Conventional Nonsteroidal Anti-inflammatory Drugs Research Articles

Motivations and perceived influences on rural and urban general practitioners when prescribing conventional non-steroidal anti-inflammatory drugs or COX-2 inhibitors

Prescribers in rural and remote locations perceive that there are different influences on their prescribing compared with those experienced by urban prescribers. The aim of this study was to compare the motivations and perceived influences on general practitioners (GPs) when prescribing COX-2 inhibitors rather than conventional non-steroidal anti-inflammatory drugs (NSAIDs) between rural and urban-based GPs in Queensland, Australia. A questionnaire was administered to two geographically distinct groups of GPs, one urban (n=67) and one rural (n=67), investigating the reasons that the GP would prescribe a COX-2 inhibitor rather than a conventional NSAID or vice versa and also focusing on patients requesting a prescription for a COX-2 inhibitor. A 51% response rate (n=68) was achieved. The difference between the rural and the urban GPs was that the urban GPs were more likely to perceive that they were influenced to prescribe COX-2 inhibitors by their patients' knowledge of these new (at the time) drugs. GPs in both the rural and urban areas perceived the COX-2 selective inhibitors to be safer than conventional NSAIDs, and that there was little difference in terms of efficacy between the two drug classes. However, GPs from both of the study areas stated that conventional NSAIDs were preferred over COX-2 selective inhibitors, primarily due to their expense, if their patients were not at risk for developing a GI bleed. The motivations and perceived influences to prescribe a COX-2 inhibitor in rural and in urban areas of Queensland, Australia were very similar. Almost all surveyed GPs in rural and urban areas had patients request a prescription, or enquire about the COX-2 inhibitors. Urban GPs were more likely to feel pressured to prescribe a COX-2 inhibitor than their rural counterparts, agreeing with other research which found that patient pressure to prescribe appears to be greater in urban general practice.

Long-term NSAID use in primary care: changes over a decade and NICE risk factors for gastrointestinal adverse events

To examine prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) in general practice and to compare the results with a 1993 study. To assess numbers at risk of gastrointestinal adverse events using the National Institute for Clinical Excellence (NICE) guidance on the use of cyclo-oxygenase (Cox) II selective drugs. Patients currently prescribed a NSAID for 2 months or more were identified from practice records. Demographic information, indications, previous gastrointestinal disease, serious co-morbidity and concomitant prescriptions were recorded. Data were compared with the 1993 survey and the NICE guidance. Seven thousand nine hundred and fifty-eight patients were registered with the practice in 2003. Two hundred and four patients were receiving repeat prescriptions for conventional NSAIDs and 63 for Cox II selective drugs. As in 1993 diclofenac (38%) and ibuprofen (24%) were the commonest individual agents and the main indication was regional pain. Seventy-three per cent of patients prescribed Cox II selective drugs and 64% of patients prescribed conventional NSAIDs had at least one NICE risk factor for gastrointestinal adverse events. Frequency of co-prescription of aspirin or antacids was similar for conventional NSAIDs and Cox II selective drugs, but prescription of antacids was higher with NICE risk factors. The indications for NSAIDs have not changed since 1993. Cox II selective drug prescribing was within the NICE guidance but a substantial proportion of patients taking other NSAIDs had risk factors for gastrointestinal adverse events. Discussion with the GPs highlighted the difficulties of balancing perceived risk of gastrointestinal adverse events with cardioprotection and further guidance is urgently needed.

Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis

Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks...

Impact of COX‐2 Inhibitors in Thai Orthopaedic Outpatients

ABSTRACTBackgroundPrescribing of cyclo‐oxygenase ‐2 inhibitors (coxibs) has had an economic impact on patients and overall healthcare costs in Thailand.AimTo analyse the pattern of coxib use and to determine the cost impact of inappropriate use.MethodA random retrospective sample was selected from two months of prescribing data. There were 519 prescriptions for coxibs and 594 prescriptions for conventional non‐steroidal anti‐inflammatory drugs (NSAIDs). Appropriate use was based on the UK National Institute for Clinical Excellence criteria.Results208 (40%) patients receiving coxibs and 113 (19%) patients receiving conventional NSAIDs were at high risk for upper gastrointestinal adverse effects. Of those receiving coxibs, 112 (22%) received coxibs alone and 159 (31%) also received gastro‐protective agents. The cost of inappropriate use of coxibs in patients at a low risk of gastrointestinal effects was 2.4 million Baht/year. The excess cost, adjusted for the most commonly prescribed conventional NSAIDs (diclofenac 25 mg, Voltaren 25 mg, and ibuprofen 400 mg), were 3.4, 1.1 and 3.2 million Baht/year, respectively.ConclusionInappropriate use of coxibs resulted in excessive expenditure and specific pharmacy intervention would be required to reduce the cost impact.

