurposeThe use of proton pump inhibitors (PPI) is recommended to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complications. The incidence of several adverse effects during the long-term use of PPI prompts the search for other alternatives. Limited studies have evaluated the efficacy of rebamipide, a widely used mucoprotective drug, as a gastroprotective agent (GPA) compared to PPI, focusing on the elderly chronic NSAID users, nor with GI risk stratification. We aimed to determine the population who would get benefit from the use of rebamipide as an alternative to PPI to prevent traditional nonsteroidal anti-inflammatory drug (tNSAID)-associated GI complications.Patients and MethodsWe identified 41,889 and 35,708 elderly chronic tNSAID users with PPI and rebamipide co-therapy, respectively, from the national claims database. Outcome was defined as hospitalization or emergency department visits due to serious GI complications. Propensity score-matched cohorts were constructed and compared within risk strata.ResultsIn high and moderate risk groups with two risk factors, rebamipide showed a higher risk of serious GI complication compared to PPI (aHR 2.63, 95% CI 1.24–5.59 and aHR 2.42, 95% CI 1.21–4.83, respectively). However, in elderly patients without risk factors, there was no significant difference in the risk of serious GI complications between PPI and rebamipide (aHR 0.69, 95% CI 0.27–1.76).ConclusionThis study suggested that rebamipide can be considered as an alternative to PPI in elderly chronic tNSAID users without risk factors. However, elderly patients with other risk factors should use PPI rather than rebamipide. Therefore, the presence of GI risk factors needs to be evaluated in elderly chronic tNSAID users to prescribe the most suitable GPA in clinical practice.

Impact of Preventive Strategies on Gastrointestinal Complications in Elderly Patients on Concomitant Use of Oral Anticoagulants and Nonsteroidal Anti-Inflammatory Drugs: A Nationwide Cohort Study.

Despite growing evidence showing an increased risk of concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants, few studies have investigated whether proton pump inhibitors can prevent gastrointestinal (GI) complications in patients receiving both NSAIDs and anticoagulants. We aimed to evaluate the risk of serious GI complications and the impact of GI preventive strategies on the concomitant use of NSAIDs and anticoagulants. Our nationwide cohort study using Korea's claims data included elderly patients (aged ≥65 years) who started anticoagulants and NSAIDs from 2016 to 2017. The outcome was serious GI complications defined as hospitalization or emergency department visits with GI bleeding or perforation. A Cox regression analysis was performed using time-dependent variables and propensity score matching. In total, 92,379 patients were identified. Compared with non-prophylaxis, proton pump inhibitors and selective cyclooxygenase-2 inhibitors were associated with a 64% [adjusted hazard ratio, 0.36 (95% confidence interval 0.25-0.53)] and 74% [adjusted hazard ratio, 0.26 (95% confidence interval 0.19-0.36)] lower risk of serious GI complications, respectively. Cyclooxygenase-2 inhibitor use was not different from the use of non-selective NSAIDs with proton pump inhibitors for the prevention of serious GI complications. H2-receptor antagonists did not reduce the risk of serious GI complications compared with non-prophylaxis during concomitant non-selective NSAID and anticoagulant therapy. Proton pump inhibitors or cyclooxygenase-2 inhibitors used as GI preventive strategies did not completely eliminate but lowered the risk of serious GI complications among elderly patients receiving both NSAIDs and anticoagulants.

Does the presence of an intact primary increase the risk of nonelective colorectal surgery in patients treated with bevacizumab?

In patients with incurable metastatic colorectal cancer (mCRC), resection of the primary tumour is debated; however, patients with intact primaries may be at a higher risk of complications requiring surgery when receiving treatment with bevacizumab. Our aim was to estimate the risk of nonelective colorectal surgery in patients undergoing bevacizumab therapy for mCRC and evaluate the association between intact primary tumours and risk of nonelective surgery. We designed a population-based, retrospective cohort study using administrative and cancer registry data in Ontario, Canada. We included patients with mCRC who received bevacizumab from 1 January 2008 to 31 December 2014. The primary outcome was nonelective colorectal surgery after initiation of bevacizumab. We determined the cumulative incidence of nonelective colorectal surgery among patients with previously resected and unresected primaries, accounting for the competing risk of death. We explored the relationship between previous resection of the primary and need for nonelective surgery using a cause-specific hazards model, controlling for patient, tumour and treatment factors. We identified 1840 (32.7%) patients with intact primaries and 3784 (67.3%) patients with prior resection. The cumulative incidence of nonelective surgery 1year after initiating bevacizumab for all patients was 3.9% (95% CI 3.4-4.5%). One-year cumulative incidence was higher in those with intact primaries than in those with resected primaries (6.1% vs 2.9%, P<0.0001). After adjustment, an intact primary remained strongly associated with nonelective colorectal surgery (hazard ratio=2.89, 95% CI 2.32-3.61; P<0.0001). Bevacizumab is associated with a low but meaningful risk for serious gastrointestinal complications, necessitating vigilance, particularly among patients with an intact primary tumour.

Gastrointestinal complications induced by sevelamer crystals.

BackgroundSevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases.MethodsWe describe three new cases of GI lesions associated with SC and review previously reported cases.ResultsWe found 16 previously reported cases of SC-induced GI lesions. The mean patient age was 61 years (interquartile range 51.5–71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC-induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non-diabetic patients, in spite of their fewer GI comorbidities.ConclusionsSC-induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications.

NEW DATA ON THE SAFETY OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS: THE CONCEPT OF THE HIGH CLASS-SPECIFIC CARDIOVASCULAR RISK OF SELECTIVE CYCLOOXYGENASE-2 INHIBITORS IS OUTDATED

The results of the PRECISION trial were published in late 2016. During this trial, a total of 24,081 patients at high cardiovascular risk took celecoxib 200-400 mg/day, naproxen 750–1000 mg/day or ibuprofen 1800–2400 mg/day for more than 1.5 years (20.3±16.0 months). The findings show that the frequency of vascular catastrophes (death, nonfatal myocardial infarction, and stroke) in patients receiving celecoxib was not higher than that of the similar complications in those taking the control drugs. At the same time, celecoxib demonstrated a statistically significant advantage in reducing the risk of serious gastrointestinal complications. New evidence refutes the concept of high cardiovascular risk that is common to all coxibs and confirms the provisions of national guidelines for the rational use of nonsteroidal anti-inflammatory drugs (NSAIDs), which were published in 2015. This review presents recent data on the risk of NSAID-related complications, including a brief description of the design and results of the PRECISION trial.

Formulation and Evaluation of Lecithin Organogel for Treatment of Arthritis

AbstractArthritis is a disease of the joint that involves inflammation of one or more joints. The common symptoms of arthritis disorders include varied levels of pain, swelling, joint stiffness, and sometimes a constant ache around the joints. More than 20 million individuals with arthritis have severe limitations in function on a daily basis. The objective of this study was to resolve conventional dosage forms of NSAIDs, which are at increased risk for serious gastrointestinal complications, when administered through oral route. Topical administration of NSAIDs could deliver lornoxicam to the site of action in rheumatic diseases which would reduce the gastrointestinal complications and side effects of the drug. The prepared organogel of lornoxicam were evaluated for its appearance, organoleptic characteristic, viscosity, gelation temperature, drug content and in vitro release study. In vivo evaluation for analgesic activity of formulation was carried out in terms of skin irritation study, hot plate method, writhing test and edema paw induce method.Keywords- Lornoxicam, lecithin, organogel, Arthritis, Topical delivery.