Development of COX-2 Selective Inhibitors - Therapeutic Perspectives

Aspirin and conventional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed for the treatment of musculoskeletal disorders with a major dose limiting gastrointestinal toxicity. However the discovery of inducible second isozyme of cyclooxygenase-2 (COX-2) opened up a new era in therapeutics. The selective COX-2 inhibitors have emerged as a class of compounds for the treatment of inflammatory disorders based on the molecular knowledge, characterization of two distinctive isozymes namely the constitutive cytoprotective cycloooxygenase-1 (COX-1) and the inducible inflammatory COX-2.The current hypothesis is that anti-inflammatory effects are mediated through the inhibition of COX-2 derived inflammatory prostaglandins (PGs), on the contrary the gastrointestinal adverse effects were due to inhibition of constitutive COX-1. The rationale approach is that the selective COX-2 inhibitors may provide a significantly improved gastrointestinal risk-benefit ratio over NSAIDs. However, the withdrawal of Vioxx by Merck & Co from worldwide markets has triggered a debate on the safety of this class as it was observed, that selective inhibition of COX-2 could lead to an imbalance of normal homeostasis resulting in potential cardiovascular risks. Evidence is emerging that the constitutively expressed COX-2 has important role in gastric mucosal protection, renal and the cardiovascular homeostasis. Suppression of endothelial prostacyclin (PGI2) by highly selective COX-2 inhibitors could lead to myocardial infarction and stroke implicating that COX-2 may have a pivotal role under certain physiological conditions.

Dual COX-Inhibitors: The Answer is NO?

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.

A Quantitative Analysis of NSAID-Induced Small Bowel Pathology by Capsule Enteroscopy

Conventional acidic nonsteroidal anti-inflammatory drugs frequently cause small bowel inflammation. Diagnosis is largely based on assay of surrogate markers of inflammation in stool, such as fecal calprotectin. However, stool markers are not widely available and the precise nature of this inflammation is uncertain. We used wireless capsule enteroscopy to quantitate and assess the nature of the small bowel damage caused by nonsteroidal anti-inflammatory drugs when taken on a short-term basis. Forty healthy volunteers underwent a baseline capsule enteroscopy and fecal calprotectin test. After taking diclofenac slow-release 75 mg twice a day (with omeprazole 20 mg twice a day for gastroprotection) for a total of 14 days, both investigations were repeated. After drug treatment, 30 subjects (75%) had increased repeat fecal calprotectin concentrations above the upper limit of normal. Capsule enteroscopy showed new pathology in 27 subjects (68%). The commonest lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%); reddened folds in 14 (35%); petechiae or red spots in 13 (33%); denuded mucosa in 8 (20%); and blood in the lumen without a visualized source in 3 (8%). Fifteen of the 27 subjects had more than one lesion concurrently. This study provides both biochemical and direct evidence of macroscopic injury to the small intestine in 68%-75% of volunteers resulting from 2 weeks' ingestion of slow-release diclofenac.

Renal Effects of Non-Steroidal Anti-Inflammatory Drugs and Selective Cyclooxygenase-2 Inhibitors

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.

Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor

Although highly selective cyclooxygenase (COX)-2 inhibitors have been shown to be less toxic to the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs (NSAIDs), their overall safety profile is questioned. Since different selective COX-2 inhibitors were found to be associated with increased cardiovascular thrombotic events, the thrombotic hazard may be a class effect. Furthermore, warnings have been issued regarding serious skin and hypersensitivity reactions associated with valdecoxib. Lumiracoxib is a novel COX-2 selective inhibitor (coxib) with improved biochemical selectivity over that of currently available coxibs. It is structurally distinct from other drugs in the class and has weakly acidic properties. Clinical studies support a once-daily dosing regimen, despite its relatively short plasma elimination half-life (3 – 6 h). In randomised, controlled clinical trials, lumiracoxib 100 – 200 mg/day has been shown to be superior to placebo in patients with symptomatic osteoarthritis, with clinical efficacy similar to diclofenac 150 mg/day, celecoxib 200 mg/day or rofecoxib 25 mg/day. Furthermore, lumiracoxib 200 – 400 mg/day appeared to be effective in patients with rheumatoid arthritis. In patients with acute pain related to primary dysmenorrhoea, dental or orthopaedic surgery, lumiracoxib 400 mg/day was found to be at least as effective as standard doses of traditional NSAIDs and other coxibs. Endoscopic studies have indicated that lumiracoxib is associated with a rate of gastroduodenal ulcer formation that is significantly lower than with ibuprofen and does not differ from celecoxib. In the Therapeutic Arthritis Research and Gastro-intestinal Trial, which enrolled 18,325 patients with osteoarthritis, the cumulative 1-year incidence of ulcer complications (primary end point) was significantly reduced by ∼ threefold on lumiracoxib 400 mg/day compared with naproxen 1000 mg/day or ibuprofen 2400mg/day (0.32 versus 0.91%). Reduction in ulcer complications was more pronounced in the population not taking low-dose aspirin (0.2 versus 0.92%, respectively). Conversely, the gastrointestinal advantage of lumiracoxib was abrogated in patients receiving low-dose aspirin (0.69 versus 0.88%, respectively, p = 0.49). Regarding cardiovascular events contributing to the trialists’ composite end point (myocardial infarction, stroke or cardiovascular death), there was no significant difference between lumiracoxib (0.65%) versus combined comparator NSAIDs (0.55%). Similarly, no significant difference was recorded in rates of myocardial infarction (clinical and silent) between the lumiracoxib (0.25%) and the combined NSAID (0.19%) treatment groups. Liver function test abnormalities were more frequent with lumiracoxib (2.57%) than with the comparator NSAIDs (0.63%). Whether or not this would result in an increased risk of cli-nical hepatitis in the real world setting is unforeseeable.

Prospective study of acute gastrointestinal bleeding attributable to anti-inflammatory drug ingestion in the Yorkshire region of the United Kingdom

Objective: To assess the general use of all non-steroidal anti-inflammatory drugs (NSAID) and their relation to upper gastrointestinal bleeding in view of National Institute for Clinical Excellence guidelines published in...

Médicaments de l’inflammation

The anti-inflammatory drugs belong to various chemical classes; they act in a purely symptomatic manner on the aspecific reaction of the tissues to an aggressive agent. The corticosteroid agents which are steroidal anti-inflammatory drugs have all a hormonal activity, concerning principally the metabolic regulations, and they cause pituitary-adrenal suppression. Some pathological states require particular attention but they are not necessarily contra-indicated for short duration prescriptions. Unerupted third molar extractions and oral dermatology are among their indications, with specific administration modalities. The non-steroidal anti-inflammatory drugs (NSAIDs) regroup various chemical classes but without any steroidal structure. The prostanoids biosynthesis inhibition by the NSAIDs is responsible for many of their pharmacological properties but also of their side-effects (essentially at the digestive, renal and cutaneous level). They can be prescribed in odontostomatology either for their analgesic properties, either for their anti-inflammatory and anti-oedematous properties, after careful analysis of the benefit/risk ratio. The new anti-inflammatory drugs (coxibs, selective inhibitors of the cyclo-oxygenase 2) have their main practical application in rheumatology, but they do not really provide notable advantages with regard to the incidence of side effects compared to conventional NSAIDs. Enzymes are anti-inflammatory drugs of modest efficiency, essentially used as anti-oedematous agents.