Economic Evaluation of the Restriction in the Use of Piroxicam in Spain

ObjectivesA retrospective economic evaluation was performed on the restriction of the use of piroxicam in Spain, a non-steroidal anti-inflammatory drug, with a proven higher risk of serious gastrointestinal complications compared to other non-steroidal anti-inflammatory drugs with the objective of putting the relevance of these activities into context. MethodsA retrospective cost-effectiveness analysis and a budget impact analysis were performed. Costs and cases of serious gastrointestinal complications were compared in the non-intervention (use of piroxicam) and the intervention scenarios (use of other non-steroidal anti-inflammatory drugs). The cost of serious gastrointestinal complications was obtained from the Diagnosis Related Groups and the cost of non-steroidal anti-inflammatory drugs from usage data in the Spanish national health system. The risk of serious gastrointestinal complications was obtained from epidemiological studies. ResultsThe regulatory intervention was the dominant option. In that sense, 0.81 euros per treated patient were saved, 2.75 cases of serious gastrointestinal complications were avoided per 10,000 patients and 578,608 euros were saved in total in Spain in the first year following the intervention. ConclusionsIt is possible to perform complete economical evaluations on pharmacovigilance actions. The intervention performed by the Spanish Agency for Medicines and Medical Devices, AEMPS on piroxicam not only achieved the objective of preventing adverse drug reactions but also resulted in significant economical savings even under conservative assumptions.

Evaluación económica de la restricción del uso de piroxicam en España

ObjectivesA retrospective economic evaluation was performed on the restriction of the use of piroxicam in Spain, a non-steroidal anti-inflammatory drug, with a proven higher risk of serious gastrointestinal complications compared to other non-steroidal anti-inflammatory drugs with the objective of putting the relevance of these activities into context. MethodsA retrospective cost-effectiveness analysis and a budget impact analysis were performed. Costs and cases of serious gastrointestinal complications were compared in the non-intervention (use of piroxicam) and the intervention scenarios (use of other non-steroidal anti-inflammatory drugs). The cost of serious gastrointestinal complications was obtained from the Diagnosis Related Groups and the cost of non-steroidal anti-inflammatory drugs from usage data in the Spanish national health system. The risk of serious gastrointestinal complications was obtained from epidemiological studies. ResultsThe regulatory intervention was the dominant option. In that sense, 0.81 euros per treated patient were saved, 2.75 cases of serious gastrointestinal complications were avoided per 10,000 patients and 578,608 euros were saved in total in Spain in the first year following the intervention. ConclusionsIt is possible to perform complete economical evaluations on pharmacovigilance actions. The intervention performed by the Spanish Agency for Medicines and Medical Devices, AEMPS on piroxicam not only achieved the objective of preventing adverse drug reactions but also resulted in significant economical savings even under conservative assumptions.

The gastroprotective properties of

The gastroprotective properties of tizanidine, a centrally acting myorelaxant, are discussed. It is noted that there is no strong evidence suggesting the ability of tizanidine to reduce the risk of serious gastrointestinal complications arising from with the use of nonsteroidal anti-inflammatory drugs and to decrease their need (average daily dose). It is stated that in inflammatory rheumatic diseases, myorelaxants (including tizanidine) are likely to be useful as a component of symptomatic therapy in a number of cases.

Safety of the Nonselective NSAID Nabumetone

Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.

Formulation Development and in vitro Characterization of Proliposomes for Topical Delivery of Aceclofenac.

Non-steroidal antiinflammatory drugs are routinely prescribed for the patients with rheumatic disease and such patients are at increased risk of serious gastrointestinal complications, when non-steroidal antiinflammatory drugs administered by oral route. The aim of the present study was to develop and characterized a vesicular drug carrier system (proliposome) for topical delivery of aceclofenac to overcome the problems related with oral route. Aceclofenac proliposome were prepared by the film-deposition on carriers method and characterized for size and surface morphology, drug content in both proliposomes and liposomal system, percent yield, in vitro drug release studies and drug permeation studies. The prepared system was also characterized for drug-excipients interaction by Fourier transform infrared spectrophotometer and stability studies. The size and surface morphology were studied using optical microscopy, scanning electron microscopy and transmission electron microscopy. A spherical shape of reconstituted aceclofenac liposome with an average vesicular size of about 500 nm was observed in photomicrographs. The maximum entrapment efficiency of reconstituted liposomes was 80.31% whereas the drug content in proliposomes was found to be more than 90%. In vitro release of drug was significantly retarded indicating sustained release of aceclofenac from proliposomes. Stability study was performed at various temperatures indicating that aceclofenac proliposomes are stable at lower temperature.

Nonsteroidal Anti-inflammatory Drugs and Abdominal Pain

1. David N. Collier, MD, PhD 1. Brody School of Medicine at East Carolina University Greenville, NC 1. Cassie Billings, PharmD 1. Pitt County Memorial Hospital Greenville, NC Acute Renal Failure Associated with Non-Steroidal Anti-Inflammatory Drugs in Healthy Children. Krause I, Cleper R, Einstein B, Davidovits M. Pediatr Nephrol. 2005;20 :1295– 1298[OpenUrl][1][CrossRef][2][PubMed][3] Analgesic-antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:687– 731 Non-steroidal Anti-inflammatory Drugs and Exacerbations of Asthma in Children. Body R, Potier K. Emerg Med J. 2004;21 :713– 724[OpenUrl][4][Abstract/FREE Full Text][5] The Effectiveness of Five Strategies for the Prevention of Gastrointestinal Toxicity Induced by Non-steroidal Anti-inflammatory Drugs: Systematic Review. Hooper L, Brown TJ, Elliot RA, et al. BMJ. 2004;329 :948[OpenUrl][6][Abstract/FREE Full Text][7] The Safety of Acetaminophen and Ibuprofen Among Children Younger Than Two Years Old. Lesko SM, Mitchell AA. Pediatrics. 1999;104 :e39[OpenUrl][8][Abstract/FREE Full Text][9] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that have analgesic, antipyretic, and anti-inflammatory properties. These effects are mediated primarily through inhibition of the cyclooxygenase enzymes (COX-1 and COX-2), which are involved in the production of prostaglandins (PGs) and thromboxanes (TXs). The COX-1 isoform is produced constitutively in a variety of tissues and organs, including the kidney, vascular endothelium, and gastric mucosa. In many tissues, expression of the COX- 2 isoform is induced by inflammatory mediators, but COX-2 also is produced constitutively in the brain, uterus, and kidneys. PGI2 and prostaglandins of the E family (PGEs) reduce the pain threshold of nociceptors, resulting in hyperalgia (the sensitization of afferent nerve endings to the effects of mechanical or chemical stimulation). Hence, NSAID-mediated inhibition of PGI2 and PGE synthesis can provide effective analgesia by … [1]: {openurl}?query=rft.jtitle%253DPediatric%2Bnephrology%2B%2528Berlin%252C%2BGermany%2529%26rft.stitle%253DPediatr%2BNephrol%26rft.aulast%253DKrause%26rft.auinit1%253DI.%26rft.volume%253D20%26rft.issue%253D9%26rft.spage%253D1295%26rft.epage%253D1298%26rft.atitle%253DAcute%2Brenal%2Bfailure%252C%2Bassociated%2Bwith%2Bnon-steroidal%2Banti-inflammatory%2Bdrugs%2Bin%2Bhealthy%2Bchildren.%26rft_id%253Dinfo%253Adoi%252F10.1007%252Fs00467-005-1966-x%26rft_id%253Dinfo%253Apmid%252F15973524%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1007/s00467-005-1966-x&link_type=DOI [3]: /lookup/external-ref?access_num=15973524&link_type=MED&atom=%2Fpedsinreview%2F28%2F2%2F75.atom [4]: {openurl}?query=rft.jtitle%253DEmergency%2BMedicine%2BJournal%26rft.stitle%253DEmerg.%2BMed.%2BJ.%26rft.issn%253D1351-0622%26rft.aulast%253DBody%26rft.auinit1%253DR.%26rft.volume%253D21%26rft.issue%253D6%26rft.spage%253D713%26rft.epage%253D714%26rft.atitle%253DNon-steroidal%2Banti-inflammatory%2Bdrugs%2Band%2Bexacerbations%2Bof%2Basthma%2Bin%2Bchildren%26rft_id%253Dinfo%253Adoi%252F10.1136%252Femj.2004.019687%26rft_id%253Dinfo%253Apmid%252F15496704%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [5]: /lookup/ijlink?linkType=ABST&journalCode=emermed&resid=21/6/713&atom=%2Fpedsinreview%2F28%2F2%2F75.atom [6]: {openurl}?query=rft.jtitle%253DBMJ.%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.38232.680567.EB%26rft_id%253Dinfo%253Apmid%252F15475342%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [7]: /lookup/ijlink?linkType=ABST&journalCode=bmj&resid=329/7472/948&atom=%2Fpedsinreview%2F28%2F2%2F75.atom [8]: {openurl}?query=rft.jtitle%253DPediatrics%26rft.stitle%253DPediatrics%26rft.issn%253D0031-4005%26rft.aulast%253DLesko%26rft.auinit1%253DS.%2BM.%26rft.volume%253D104%26rft.issue%253D4%26rft.spage%253De39%26rft.epage%253De39%26rft.atitle%253DThe%2BSafety%2Bof%2BAcetaminophen%2Band%2BIbuprofen%2BAmong%2BChildren%2BYounger%2BThan%2BTwo%2BYears%2BOld%26rft_id%253Dinfo%253Adoi%252F10.1542%252Fpeds.104.4.e39%26rft_id%253Dinfo%253Apmid%252F10506264%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [9]: /lookup/ijlink?linkType=ABST&journalCode=pediatrics&resid=104/4/e39&atom=%2Fpedsinreview%2F28%2F2%2F75.atom