The Effect of Cyclooxygenase-2 Inhibition on Analgesia and Spinal Fusion

Cyclooxygenase (COX)-2-specific inhibitors demonstrate analgesic efficacy comparable with that of conventional nonsteroidal anti-inflammatory drugs but are associated with reduced gastrointestinal side effects and an absence of antiplatelet activity. Thus, they can be administered to patients undergoing spinal fusion surgery without an added risk of bleeding. However, concerns regarding a possible deleterious effect on bone-healing have limited their routine use. Celecoxib, a COX-2 inhibitor, recently was approved for the treatment of acute pain. The goals of the present study were to examine the analgesic efficacy of celecoxib and to determine the incidence of nonunion at one year following spinal fusion surgery. Eighty patients who were scheduled to undergo spinal fusion received either celecoxib or placebo one hour before the induction of anesthesia and every twelve hours after surgery for the first five postoperative days. Pain scores and morphine use were recorded one hour after arrival in the post-anesthesia care unit and at four, eight, twelve, sixteen, twenty, and twenty-four hours later. Intraoperative blood loss was recorded. The status of the fusion was determined radiographically at the time of the one-year follow-up. There were no differences in demographic data or blood loss between the two groups. Pain scores were lower in the celecoxib group at one, four, eight, sixteen, and twenty hours postoperatively. There were no differences between the two groups with regard to the pain scores at twelve and twenty-four hours postoperatively. Morphine use was lower in the celecoxib group at all postoperative time-intervals. There was no difference between the celecoxib group and the placebo group with regard to the incidence of nonunion at the time of the one-year follow-up (7.5% [three of forty] compared with 10% [four of forty]). The perioperative administration of celecoxib resulted in a significant reduction in postoperative pain and opioid use following spinal fusion surgery. In addition, the short-term administration of this COX-2-specific non-steroidal anti-inflammatory drug had no apparent effect on the rate of nonunion at the time of the one-year follow-up.

Screening New Drugs for Immunotoxic Potential: I. Assessment of the Effects of Conventional Nonsteroidal Anti-Inflammatory Drugs and Selective COX-2 Inhibitors on In Vitro and In Vivo Phagocytic Activity

Although both experimental and clinical literature contain reports suggestive of associations between enhanced susceptibility to soft tissue infections and nonsteroidal anti-inflammatory drug (NSAID) use, the immunotoxicological potential of this class of therapeutic agents has not been thoroughly investigated. In consideration of the widespread clinical use of these agents, we have initiated studies of the interaction between NSAIDs (both nonselective and selective COX-2 inhibitors) and the immune system. This communication describes the conduct and results of assessments of the effects of NSAIDs on the in vitro phagocytic activity of rat macrophages and canine neutrophils and on the functional activity of the intact murine mononuclear phagocytic system. During in vitro experiments 0.1 to 10 μM concentrations of naproxen, indomethacin, and experimental selective COX-2 inhibitors, SC-236, SC-245 and SC-791, caused marginal, but statistically significant, reductions in phagocytic activity of resident rat peritoneal macrophages. The effects were consistently small and there was no evidence of concentration-response relationships. An in vitro concentration of 10 μM of either SC-236 or SC-791 was required to decrease phagocytosis by dog neutrophils. Repeated oral doses of either naproxen or SC-236 (3, 10, or 30 mg/kg twice daily for 3 days) were without effect on the intact phagocytic system of the mouse. A potential immunotoxicologic effect based on direct impairment of phagocytic processes seems an unlikely explanation for drug-induced susceptibility to infection reported earlier. However, the results of these experiments do not support an unequivocal conclusion relative to immunotoxicological potential of either conventional NSAIDs or selective COX-2 inhibitors. Further studies on other components of the immune system are needed to fully explore possible immunomodulatory effects of NSAIDs.

Evidence-Based Recommendations for Short- and Long-Term Management of Uninvestigated Dyspepsia in Primary Care: An Update of the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool

The present paper is an update to and extension of the previous systematic review on the primary care management of patients with uninvestigated dyspepsia (UD). The original publication of the clinical management tool focused on the initial four- to eight-week assessment of UD. This update is based on new data from systematic reviews and clinical trials relevant to UD. There is now direct clinical evidence supporting a test-and-treat approach in patients with nondominant heartburn dyspepsia symptoms, and head-to-head comparisons show that use of a proton pump inhibitor is superior to the use of H2-receptor antagonists (H2RAs) in the initial treatment of Helicobacter pylori-negative dyspepsia patients. Cisapride is no longer available as a treatment option and evidence for other prokinetic agents is lacking. In patients with long-standing heartburn-dominant (ie, gastroesophageal reflux disease) and nonheartburn-dominant dyspepsia, a once-in-a-lifetime endoscopy is recommended. Endoscopy should also be considered in patients with new-onset dyspepsia that develops after the age of 50 years. Conventional nonsteroidal anti-inflammatory drugs, acetylsalicylic acid and cyclooxygenase-2-selective inhibitors can all cause dyspepsia. If their use cannot be discontinued, cotherapy with either a proton pump inhibitor, misoprostol or high-dose H2RAs is recommended, although the evidence is based on ulcer data and not dyspepsia data. In patients with nonheartburn-dominant dyspepsia, noninvasive testing for H pylori should be performed and treatment given if positive. When starting nonsteroidal anti-inflammatory drugs for a prolonged course, testing and treatment with H2RAs are advised if patients have a history of previous ulcers or ulcer bleeding.

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.

Coxibs: can this class of drugs survive?

Coxibs: can this class of drugs survive?

Nephrotoxicity Related to New Therapeutic Compounds

Toxic nephropathy is an important cause of reversible renal injury. This article focuses on the nephrotoxicity of several new therapeutic compounds. Selective cyclooxygenase-2 inhibitor is associated with sodium retention, hypertension, ankle edema, and acute renal failure. The incidence of renal complication is similar to conventional nonsteroidal anti-inflammatory drugs. Bisphosphonates, especially when used in high dose for prolonged duration, can cause toxic acute tubular necrosis and renal failure. Pamidronate is also associated with a specific form of collapsing focal segmental glomerulosclerosis similar to one found in patients with human immunodeficiency virus (HIV) infection. Acyclic nucleoside phosphonate, a new group of antiviral agents, can cause Fanconi-like syndrome and progressive renal impairment. On the other hand, indinavir, a potent protease inhibitor for the treatment of HIV infection, can cause crystalluria, renal stone, acute tubular obstruction and chronic interstitial nephritis. Intravenous immune globulin and hydroxyethyl starch, a new plasma expander, are associated with acute renal failure with characteristic renal histology known as osmotic nephrosis. In short, physicians should be cautious about possible renal toxicity during the use of any new therapeutic agents.

NSAIDs increase GM-CSF release by human synoviocytes: comparison with nitric oxide-donating derivatives

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E 2 (PGE 2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE 2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE 2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE 2 mediated cyclic (c) AMP pathway because PGE 2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE 2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE 2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.

Celecoxib does not induce convulsions nor does it affect GABA A receptor binding activity in the presence of new quinolones in mice

We sought to determine whether celecoxib would induce convulsions when coadministered with new quinolone antimicrobial agents in mice. The oral administration of celecoxib (500 mg/kg) alone or in combination with enoxacin (500 mg/kg), lomefloxacin (1000 mg/kg), ciprofloxacin (1000 mg/kg), or levofloxacin (1000 mg/kg) induced no convulsions in mice. In contrast, some nonsteroidal anti-inflammatory drugs (NSAIDs), fenbufen (200 mg/kg), indomethacin (500 mg/kg), and naproxen (500 mg/kg) induced convulsions in combination with the majority of the new quinolones tested. γ-Aminobutyric acid (GABA) A receptor blockade-mediated neuronal excitation is assumed to be involved in these toxic convulsions. Enoxacin (100 μM) and lomefloxacin (100 μM) only slightly reduced [ 3H]muscimol binding to GABA A receptors in mouse whole brain membrane. However, these reductions were markedly enhanced by the addition of fenbufen (100 μM), indomethacin (100 μM), or naproxen (100 μM). Conversely, celecoxib (100 μM) had no apparent effect on [ 3H]muscimol binding when applied alone or in combination with enoxacin or lomefloxacin. These results suggest that celecoxib may be a more desirable anti-inflammatory agent with respect to drug interactions with new quinolones compared with some conventional NSAIDs.

NSAID and Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal Models

Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional NSAIDs, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble Abeta rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both Ab production (APP, beta- and gamma-secretases) and post-production pathways (those affecting Abeta aggregation or clearance: e.g., IL-1 or alpha1ACT) are potentially involved in ibuprofen and other NSAID anti-AD activities. The post-production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen that do not lower Abeta42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti-inflammatory omega-3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted Abeta and was also effective in other models, warranting further preclinical and clinical exploration.