Late-Onset Ankylosing Spondylitis and Related Spondylarthropathies

Ankylosing spondylitis is the prototype of related diseases commonly called spondylarthropathies which include reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel diseases (enteropathic arthritis) and undifferentiated spondylarthropathies. Ankylosing spondylitis and spondylarthropathies are generally observed in young patients but can be observed later in life or in persons >50 years of age. All the spondylarthropathy subgroups are represented in the elderly with some features particular to this age group. Indeed, radiological aspects of ankylosing spondylitis may be difficult to interpret because of the radiological changes induced by aging. Late-onset peripheral spondylarthropathies are characterised by severe disease, marked elevation of laboratory parameters of inflammation, oligoarthritis involving the lower limbs and oedema of the extremities. Psoriatic arthritis is more severe in the elderly and is associated with worse outcomes than in young patients. The clinical presentation of undifferentiated spondylarthropathy is as varied in the elderly as in young and middle-aged adults. Reactive arthritis and enteropathic arthritis are observed in the elderly more rarely. The effects of aging on drug metabolism and pharmacokinetics, together with the existence of co-morbidities and polypharmacy, are responsible for difficulties in the therapeutic management of late-onset ankylosing spondylitis or spondylarthropathies. Indeed, NSAIDs should be used with caution in older patients because of the high risk of serious gastrointestinal complications. Sulfasalazine and methotrexate have been used as disease-controlling drugs but did not prove very effective. Pamidronate and tumour necrosis factor (TNF)-alpha antagonists offer a therapeutic alternative but have not been specifically tested in the elderly. Pamidronate has been tested in young-onset ankylosing spondylitis and spondylarthropathies with conflicting results but can be used in older patients without risk of major adverse effects. TNFalpha antagonists have been adequately evaluated in ankylosing spondylitis and spondylarthropathies and are associated with dramatic improvement in clinical and biological parameters of disease activity. However, the safety profile of these agents in the elderly is not currently known and careful surveillance, in particular for the risk of infection such as tuberculosis, and/or exacerbation of chronic heart failure, is thus required when using these drugs in this age group.

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review

Objectives To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)—H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol...

Flaws in a Recent Vertebral Artery Dissection Study by Smith et al

Flaws in a Recent Vertebral Artery Dissection Study by Smith et al

Risk of Upper Gastrointestinal Injury and Events in Patients Treated With Cyclooxygenase (COX)-1/COX-2 Nonsteroidal Antiinflammatory Drugs (NSAIDs), COX-2 Selective NSAIDs, and Gastroprotective Cotherapy

Numerous studies using varying methodologies and outcome measures have examined the gastrointestinal risks of aspirin and nonaspirin nonsteroidal antiinflammatory drug (NSAID) use. Despite the large volume of literature, clarity regarding the key risk factors and their quantitative importance is lacking. We performed a comprehensive review of the literature to summarize the incidence of gastrointestinal injury in populations with varying risk characteristics using agents that inhibit both isoforms of cyclooxygenase and those that selectively inhibit only cyclooxygenase-2 (COX-2).Although risk estimates vary, the risk of serious gastrointestinal complications in NSAID users is approximately 2.5 to 4.5 times that of nonusers. The risk of NSAID-related gastrointestinal bleeding is augmented by concomitant low-dose aspirin and could approach double the risk of NSAID use alone. The preponderance of evidence shows that the risk of NSAID-related gastrointestinal bleeding is reduced approximately 50% with a coxib as compared with traditional NSAID. The relative risk of hospitalization resulting from upper gastrointestinal bleeding for patients treated with a nonselective NSAID was 4.4 (95% confidence interval [CI], 2.3-8.5) and 1.9 (95% CI, 1.0-3.5) when compared with celecoxib and rofecoxib, respectively. Aspirin increases the risk of NSAID-related gastrointestinal bleeding in patients taking COX-2 selective inhibitors, with odds ratios ranging from 5.8 to 7.7; however, it is unknown whether this risk is greater than the risk from aspirin alone. The risks from both traditional NSAIDs and COX-2 inhibitors are increased in the elderly, patients on anticoagulation, and patients with prior gastrointestinal events.Gastroprotective agents have been found to significantly reduce the risk for gastrointestinal injury in patients receiving NSAID therapy, especially those receiving concurrent low-dose cardioprotective doses of aspirin. Proton pump inhibitors (PPIs) and misoprostol both reduce the incidence of gastric and duodenal ulcers, as well as recurrence of ulcer complications in patients receiving NSAIDs. The relative risk for gastric ulcers ranged from 0.17 to 0.38, whereas for duodenal ulcers, the range was 0.11 to 0.28. Although misoprostol is slightly more effective in preventing gastric ulcers in these patients, PPIs are better tolerated. Although NSAIDs appear safe in "low-risk" populations, our review suggests that the use of gastroprotective cotherapy should be considered in patients at higher risk of NSAID-related upper gastrointestinal bleeding.

Relationship of clinical factors to the use of Cox-2 selective NSAIDs within an arthritis population in a large HMO.

To investigate the degree to which physicians use clinical factors to focus use of Cox-2 selective NSAIDs within an arthritis population. Diagnostic codes in the medical records of a large group-model HMO in northern California with approximately 3 million members were examined to identify patients with either rheumatoid arthritis (RA) or non-RA (osteoarthritis or degenerative joint disease). RA and non-RA patients were stratified in deciles of relative risk for gastrointestinal (GI) complications according to patient characteristics identified on the Standardized Calculator of Risk for Events (SCORE) that were associated with use of Cox-2 selective NSAIDs. (The SCORE tool stratifies patients by risk of serious GI complications using patient characteristics that are assigned points during an office visit, including age, health status, diagnosis of rheumatoid arthritis, corticosteroid use, and history of GI ulcer or bleed.) The second stage of analysis examined the percentage of arthritis patients in each SCORE-risk decile who received a Cox-2 selective NSAID, lower-risk NSAID, or traditional NSAID during calendar year 1999. The study population consisted of 144,360 members with an arthritis diagnosis, approximately 4.8% of members in this HMO. The mean age was 62.8 years (SD = 14.1), 61% were female, 10,449 (7%) had rheumatoid arthritis (RA), and 133,911 (93%) had non-rheumatoid arthritis. A diagnosis of RA was the most significant predictor of Cox-2 NSAID use (OR=2.4; 95% CI=1.6-3.5), followed by a history of GI problems (OR=1.5; 95% CI=1.4- 1.6). Female gender, chronic steroid use, and age each increased the odds of receiving a Cox-2 selective NSAID by about 35% (P<0.001 for all). Approximately 8.3% of patients in the highest decile of risk and 1.5% of patients in the lowest decile of risk received a Cox-2 selective NSAID. Clinical characteristics of patients identified on the SCORE (GI-risk) tool were strongly associated with use of Cox-2-selective NSAIDs in this HMO. A 5.5-fold difference in utilization of Cox-2 selective NSAIDs was found among patients determined to be in the highest-risk decile versus patients in the lowest-risk decile. Future research should investigate how nonclinical factors play a role in the treatment decisions made by physicians.

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis

To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. Hospital and community based case-control and cohort studies. (a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. 12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.